Original Article - Arquivos Brasileiros de Cardiologia

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Original Article - Arquivos Brasileiros de Cardiologia
www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 101, Nº 4, October 2013
Figure 1 - Cardiac magnetic resonance in
short axis, two chambers (heart mid section),
after injecting gadolinium to evaluate the delayed
myocardial enhancement in a 26-year old patient
with idiopathic pulmonary arterial hypertension
at Clementino Fraga Filho University Hospital.
It was observed a delayed myocardial enhancement
in the anterior and posterior portions of the
interventricular septum, on the right ventricular
insertion points (red arrows). Page 338
Editorial
Review Article
Impact of National Scientific Production in Cardiology on the Rating of
Renal Sympathetic Denervation for Resistant Hypertension Treatment
Journals Published in Brazil
- Current Perspectives
Original Articles
Letter to the Editor
Relationship between Anthropometric Measures and Cardiovascular
Impact on Hypertension Reclassification by Ambulatory Blood
Risk Factors in Children and Adolescents
Pressure Monitoring (ABPM) according to the V Brazilian Guidelines
Influence of Carotid Injury in Post-Myocardial Revascularization
on ABPM
Surgery and Its Late Evolution
Carvedilol Enhances the Antioxidant Effect of Vitamins E and C in
Prognostic Factors in Patients with Acute Coronary Syndrome without
ST-segment Elevation
Chronic Chagas Heart Disease
Early Change of Extracellular Matrix and Diastolic Parameters in
Metabolic Syndrome
Nonlinear Methods to Assess Changes in Heart Rate Variability in
Type 2 Diabetic Patients
Eletronic Pages
Clinicoradiological Session
Case 5/2013 - A Four-Year-Old Boy with a Rhabdomyoma-
Medical Students Teaching Cardiopulmonary Resuscitation to Middle
Type Cardiac Tumor in Both Ventricles and Repeated Ventricular
School Brazilian Students
Tachycardia
Pulmonary Arterial Hypertension: Use of Delayed Contrast-Enhanced
Case Report
Cardiovascular Magnetic Resonance in Risk Assessment
Big Endothelin-1 and Nitric Oxide in Hypertensive Elderly Patients
with and without Obstructive Sleep Apnea-Hypopnea Syndrome
Renal Denervation by Ablation with Innovative Technique in Resistant
Hypertension
Exuberant Pattern of Late Gadolinium Enhancement in Hypertrophic
Genetic Polymorphism G894T and the Prognosis of Heart Failure
Cardiomyopathy
Outpatients
Viewpoint
Features of the Onset of Takayasu’s Arteritis According to Gender
Paternalism, Autonomy and Ontology
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Editorial
Impact of National Scientific Production in Cardiology on the Rating of Journals Published in
Brazil
Luiz Felipe P. Moreira
.....................................................................................................................................................................page 286
Original Articles
Pediatric Cardiology
Relationship between Anthropometric Measures and Cardiovascular Risk Factors in Children
and Adolescents
Miria Suzana Burgos, Leandro Tibiriçá Burgos, Marcelo Dias Camargo, Silvia Isabel Rech Franke, Daniel Prá,
Antônio Marcos Vargas da Silva, Tássia Silvana Borges, Pâmela Ferreira Todendi, Miriam Beatris Reckziegel,
Cézane Priscila Reuter
.....................................................................................................................................................................page 288
Heart Surgery - Adults
Influence of Carotid Injury in Post-Myocardial Revascularization Surgery and Its Late Evolution
Maria Sol Calero Revelo, Daniel Pio de Oliveira, Flávia Bittar Britto Arantes, Camila Camarço Batista, João Italo
Dias França, Silmara Cristina Friolani. Jorge Eduardo Assef, José Eduardo Martins Barbosa, Ana Claudia Petisco,
Pedro Silvio Farsky
.....................................................................................................................................................................page 297
Chagas’ Disease
Carvedilol Enhances the Antioxidant Effect of Vitamins E and C in Chronic Chagas Heart Disease
Patrícia Budni, Roberto Coury Pedrosa Eduardo Monguilhott Dalmarco, Juliana Bastos Dalmarco, Tânia Sílvia
Frode, Danilo Wilhelm Filho
.....................................................................................................................................................................page 304
Echocardiography (Adults)
Early Change of Extracellular Matrix and Diastolic Parameters in Metabolic Syndrome
Angela B. S. Santos, Mauricio Junges, Daiane Silvello, Adriana Macari, Bruno S. de Araújo, Beatriz G. Seligman,
Bruce B. Duncan, Luis Eduardo P. Rohde, Nadine Clausell, Murilo Foppa
.....................................................................................................................................................................page 311
Electrocardiography
Nonlinear Methods to Assess Changes in Heart Rate Variability in Type 2 Diabetic Patients
Bhaskar Roy and Sobhendu Ghatak
.....................................................................................................................................................................page 317
Arquivos Brasileiros de Cardiologia - Volume 101, Nº 4, October 2013
Emergencies
Medical Students Teaching Cardiopulmonary Resuscitation to Middle School Brazilian Students
Lucas Gaspar Ribeiro, Rafael Germano, Pedro Lugarinho Menezes, André Schmidt, Antônio Pazin-Filho
.....................................................................................................................................................................page 328
Pulmonary Hypertension
Pulmonary Arterial Hypertension: Use of Delayed Contrast-Enhanced Cardiovascular Magnetic
Resonance in Risk Assessment
Luiz Gustavo Pignataro Bessa, Flávia Pegado Junqueira, Marcelo Luiz da Silva Bandeira, Marcelo Iorio Garcia,
Sérgio Salles Xavier, Guilherme Lavall, Diego Torres, Daniel Waetge
.....................................................................................................................................................................page 336
Systemic Hypertension
Big Endothelin-1 and Nitric Oxide in Hypertensive Elderly Patients with and without Obstructive
Sleep Apnea-Hypopnea Syndrome
Iara Felicio Anunciato, Rômulo Rebouças Lobo, Eduardo Barbosa Coelho, Waldiceu Aparecido Verri Jr., Alan
Luiz Eckeli, Paulo Roberto Barbosa Évora, Fernando Nobre, Júlio César Moriguti, Eduardo Ferriolli, Nereida
Kilza da Costa Lima
.....................................................................................................................................................................page 344
Heart Failure
Genetic Polymorphism G894T and the Prognosis of Heart Failure Outpatients
Oziel Marcio Araujo Tardin, Sabrina Bernardez Pereira, Monica Wanderley Monçores Velloso, Henrique Miller
Balieiro, Bruno Costa, Thiago Oliveira e Alves, Camila Giro, Leandro Pontes Pessoa, Georgina Severo Ribeiro,
Evandro Tinoco Mesquita
.....................................................................................................................................................................page 352
Aortic Diseases
Features of the Onset of Takayasu’s Arteritis According to Gender
Andrea Rocha de Saboia Mont’Alverne, Luiz Eduardo de Paula, Samuel Katsuyuki Shinjo
.....................................................................................................................................................................page 359
Review Article
Renal Sympathetic Denervation for Resistant Hypertension Treatment - Current Perspectives
Andréa Araujo Brandão, Erika Maria Gonçalves Campana, Maria Eliane Campos Magalhães, Esmeralci Ferreira
.....................................................................................................................................................................page 364
Letter to the Editor
Impact on Hypertension Reclassification by Ambulatory Blood Pressure Monitoring (ABPM)
according to the V Brazilian Guidelines on ABPM
Guilherme Brasil Grezzana, Airton Tetelbon Stein, Lúcia Campos Pellanda
.....................................................................................................................................................................page 372
Prognostic Factors in Patients with Acute Coronary Syndrome without ST-segment Elevation
Sinan İşcen
.....................................................................................................................................................................page 373
Arquivos Brasileiros de Cardiologia - Volume 101, Nº 4, October 2013
Arquivos Brasileiros de Cardiologia - Eletronic Pages
Clinicoradiological Session
Case 5/2013 - A Four-Year-Old Boy with a Rhabdomyoma-Type Cardiac Tumor in Both Ventricles
and Repeated Ventricular Tachycardia
Edmar Atik
....................................................................................................................................................................page 74
Case Report
Renal Denervation by Ablation with Innovative Technique in Resistant Hypertension
Luiz Aparecido Bortolotto, Thiago Midlej-Brito, Cristiano Pisani, Valéria Costa-Hong, Maurício Scanavacca
....................................................................................................................................................................page 77
Exuberant Pattern of Late Gadolinium Enhancement in Hypertrophic Cardiomyopathy
Elsa Fernandes, Gabriel C. Camargo, Maria Eduarda Derenne, Tamara Rothstein, Ilan Gottlieb
....................................................................................................................................................................page 80
Viewpoint
Paternalism, Autonomy and Ontology
Max Grinberg and Antonio Sergio de Santis Andrade Lopes
....................................................................................................................................................................page 83
* Indicate manuscripts only in the electronic version. To view them, visit: http://www.arquivosonline.com.br/2013/english/10104/edicaoatual.asp
Arquivos Brasileiros de Cardiologia - Volume 101, Nº 4, October 2013
www.arquivosonline.com.br
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Scientific Director
Interventionist Cardiology
Luiz Alberto Piva e Mattos
Pedro A. Lemos
Chief Editor
Pediatric/Congenital Cardiology
Luiz Felipe P. Moreira
Associated Editors
Clinical Cardiology
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Surgical Cardiology
Paulo Roberto B. Evora
Antonio Augusto Lopes
Arrhythmias/Pacemaker
Mauricio Scanavacca
Non-Invasive Diagnostic Methods
Carlos E. Rochitte
Basic or Experimental Research
Leonardo A. M. Zornoff
Epidemiology/Statistics
Lucia Campos Pellanda
Arterial Hypertension
Paulo Cesar B. V. Jardim
Ergometrics, Exercise
and Cardiac Rehabilitation
Ricardo Stein
First Editor (1948-1953)
† Jairo Ramos
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Arquivos Brasileiros de Cardiologia
Volume 101, Nº 4, October 2013
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Back to the cover
Editorial
Impact of National Scientific Production in Cardiology on the Rating
of Journals Published in Brazil
Luiz Felipe P. Moreira
Instituto do Coração - INCOR - São Paulo, SP – Brazil
The significant advances in the scientific production in the
health sciences area in recent years have been accompanied
by the indexing of several journals published in Brazil in
the main international databases and a significant increase
in the number of Brazilian publications in the cardiology
and cardiovascular medicine areas has also been observed.
According to the Scopus-Scimago index, we currently occupy
the 15th position in international publications in this field of
research, with the publication of approximately 750 articles per
year. To this number are added many publications ​​by Brazilian
researchers in other international journals, demonstrating the
wide inclusion achieved by our cardiological science.
The growing increase in the number and quality of
publications in cardiology in our country is explained by better
education of Brazilian researchers, from the training provided
by sensu stricto post-graduation programs1,2, by increasing the
number of researchers registered with the National Research
Council (CNPq)3,4 and incentive programs aimed at training
and scientific production sponsored by medical societies . In
this sense the Brazilian Society of Cardiology has implemented
a research training program in collaboration with U.S. Duke
University5, which was responsible for the training of more
than 50 researchers from 24 centers or universities. In
parallel, the implementation of several multicenter registries
regarding major cardiovascular diseases has been supported
by the society, aiming at expanding knowledge of the national
situation regarding its incidence and regional characteristics6-9.
In the presence of a current scientific scenario with
great perspectives, the challenge of journals published in
Brazil is also growing. The authors prefer to publish their
articles in journals of high quality, credibility and greater
impact, justifying the publication of the best quality research
performed in the country in the major journals in the field of
cardiology at the international level. This situation, which is
often based on the Impact Factor of journals10, leads to the
maintenance of a lower rating of our journals, a situation that
can only be modified through the continuous improvement of
our disclosure methods, associated with greater collaboration
from our researchers11.
The Brazilian Archives of Cardiology is still the main vehicle
of Brazilian research disclosure, concentrating more than
25% of national publications in its field. In parallel to the
improvement of the quality of Brazilian scientific research, the
journal has also shown increasing levels of citation of articles
published in it, a situation unquestionably due to a more
detailed and consistent peer-review process12. As perspective,
we expect to continue to see the continuous evolution of the
impact of our publications internationally, whereas we increase
the rating and inclusion of our journals.
Keywords
Bibliometrics, scientific research, scientific publications and
techniques citation databases
Mailing Address: Luiz Felipe P. Moreira •
Av. Dr. Enéas Carvalho Aguiar, 44 - 2º andar, Bloco 2, Sala 13 - Cerqueira
César - Postal Code 05403-000 - São Paulo, SP - Brazil
E-mail: [email protected]
Manuscript received October 07, 2013; revised manuscript October 07,
2013; accepted October 07, 2013.
DOI: 10.5935/abc.20130209
286
Moreira
Scientific Production and the Rating of Journals Published in Brazil
Editorial
References
1. Brock L, Cunha E, Tavares JR, Gonçalves I Jr, Paola AA, Moisés V, et al.
[Graduates from a postgraduate program in cardiology: are the results of
almost 30 years adequate?]. Arq Bras Cardiol. 2010;94(4):500-6.
2. Hueb W, Mady C, Ramires JA. [Thirty years of postgraduation in
cardiology]. Arq Bras Cardiol. 2005;85(6):385-7.
3. Martelli-Junior H, Martelli DR, Quirino IG, Oliveira MC, Lima LS,
Oliveira EA. CNPq-supported medical researchers: a comparative study
of research areas. Rev Assoc Med Bras. 2010;56(4):478-83.
4. Oliveira EA, Ribeiro AL, Quirino IG, Oliveira MC, Martelli DR, Lima
LS, et al. Profile and scientific production of CNPq researchers in
cardiology. Arq Bras Cardiol. 2011;97(3):186-93.
5. Pellanda LC, Cesa CC, Belli KC, David VF, Rodrigues CG, Vissoci JR, et
al. Research training program: Duke University and Brazilian Society
of Cardiology. Arq Bras Cardiol. 2012;99(6):1075-81.
6. BREATHE investigators. Rationale and design: BREATHE registry--I
Brazilian Registry of Heart Failure. Arq Bras Cardiol. 2013;100(5):390-4.
287
Arq Bras Cardiol. 2013;101(4):286-287
7. Fenelon G, Scanavacca M, Atié J, Zimerman L, Magalhães LP, Lorga
Filho A, et al. Atrial fibrillation ablation in Brazil: results of the registry
of the Brazilian Society of Cardiac Arrhythmias. Arq Bras Cardiol.
2007;89(5):258-62.
8. Mattos LA. Rationality and methods of ACCEPT registry - Brazilian
registry of clinical practice in acute coronary syndromes of the Brazilian
Society of Cardiology. Arq Bras Cardiol. 2011;97(2):94-9.
9. Mattos LA. Rationality and methods: registry of clinical practice in highrisk cardiovascular patients. Arq Bras Cardiol. 2011;97(1):3-7.
10. Thomaz PG, Assad RS, Moreira LF. Using the impact factor and
H index to assess researchers and publications. Arq Bras Cardiol.
2011;96(2):90-3.
11. Grinberg M, Solimene MC, Barreto Mdo C. Why publish in national
journals? Arq Bras Cardiol. 2012;98(3):e62-3.
12. Araújo CG. Peer review: a constantly-evolving scientific process. Arq
Bras Cardiol. 2012;98(2):e32-5.
Original Article
Back to the cover
Relationship between Anthropometric Measures and Cardiovascular
Risk Factors in Children and Adolescents
Miria Suzana Burgos1,2, Leandro Tibiriçá Burgos1, Marcelo Dias Camargo3, Silvia Isabel Rech Franke1,2, Daniel
Prá1,2, Antônio Marcos Vargas da Silva4, Tássia Silvana Borges1,2, Pâmela Ferreira Todendi1,2, Miriam Beatris
Reckziegel1, Cézane Priscila Reuter1,2
Universidade de Santa Cruz do Sul - UNISC1, Santa Cruz do Sul, RS; Programa de Pós-graduação - Mestrado em Promoção da Saúde - UNISC2; Grupo
de Pesquisa em Cardiologia do Exercício HCPA/UFRGS3, Porto Alegre, RS; Universidade Federal de Santa Maria - UFSM4, Santa Maria, RS - Brazil
Abstract
Background: Obesity has been identified as an important risk factor in the development of cardiovascular diseases;
however, other factors, combined or not with obesity, can influence cardiovascular risk and should be considered in
cardiovascular risk stratification in pediatrics.
Objective: To analyze the association between anthropometry measures and cardiovascular risk factors, to investigate
the determinants to changes in blood pressure (BP), and to propose a prediction equation to waist circumference (WC)
in children and adolescents.
Methods: We evaluated 1,950 children and adolescents, aged 7 to 18 years. Visceral fat was assessed by WC and
waist‑hip relationship, BP and body mass index (BMI). In a randomly selected subsample of these volunteers (n = 578),
total cholesterol, glucose and triglycerides levels were evaluated.
Results: WC was positively correlated with BMI (r = 0.85; p < 0.001) and BP (SBP r = 0.45 and DBP = 0.37; p < 0.001).
Glycaemia and triglycerides showed a weak correlation with WC (r = 0.110; p = 0.008 e r = 0.201; p < 0.001,
respectively). Total cholesterol did not correlate with any of the variables. Age, BMI and WC were significant predictors
on the regression models for BP (p < 0.001). We propose a WC prediction equation for children and adolescents:
boys: y = 17.243 + 0.316 (height in cm); girls: y = 25.197 + 0.256 (height in cm).
Conclusion: WC is associated with cardiovascular risk factors and presents itself as a risk factor predictor of
hypertension in children and adolescents. The WC prediction equation proposed by us should be tested in future
studies. (Arq Bras Cardiol. 2013;101(4):288-296)
Keywords: Cardiovascular Diseases; Risk Factors; Obesity; Body Mass Index; Abdominal Circumference; Child; Adolescent.
Introduction
Obesity has been identified as an important risk factor
for cardiovascular disease development; however, other
factors, combined to obesity or not, also exert influence
on this risk and must be considered in cardiovascular risk
stratification in pediatrics1. Among these factors, we highlight
waist circumference (WC) as a visceral fat indicator which
has already been well explored in the adult population and
has more recently been identified as a risk factor in children
and adolescents1,3. Evidences suggest the importance of
measuring abdominal obesity besides general obesity for the
evaluation of health risks in the first decades of life4.
Mailing Address: Cézane Priscila Reuter •
Avenida Independência, 2293, bloco 42, sala 4206, Universitário.
Postal Code 96815-900, Santa Cruz do Sul, RS - Brazil
E-mail: [email protected], [email protected]
Manuscript received July 0, 2012; revised manuscript July 31, 2012;
accepted April 23, 2013.
DOI: 10.5935/abc.20130169
288
The growing child obesity rate is associated to an
increase in the diagnosis of systemic arterial hypertension
(SAH) in children and adolescents5,8. The prevalence of
primary SAH in childhood and adolescence in Brazilian
epidemiologic studies varied between 0.8-8.2% 9,10 ,
which means it is a phenomenon of great epidemiologic
importance. Besides SAH, obesity is associated to other
comorbidities, such as increased peripheral insulin
resistance and serum cholesterol and triglyceride levels,
which represent a major risk of chronic disease in
adult life11,12.
The association between body mass index (BMI) and
arterial blood pressure in children has already been
demonstrated in other studies13,15. It must be highlighted
that the association between visceral fat, accessed by the
waist circumference, and arterial blood pressure, has been
largely reported in the adult population. However, until
now, a predictive value of waist circumference related to
blood pressure levels has not been suggested for children
and adolescents. Besides, prediction values for WC
were also not found for children and adolescents in the
Brazilian population.
Burgos et al.
Anthropometric measures and cardiovascular risk
Original Article
Taking these perspectives into account, the present
study in children and adolescents aims to: a) analyze the
association among visceral obesity, arterial blood pressure,
generalized obesity and biomarkers (total cholesterol,
triglycerides and glucose levels); b) evaluate these variables’
predictive value in relation to arterial blood pressure; and c)
propose a prediction equation for WC.
Methods
In this transversal study, 1,950 children and adolescents
were evaluated. Their ages ranged from 7 to 18 years old; 902
were male (46.3%) and 1,048 were female (53.7%). They were
randomly selected from a sample stratified by conglomerates
(center and north, south, east and west areas of the peripheral
urban zone and north, south, east and west rural zone), and
were enrolled in 16 schools (12 in the urban zone and 4 in
the rural zone) of Santa Cruz do Sul (RS). A randomly selected
sub sample (n = 578) was employed for total cholesterol,
triglyceride and glucose assessment. Arkin and Colton formula16
was used for calculating sample size.
Waist circumference was measured with an inelastic tape
measure at the medium point between iliac crest and the
external side of the last costal arch, and the hip measurement
obtained at the widest part of the buttocks; both are used for
calculating the waist/hip ratio− (WHR = waist circumference/
hip circumference)17.
Blood pressure was evaluated according to the
VI Brazilian Guidelines on Hypertension 6 using the
auscultation method, with aneroid devices calibrated
less than three months before measurement. Each device
had three different sized cuffs, so the researchers could
select the ones that were adequate to arm circumference,
respecting the 1:2 width/length proportion. Values below
the 90th percentile (if were inferior to 120/80 mmHg)
were considered normotensive; values between the
90th - 95th percentiles were considered borderline; values
equal or superior to the 95th percentile were considered
hypertensive. It must be highlighted that any value equal or
superior to 120/80 mmHg in adolescents, even if inferior to
the 95th percentile, was considered borderline.
Obesity was defined according to the child growth
standards of the World Health Organization18, which is based
on different populations, including a sample of Brazilian
children; it recommends that children with BMI (weight
in kilograms divided by the square of the height in meters)
greater than the 95th percentile are classified as obese, and
those with BMI between the 85th and the 95th percentile
are considered overweight. Subjects with IMC ≥ 25 kg/m2
were also excluded.
was used for comparing continuous variables between
genders, chi-square was used for comparing categorical
variables and multiple linear regression analysis. The data
identified as asymmetrical by the Kolmogorov-Smirnov test
were converted to logarithm (log10). The correlations were
analyzed by Pearson’s correlation coefficient and classified
according to the correlation magnitude scale proposed by
Cohen19. Values are expressed as mean ± standard deviation,
frequency distribution analysis and 95% confidence levels,
considering a 5% significance level (p < 0.05).
This study was approved the Institutional Research Ethics
Committee of the Santa Cruz do Sul University - Unisc (process
1.189/05), according to the Helsinki Statement. Parents and
responsible for the students of the schools involved authorized
their participation by signing an informed consent.
Results
Table 1 presents the characteristics of the subjects and
the distribution of body mass index and blood pressure,
pooled by gender and considered as a single group. Among
the 902 boys and 1,048 girls evaluated, no differences
were found between genders regarding age (p = 0.50),
BMI (p = 0.77), systolic blood pressure (p = 0.24) and
diastolic blood pressure (p = 0.26). However, boys’ WHR
and WC measurements were larger than girls’ (p < 0.001
for both). The prevalences of hypertension (p = 0.12),
overweight (p = 0.65) and obesity (p = 0.57) showed no
difference between genders.
Visceral fat, measured as WC, showed a positive correlation
with BMI (Graph 1), systolic blood pressure (Graph 2) and
diastolic pressure (Graph 3). WC was also correlated to age
(r = 0.449; p < 0.001) and WHR (r = 0.206; p < 0.001).
However, WHR did not show a significant correlation with
BMI and was weakly related to SBP (r = 0.192; p < 0.001)
and DBP (r = 0.182; p < 0.001). BMI showed a significant
correlation with both SBP (r = 0.437; p < 0.001) and
DBP (r = 0.360; p < 0.001).
Total cholesterol, glucose and triglyceride levels were
measured in 578 volunteers (244 boys and 334 girls).
No significant difference was found between boys
(156.65 ± 16.75 mg/dL) and girls (156.63 ± 14.64 mg / dL;
p = 0.991) regarding total cholesterol levels. No significant
difference was found between boys (63.88 ± 15.44 mg / dL)
and girls (60.77 ± 15.13 mg/dL; p = 0.016) regarding
total cholesterol levels. However, mean triglyceride levels
were higher in girls (123.62 ± 62.23 mg/dL) than boys
(107.00 ± 55.86 mg/dL; p < 0.001).
Total cholesterol, triglycerides and glucose levels
were measured in a sub sample of 578 children and
adolescents after 12 h fast with an Accutrend GTC monitor
(Roche, Germany) and finger stick testing, according to
recommendations of the I Guideline for Prevention of
Atherosclerosis in Childhood and Adolescence7.
No significant correlations were found between total
cholesterol levels and the other studied variables. Glucose
blood levels were weakly correlated with BMI (r = 0.112;
p = 0.007), WC (r = 0.110; p = 0.008), SBP (r = 0.153;
p < 0.001) and DBP (r = 0.134; p = 0.001). Triglyceride
blood levels were weakly correlated with BMI (r = 0.213;
p = 0.001), WC (r = 0.201; p = 0.001), SBP (r = 0.145;
p < 0.001) and DBP (r = 0.144; p = 0.001).
The data were analyzed with the software Statistical
Package for the Social Science 20.0 (SPSS 20.0) and
Winpepi version 11.1. The non-paired Student t-test
The results involving variables that interfere in SBP,
calculated by multiple regression analysis, are presented on
Table 2. Age, BMI and WC were significant predictors of
Arq Bras Cardiol. 2013;101(4):288-296
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Burgos et al.
Anthropometric measures and cardiovascular risk
Original Article
Table 1 - Subject characterization and distribution regarding body mass index and arterial blood pressure
Indicators
Boys (n = 902)
n (%)
Girls (n = 1048)
n (%)
Total (n = 1950)
n (%)
Age (years)*
11.48 ± 2.76
11.56 ± 2.55
11.52 ± 2.65
BMI (kg/m2)
18.91 ± 3.53
18.87 ± 3.26
18.89 ± 3.38
Low weight
37 (4.1)
30 (2.9)
67 (3.4)
Low weight risk
81 (9.0)
91 (8.7)
172 (8.8)
Eutrophic
601 (66.6)
757 (72.2)
1358 (69.6)
Overweight
124 (13.7)
117 (11.2)
241 (12.4)
59 (6.5)
53 (5.1)
112 (5.7)
Obesity
Waist-−hip ratio*
0.82 ± 6.82
0.79 ± 6.88
0.81 ± 7.07
Waist circumference (cm)*
66.36 ± 9.23
64.60 ± 8.15
65.41 ± 8.71
104.48 ± 14.81
103.70 ± 14.41
104.06 ± 14.60
812 (90.0)
937 (89.4)
1749 (89.7)
Borderline
39 (4.3)
43 (4.1)
82 (4.2)
51 (5.7)
68 (6.5)
119 (6.1)
61.98 ± 12.12
61.37 ± 11.83
61.65 ± 11.97
859 (95.2)
985 (94.0)
1844 (94.6)
Borderline
30 (3.3)
43 (4.1)
73 (3.7)
Hypertensive
13 (1.4)
20 (1.9)
33 (1.7)
Systolic blood pressure (mmHg)*
Normotensive
Hypertensive (%)
Diastolic blood pressure (mmHg)*
Normotensive
*Values expresses as mean ± standard deviation, BMI: body mass index.
SBP increase. For each 1 year increase in age, there was an
1.8 mmHg increase in blood pressure; for each 1 unit increase
in BMI, blood pressure increased 0.8 mmHg and for each unit
increase in WC, SBP increased 0.2 mmHg.
Table 3 presents age, BMI and WC as predictors of DBP
increase. For each 1 year increase in age, there was an
1.3 mmHg increase in blood pressure; for each 1 unit increase
in BMI, blood pressure increased 0.5 mmHg and for each unit
increase in WC, SBP increased 0.2 mmHg.
In a better multiple linear regression model, a WC
prediction equation for children and adolescents is proposed,
excluding individuals with BMI > 25 kg/m2 and including
variables such as gender and height in the model:
Boys’ WC: y = 17.243 + 0.316 (height in cm); estimated
standard error = 5.59; R2 = 0.478.
Girls’ WC: y = 25.197 + 0.256 (height in cm); estimated
standard error = 5.95; R2 = 0.244.
The ROC curve (Graph 4) shows that waist measurement’s
sensitivity was close to 100% (98.15%) for SBP; however,
regarding specificity, as expected, it was inferior to 20%
(19.93%). On the other side, the ROC curve (Graph 5) of waist
measurement to DBP demonstrated a very similar behavior,
with a 97,96% sensitivity and 21,64% specificity.
Discussion
Among the main findings of our study is the association of
WC with blood pressure and BMI. We found weak evidence
of association between biomarkers and visceral fat (WC and
290
Arq Bras Cardiol. 2013;101(4):288-296
WHR), BMI and blood pressure. Age, BMI and WC showed
significant predictive value for blood pressure change in a
better multiple linear regression model with. Our results
made possible the establishment of a WC prediction equation
in children and adolescents.
The hypertension prevalence and diagnosis rates in
children and adolescents have been increasing noticeably20.
Evidences suggest that childhood arterial hypertension can
lead to arterial hypertension in adult life15,20 and to the
early development of coronary artery disease observed as
atherosclerosis in children and young adults12. Our findings
showed a prevalence of arterial hypertension of 5.7% of
boys and 6.5% of girls, with a global prevalence of 6.1%.
These values agree with other reports which showed a
prevalence of arterial hypertension with 3% in Santos (SP)21,
5% in Goiânia (GO)22 and 7,7% in Maceió (AL)23.
Our results showed that WC and WHR were higher
in males, similarly to what was seen in other studies24,25.
Our studies showed that a higher association of blood pressure
with WC than WHR, suggesting that visceral fat, accessed by
WC, can be a better predictor of hypertension in childhood
and adolescence. It must be highlighted, however, that
WC is secondary measurement of visceral fat. Our study
demonstrated a moderate correlation of CC with SBP and
DBP, while Lee et al4, evaluating 1,254 obese children aged
6‑12 years old, showed a strong correlation among these
variables. Sarni et al8 did not find correlation between WC
and SBP or DBP in a sample of 65 preschoolers of low
socioeconomic status. It must be highlighted that care must
Burgos et al.
Anthropometric measures and cardiovascular risk
Original Article
BMI (kg/m2)
R = 0.847; p<0.001
Waist circumference (cm)
Graph 1 - BMI to waist circumference ratio.
be taken when comparing studies, since differences can be
seen regarding age, socioeconomic status and body mass.
We observed a stronger association of WC with SBP (r = 0.449)
than with DBP (r = 0.374), suggesting that visceral fat exerts
greater influence in SBP levels.
Various mechanisms may explain the association
between visceral obesity and arterial blood pressure26,28.
Visceral fat can be distinguished from fat localized in
other anatomic regions by its functional and metabolic
characteristics, inducing hepatic insulin resistance due to
lipotoxicity26, releasing more free fatty acids in hepatic
portal vein and increasing substrate levels for atherogenic
lipoprotein production27. The greater quantity of visceral
fat may favor an increase in sympathetic activity mediated
by the associated insulin resistance, besides potentializing
the activity of the renin-angiotensin-aldosterone system
due to the increased angiotensinogen secretion by visceral
adipocytes, when compared to the subcutaneous fat28.
The visceral fat accumulation could also exert a mechanical
effect, inducing renal compression and promoting arterial
blood pressure exacerbation29. As recently demonstrated
in young individuals, WC correlates with insulin resistance
markers, independent from BMI30, predicting individual
components of metabolic syndrome, such as high
blood pressure and dyslipidemia31. Other studies have
demonstrated that WC is associated with inflammatory
biomarkers, such as C-reactive protein and adiponectin in
young individuals32,33.
The best association found in our study was found in BMI
and WC (r = 0.847). This correlation’s magnitude is similar
to the one that was found by Soar et al24 (r = 0.87) and
Beauloye et al34 (r = 0.74). The literature documents fairly
well the greater importance of visceral obesity to the detriment
of overweight in the risk assessment for the development of
cardiovascular and metabolic dysfunction35,36. However, the
combination of WC and BMI measurements have become
more efficient for cardiovascular dysfunction prediction than
the isolated utilization of only one of the anthropometric
indicators37. In light of this, we evidenced a better multiple
regression model both for SBP and DBP, with both models
involving age combined to BMI and WC. As expected, age
was a stronger predictor than SBP and DBP, followed by BMI
and WC. BMI, representing generalized obesity, was a stronger
predictor of blood pressure change than WC measurement in
the studied sample. On the other hand, our data demonstrate
an absence of significant correlation between BMI and
WHR, as referred previously in preliminary studies in Dutch
children38. Thus, we suggest that WHR may not be the better
Arq Bras Cardiol. 2013;101(4):288-296
291
Burgos et al.
Anthropometric measures and cardiovascular risk
Original Article
Systolic blood pressure (mmHg)
R = 0.449; p<0.001)
Waist circumference (cm)
Graph 2 - Systolic blood pressure to waist circumference ratio.
indicator of childhood obesity. Besides that, in a previous study
in adults, WHR was reported as a weak predictor of visceral
fat change evaluated by magnetic resonance39.
It is not clear why age seems to be a better predictor of
arterial blood pressure than anthropometric measurements.
Freedman et al 2 indicate that arterial blood pressure
changes in a certain population do not necessarily correlate
to obesity changes. Besides that, Li et al13 indicated that
the intensity of the association between BMI and arterial
blood pressure increases with age. These evidences suggest
that anthropometric’s influence on hypertension is quite
complex and needs to be better investigated.
Some reports demonstrate and association between arterial
blood pressure and BMI, suggesting that obesity is a strong risk
factors for high blood pressure development in childhood and
adult life13,15. Our findings suggest that body mass increase exerts
greater influence in SBP than DBP, as seen with the stronger
correlation found between BMI and SBP. This observation
corroborates other studies’ findings that have also demonstrated
that SBP is more affected by BMI than DBP13,20. According
to this, the data presented by the Bogalusa Heart Study
(Louisiana, USA), which evaluated pressure measurements in
11,478 children and adolescents aged 5 to 17 years old, from
1974 to 1993, showed SBP reductions throughout this period2.
292
Arq Bras Cardiol. 2013;101(4):288-296
Our study identified a smaller number of associations
between biomarkers (total cholesterol, glucose and
triglyceride levels) and WC, SBP, DBP and BMI. Even when
considered significant, the correlations involving these
variables were classified as weak. This tendency was also
identified in preliminary studies, which demonstrated the
absence of a correlation between BMI and WC and total
cholesterol and glucose levels, and the weak correlation
of BMI and triglycerides in obese children between 8 and
18 years old34. Sarni et al8 reported that WC is not related
to total cholesterol and triglyceride levels in preschoolers.
Our findings suggest an absent or weak association between
obesity, visceral obesity and arterial pressure and the
accessed biomarkers, possibly due to the younger age group
of the volunteers or to the fact that the biomarkers’ mean
levels are within the normal range for the studied sample.
It must be highlighted that the limited sub sample size used
for biochemical evaluation may have limited study power for
detecting the association between biochemical variables and
the other variables.
We also highlight that we chose to exclude the individuals
with BMI ≥ 25 kg/m2 due to the simple fact that these
individuals are already considered overweight and obese,
and do not need a predictor factor for WC. We currently
Burgos et al.
Anthropometric measures and cardiovascular risk
Original Article
Diastolic blood pressure (mmHg)
R = 0.374; p<0.001)
Waist circumference (cm)
Graph 3 - Diastolic blood pressure to waist circumference ratio.
Table 2 - Multiple linear regression model of SBP as a dependent variable
Independent variables
Non-standardized coefficients
95% confidence interval for B
Statistical analysis
2.159
48.148 - 56.615
< 0.001
0.117
1.596 - 2.055
< 0.001
0.841
0.154
0.539 - 1.143
< 0.001
0.226
0.062
0.105 - 0.347
< 0.001
95% confidence interval for B
Statistical significance
B
SD
(Constant)
52.382
Age
1.826
BMI
WC
BMI: body mass index; WC: waist circumference.
Table 3 - Multiple linear regression model of DBP as a dependent variable
Independent variables
Non-standardized coefficients
B
SD
(Constant)
25.947
1.875
22.270 - 29.625
< 0.001
Age
1.319
0.102
1.120 - 1.519
< 0.001
BMI
0.512
0.134
0.249 - 0.774
< 0.001
WC
0.166
0.054
0.061 - 0.271
0.002
BMI: body mass index; WC: waist circumference.
Arq Bras Cardiol. 2013;101(4):288-296
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Burgos et al.
Anthropometric measures and cardiovascular risk
Sensitivity
Original Article
Specificity
Sensitivity
Graph 4 - ROC curve - waist: systolic blood pressure.
Specificity
Graph 5 - ROC curve - waist: diastolic blood pressure.
already have excellent references that properly discuss
obesity and health risk issues to children and adolescents2,3,11.
Some studies suggest that obesity duration is directly associated
to cardiovascular morbimortality1,5,27. This was not our first
objective. The other variables (gender and height) were chosen
294
Arq Bras Cardiol. 2013;101(4):288-296
due to our belief that they would better represent the study
sample population (children and adolescents).
WC normal values were proposed due to the importance
of this measurement, which has already been described in the
literature as a better cardiovascular risk predictor than BMI40,
Burgos et al.
Anthropometric measures and cardiovascular risk
Original Article
and also aiming to facilitate the early diagnosis of visceral fat
in the first decades of life. In the equation for WC prediction
proposed by our study, the determination coefficient was
different for boys (R2 = 0.478) and girls (R2 = 0.244), suggesting
that the applicability of the proposed model can be better in the
male population. Besides that, it is necessary that this equation is
tested in additional studies; local waist measurement standards
determination must be considered in studies conducted in
other regions with different ethnicity, socioeconomic status
and lifestyle, which can influence the measurement and make
the predicted values inaccurate or not applicable in different
populations. In view of this, it must be highlighted that the city
of Santa Cruz do Sul (RS), at the Rio Pardo Valley, is a region
of German colonization. Its economy is based in services and
tobacco cultivation and is located 150 km from Porto Alegre.
The ethnic diet in the city is marked by a great quantity of
sweets, breads and cakes, whose role in cardiovascular risk
must be better studied in future studies.
Conclusion
The present studied showed an important association
between WC, BMI and arterial blood pressure. Our results
made possible, for the first time, that a WC prediction
equation, more robust in boys, was proposed for Brazilian
children and adolescents. This study generated a WC
prediction equation, based in Brazilian children and
adolescent data. Of note, the studies available up to now in
the literature dealed with the North American population.
A weak association was also observed between biochemical
and anthropometric variables, indicating little biochemistry
change in the studied age range. Blood pressure and
WC assessment should be part of family health programs
even in the first two decades of life, and should also be
part of interventions directed at health and quality of life
maintenance in childhood.
Author contributions
Conception and design of the research: Burgos MS, Reuter
CP, Burgos LT, Franke SIR, Prá D, Silva AMV, Reckziegel MB;
Acquisition of data: Burgos MS, Reuter CP, Burgos LT, Franke
SIR, Prá D, Silva AMV, Borges TS, Todendi PF, Reckziegel MB;
Analysis and interpretation of the data: Burgos MS, Reuter
CP, Camargo MD, Silva AMV, Reckziegel MB; Statistical
analysis: Reuter CP, Camargo MD, Silva AMV; Writing of the
manuscript: Burgos MS, Reuter CP, Camargo MD, Franke SIR,
Prá D, Silva AMV, Borges TS, Todendi PF, Reckziegel MB;
Critical revision of the manuscript for intellectual content:
Burgos MS, Reuter CP, Burgos LT, Camargo MD, Franke SIR,
Prá D, Silva AMV, Borges TS, Todendi PF, Reckziegel MB.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
Cézane Priscila Reuter, Tássia Silvana Borges and Pâmela
Ferreira Todendi are recipients of PROSUP/Capes research
grants.
Study Association
This article is part of the thesis of master submitted by
Cézane Priscila Reuter from Universidade de Santa Cruz
do Sul.
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Back to the cover
Original Article
Influence of Carotid Injury in Post-Myocardial Revascularization
Surgery and Its Late Evolution
Maria Sol Calero Revelo, Daniel Pio de Oliveira, Flávia Bittar Britto Arantes, Camila Camarço Batista, João
Italo Dias França, Silmara Cristina Friolani. Jorge Eduardo Assef, José Eduardo Martins Barbosa, Ana Claudia
Petisco, Pedro Silvio Farsky
Instituto Dante Pazzanese de Cardiologia. São Paulo. SP - Brazil
Abstract
Background: Approximately 30% of perioperative CVA of myocardial revascularization surgery (MRS) are a result of carotid
injuries, without reduction of risk confirmed by perioperative intervention.
Objectives: Evaluate the impact of carotid disease and perioperative intervention in patients subjected to MRS.
Methods: Observational, retrospective study, evaluating 1169 patients aged ≥ 69 years undergoing MRS from January, 2006
and December, 2010, monitored, on average, for 49 months. All patients were subjected to ultrasonography of carotids before
MRS. It was defined as carotid disease when lesion ≥ 50%. The primary outcome was composed of CVA incidence, transitory
ischemic accident (TIA) and death due CVA.
Results: Prevalence of carotid disease was of 19.9% of patients. The incidence of primary outcome between unhealthy
and healthy patients was of 6.5% and 3.7%, respectively (p = 0.0018). In the first 30 days, there were 18.2% of events.
Were related to carotid disease: renal dysfunction (OR 2.03, IC95% 1.34-3.07; p < 0.01), peripheral arterial disease (OR
1.80, IC95% 1.22-2.65; p < 0.01) and previous myocardial infarction (OR 0.47, IC95% 0.35-0.65; p < 0.01). Regarding
the primary outcome, were associated the previous TIA (OR 5.66, IC95% 1.67-6.35; p < 0.01) and renal dysfunction (OR
3.28, IC95% 1.67-6.45; p < 0.01). In patients with lesion ≥70%, perioperative carotid intervention demonstrated an
incidence of 16% in primary outcome compared to 4.3% in conservatory treatment (p = 0.056) with no difference between
percutaneous and surgical approaches (p = 0.516).
Conclusion: Carotid disease increases the risk of CVA, TIA or death due to CVA in MRS. However, the carotid intervention was
not related to reduction of primary outcome. (Arq Bras Cardiol. 2013;101(4):297-303)
Keywords: Carotid Stenosis / complications; Myocardial Revascularization; Peri operative Care.
Introduction
Cerebrovascular accident (CVA) is one of the risks related to
myocardial revascularization surgery (MRS), which leads to a death
rate of 19% and it has a significant social and functional impact1.
About 30% of perioperative CVA result from lesions in carotids,
and the more significant the vessel obstruction level and when both
carotids are injured, the greater is the risk of this event2.
Current recommendations regarding the treatment of
carotid disease (CD) in MRS context are contradictory.
Brazilian guidelines on surgical treatment for myocardial
revascularization, valvulopathies and aorta recommend that
patients with transitory ischemic accident (TIA), amaurosis,
peripheral obstructive disease and age above 60 years carry
out Doppler ultrasonography and arteriography. In case of
carotid injury, symptomatic patient with injury above 60% and
unstable angina, stem and multiarterial injury, simultaneous
surgery is recommended; in case of stable angina, simultaneous
or staged surgery. If the patient is asymptomatic and has lesion
below 60%, MRS is recommended3. However, according to the
American College of Cardiology, in patients with indication for
MRS and previous CVA or TIA, with significant carotid stenosis,
it is reasonable to consider a carotid revascularization with
MRS. But in patients with no history of CVA or TIA, intervention
is considered if there are no significant bilateral carotid injuries
or severe unilateral stenoses with contralateral occlusion4.
This study was designed to evaluate the prevalence of significant
carotid injury, its association with more relevant cerebrovascular
events (CVA, TIA, death) and clinical, demographic and
angiographic characteristics of patients, considering population
above the age of 65 years, subjected to MRS.
Methods
Mailing Address: Pedro Silvio Farsky •
Av Dante Pazzanese 500, Postal Code 04012-180, Sao Paulo SP - Brazil
E-mail: [email protected]
Manuscript received December 07, 2012; revised manuscript May 22, 2013;
accepted June 07, 2013.
DOI: 10.5935/abc.20130183
297
Study population
An observational, retrospective study was carried out,
evaluating data obtained from medical charts of patients aged
65 or older, consecutively subjected to MRS, between January
2006 and December 2010, and prospectively followed-up for
Calero et al.
Carotid injury and myocardial revascularization
Original Article
a period of 49 months. A retrospective analysis of outcomes
and demographic and clinical data was then performed.
The study was approved by the local ethics committee,
which was carried out with resources from the sector itself.
From all patients subjected to MRS within the period,
approximately 44% were at the age of 65 or older and, of
these patients, 92.7% (1,169) were subjected to pre-operative
investigation for carotid disease. Among the reasons for which
patients did not undergo Doppler ultrasonography of carotids,
were unstable coronary disease and emergency MRS.
Evaluation of carotid disease
The definition of carotid disease was based on peak systolic
velocity in the internal carotid artery evaluated by Doppler
ultrasonography and classified according to injury level: absent
or mild stenosis (< 50%), moderate stenosis (50-69%), severe
stenosis (70-99%) and occlusion (100%)5. In this study, significant
and severe carotid disease were those classified with stenosis of
level ≥ 50% and ≥ 70%, respectively, considered in the presence
of unilateral or bilateral disease.
Surgical procedures, indication and technique applied
MRS indication followed the guidelines for myocardial
revascularization surgery3. Surgical procedure was carried out
using median sternotomy, using electrical scalpel and opening
of pericardium with inverted ‘T’ incision. The internal thoracic
artery was used in almost all cases associated with the greater
saphenous vein when necessary.
The surgical procedure was carried out with the aid of
extracorporeal circulation in 97.4% of cases. Extracorporeal
circulation was performed with membrane oxygenator; it was
filled with saline.
Myocardial protection was achieved with intermittent
clamping of aorta (anoxic clamping), clamping with no longer than
15 minutes and a two-minute interval between the clamping.
The decision for carotid procedure associated with
MRS was made by the medical team. In cases where
percutaneous implantation of endoprostheses was chosen, it
was associated with acetylsalicylic acid the use of clopidogrel,
75mg, daily for 30 days.
Combined surgery
Combined surgery was indicated in the presence of
symptomatic carotid disease associated with unstable or
critical coronary disease. However, therapeutic options
were individualized, case by case, and decided by a
multidisciplinary team.
Before the myocardial revascularization procedure, a neck
incision was performed. The carotid artery had its plate removed.
A patch could be used to close the artery. After revascularization
and use of protamine, skin and subcutaneous tissue were sutured.
All patients underwent surgical procedures on aspirin.
Statistical analysis
For comparisons of categorical variables, Fisher’s exact test
was applied and, for continuous variables, Student t-test. Values
of p < 0.05 were considered statistically significant. A univariate
analysis evaluating the relation between risk factors and level
of carotid disease was performed. Variables that showed values
of p ≤ 0.1 in univariate models were analyzed by multivariate
regression.
Objectives
Defined as primary outcome associated with carotid disease
was the incidence of compound event CVA, TIA and death due
to CVA, being CVA defined as clinical and persistent neurological
deficit after 24 hours of its installation, confirmed or not by imaging
test, and TIA as reverted deficit within 24 hours after installation.
Secondary outcome was defined as all-cause mortality.
Results
We evaluated 1,169 patients, in which we found prevalence of
significant carotid disease (injury on vessel ≥ 50%) was of 19.9%.
It was observed severe lesions (injury on vessel ≥ 70%) in 8.6% of
patients, and 2% of these showed total occlusion in at least one
vessel (Table 1).
Mean age of study patients was of 71.6 years (SD ± 4.9), ranging
from 65-95 years old. Among those with significant carotid injury,
mean age was of 72.1 years old (SD ± 5.2) and, among those
without significant disease, 71.4 years old (SD ± 4.8) (p = 0.127).
For severe CD, mean age was of 73.1 years old (SD ± 5.4), while
for patients without severe CD was of 71.4 years old (SD ± 4.8)
(p = 0.002).
We found as predictors of significant carotid disease, in
univariate analysis, systemic arterial hypertension (SAH), previous
TIA, renal dysfunction and peripheral arterial disease (Table 2).
Multivariate analysis showed the following predictors: renal
dysfunction and peripheral vasculopathy (Table 3). In both, AMI
was observed as protective factor.
Table 1 - Distribution of patients according to the carotid stenosis level according to Doppler ultrasonography of the carotid
Level of carotid stenosis
Absolute number of patients
Percentage of patients in relation to the general population
Without injury
148
12.7
<50%
789
67.5
50-69%
132
11.3
70-99%
77
6.6
Total occlusion
23
2.0
1.169
100
Total
Arq Bras Cardiol. 2013;101(4):297-303
298
Calero et al.
Carotid injury and myocardial revascularization
Original Article
Table 2 - Clinical characteristics of patients with significant carotid disease (≥ 50%)
CD < 50%
(n = 937)
CD ≥ 50%
(n = 232)
Odds ratio
p
Female
34.7%
40.5%
0.78 (0.58-1.05)
0.10
SAH
88.4%
93.5%
1.89 (1.08-3.31)
0.02
DM2
46.4%
43.1%
0.88 (0.66-1.17)
0.37
FH CD
10.7%
10.8%
1.01 (0.63-1.60)
1.00
Smoking
10.4%
10.8%
-
0.77
Previous CVA
4.4%
5.6%
1.29 (0.68-2.45)
0.48
Previous TIA
1.6%
3.9%
2.47 (1.07-5.72)
0.03
Renal dysfunction
10.9%
18.1%
1.80 (1.22-2.67)
<0.01
Peripheral vasculopathy
12.2%
20.3%
1.83 (1.26-2.67)
<0.01
Variables
Dyslipidemia
9.9%
9.5%
0.96 (0.60-1.56)
1.00
Previous AMI
50.9%
34.1%
0.50 (0.37-0.67)
< 0.01
TIA: transitory ischemic accident; CVA: cerebrovascular accident; CD: carotid disease; DM2: diabetes mellitus type 2; SAH: systemic arterial hypertension;
FH CD: family history of coronary disease; AMI: acute myocardial infarction.
Table 3 - Multivariate analysis of clinical characteristic of patients with significant carotid disease (≥ 50%) which p < 0.10
Clinical characteristic
Odds ratio
p
Sex
0.75 (0.55-1.02)
0.06
SAH
1.71 (0.97-3.04)
0.06
TIA
2.03 (0.85-4.82)
0.11
Peripheral vasculopathy
1.80 (1.22-2.65)
<0.01
Renal dysfunction
2.03 (1.34-3.07)
<0.01
Previous TIA
0.47 (0.35-0.65)
<0.01
TIA: transitory ischemic accident; SAH: systemic arterial hypertension.
The incidence of primary outcome was of 3.7%, with
18.2% having occurred in the first 30 days after surgery. From
the total events, 3% were observed in the group without
carotid injury and 6.5% in the group with significant carotid
injury (p = 0.0018). Only previous TIA (OR 5.66, IC95%
1.67-6.35; p < 0.01) and renal dysfunction (OR 3.28, IC95%
1.67-6.45; p < 0.01) were defined as predictors for the
primary outcome in univariate analysis (Table 4). All-cause
mortality at the end of the follow-up was of 11.1%, and in
6.8% the basic cause was CVA.
Among patients with severe CD (lesion ≥ 70% and
< 100%) and underwent an intervention for its treatment in
the perioperative period, the incidence of primary outcome
was of 12.5%. But among those who, as decided by the
medical team, were not subjected to any procedure, the
incidence of primary outcome was of 3.4% (p = 0.24).
As for the type of approach (percutaneous versus surgical),
when compared with each other, there was no statistical
difference in the primary outcome incidence (p = 0.516)
(Table 5).
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Arq Bras Cardiol. 2013;101(4):297-303
In the first 30 days after MRS, the incidence of
neurological events was of 12% among patients who
underwent procedures against 4.5% among those who were
not subjected to procedures, with p = 0.28. After 30 days
of MRS and until the end of the follow-up, the incidence of
neurological event was of 0% in the group without procedure
and 7% in the group with procedure, with p = 0.24.
Survival in 60 months for patients without carotid injury
was of 90.7% and, in the group with carotid disease above
50%, was of 83.5%, (HR = 1.9, IC95% 1.3-2.8), p = 0.001
(Figure 1).
Discussion
The incidence of primary outcome in this population was
3.7% and correlated with data from the literature, which values
range from 2-6%6,7. It is estimated that such data may be
underestimated, once studies show that neurological disorders
such as delirium, agitation, memory loss and cognition loss, in
post-MRS, show incidences of up to 13.8%, with many related
to cerebral infarction6.
Calero et al.
Carotid injury and myocardial revascularization
Original Article
Table 4 - Multivariate analysis of clinical characteristic of patients with primary outcome
No event
Event
Odds ratio
p
SAH
89.3%
93.0%
1.59 (0.49-5.23)
0.61
DM2
46.2%
32.6%
0.56 (0.29-1.07)
0.09
FH CD
10.9%
7.0%
0.61 (0.19-2.02)
0.61
Smoking
16.3%
10.2%
−
−
Previous CVA
4.5%
9.3%
2.20 (0.76-6.40)
0.13
Previous TIA
1.8%
9.3%
5.66 (1.85-17.34)
0.01
Renal dysfunction
11.7%
30.2%
3.28 (1.67-6.45)
<0.01
Peripheral vasculopathy
13.5%
20.9%
1.69 (0.79-3.59)
0.17
Dyslipidemia
9.7%
11.6%
1.22 (0.47-3.17)
0.60
Previous AMI
47.7%
41.9%
0.79 (0.42-1.46)
0.53
Prior AMI
11.8%
14.0%
1.22 (0.50-2.94)
0.63
Previous PCA
1.9%
4.7%
2.56 (0.58-11.28)
0.21
Arrhythmia
18.0%
20.5%
1.17 (0.53-2.59)
0.67
Transoperative AMI
21.6%
27.9%
1.40(0.71-2.78)
0.35
3.7%
4.7%
1.28 (0.30-5.49)
0.67
3.2%
2.3%
0.72 (0.10-5.37)
1.00
33.1%
33.3%
1.01 (0.48-2.11)
1.00
97.4%
97.7%
1.11 (0.15-8.37)
1.00
71.6
71.4
−
0.85
54.4
59.4
−
0.18
81.2
89.9
−
0.16
Variables
Postoperative AF
Previous heart surgery
LMCA injury
ECC
Age
Time of anoxia (min)
Time of ECC (min)
TIA: transitory ischemic accident; PCA: percutaneous coronary angioplasty; CVA: cerebrovascular accident; ECC: extracorporeal circulation; DM2: diabetes
mellitus type 2; AF: atrial fibrillation; SAH: systemic arterial hypertension; FH CD: family history of coronary disease; AMI: acute myocardial infarction; LMCA:
left main coronary artery.
Table 5 - Incidence of primary outcome in relation to carotid disease approach
Procedure
Primary outcome
(n = 1.169)
Primary outcome related to CD approach (n=9)
p
−
None
79.1%
−
Previous endarterectomy
2.3%
6.7%
Endarterectomy during MR or until 30 days later
7%
17.2%
Stent pre-MRS
11.6%
20%
Stent post-MRS
0
0
p = 0.516
CD: carotid disease; MRS: myocardial revascularization surgery.
Arq Bras Cardiol. 2013;101(4):297-303
300
Calero et al.
Carotid injury and myocardial revascularization
Original Article
Survival curve
carotid disease < 50%
carotid disease > 50%
Time
Figure 1 - Kaplan-Meier curves for survival free from events in 60 months of follow-up.
In the primary outcome, 18.2% of events occurred in
the first 30 days after surgery. Even though 34.5 of total
CVA of study population had occurred in the group without
significant carotid disease, the presence of carotid disease
≥ 50% aggregates an OR = 2.2 (p = 0.0018) for compound
outcome of CVA, TIA and death due to cardiovascular.
In the literature, the relation between carotid disease
and post-CVA is controversial. Even though it is related
that the risk for CVA is higher than 2% among those with
non‑significant CD against 5% in the group with significant
CD, reaching 11% in case of occlusion, most perioperative
CVA are not related to carotid disease2. In previous studies
with patients subjected to MRS, only 23.7% had significant
carotid disease, suggesting that alternative causes were
related to the development of the event8.
It is recognized that 50-79% of CVA cannot be
attributed to CD alone, with contribution of embolic events
secondary to extracorporeal circulation, postoperative
arrhythmias, hypotension, state of hypofibrinolysis and
aortic calcification such as etiological factors6,9-11. In the
literature are also identified as predictors of perioperative
CVA: age, female gender, diabetes mellitus, SAH, peripheral
vasculopathy, polytransfusion and emergency surgery12,13.
In our study, only previous TIA and renal dysfunction were
defined as predictors for the primary outcome.
In the current cohort, the prevalence of significant
carotid disease of 19.9% was similar to that from the
literature, which values range between 4-18.7%14,15. The
prevalence of unilateral occlusion (2%) was higher than that
301
Arq Bras Cardiol. 2013;101(4):297-303
from the literature (0.06%), however there were no cases of
bilateral occlusion, which prevalence is estimated at 0.04%.
For preoperative carotid evaluation in MRS, we currently
recommend screening with Doppler ultrasonography of
patients aged 65 or older, in addition to those with stenosis
of the left main coronary artery and previous CVA or TIA,
SAH, DM23,4. In this study, CD ≥50% predictors, after
multivariate analysis, were the factors: renal dysfunction,
peripheral arterial disease and previous myocardial
infarction, this as protective factor. It has been hypothesized
that the presence of previous AMI as protective factor
can be explained by the current conduct of initiating
the treatment with inhibitors of angiotensin-converting
enzymes (ACE), angiotensin II receptor blockers (ARB) and
statins, medications that have impact on the evolution of
atherosclerotic disease16.
Despite divergent, international guidelines recommend
intervention on symptomatic carotid stenoses above 70%
and asymptomatic above ≥ 80%4. In our study, there was
no difference in compound outcome between patients
with CD≥70% evaluated by Doppler ultrasonography
who underwent or not an intervention in carotid disease
(p = 0.24). Moreover, when compared with each other,
there was no statistical difference in the primary outcome
incidence between the different approaches (percutaneous
versus surgical – p = 0.516). Some studies indicate that
performing the correction of carotid injury associated with
MRS can also increase the risk of postoperative CVA and
death17,18.
Calero et al.
Carotid injury and myocardial revascularization
Original Article
The type of intervention related to the lower number of
neurological events and the best moment for approaching
CD remain controversial. In our results, the difference
between these factors was not statistically significant.
a better assessment on the impact of CD approach in
perioperative MRS.
In the literature, studies are divergent. In one study
analyzing patients with carotid disease which underwent
MRS, it was observed that the incidence of postoperative
CVA was of 15.1% among patients subjected to MRS
combined with endarterectomy and of 20% in patients
who underwent angioplasty with stent prior to surgery.
There was no postoperative CVA in patients with CD
≥70% who did not underwent a carotid revascularization
procedure 8 . Levi et al 19 monitored 80 patients who
underwent endarterectomy combined with MRS and
found a neurological events rate of 7.6% in 10 years.
This is a retrospective study, based on the analysis of
medical charts. The choice of clinic therapeutic strategy,
surgery strategy or stenting was decided by the medical
team responsible for the patient, which did not allow the
comparative analysis of results.
In this study, the incidence of CVA in the group
subjected to endarterectomy prior to MRS was of 6.7%.
Van der Heyden et al20 evaluated endarterectomy followed
by MRS in 356 patients neurologically asymptomatic, in
a 30-day follow-up; rate of death and CVA was of 4.8%.
Ziada et al 21 compared endarterectomy and carotid
angioplasty with stent, followed by heart surgery. There
was a smaller proportion of CVA in a 30-day follow-up
in the group which was subjected to carotid angioplasty
with stent. On the other hand, a metanalysis of 11
studies comparing carotid endarterectomy and carotid
angioplasty with stent prior to MRS found similar rates
of CVA and AMI 22. Currently, the European directive
of myocardial revascularization, published in 2011,
recommends the carotid intervention on symptomatic
patients when stenosis 70-99%; the procedure can be
considered for asymptomatic male patients with bilateral
stenosis of 70-99% or stenosis of 70-99% associated with
contralateral occlusion. The same directive claims the
approach of CD in MRS is controversial and hypothesizes
the decision to intervene and the type of procedure to be
performed (surgery or angioplasty) must be individualized
after discussion by a multidisciplinary team, including a
neurologist23.
Currently, conflicting results could be justified by the
fact that in the literature, studies on this topic are based
on retrospective studies. Limitations on this study are
due to the presence of possible variables not balanced
in the sampling. Randomized studies are necessary for
Study limitations
Conclusion
Carotid disease is an important marker of neurological events
related to MRS. The presence of significant carotid injury is a risk
factor for CVA, TIA or death due to CVA in patients subjected
to MRS. However, the surgical approach for carotid disease was
not significantly related to the primary outcome.
Author contributions
Conception and design of the research: Batista CC, Petisco
AC, Oliveira DP, Farsky PS, Arantes FBB, Assef JE, Barbosa
JEM, Friolani SC, Revelo MSC; Acquisition of data: Batista CC,
Petisco AC, Oliveira DP, Arantes FBB, Barbosa JEM, Revelo
MSC; Analysis and interpretation of the data: Batista CC, Petisco
AC, Oliveira DP, Farsky PS, Arantes FBB, França JID, Barbosa
JEM, Friolani SC, Revelo MSC; Statistical analysis: França JID,
Revelo MSC; Writing of the manuscript: Batista CC, Oliveira
DP, Farsky PS, Arantes FBB, Friolani SC, Revelo MSC; Critical
revision of the manuscript for intellectual content: Batista CC,
Petisco AC, Oliveira DP, Farsky PS, Arantes FBB, Assef JE, Friolani
SC, Revelo MSC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is a study of medical cardiology residency by
Maria Sol Calero Revelo, from Instituto Dante Pazzanese.
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Back to the cover
Original Article
Carvedilol Enhances the Antioxidant Effect of Vitamins E and C in
Chronic Chagas Heart Disease
Patrícia Budni1, Roberto Coury Pedrosa2,3 Eduardo Monguilhott Dalmarco1, Juliana Bastos Dalmarco1, Tânia Sílvia
Frode1, Danilo Wilhelm Filho1
Universidade Federal de Santa Catarina1, Florianópolis, SC; Universidade Federal do Rio de Janeiro2; Hospital Universitário Clementino Fraga
Filho3, Rio de Janeiro, RJ - Brazil
Abstract
Background: Chagas disease is still an important endemic disease in Brazil, and the cardiac involvement is its more
severe manifestation.
Objective: To verify whether the concomitant use of carvedilol will enhance the antioxidant effect of vitamins E and C in
reducing the systemic oxidative stress in chronic Chagas heart disease.
Methods: A total of 42 patients with Chagas heart disease were studied. They were divided into four groups according
to the modified Los Andes classification: 10 patients in group IA (normal electrocardiogram and echocardiogram; no
cardiac involvement); 20 patients in group IB (normal electrocardiogram and abnormal echocardiogram; mild cardiac
involvement); eight patients in group II (abnormal electrocardiogram and echocardiogram; no heart failure; moderate
cardiac involvement); and four patients in group III (abnormal electrocardiogram and echocardiogram with heart failure;
severe cardiac involvement). Blood levels of markers of oxidative stress were determined before and after a six-month
period of treatment with carvedilol, and six months after combined therapy of carvedilol with vitamins E and C. The markers
analyzed were as follows: activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase
and reductase, myeloperoxidade and adenosine deaminase; and the levels of reduced glutathione, thiobarbituric-acid
reactive substances, protein carbonyls, vitamin E, and nitric oxide.
Results: After treatment with carvedilol, all groups showed significant decrease in protein carbonyls and reduced
glutathione levels, whereas nitric oxide levels and adenosine activity increased significantly only in the less severely
affected group (IA). In addition, the activity of most of the antioxidant enzymes was decreased in the less severely
affected groups (IA and IB). By combining the vitamins with carvedilol, a reduction in protein damage, in glutathione
levels, and in the activity of most of the antioxidant enzymes were observed.
Conclusions: The decrease in oxidative stress levels observed by means of the markers tested was more significant when
carvedilol was used in combination with the antioxidant vitamins. The findings suggest that both carvedilol alone and in
combination with the vitamins were effective in attenuating the systemic oxidative stress in patients with Chagas heart
disease, especially those less severely affected, thus suggesting the possibility of synergism between these compounds.
(Arq Bras Cardiol. 2013;101(4):304-310)
Keywords: Chagas, Cardiomyopathy / therapy; Adrenergic Beta-Antagonists; Antioxidants; Vitamin E; Vitamin C.
Introduction
Cardiac involvement is the most severe and common
manifestation in the chronic phase of Chagas disease in
endemic areas, and is the main death cause in patients
aged between 30-50 years1.
Mailing address: Patricia Budni •
Universidade Federal de Santa Catarina, Centro de Ciências Biológicas,
Cidade Universitária, Trindade. Postal Code 80040-900, Florianópolis,
SC - Brazil
E-mail: [email protected]
Manuscript received January 03, 2013; revised manuscript January 07, 2013;
accepted April 30, 2013
DOI: 10.5935/abc.20130184
304
The pathogenesis of chronic Chagas heart disease
(CCHD) is not yet fully understood, partly because the
disease progression depends on a complex parasite-host
interaction. Some mechanisms have been proposed to
explain the pathogenesis of CCHD, one of which is the
hypothesis of an amplified immune-inflammatory response,
among other processes, resulting from the generation
of oxygen-reactive species (ORS) in the presence of the
parasite or its antigen2,3.
Conventional treatment strategies for heart failure, such
as betablockers, have shown a significant improvement
in survival and progression of heart failure (HF).
However, strategies focusing specifically on CCHD are
still scarce4,5.
Budni et al.
Carvedilol and antioxidants in Chagas heart disease
Original Article
Carvedilol is a combination of beta-1 with alpha-1
adrenergic blockers approved for the treatment of heart
failure and left ventricular dysfunction. Many experimental
and clinical evidences suggest that, in addition to
its adrenergic blockade, the drug also has a potent
antioxidant activity6.
We have recently shown that increased oxidative stress
is associated with the progression of Chagas disease7, and
that the use of antioxidants was effective in reducing it,
thus potentially being able to influence the course of the
disease 8,9. Our group has also recently shown that the
administration of carvedilol was effective in attenuating
oxidative stress in the different stages of the disease, an
effect that may be particularly important in CCHD10.
The main objective of this study was to investigate
whether carvedilol would enhance the antioxidant effect
of vitamins E and C, previously demonstrated in studies
conducted in our laboratory, by means of biomarkers of
inflammatory and oxidative stress in the blood of patients
with CCHD.
Methods
Study design
This is a prospective therapeutic intervention study (RBR-95,
JNQP) of a sample from an open cohort comprised of patients
followed up in the Service of Cardiology of Clementino Fraga
Filho University Hospital (HUCFF-UFRJ).
Patient selection
The study sample was comprised of patients who had
spontaneously followed the treatment flowchart of the
HUCFF‑UFRJ Chagas disease outpatient clinic. Only patients
with chronic Chagas disease aged between 21-70 years, who
had maintained their nutritional habits, had no associated
diseases, and had been away from endemic zones for more
than 20 years were included in the study. Patients with
arterial hypertension, chronic obstructive pulmonary disease,
cardiomyopathy of an etiology other than Chagas disease, heart
valve disease, thyroid dysfunction, excessive tobacco/alcohol
intake, known immune diseases, abnormal serum electrolyte
levels (potassium and calcium), or systemic disease were
excluded from the study. The study project was approved by
the HUCFF-UFRJ Research Ethics Committee (CEP resolution
no. 053/07). All patients received information about the study
and gave written informed consent.
The patients were followed up by the same team of physicians.
Medical visits were scheduled regularly on an outpatient basis at
mean intervals of four months and, when necessary, the patients
underwent laboratory tests. All patients had been clinically stable
for at least three months when their blood sample was collected
for the present study. The patients’ diet was poor in major
nutritional antioxidants and, therefore, the intake of vitamins C
and E was considered negligible. Medications that interfered with
the fluid and electrolyte balance were discontinued for 48 hours
prior to the laboratory and clinical tests, and no clinical events
were recorded during this period.
The patients were divided into four groups according
to the modified Los Andes classification11: 10 patients in
group IA (normal electrocardiogram and echocardiogram;
no cardiac involvement); 20 patients in group IB (normal
electrocardiogram and abnormal echocardiogram; mild
cardiac involvement); eight patients in group II (abnormal
electrocardiogram and echocardiogram; no heart failure;
moderate cardiac involvement); and four patients in group
III (abnormal electrocardiogram and echocardiogram with
heart failure; severe cardiac involvement).
The levels of biomarkers of oxidative stress were
determined prior to and six months after treatment with
carvedilol alone (at a dose of 12.5mg TID, in a total daily
dose of 37.5 mg) and prior to and after six months of the
combination of carvedilol with vitamins E (800IU) and
C (500mg) in a single daily dose. Between the phases of
carvedilol used alone and in combination with the vitamins,
there was an interval of six months with no medication.
Serological diagnosis of Chagas disease
The serological diagnosis of Chagas disease was made
in all patients by means of anti-T. cruzi antibody detection
using two methods. The dilution considered as a positive
serological reaction was that established by the laboratory
of the Manguinhos-Fiocruz/RJ reference center.
Patients were considered as testing positive when they
showed two positive serological tests in two samples
collected separately. In case of doubtful results of the
two methods, the serum samples were retested using the
immunofluorescence method; if discrepancy persisted, the
result of immunofluorescence prevailed. Blood samples were
always collected by the same person, on the same day of the
week, in the morning, and with the patients fasted.
Medications and reagents
Carvedilol, (RS)-1-(9H-carbazol-4-yloxy)-3-[2-(2ethoxyphenoxyl) ethylamine] propan-2-ol, and vitamins
E (E-Tabs) and E (Energil C) were kindly supplied by a
pharmaceutical industry from the State of São Paulo (Brazil),
of the EMS Sigma Farma group.
The reagents used for the analyses of oxidative stress
biomarkers were obtained from Sigma Chemical Co.
(St. Louis, USA).
Statistical analysis
Statistical comparisons of inflammatory and oxidative
stress markers within the different groups were made using
the one-factor analysis of variance (ANOVA) complemented
by the Tukey-Kramer test. Data were analyzed using the
generalized linear models for repeated measures. The SPSS
version 11.5.0 acquired under license by Federal University
of Santa Catarina in 9/6/2002 was used for all analyses.
The level of significance was set at 5%.
Arq Bras Cardiol. 2013;101(4):304-310
305
Budni et al.
Carvedilol and antioxidants in Chagas heart disease
Original Article
Results
The radiological assessment showed that the cardiothoracic
index increased with the degree of cardiac involvement
(p = 0.0001) and was considered as cardiomegaly when
values were greater than 0.50. Echocardiography showed
ejection fraction values significantly lower in group III
patients than in patients of the other groups (p = 0.0001).
The left ventricular end-diastolic diameter was corrected for
body surface, and values above 32 mm/m2 were considered
abnormal. Based on this criterion, 12 patients showed left
ventricular dilatation. Right myocardial impairment, as
expressed by pulmonary hypertension, was observed in
groups II and III patients (Table 1).
The analysis of the profile of the different groups showed that
group IA patients had significantly decreased GSH levels, both
after treatment with carvedilol (0.18 ± 0.12 µmol ml−1) and
after treatment with carvedilol combined with the antioxidant
vitamins (0.14 ± 0.10 µmol ml−1), in comparison with untreated
individuals (0.31 ± 0.17 µmol ml−1).
TBARS and vitamin E levels remained unchanged when
compared to the treatment with carvedilol alone. However,
after combination with vitamins, plasma TBARS levels
significantly decreased in comparison to those of untreated
patients (13.11 ± 9.98 nmol ml−1 – 6.10 ± 3.02 nmol ml−1),
whereas plasma vitamin E levels increased in relation to the
treatment with carvedilol alone (12.44 ± 2.85 µmol L−1 –
16.18 ± 3.45 µmol L−1) (Table 2). However, the protein
carbonyls (PC) level was significantly decreased in patients
treated with carvedilol (0.04 ± 0.01 nmol mg−1) and vitamins
(0.09 ± 0.03 nmol mg−1), in comparison to that of untreated
patients (0.15 ± 0.07 nmol mg−1). When we compared the
activity of the antioxidant enzymes SOD, GST and GPx within
group IA, we observed a significant reduction in relation
to untreated patients in both treatment regimens, whereas
CAT activity was initially higher with carvedilol and then
remained unchanged with the combination with vitamins.
GR activity remained unchanged with treatment with carvedilol
(5.02 ± 0.71 µmol min−1 ml−1 – 4.78 ± 1.26 µmol min−1 ml−1,
respectively) and decreased significantly with the combination
with vitamins (3.89 ± 0.71 µmol min−1 ml−1) (Table 3).
As for the inflammatory markers, after treatment with
carvedilol there was a significant increase in nitric oxide
(NO) levels in comparison to those of untreated patients
(10.93 ± 3.19 µM and 17.96 ± 3.24 µM, respectively)
followed by a decrease after the combination with vitamins
(9.09 ± 1.00 µM). A significant increase in ADA activity
was observed after both interventions (10.03 ± 1.28 Ul−1,
17.17 ± 2.49 Ul−1 and 17.58 ± 2.21 UI−1), whereas MPO
activity remained unchanged (Table 2).
Group IB patients treated with carvedilol plus vitamins
showed a very similar response to that of group IA patients.
GSH levels (0.16 ± 0.13 µmol ml−1 – 0.11 ± 0.09 µmol
ml −1, respectively) were also significantly lower when
compared to those of untreated patients (0.22 ± 0.17 µmol
ml−1) in both interventions, whereas TBARS and vitamin
E levels remained unchanged when compared to those of
patients receiving treatment with carvedilol alone. However,
in the combination with vitamins, TBARS levels decreased
significantly in comparison to those of untreated patients
(10.02 ± 6.18 nmol ml−1 – 6.52 ± 2.92 nmol ml−1, respectively),
whereas vitamin E levels increased in relation to those of
carvedilol (15.70 ± 4.68 µmol L−1 – 22.02 ± 11.0 µmol L1,
respectively; Table 2). In addition, like in group IA patients, CP
levels significantly decreased in patients treated with carvedilol
alone (0.05 ± 0.02 nmol mg−1) and with carvedilol plus the
combination of vitamins (0.09 ± 0.08 nmol mg−1) when
compared to those of untreated patients (0.6 ± 0.19 nmol
mg−1). The profile of the antioxidant enzymes activity in this
group was also very similar to that of group IA, whereas the
inflammatory markers remained unchanged, except for the
MPO activity, which increased significantly in relation to
patients treated with carvedilol combined with antioxidant
vitamins (420.70 ± 27.88 μM – 531.54 ± 25.84 μM,
respectively) (Table 2).
Table 1 - Radiologic, electrocardiographic and echocardiographic data of the chagasic patients
Variable
IA (n = 10)
IB (n = 20)
II (n = 8)
III (n = 4)
ANOVA p
0.45 ± 0.02
0.45 ± 0.02
0.48 ± 0.04
0.52 ± 0.02
0.0001*
0
0
20
100
0.001†
RBBB (%)
0
55.7
62.3
97.8
0.001‡
RBBB + LAHB (%)
0
68.9
72.1
99.1
0.003‡
Inactive area (%)
0
2
55
89.3
0.001‡
Chest radiography
Cardiothoracic index (m ± sd)
consistent with CHF (%)
Electrocardiography
Echocardiography
LVEF (%)
LVEDDI (mm/m2)
Pulmonary hypertension (%)
65.2
61.6
42.4
37.6
0.0001§
28.3 ± 1.8
29.2 ± 1.2
32.3 ± 4.8
35.9 ± 1.9
0.001§
0
0
25
44
0.001§
RBBB: complete right bundle branch block; LVEF: left ventricular ejection fraction; LAHB: left anterior hemiblock; LVEDDI: left ventricular end-diastolic diameter index;
Tukey (IA ¹ III)*·; (IA ¹ III) †; (IB ¹ III) ‡; (IA ¹ III) §
306
Arq Bras Cardiol. 2013;101(4):304-310
10.93 ± 3.19
417.3 ± 40.1
NO
MPO
9.5 ± 4.28
544.18 ± 70.05
17.96 ± 3.2 α*
17.17 ± 2.5α*
12.44 ± 2.85
0.18 ± 0.12α*
0.04 ± 0.01α**
6.10 ± 3.02β*
553.96 ± 39.21
9.09 ± 1.00γ*
17.58 ± 2.21β*
16.18 ± 3.45γ*
0.14 ± 0.10β**
0.09 ± 0.03β**γ**
7.71 ± 1.17
16.07 ± 1.50
15.36 ± 2.29
15.70 ± 4.68
0.16 ± 0.13α**
0.05 ± 0.02α*
430.97 ± 31.53 420.70 ± 27.9
11.18 ± 1.38
10.67 ± 1.08
17.12 ± 8.93
0.22 ± 0.17
0.16 ± 0.19
10.02 ± 6.18
Untreated
531.54 ± 25.84γ*
13.70 ± 1.53
16.01 ± 0.92
22.02 ± 11.0γ*
0.11 ± 0.09β**
0.09 ± 0.1β**γ***
6.52 ± 2.92β*
After 6 months
of combined
treatment
After 6 months
of treatmen
with Carvedilol
After 6 months
of combined
treatment
After 6 months
of treatmen
with Carvedilol
18.86 ± 2.60
12.90 ± 2.14
12.24 ± 2.18
0.18 ± 0.11α*
0.05 ± 0.01α***
8.33 ± 1.55
After 6 months
of treatmen with
Carvedilol
409.54 ± 80.95 352.13 ± 50.36
15.49 ± 3.42
14.02 ± 2.27
19.64 ± 9.25
0.29 ± 0.10
0.17 ± 0.07
11.34 ± 4.60
Untreated
13.17 ± 4.62
10.63 ± 3.52
11.72 ± 3.40
0.38 ± 0.15
0.15 ± 0.10
15.19 ± 5.04
Untreated
12.10 ± 1.00
9.05 ± 4.06
11.18 ± 3.83
0.16 ± 0.09*α
0.05 ± 0.01α*
9.50 ± 2.22
10.92 ± 1.98
16.01 ± 0.59
20.76 ± 3.38β*γ*
0.18 ± 0.10β*
0.09 ± 0.12β*γ*
7.25 ± 4.06
After 6
After 6 months
months of
of combined
treatmen with
treatment
Carvedilol
Group III (n = 4)
707.42 ± 104.83β**γ*** 440.92 ± 68.15 395.08 ± 60.10 559.04 ± 66.62
17.17 ± 1.89
14.94 ± 1.41
29.40 ± 15.08γ*
0.16 ± 0.06β*
0.10 ± 0.03β*γ***
7.13 ± 3.40
After 6 months of
combined treatment
Group II (n = 8)
8.87 ± 2.55
30.61 ± 2.58
5.02 ± 0.71
CAT
GST
GR
4.78 ± 1.26
24.0717 ± 3.68*
13.27 ± 3.88α*
3.89 ± .71β*
17.68 ± 3.52β**γ**
10.25 ± 5.06
1.19 ± 0.60β***
59.44 ± 3.76β***
After 6 months
of combined
treatment
Untreated
4.94 ± 1.43
35.41 ± 9.42
9.21 ± 2.01
2.32 ± 0.35
10.67 ± 2.07
1.05 ± 0.47β***γ***
8.43 ± 3.14
2.75 ± 0.73
9.50 ± 4.06
2.36 ± 0.35
4.86 ± 1.70
4.11 ± 0.79β*
−1
4.76 ± 1.16
4.00 ± 1.09
24.58 ± 9.64α*** 17.63 ± 4.70β***γ*** 34.10 ± 5.64 20.81 ± 2.9α***
11.62 ± 4.10α*
1.49 ± 0.39α***
9.46 ± 3.65
2.27 ± 0.41
68.05 ± 4.75 β**
After 6 months
of combined
treatment
4.20 ± 0.65
19.08 ± 1.52β***
Group II (n = 8)
After 6 months
of treatmen
with Carvedilol
171.52 ± 41.16 66.37 ± 8.56α*** 59.89 ± 4.36β*** γ** 141.26 ± 46.6 70.9 ± 11.2 α**
Untreated
Group IB (n = 20)
After 6 months
After 6 months of
of treatmen with
combined treatment
Carvedilol
4.69 ± 0.81
26.66 ± 7.51
7.54 ± 3.93
2.48 ± 0.17
145.4 ± 44.1
Untreated
4.73 ± 1.52
23.28 ± 5.33
12.51 ± 6.43
2.14 ± 0.40
69.20 ± 6.54α*
−1
Group III (n = 4)
After 6 months
of treatmen with
Carvedilol
−1
−1
−1
−1
−1
−1
4.67 ± 0.27
21.93 ± 2.58
12.56 ± 3.89
2.13 ± 0.33
68.91 ± 5.01β**
After 6 months
of combined
treatment
CAT: catalase (mmol min ml ); GPx: glutathione peroxidase (μmol min ml ); GR: glutathione reductase (μmol min ml ); GST: glutathione S-transferase (μmol min ml ); SOD: superoxide dismutase (U SOD ml ).
Values are expressed as mean ± standard-deviation. *p < 0.05, **p < 0.01,***p < 0.001 represent significant differences within the same chagasic group.
−1
2.35 ± 0.22
GPx
1.48 ± 0.54α***
144.99 ± 29.0 64.04 ± 6.05α***γ*
SOD
Untreated
After 6 months
of treatmen with
Carvedilol
Group IA (n = 10)
Table 3 – Comparison, within the same group, of antioxidant enzymes in the blood of chagasic patients at three different treatment times
ADA: adenosine deaminase (UI-1); GSH: reduced glutathione (μmol ml−1); PC: protein carbonyl (nmol mg−1); •NO: nitric oxide (µM); MPO: myeloperoxidase (mU ml−1); TBARS: thiobarbituric-acid reactive substances (nmol ml−1); vitamin
E (μmol ml−1).
Values are expressed as mean ± standard deviation *p < 0.05, **p < 0.01,***p < 0.001 represent significant differences within the same chagasic group.
10.03 ± 1.28
ADA
•
0.31 ± 0.17
17.36 ± 8.11
Vit. E
0.15 ± 0.07
PC
GSH
13.11 ± 9.98
TBARS
Untreated
Group IB (n = 20)
Group IA (n = 10)
Table 2 - Comparison, within the same group, of GSH, TBARS, PC, vitamin E and •NO levels and MPO and ADA activities, in the blood of chagasic patients at three different treatment times
Budni et al.
Carvedilol and antioxidants in Chagas heart disease
Original Article
Arq Bras Cardiol. 2013;101(4):304-310
307
Budni et al.
Carvedilol and antioxidants in Chagas heart disease
Original Article
In group II patients, the behavior of the parameters
analyzed was also very similar to that found in the less
severely affected patients (groups IA and IB) (Table 2).
GSH levels were significantly lower when patients treated
with carvedilol and with carvedilol plus vitamins were
compared to those of untreated individuals (0.18 ± 0.11
– 0.16 ± 0.06 and 0.29 ± 0.10 µmol ml−1, respectively),
whereas no significant difference in TBARS levels and a
significant increase in vitamin E levels were found when
compared to those of patients receiving the combined
treatment with vitamins (29.40 ± 15.08 µmol L −1) and
those of untreated patients (19.64 ± 9.25 µmol L −1).
Again, PC values were significantly lower after treatment
with carvedilol alone (0.05 ± 0.01 nmol mg−1) as well as after
the combination with vitamins (0.10 ± 0.03 nmol mg−1),
in comparison to those of untreated individuals
(0.17 0.07 nmol mg−1). After treatment with carvedilol
combined with vitamins, the levels of inflammatory markers
remained unchanged, except for MPO, which significantly
increased (707.42 ± 104.83 μM) in comparison to values
of untreated patients (409.54 ± 80.95 μM) and of those
treated with carvedilol alone (352.13 ± 50.3 μM) (Table 2).
SOD and GST activities decreased significantly with both
treatments, whereas CAT, CR and GPx activities were not
significantly different in comparison to those of untreated
patients (Table 3).
Similar to what was found in the other groups, GSH levels
of patients classified as group III decreased significantly when
compared to those of patients treated with carvedilol alone
(0.16 ± 0.09 µmol ml−1), with the combination carvedilol
plus vitamins (0.18 0.10 µmol ml−1) and untreated patients
(0.38 ± 0.15 µmol ml−1) (Table 2). Also, same as for the values
found in groups IA, IB and II, no significant differences were
observed in TBARS levels of patients treated with carvedilol
alone and after combination with vitamins. Vitamin E levels
increased in patients treated with vitamins when compared to
those of untreated patients (11.72 ± 3.40 µmol ml−1 – 20.76
3.38 µmol ml−1), whereas CP values were decreased, both in
patients treated with carvedilol alone (0.05 ± 0.01 nmol mg−1)
and in those treated with the combination of carvedilol plus
vitamins (0.09 ± 0.12 nmol mg−1), when compared to those
of untreated patients (0.15 ± 0.06 nmol mg−1) (Table 2).
CAT, GR, GST and GPx activities were not significantly different
in relation to the therapy used. However, SOD activity
was decreased in individuals treated with carvedilol alone
(69.20 ± 6.54 ml−1) and with the combination carvedilol
plus vitamins (68.91 ± 5.01 ml−1) when compared to that of
untreated individuals (145.44 44.12 USOD ml−1). Same as for
the results obtained in other groups, the levels of inflammatory
markers remained unchanged after treatment with carvedilol
alone and in combination with the vitamins (Table 2).
Discussion
In the present study, the patients showed increased
oxidative damage in lipids and proteins prior to the antioxidant
therapy in comparison to that in the post-treatment period.
A generalized increase in the activity of most of the antioxidant
enzymes was also observed prior to treatment.
308
Arq Bras Cardiol. 2013;101(4):304-310
In an animal model of infection by Trypanosoma cruzi,
increased oxidative modification of cell proteins12,13 was
detected, as well as increased levels of malondialdehyde (MDA,
a major product of lipid peroxidation), findings that corroborate
those of the present study. The first studies with carvedilol
showed that this drug is much more potent in inhibiting the
production of hydroxyl radicals (OH) in comparison to other
betablockers, and that it is able to inhibit lipid peroxidation14.
We observed a significant decrease in levels of the marker of
protein damage in all groups with CCHD as well as a decrease
in TBARS levels, which could be attributed to the potent
antioxidant properties of carvedilol11. In another similar study,
carvedilol also prevented lipid peroxidation in the myocardial
cell membranes, initiated by oxygen radicals generated by
chemical, enzymatic or cell systems, both in vitro and in vivo15.
The inflammatory process that characterizes Chagas
disease is more pronounced in the acute phase and
seems to be correlated with the severity of the heart
disease 16. In this study, we observed that the levels of
most of the inflammatory markers (NO, ADA and MPO)
remained unchanged with the treatment with carvedilol,
thus suggesting an additional effect of this drug on the
inflammatory process. The anti-inflammatory activity of
carvedilol has been demonstrated in studies by means
of the reduction of C-reactive protein, amyloid protein,
and monocyte chemotactic protein17. This effect could
be related to its antioxidant ability to decrease ROS
generation and impair inflammatory cells infiltration in
the myocardium18,19. Increased ADA and NO levels were
observed only in group IA patients, classified as the group
less severely affected by CCHD. Histopathological findings
in individuals with heart disease have shown an increase
in mononuclear cells with TNF-α production by activated
macrophages and T lymphocytes 20. This finding could
justify the increase in ADA, which is an enzyme released
by mononuclear cells. Increased NO levels in this group
of patients could indicate a response against infection by
T. cruzi, since these patients are less severely affected in
comparison to those of the other groups. By combining the
antioxidant vitamins with the treatment with carvedilol,
it is possible to suggest a synergistic association of this
combination of the three non-enzymatic antioxidants.
This synergy could be reflected in the significant reduction
in the levels of most of both the lipid and protein markers
of damage, in comparison to those of untreated patients.
A significant increase in vitamin E plasma levels was
observed in all groups, thus indicating that vitamin E was
properly absorbed by the patients. These results corroborate
those of Bhogade et al21 in which, after supplementation
with vitamin E, there was elevation of its plasma levels, with
a concomitant decrease in MDA levels.
The activity of most of the antioxidant enzymes decreased
significantly or remained unchanged, and this could be
explained by synergy between the three antioxidants used in
the prevention of the oxidative damage.
The levels of the inflammatory marker NO decreased only
in group IA after combination of carvedilol with the vitamins,
an effect that could be attributed to the ability of vitamin E to
prevent NO toxicity via peroxynitrite formation22.
Budni et al.
Carvedilol and antioxidants in Chagas heart disease
Original Article
The increased MPO activity observed in group II
after combination of vitamins with carvedilol could be
justified by the relationship that this enzyme has with the
progression and severity of the heart disease. Lobbes et al23
showed that increased serum MPO levels were significantly
associated with coronary artery disease in patients with
acute myocardial infarction in comparison with those
of healthy controls. Bellotti et al24 sought to investigate
the presence of parasites in the hearts of chronic Chagas
disease patients, and frequently found them. The authors
correlated this finding with the severity of the myocardial
inflammatory process, thus supporting the perception of
the important role of the parasites in the pathophysiology
of the chronic phase25.
On the other hand, the use of both carvedilol alone and in
combination with the antioxidant vitamins were apparently
unable to halt the progression of the inflammatory process,
as indicated by the increase in ADA and MPO levels in the
two intervention moments.
Author contributions
Conception and design of the research: Budni P,
Pedrosa RC, Wilhelm Filho D; Acquisition of data, Analysis
and interpretation of the data and Critical revision of the
manuscript for intellectual content: Budni P, Pedrosa RC,
Dalmarco EM, Dalmarco JB, Frode TS, Wilhelm Filho D;
Statistical analysis and Writing of the manuscript: Budni P,
Wilhelm Filho D.
Conclusion
Based on the findings of this study, we can conclude that
both the treatment with carvedilol alone and in combination
with antioxidant vitamins were effective in attenuating the
systemic oxidative stress in the blood of patients with chronic
Chagas heart disease (CCHD), as evidenced by the reduction
in TBARS and PC levels, and the reduction in the activity
of most of the antioxidant enzymes. The combination of
carvedilol with vitamins E and C indicates the possibility of
synergism between these three nonenzymatic antioxidants
in reducing the oxidative damage associated with CCHD.
It is clear that the reduction in the oxidative stress levels, as
verified by means of the markers tested, was more significant
when carvedilol was combined with the antioxidant vitamins.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is part of the thesis of doctoral submitted by
Patrícia Budni, from Universidade Federal de Santa Catarina
- UFSC.
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Back to the cover
Original Article
Early Change of Extracellular Matrix and Diastolic Parameters in
Metabolic Syndrome
Angela B. S. Santos1,2, Mauricio Junges2, Daiane Silvello2, Adriana Macari2, Bruno S. de Araújo2, Beatriz G.
Seligman1,2, Bruce B. Duncan2, Luis Eduardo P. Rohde1,2, Nadine Clausell1,2, Murilo Foppa1,2
Hospital de Clínicas de Porto Alegre1; Universidade Federal do Rio Grande do Sul2, Porto Alegre, RS – Brazil
Abstract
Background: Metabolic syndrome (MS) is associated with increased cardiovascular risk. It is not clear whether myocardial
changes showed in this syndrome, such as diastolic dysfunction, are due to the systemic effects of the syndrome, or to
specific myocardial effects.
Objectives: Compare diastolic function, biomarkers representing extracellular matrix activity (ECM), inflammation and
cardiac hemodynamic stress in patients with the MS and healthy controls.
Methods: MS patients (n = 76) and healthy controls (n=30) were submitted to a clinical assessment, echocardiographic
study, and measurement of plasma levels of metalloproteinase-9 (MMP9), tissue inhibitor of metalloproteinase-1
(TIMP1), ultrasensitive-reactive-C-Protein (us-CRP), insulin resistance (HOMA-IR) and natriuretic peptide (NT-proBNP).
Results: MS group showed lower E’ wave (10.1 ± 3.0 cm/s vs 11.9 ± 2.6 cm/s, p = 0.005), increased A wave (63.4 ± 14.1 cm/s
vs. 53.1 ± 8.9 cm/s; p < 0.001), E/E’ ratio (8.0 ± 2.2 vs. 6.3 ± 1.2; p < 0.001), MMP9 (502.9 ± 237.1 ng / mL vs.
330.4±162.7 ng/mL; p < 0.001), us-CRP (p = 0.001) and HOMA-IR (p < 0.001), but no difference for TIMP1 or
NT‑proBNP levels. In a multivariable analysis, only MMP9 was independently associated with MS.
Conclusion: MS patients showed differences for echocardiographic measures of diastolic function, ECM activity,
us-CRP and HOMA-IR when compared to controls. However, only MMP9 was independently associated with
the MS. These findings suggest that there are early effects on ECM activity, which cannot be tracked by routine
echocardiographic measures of diastolic function. (Arq Bras Cardiol. 2013;101(4):311-316)
Keywords: Metabolic Syndrome; Risk Factors; Extracellular Matrix; Diastole / physiopathology.
Introduction
The metabolic syndrome (MS) is defined as a combination
of several risk factors associated with cardiovascular disease
and type 2 diabetes; estimates suggest that this disease affects
approximately 35% of the adult population1,2. It is unclear
whether myocardial changes associated with the metabolic
syndrome are consequences of the systemic effects of the
syndrome or due to direct myocardial effects.
The diastolic function evaluation has been used to identify
cardiac preclinical changes. Diastolic dysfunction is prevalent
in patients with MS, even in the absence of hypertension
and diabetes3, and regardless the left ventricular mass4,5.
Diastolic dysfunction predicts a worse outcome independently
of any other co-morbidity6. In MS, diastolic dysfunction is
Mailing Address: Angela Barreto Santiago Santos •
Hospital de Clinicas de Porto Alegre - Divisão Cardiovascular, Rua Ramiro
Barcelos, 2350, Sala 2061. Postal Code 90035-903, Porto Alegre, RS – Brazil
E-mail: [email protected]
Manuscript received December 01, 2012; revised manuscript June 05,
2013; accepted July 06, 2013.
DOI: 10.5935/abc.20130182
311
usually attributed to the increased hemodynamic stress7,8.
Alternatively, diastolic dysfunction may also be secondary
to changes in the cardiac extracellular matrix resulting from
the altered metabolic-inflammatory milieu and glucose
metabolism9. Extracellular matrix collagen turnover is tightly
regulated by the interaction between metalloproteinases
and its plasma tissue inhibitors. Changes in this balance may
therefore influence ventricular relaxation and compliance10.
Aiming to a better understand on the underlying processes
involved in the cardiovascular abnormalities seen in MS,
we studied echocardiographic parameters of diastolic
function and quantified plasma levels of metalloproteinase-9
(MMP9), tissue inhibitor of metalloproteinase-1 (TIMP1),
ultrasensitive-reactive-C-Protein (us-CRP), insulin resistance
(HOMA-IR) and natriuretic peptide (NT-proBNP) in patients
with MS compared to healthy controls.
Methods
Population
In this cross-sectional analysis, we selected subjects
ranging from 30-55 years of age with MS and healthy
controls (CTR). The MS group consisted of all subjects
Santos et al.
MMP9, diastolic function and metabolic syndrome
Original Article
recruited for a randomized clinical trial whose protocol
and results have already been published 11. From the
initial sample of 471 evaluated volunteers, 76 matched
the clinical trial eligibility criteria, which were: Body
Mass Index (BMI) ≥ 30 kg/m 2 and ≤ 40 kg/m 2, waist
circumference ≥ 95 cm and at least two other Metabolic
Syndrome criteria according to the National Cholesterol
Education Program Adult Treatment Panel III (NCEP/ATP
III)12. Moreover, all patients had an oral glucose tolerance
test that was negative for diabetes. The exclusion criteria
were pregnancy, lactation, creatinine ≥ 1.5 mg/dL,
musculoskeletal dysfunction, inflammatory or chronic liver
disease, thyroid dysfunction and/or use of corticosteroids
or anorectic drugs. The baseline data in this group were
compared with locally recruited healthy subjects of same
gender and age range as that of MS group. The study was
approved by the Ethics Committee of our Institution and
by the Research Committee, and all participants signed a
written informed consent prior to enrollment.
Clinical Assessment
Blood pressure and heart rate were measured in
triplicate after five minutes at rest using an aneroid
sphygmomanometer (Tycos, Welch Allyn, USA), with
reported average. Height was measured by a wall-mounted
stadiometer, and patients had their weight measured by an
electronic scale, wearing light clothes and no shoes. Waist
circumference was measured midway between the costal
border and the iliac crest.
Biochemical Analysis
Blood samples were collected in a fasting state. Insulin
was measured via electrochemiluminescence (Roche,
Switzerland), and ultra-sensitive plasma C-reactive protein
(us-CRP) was measured via immunonephelometry (Roche,
Switzerland). The lipid profile was enzymatically measured
(Roche, Switzerland), and the LDL-cholesterol level was
calculated according to the Friedewald formula whenever the
triglycerides were below 400 mg/dL. The homeostasis model
assessment for insulin resistance (HOMA-IR) was performed
to determine insulin resistance13. The coefficients of variation
for these parameters were all below 6%.
Echocardiographic Study
Images were obtained with an EnVisor C HD ultrasound
system (Philips Medical, Andover, MA, USA) equipped with
a 4 to 2 MHz sectorial transducer. The cine loops and static
images were digitally recorded, including the M-mode,
2-dimensional, and Doppler modalities. Images were read
off-line in a dedicated workstation (ComPACS, Medimatic
Srl, Italy) by a single investigator.
The left ventricle (LV) internal dimension, septum and
posterior wall thicknesses were measured from the parasternal
longitudinal two-dimensional image. The left atrial volume
index (LAVi) was measured at the end-ventricular systole from
the apical 4-chamber view, using the simple Simpson’s rule
and indexed to the body surface area.
The diastolic function was evaluated from the mitral
inflow Doppler 14 and tissue Doppler 15 measurements,
including: mitral inflow early (E wave) and late (A wave)
diastolic velocities, deceleration time (DT) of early
diastolic velocity, and early (E’ wave) and late (A’ wave)
diastolic annular velocities assessed at the septal mitral
anulus. The E/A ratio and the E/E’ ratio were calculated
from previous parameters.
All measurements and definitions of relevant cut-offs
followed the American Society of Echocardiography
recommendations; all of the data were an average of up
to 3 consecutive cardiac cycles16,17. Left ventricle volume
and ejection fraction were calculated using the Teichholz
formula. Left ventricle mass index (LVMI) was calculated
according to the American Society Echocardiography
formula (16) and indexed to the body height to the
power of 2.718. Relative wall thickness (RWT) was defined
as (septum + posterior wall thickness)/LV diastolic
diameter. The intra‑reader reproducibility was assessed
in 16 participants as a coefficient of variation (CV) and
intra‑class correlation (ICC), which were, respectively, E’
wave (CV: 5.2% and ICC: 0,99;95%CI: 0.97-0.99), E wave
(CV 4.5% and ICC: 0.98; IC95% 0.96-0.99) and A wave
(CV 3.5% and ICC: 0.98;IC95% 0.97-0.99). Additionally, for
the two‑dimensional measurements, CVs ranged between
8% and 13% and ICCs were above 0.75, whose values are
similar to those described in previous studies19,20.
ELISA Assays
Fasting venous blood samples (15 mL) were collected
in ethylenediamine tetraacetic acid-containing tubes.
Samples were immediately centrifuged at 4°C at 3,000 x g
for 20 min, and the plasma removed and stored at –70°C.
The plasma samples were all blinded analyzed simultaneously
by a laboratory technician. MMP9 and TIMP1 levels were
measured in duplicate using commercially available ELISA
kits (R & D Systems, Minneapolis, MN, USA). The MMP9
assay sensitivity was <0.156 ng/mL, and the TIMP1 assay
sensitivity was <0.08 ng/mL; the intra- and inter-assay
coefficients of variation were 6% and 10%, respectively.
The NT-proBNP level was also measured with a commercial
ELISA kit (Roche Diagnostic, France). The NT-proBNP assay
sensitivity was <0.6 pmol/L with intra- and inter-assay
coefficients of variation of 1.9% and 3.1%, respectively.
Statistical Analysis
Results are expressed as mean and SD, or as percentage.
Groups were compared with a Chi-square or independent
Student’s t test analysis. The associations between continuous
variables were tested with Pearson correlation coefficient.
Multivariable linear regression analyses models were
performed to identify which variables were independently
associated with the presence of the MS.
We calculated a sample size of 66 MS and 33 CTR,
considering an alpha value of 0.05, a power of 0.8 and
0.6 standard deviation of difference in MMP9 levels
between groups. This value was estimated based on
Arq Bras Cardiol. 2013;101(4):311-316
312
Santos et al.
MMP9, diastolic function and metabolic syndrome
Original Article
MMP9 differences described by Tayebjee et al21 - between
hypertensive patients – which frequently showed diastolic
dysfunction - and normal controls. P values <0.05 were
considered to be statistically significant. All of the statistical
analyses were performed with the SPSS software package
(SPSS 15.0 Inc., USA).
In a multiple linear regression, we investigated the
independent associations of blood pressure, BMI, waist
circumference, HDL-cholesterol, triglyceride, HOMA-IR,
us‑CRP, MMP9, TIMP1, NT-proBNP, E wave, A wave, E’ wave,
and A’ wave with MS. Only MMP9 (β = 0.13, p = 0.03) was
independently associated to MS.
Results
Discussion
We studied 76 patients in the MS group (43.3 ± 7.9 years,
65% male), and 30 healthy controls (CTR; 40.9 ± 6.6 years,
63% male). Further clinical characteristics and laboratory
parameters of the groups are shown in Table 1. The MS group,
as expected, had increased weight, waist circumference,
heart rate, blood pressure, and cholesterol levels when
compared with the CTR group.
In this study, the MS group showed difference in diastolic
function parameters and higher levels of HOMA-IR, us-CRP
and MMP9 when compared to healthy controls, with no
difference in TIMP1 and NT-proBNP levels. However, when
adjusted for covariates, only MMP9 was independently
associated with the MS.
The diastolic function parameters showed that MS had
higher A wave (63.4 ± 14.1 cm/s vs. 53.1 ± 8.9 cm/s;
p < 0.001), and lower E’ wave (10.1 ± 3.0 cm/s vs.
11.9 ± 2.6 cm/s; p = 0.005) compared with controls, but with
mean values within the normality range17. These differences
resulted in a reduced E/A ratio (p = 0.05) and an increased
E/E’ ratio (p < 0.001) in the MS group. E wave (p = 0.45)
and deceleration time (p = 0.98) did not differ between the
groups (Table 2).
De las Fuentes et al4, investigating echocardiographic
parameters of diastolic function in MS patients, showed
increased A wave, decreased E’ wave, and no difference
in E wave. Although we have found similar results for these
parameters, they were not independently associated with
MS after adjustment for covariates, whereas MMP9 was
still significant. We could infer that, in the early phases
of metabolic syndrome, modulations in ECM activity
measured by the increase in MMP9 levels, anticipate
measurable changes in cardiac pressures measured by
diastolic Doppler parameters, NT- proBNP levels or left
atrial dimensions, which are frequently used as surrogate
markers of loading conditions22,23.
Extracellular matrix activity biomarkers showed that MMP9
levels were higher in the MS group (502.9 ± 237.1 ng / mL
vs. 330.4 ± 162.7 ng/mL; p < 0.001), but with no differences
in TIMP1 (210.2 ± 55.6 ng/mL vs 220.2 ± 57.2 ng/mL;
p = 0.41) levels (Figure 1). Insulin resistance measured by
HOMA-IR (p < 0.001) and us-CRP (p = 0.001) levels were
higher in the MS group, while NT-proBNP levels (p = 0.19)
did not show statistically significant difference between the
groups (Table 3).
Extracellular matrix activity has been associated with
relaxation and LV stiffness9. The increased MMP9 in the
metabolic syndrome may represent a collagen turnover state
in the extracellular matrix, which may contribute to adverse
ventricular remodeling and left ventricular stiffness. Gonçalves
et al24, studying 25 patients with MS and 25 healthy controls,
found increased levels of both MMP9 and TIMP1 in the MS
group; reflecting the advanced dysmetabolic state in those
patients compared to our sample.
Left ventricular mass index was higher in the MS group
(Table 2). Left atrial volume index and ejection fraction did
not differ between groups.
Table 1 – Clinical characteristics and laboratory parameters of the metabolic syndrome (MS) and healthy control (CTR) groups
MS (n = 76)
Male (%)
CTR (n = 30)
p
65.3
63.3
0.85
43.3(7.9)
40.9(6.6)
0.14
BMI (kg/m²)
34.7(2.8)
24.9(2.6)
< 0.001
Waist (cm)
106.7(7.3)
86.1(8.9)
< 0.001
SBP (mmHg)
128.0(12.7)
115.8(10.2)
< 0.001
DBP (mmHg)
81.2(9.7)
76.3(9.1)
0.02
Age (y)
Heart rate (bpm)
86.6(10.4)
69.9(11.0)
< 0.001
Total cholesterol (mg/dL)
215.8(38.9)
194.1(31.8)
0.01
HDL-cholesterol (mg/dL)
45.6(10.9)
49.2(14.4)
0.17
Triglyceride (mg/dL)
189.6(224)
124.7(80.2)
0.13
Glucose (mg/dL)
93.8(8.45)
86.7(7.4)
< 0.001
Values showed as mean (SD) or percentage. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure.
313
Arq Bras Cardiol. 2013;101(4):311-316
Santos et al.
MMP9, diastolic function and metabolic syndrome
Original Article
Table 2 - Echocardiographic parameters and diastolic function of the metabolic syndrome (MS) and healthy control (CTR) groups
MS (n = 76)
CTR (n = 30)
p
LVMI (g/m )
37.8(7.5)
32.4(7.2)
0.001
Relative Wall Thickness
0.39(0.07)
0.36(0.05)
0.17
LV Ejection Fraction (%)
68.5(5.4)
66.9(7.1)
0.22
LAVI (mL/m²)
24.3(6.0)
25.6(5.9)
0.35
E wave (cm/s)
76.9(15.7)
74.4(15.6)
0.45
A wave (cm/s)
63.4(14.1)
53.1(8.9)
< 0.001
Deceleration time (ms)
2.7
205.2(28.6)
205.3(35.3)
0.98
E’ wave(cm/s)
10.1(3.0)
11.9(2.6)
0.005
A’ wave (cm/s)
11.0(2.3)
10.1(1.9)
0.04
E/A ratio
1.26(0.38)
1.42(0.3)
0.05
E/E’ ratio
8.0(2.2)
6.3(1.2)
< 0.001
Values showed as mean (SD). LVMI: left ventricular mass index; LAVI: left atrial volume index; E wave: mitral inflow early diastolic velocity; A wave: mitral inflow late
diastolic velocity; E’ wave: early diastolic annular velocity; A’ wave: late diastolic annular velocity.
Figure 1 - Circulating biological markers of cardiac remodeling in the metabolic syndrome (MS) and healthy control (CTR) groups. A. Metalloproteinase-9 levels (MMP9).
B. Plasma Tissue Inhibitor of Metalloproteinase-1 levels (TIMP1).
Table 3 – Circulating biomarkers in the metabolic syndrome (MS) and healthy control (CTR) groups
MS (n = 76)
CTR (n = 30)
p
MMP9 (ng/mL)
502.9(237.1)
330.4(162.7)
< 0.001
TIMP1 (ng/mL)
210.2(55.6)
220.2(57.2)
0.41
NT-proBNP (ng/mL)
29.9(21.9)
23.6(21.7)
0.19
HOMA-IR units
3.4(1.6)
1.6(0.8)
< 0.001
us-CRP (mg/dL)
3.9(3.6)
1.5(1.5)
0.001
Values showed as mean (SD). MMP9: metalloproteinase 9; TIMP1: Plasma Tissue Inhibitor of Metalloproteinase-1; NT-proBNP: natriuretic peptide; HOMA‑IR: homeostasis
model assessment for insulin resistance; us-CRP: ultrasensitive C-reactive protein.
Arq Bras Cardiol. 2013;101(4):311-316
314
Santos et al.
MMP9, diastolic function and metabolic syndrome
Original Article
Oversimplification of multifactorial mechanisms based
upon a limited subset of markers is inherent to this study
design and precludes causal inferences. A potential bias
of this analysis was the non-blinded echocardiographic
acquisition for the groups, minimized by the off-line reading
by a single investigator. It must also be brought to attention
the potential role of newer technologies, such as the speckle
tracking, which could more accurately find these early
adaptive changes related to the metabolic syndrome.
Conclusions
We have found that patients with MS showed differences
in echocardiographic measures of diastolic function, in
ECM activity measured by MMP9, us-CRP and HOMA-IR
when compared to healthy controls. However, only MMP9
was independently associated with the MS. These findings
suggest that there are early effects on extracellular matrix
activity in metabolic syndrome, which cannot be tracked by
routine echocardiographic measures of diastolic function.
Author contributions
Conception and design of the research: Santos ABS, Junges
M, Silvello D, Macari A, Araújo BS, Seligman BG, Duncan BB,
Clausell N, Foppa M; Acquisition of data: Santos ABS, Junges
M, Silvello D, Macari A, Araújo BS, Seligman BG, Foppa M;
Analysis and interpretation of the data: Santos ABS, Junges
M, Silvello D, Seligman BG, Rohde LEP, Clausell N, Foppa M;
Statistical analysis: Santos ABS, Foppa M; Obtaining funding:
Santos ABS, Duncan BB, Foppa M; Writing of the manuscript:
Santos ABS, Seligman BG, Duncan BB, Clausell N, Foppa M;
Critical revision of the manuscript for intellectual content:
Santos ABS, Seligman BG, Duncan BB, Rohde LEP, Clausell
N, Foppa M.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was funded by CNPq and FIPE/HCPA.
Study Association
This article is part of the thesis of master submitted by
Angela Barreto Santiago Santos from Universidade Federal
do Rio Grande do Sul.
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Back to the cover
Original Article
Nonlinear Methods to Assess Changes in Heart Rate Variability in
Type 2 Diabetic Patients
Bhaskar Roy1, 2 and Sobhendu Ghatak1
Indian Institute of Technology1, India; University of Connecticut, Farmington2, CT, USA
Abstract
Background: Heart rate variability (HRV) is an important indicator of autonomic modulation of cardiovascular
function. Diabetes can alter cardiac autonomic modulation by damaging afferent inputs, thereby increasing the risk of
cardiovascular disease. We applied nonlinear analytical methods to identify parameters associated with HRV that are
indicative of changes in autonomic modulation of heart function in diabetic patients.
Objective: We analyzed differences in HRV patterns between diabetic and age-matched healthy control subjects using
nonlinear methods.
Methods: Lagged Poincaré plot, autocorrelation, and detrended fluctuation analysis were applied to analyze HRV in
electrocardiography (ECG) recordings.
Results: Lagged Poincare plot analysis revealed significant changes in some parameters, suggestive of decreased
parasympathetic modulation. The detrended fluctuation exponent derived from long-term fitting was higher than
the short-term one in the diabetic population, which was also consistent with decreased parasympathetic input. The
autocorrelation function of the deviation of inter-beat intervals exhibited a highly correlated pattern in the diabetic
group compared with the control group.
Conclusion: The HRV pattern significantly differs between diabetic patients and healthy subjects. All three statistical
methods employed in the study may prove useful to detect the onset and extent of autonomic neuropathy in diabetic
patients. (Arq Bras Cardiol. 2013;101(4):317-327)
Keywords: Heart Failure; Diabetes Mellitus, Type 1; Systole; Measurements, Methods and Theories; Statistics as Topic.
Introduction
Heart rate is dynamically regulated by intrinsic and extrinsic
control systems, maintaining homeostasis. The major extrinsic
control is provided by the autonomic nervous system. Heart
rate variability (HRV) is a measure of the fluctuation in the
interval between sequential sinus heartbeats, and reflects
cardiac autonomic regulation 1-3. Diabetes leads to autonomic
neuropathy 4, thereby disrupting a major component of
cardiovascular regulation and contributing to an increased
incidence of cardiovascular diseases in diabetic patients, such
as heart attack, sudden cardiac death, and silent ischemia 5-8.
Early diagnosis of autonomic diabetic neuropathy is difficult
and the detection methods available, e.g., the Ewing Test
Battery, are cumbersome and have poor sensitivity and
reproducibility. In contrast, HRV analysis is noninvasive
and the input data are easily obtained by conventional
Mailing Address: Bhaskar Roy •
263 Farmington Avenue, Farmington, CT, 06030
E-mail: [email protected], [email protected]
Manuscript received July 17, 2012, revised manuscript September 09 2012;
accepted April 26, 2013.
DOI: 10.5935/abc.20130181
317
electrocardiography (ECG)9-12. However, because of the
nonlinear heart dynamics, conventional time and frequency
domain parameters of HRV may not always represent the
nonstationary characteristics of ECG. Nonlinear methods such
as the Poincaré plot, detrended fluctuation analysis (DFA),
tone/entropy analysis and HR complexity analysis are newly
developed tools used for identifying nonlinear patterns within
ECG data 13-18.
In this study, we used nonlinear analytical methods to
study the differences in HRV patterns between diabetic and
healthy individuals. The purpose of this study was to identify
new parameters useful for detecting autonomic dysregulation
in diabetes.
Methods
The patient group consisted of 23 type 2 diabetes mellitus
patients with no history of cardiac, neurological, psychiatric, or
sleep disorders. Patients on heart rate-altering medications were
excluded from the study. The study was approved by the ethical
committee of the Indian Institution of Technology, Kharagpur,
India. A total of 23 healthy subjects were selected as a control
group using the same exclusion criteria. All participants provided
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
written informed consent prior to inclusion in the study. Subjects
were instructed to avoid caffeine, alcohol, and physical exertion
the day before the study was performed. A 10-min ECG recording
was acquired from the patients while on supine position following
a 15-min relaxation period. All ECGs were recorded at a fixed time
of day to avoid the effects of diurnal variations on HRV.
Matlab and SPSS software packages were used for statistical
analysis. For comparative analysis between the groups, unpaired
t-tests were applied as appropriate. Other statistical methods are
individually described in details.
Poincaré Plot
The Poincaré plot is a scatter plot of RRn vs. RRn+1 where RRn
is the time between two successive R peaks and RRn+1 is the time
between the next two successive R peaks. When the plot is adjusted
by the ellipse-fitting technique, the analysis provides three indices:
the standard deviation of instantaneous beat-to-beat interval
variability (SD1), the continuous long-term R/R interval variability
(SD2), and the SD1/SD2 ratio (SD12)15. On the Poincaré plot, SD1
it is the width and SD2 the length of the ellipse. In addition to this
conventional plot (RRn+1 vs. RRn), we also used the generalized
Poincaré plot with different intervals, including the m-lagged
Poincaré plot (the plot of RRn+m versus RRn). The values of SD1 and
SD2 were calculated for lag = m from the relations
SD1 = (Φ(m) − Φ(0))1/2 and SD2 = (Φ(m) + Φ(0))1/2, where
the autocovariance function Φ(m) is given by
Φ(m) = E[(RRn − RR) (RRn+m − RR)]
and RR is the mean RRn14. For the purpose of our study, we
set m at 1, 5, and 9. We then extended our analysis to reveal the
association between these standard deviation (SD) values and m
by using the Padé approximation19. We assumed a simple form of
the Padé approximation for SD values as the ratio of polynomial
in M of degree one.
Y=
a + bM
1 + βM
= χ
c + dM
1 + γM
defined as r(ti) = ∑ij [R(tj) – <R>], i = 1,N, where <R> is the
mean of R(ti). The integrated series was divided into segments
of equal duration, τ = n δt and a linear function used to fit
the data within each segment. The fluctuation function F(τ)
was calculated as the root mean square fluctuation relative
to the linear trend and alpha was obtained by fitting the
data to a power law function. It has been observed that an
acceptable estimate of the scaling exponent alpha (from
DFA) can be obtained from analysis of data sets with 256
samples or longer (equivalent to approximately 3.5 min
of RR data at a heart rate of 70 beats/min). The analysis
of RR data from an ECG recording period of 10 min was
therefore expected to provide an adequate measure of the
scaling exponent 21. However, the alpha value obtained from
this calculation may be under the mixed influence of both
short-term scaling, reflecting parasympathetic control, and
long-term scaling, reflecting sympathetic control, and thus
may fail to fully distinguish parasympathetic and sympathetic
influences. A separate analysis of both short- and long-term
scaling is supposed to nullify the mutual effect and reveal the
exact scaling variation 22. Thus, we analyzed separate alpha
values, short-term αs and long-term αl. For αs, data from 25
beats were included, whereas for αl, data from 30 to N/4
beats were included.
Correlation between successive differences in RRn interval
The coherence of the RRn interval can be assessed from
the map of interval variation:
rrn+1 =
RRn+2 + RRn+1
(RRn)
VS.
rrn =
RRn+1 – RRn
(RRn)
where <RRn> is the mean interval. This plot is expected
to show the correlation between the variability of three
consecutive R–R intervals.
Autocorrelation of fluctuation of RRn
(1)
Here Y = SD1, SD2, or SD12 and χ = a/c. The terms
β = b/a and γ = d/c are the new unknown parameters.
In order to determine if these parameters are of value for
assessing cardiovascular health, we considered eq. (1) for the
case of small m. In this limit, equation (1) can be approximated as
Y = C + LM + QM2, where the slope is L = χ (β − γ) and the
curvature is Q = γL. The slope and curvature of the plot of SD vs.
m were determined by the fitted parameters χ, β, and γ.
We explored the autocorrelation of the deviation
of RRn from the mean <RRn>. The autocorrelation function
C(m) of a particular subject was calculated from
N
C(m) = ∑ ∆RRn+m ∆RRn ∕ ∑ ∆RR2n
n=1
where the deviation is ∆RRn = RRn – (RRn) and N is the
total number of RRn intervals.
Detrended Fluctuation Analysis
Results
Another analytic method to assess long-term correlation
in the R–R-time sequence is based on DFA 20. The measure
of correlation was given by a scaling exponent (α) of the
fluctuation function F(τ) ≈ τα. The fluctuation function F(τ)
was computed as follows. For a given time sequence R(ti),
ti = iδt, where δt is the characteristic time interval for the
sequence and i = 1, N is an integrated time series, r(ti) was
In the Poincaré plot analysis, plot scatter increased with
lag number, yielding higher width (SD1) and length (SD2)
The mean heart rate was 74.7 ± 6.1 beats/min in the
diabetic group and 72.4 ± 6.7 beats/min in the healthy control
group. Mean age in the diabetic group was 46.3 years (range,
36−56 years) and 47.4 years (range, 39−57 years) in the
control group. All study subjects were normotensive.
Arq Bras Cardiol. 2013;101(4):317-327
318
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
Figure 1 – Poincaré plot of RRn+m vs. RRn from HRV analyses of one diabetic (D, left panels) and one nondiabetic subject (ND, right panels). In the upper panel,
the lag factor m = 1, in the middle panel, m = 5, and in the bottom panel, m = 9. Note the greater scatter in the ND subjects, particularly as the lag factor is increased.
319
Arq Bras Cardiol. 2013;101(4):317-327
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
Figure 2 – Variation of mean SD1 (upper panel), mean SD2 (middle), and mean SD12 (lower) with lag number m for diabetic (D) and nondiabetic (ND) groups (n = 23
subjects each).
values. The incremental increase in width of the plot RRn+m
vs. RRn as m increased was smaller in the diabetes group (Figure
1, D) than in the control group (Figure 1, ND). Differences
in the values of SD1, SD2, and SD12 between the diabetes
group and the control group were statistically significant
(p < 0.001 for all). The values of SD1 and SD12 were higher in
the control group, whereas SD2 was higher in the diabetic group.
The difference in SD12 increased with lag number (Figure 2).
An excellent fit of the data with equation (1) (solid line on
the curve, R2 = 0.999) was found with the χ, β, γ value sets
listed in Table 1. The values for L and Q as obtained by fitting
of the data to eq. (1) are also presented in Table 1. The general
features were that the slope (L) was positive but curvature (Q)
was negative for all parameters and curvature was nearly one
order of magnitude smaller than the slope.
From DFA, the mean value of alpha in the control group
was smaller than that in the diabetic group (0.88 ± 0.17 vs.
1.02 ± 0.13; p < 0.001) (Figure 3). In control subjects, αs was
slightly larger than αl (1.01 ± 0.14 vs. 0.80 ± 0.19), whereas
αl was larger than αs for the diabetic group (αs = 1.09 ± 0.17;
Arq Bras Cardiol. 2013;101(4):317-327
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Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
Table 1 - The values of parameters χ, β, γ obtained by fitting the data to eq. (1), as well as respective R2 values. The L and Q parameters are the
coefficients of the linear and quadratic terms in expansion of Y in terms of m. Values of χ, L and Q for SD1 and SD2 are expressed in seconds
SD1
SD2
SD12
χ × 10−2
β × 10−2
γ × 10−2
R2 × 10−2
L × 10−3
−Q × 10−4
ND
1.3 ± 0.03
39.1 ± 2.0
3.2 ± 0.2
99.9
4.7 ± 0.4
1.5 ± 0.2
D
1.0 ± 0.02
38.2 ± 1.4
2.0 ± 0.1
99.9
3.6 ± 0.08
0.7 ± 0.02
ND
3.2 ± 0.06
20.3 ± 1.1
3.5 ± 0.2
99.9
5.4 ± 0.4
1.9 ± 0.2
D
3.1 ± 0.07
26.4 ± 1.6
4.4 ± 0.3
99.9
6.8 ± 0.6
3.0 ± 0.5
ND
40.2 ± 0.5
25.0 ± 1.8
12.2 ± 0.9
99.9
51.3 ± 6.4
62.7 ± 2.4
D
33.0 ± 0.3
15.3 ± 0.8
6.5 ± 0.4
99.9
29.0 ± 2.6
18.9 ± 2.8
Figure 3 - The DFA exponent α for healthy (nondiabetic) and diabetic subjects.
αl = 1.18 ± 0.19). When αs was plotted against αl (Figure 4),
the diabetic and nondiabetic populations tended to form two
separate clusters.
In the correlation plot, points were crowded around the
origin for diabetic patients. In contrast, there was greater
scattering about the origin and more asymmetry in the plot
of control subjects (Figure 5, ND1, ND2). The strength of
heart rhythm correlation was estimated by considering the
autocorrelation of fluctuation in RRn. Representative results
from one control and one diabetic patient are plotted in Figure
6. The autocorrelation functions for diabetic and control
patients were distinct. For diabetic subjects, the correlation
function C(m) decreased slowly (black and green curve in the
321
Arq Bras Cardiol. 2013;101(4):317-327
upper figure) with lag time. The time dependence was close
to the sum of the two exponentials with superimposed small
amplitude oscillation of low frequency. On the other hand,
C(m) from the healthy subjects demonstrated a more rapid
(exponential) fall as correlation time decreased compared with
the diabetic cases. To confirm this difference in correlation
pattern between control and diabetic subjects, we shuffled
the actual time series of R–R interval using Matlab software
and the autocorrelation functions of the shuffled data (red
and blue for subjects 1 and 2 respectively) were plotted in
Figure 6. The autocorrelation functions of the shuffled data
from all subjects (2 diabetics and 2 healthy controls) were
nearly identical.
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
Figure 4 - Scatter plot of DFA exponent long-term alpha (AlphaL) vs. short-term alpha (AlphaS) for nondiabetic subjects (red circles) and diabetic subjects (black
squares).
We also characterized properties of ∆RRn by the probability
distribution function P(∆RRn) (Figure 7). For diabetic patients,
the probability distribution was almost symmetrical and could
be fit by a Gaussian function (R2 = 0.93) with width = 0.023.
For healthy subjects, the probability distribution P was
asymmetrical with positive mean and higher width = 0.036
as obtained by the Gaussian fit (R2 = 0.93).
Discussion
We found marked differences in HRV pattern between
diabetic and healthy control subjects using nonlinear
analyses. Subjects were matched for both mean age and
resting heart rate, the two major determinants of HRV 23,
so that the difference in distribution would reflect changes
in cardiovascular regulation resulting from the diabetic
condition only.
Several modifications of the simple Poincaré plot have been
proposed to more effectively reveal changes in HRV patterns,
including the lagged plot. The concept of this m lagged plot
emerged from the recognition that any given R–R interval
can influence up to eight subsequent R–R intervals 24,25. It has
been shown that SD1 correlates with the short-term variability
of heart rate and is mainly influenced by parasympathetic
modulation, whereas SD2 is a measure of long-term variability
14,26
and reflects sympathetic activation. The lower SD1 in
diabetic subjects indicates that parasympathetic regulation
is weakened by the disease, presumably by peripheral
neuropathy, whereas higher SD2 in diabetic patients indicates
increased long-term variability because of compensatory
sympathetic input.
The results from Poincaré plot analysis are further revealed
by the slope (L) and curvature (-Q) of the plot. In the diabetic
group, L and -Q for SD1 and SD12 were smaller, whereas L
and -Q values for SD2 were higher than in the control group.
The difference in Q was larger than the difference in L. In
particular, the Q value for SD12 in the control group was
>3 times greater than that for diabetic group. Low values of
curvature are found in patients with cardiovascular disease 24.
These data strongly suggest decreased parasympathetic activity
and excessive influence of sympathetic activity in the diabetic
heart. In addition, this result provides indirect support for the
notion that higher sympathetic influence over cardiovascular
function is correlated with cardiac morbidity 27,28. An increased
SD12 is considered a good indicator of healthy heart dynamics,
and the lower value in diabetic patients again supports altered
sympathovagal balance in diabetes.
Previous reports using DFA showed that αs > αl in healthy
subjects, whereas the reverse was the case for subjects with
cardiovascular disease 20. We found a similar trend in this study,
again confirming the adverse effect of diabetes on the heart.
In the absence of external modulation, the correlation plot
is expected to scatter close to the point of origin, whereas
random input will produce a uniform distribution. We observed
a high density of points around the origin with greater symmetry
in diabetic patients when compared with controls. Plots from
Arq Bras Cardiol. 2013;101(4):317-327
322
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
Figure 5 - Plot of rrn+1 and rrn for two subjects from each group. Subjects were age matched (1 from each group in their mid-fifties, one from each group in their late
thirties). The quantity rrn is the relative difference between RRn+1 and RRn normalized to the mean RRn of all intervals.
healthy controls were generally asymmetrically scattered with
large RRn values. These results suggest that mechanisms for
decelerating and accelerating HR over different time frames are
substantially impaired in diabetic patients.
Application of autocorrelation to HRV analysis is a recent idea
that regards HRV as the outcome of the interaction between
coupled oscillators of various frequencies 29. The degree of
autocorrelation can also reflect on the embedded time scales
within the HRV pattern. It is thought that each of these time
scales in the coupled oscillator is represented by a separate
323
Arq Bras Cardiol. 2013;101(4):317-327
self-oscillator, interacting with other oscillators with different
physiological functions 18. The lack of exponential fall in C(m)
indicates the presence of a long-term memory effect in the
diabetic condition and strongly suggests that mechanisms for
short-term variation in heart rate are weakened or lacking in
diabetic patients.
Heart rate variability analysis based on nonlinear dynamics
has been shown to be superior to conventional methods for
identifying hidden changes in cardiac autonomic modulation in
various disease conditions. Previous reports have demonstrated
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
Figure 6 - Plot of the correlation function C(m) with m for two diabetic (D) (left) and two control (ND) subjects. The lower curves were obtained from shuffled RRn intervals.
Figure 7 - The plot of probability distribution P as a function of rrn for the two groups (upper panel is the diabetic group and the lower is the nondiabetic healthy group).
Continuous Guassian curves are fitted to the distributions.
324
Roy & Ghatak
Nonlinear HRV in diabetes
Original Article
differences in Poincaré plots, DFA, and sample entropy analysis
between the hearts of diabetic and nondiabetic patients 17,30,
but these differences often did not reach statistical significance
because of the small sample sizes 17. Our study not only enrolled
larger numbers of patients and controls but also used multiple
nonlinear analytic tools, including Poincaré plot analysis, DFA,
and autocorrelation analysis to reveal changes in HRV due to
diabetic neuropathy.
to assess changes in the autonomic regulation of the diabetic
heart. To our knowledge, this is the first attempt to distinguish
normal from diabetic heart function using autocorrelation
analysis. We believe these methods have the potential
to identify diagnostic and prognostic markers for cardiac
autonomic neuropathy in diabetes.
The major limitation of this study is the heterogeneous patient
population. The duration of illness in the patient group was
variable and many were on different antidiabetic medications.
Moreover, a population of 23 patients may be sufficient to
identify differences in HRV pattern between diabetic and healthy
nondiabetic subjects, but a much larger group of patients is
required to confirm the true diagnostic and prognostic values of
the parameters derived from the analytic methods. Intra-group
analysis in a larger group of diabetic patients of variable disease
duration to assess progressive changes in HRV pattern is the next
logical step. Our study establishes the potential of nonlinear
methods of heart rate variability analysis to assess changes in
HRV pattern indicative of cardiovascular disease, including effects
associated with diabetes mellitus.
Author contributions
Conclusions
In summary, we have shown the effectiveness of nonlinear
analytical methods to study differences in HRV patterns
between diabetic patients and healthy-matched controls.
We also emphasized the novelty of autocorrelation analysis
Conception and design of the research, Acquisition of data,
Analysis and interpretation of the data, Statistical analysis,
Writing of the manuscript, Critical revision of the manuscript
for intellectual content: Roy, B, Ghatak S.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation
program.
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Back to the cover
Original Article
Medical Students Teaching Cardiopulmonary Resuscitation to Middle
School Brazilian Students
Lucas Gaspar Ribeiro, Rafael Germano, Pedro Lugarinho Menezes, André Schmidt, Antônio Pazin-Filho
Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo - FMRP/USP, Ribeirão Preto, SP – Brazil
Abstract
Background: Diseases of the circulatory system are the most common cause of death in Brazil. Because the general
population is often the first to identify problems related to the circulatory system, it is important that they are trained.
However, training is challenging owing to the number of persons to be trained and the maintenance of training.
Objectives: To assess the delivery of a medical-student led cardiopulmonary resuscitation (CPR) training program and to
assess prior knowledge of CPR as well as immediate and delayed retention of CPR training among middle school students.
Methods: Two public and two private schools were selected. CPR training consisted of a video class followed by practice
on manikins that was supervised by medical students. Multiple choice questionnaires were provided before, immediately
after, and at 6 months after CPR training. The questions were related to general knowledge, the sequence of procedures,
and the method to administer each component (ventilation, chest compression, and automated external defibrillation).
The instructors met in a focus group after the sessions to identify the potential problems faced.
Results: In total, 147 students completed the 6-month follow-up. The public school students had a lower prior knowledge,
but this difference disappeared immediately after training. After the 6-month follow-up period, these public school students
demonstrated lower retention. The main problem faced was teaching mouth-to-mouth resuscitation.
Conclusions: The method used by medical students to teach middle school students was based on the watch-andpractice technique. This method was effective in achieving both immediate and late retention of acquired knowledge.
The greater retention of knowledge among private school students may reflect cultural factors. (Arq Bras Cardiol.
2013;101(4):328-335)
Keywords: Cardiopulmonary Resuscitation / education; Students, Medical; Education, Primary and Secondary.
Introduction
Diseases of the circulatory system are the most common
cause of death in Brazil, accounting for approximately 29%
of all deaths. Approximately 50% of these cases involve
sudden death due to ventricular fibrillation as a complication
of acute myocardial infarction. Because this is a pre-hospital
manifestation, improved education of the general population
could potentially reduce mortality by helping people identify
the situation and provide appropriate first aid1.
Various methods of habilitating the general population
include mass training; self-learning through commercially
available programs; as well as training of individuals
occupying strategic positions with respect to the guidance
and care of the population (security guards, firemen,
policemen), those working at sites of a higher incidence of
Mailing Address: Lucas Gaspar Ribeiro •
Rua Comandante Marcondes Salgado, 866, Apto 502, Centro.
Postal Code 14010-150, Ribeirão Preto, SP - Brazil
E-mail: [email protected], [email protected]
Manuscript received November 17, 2012; revised December 3, 2012;
accepted April 23, 2013.
DOI: 10.5935/abc.20130165
328
events (gyms), those working at places difficult to access
(planes), and relatives of at-risk individuals. Education has
recently been directed at primary schools because this
permits early access to information, with the possibility of
repeated exposure during the school year and subsequent
transmission of knowledge to the relatives of pupils2,3.
Regardless of the population section targeted, the
teaching methodology employed has been the main
concern. In contrast with health professionals, the interest
in the topic and the time that can be devoted to training are
limited. Furthermore, because many instructed individuals
will never be confronted with a real-life situation,
knowledge retention is a problem. To circumvent these
problems, there has been an increased use of video-based
teaching, with practice on manikins, also known as the
watch-and-practice technique. One of the advantages of
this technique is the partial or total independence regarding
instructors, persons difficult to recruit for the large segment
of the population to be habilitated. It has been proposed
that medical students can function as instructors, but they
should be appropriately trained and supervised by qualified
professionals through the concept of a “training tree”4.
The objective of the present study was to test a
commercially available kit for teaching cardiopulmonary
resuscitation (CPR), supervised by medical students in
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
Brazilian middle schools (13–15-year-old students) and to
determine its efficacy in terms of both immediate and late
(6 months) retention.
Methods
Study Population
Students aged 13 to 15 years were selected from four
middle schools; two were public (low socioeconomic
level) and two were private (high socioeconomic level).
Students were taught in classes of 25–46 and were
invited to voluntarily participate. Informed signed consent
was obtained from both the students and their parents.
The directors of each of these schools approved the
project prior to any student being approached. The project
was approved by the Research Ethics Committee of the
University Hospital of Ribeirão Preto, São Paulo, FMRP-USP
(CAE – 0078.0.004.000-09).
Teaching Material
A commercially available kit termed “Family &
Friends. CPR Any Time. Self-Learning Program” produced
by the American Heart Association (AHA) was used.
The kit contained a video presentation in Portuguese and
an inflatable manikin for practicing ventilation and chest
compression1. Individual face masks were provided for the
practice of artificial ventilation.
Instructors
Three medical students from the Faculty of Medicine
of Ribeirão Preto (FMRP) were trained to be instructors by
the professor in charge of the Clinical Emergencies course
accredited by the American Heart Association5. The students
participated in all the practical activities, and the content taught
was tested in a pilot study.
Instrument for Analysis
A questionnaire comprising 25 multiple choice questions was
used. Each question had 4 possible responses, of which only
one was correct (see enclosure). The questionnaire was based
on the content presented during the AHA video and assessed
the following domains: general knowledge in 7 questions;
the sequence of procedures in 7 questions; and the correct
method of administering each component in 11 questions.
The latter section was further broken down as follows: 4 questions
concerned ventilation, 3 concerned chest compression, and
4 concerned the use of an automated external defibrillator (AED).
The questionnaire was given to a pilot group and to volunteer
medical students who had undertaken the first aid course.
After further development, two versions of the final questionnaire
were prepared that differed only in the order of the questions.
The first questionnaire (Version 1) was provided both before
and at 6 months after training, and the second questionnaire
(Version 2) was provided immediately after training.
Intervention
Each teaching session lasted an average of 120 min.
At the beginning of each class, the students completed
Version 1 of the questionnaire. After the test, the students
were divided into training groups with 1 manikin per
2 students. The video was then shown with predetermined
pauses for the separate practice of individual skills (ventilation
and chest compression) and to allow coordinated practice
(2 ventilations for every 30 chest compressions). The full
sequence of care was then presented from the recognition
of cardiac arrest to the coordinated implementation of aid,
ventilation, and chest compression. Finally, the use of AED
was demonstrated.
During practical exercises the instructors assisted the
students, corrected improper techniques, and sought to
resolve any queries that arose. The instructors intervened
only if a problem presented itself or if the students
requested their help. The students were continuously
observed and were encouraged to resolve problems
between themselves, with the instructors only intervening
when this was incorrect or if the problem remained
unresolved. After the practical sessions, Version 2 of
the questionnaire was completed. Six months after the
completion of training, the students were tested again
with Version 1 of the questionnaire.
Qualitative Analysis
After intervention, the research group held discussion
sessions in a focus group according to a previously
established methodology. The potentialities and problems
detected were isolated by content evaluation6.
Statistical Analysis
Statistical analysis was performed using the Stata
10 software. The categorical variables have been reported
as a percentage using the Fisher test. Quantitative variables
have been reported as mean ± SD, and central tendency
measures were analyzed by the Student t-test. The results
of qualitative analysis were descriptive.
Results
A total of 387 students were trained, of which 202
were considered for analysis by corresponding to the
first session in each school. Four schools received classes;
two were public (public 1 and 2), and two were private
(private 1 and 2). The composition was as follows: public
1 included 24 students (11.88%); public 2 included
57 students (28.22%); private 1 included 89 students
(44.06%); and private 2 included 32 students (15.84%).
No statistically significant differences were detected
between either the two public school groups or the two
private school groups. Therefore, the subjects were pooled
into two main groups: Public (81 students; 47.6% males)
and Private (121 students; 52.4% males).
Arq Bras Cardiol. 2013;101(4):328-335
329
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
Immediate Retention
Data have been reported quantitatively in Table 1 as
absolute values (mean ± SD for correct responses before
and after training and absolute increase in performance)
and relative values (percent of correct responses in relation
to the initial test). Data have been reported in a stratified
manner according to content domain and institution. In
the pre-test questionnaire, a difference was observed only
between the public and private schools in the general
knowledge domains. This difference was lost after the
training intervention.
Retention after 6 Months
At 6 months, 53 students were lost to follow-up: 26%
and 26.5% from the public and private schools, respectively.
Therefore, 149 of the 202 students (73.7%) were included in
this part of the study (60 from public schools; 89 from private
schools). The results have been reported in Table 2 as the
percent of correct response after 6 months. There was greater
retention in the students from private schools, particularly in
terms of the correct determination of the sequence of technical
and ventilation actions.
Qualitative Analysis
The results are presented in Tables 3 and 4.
Discussion
This study has demonstrated the effectiveness of a
commercially available training kit (using a video and
manikin) in the immediate and late retention of knowledge.
Superior knowledge was initially found in the private school
group prior to the course, but this immediately equalized
following the course. Further, in the domain relating to the
correct sequence of actions and ventilation technique, late
retention was better in the private school students.
The education of the general population is an important
goal, considering that cardiac arrest is a phenomenon that
predominantly occurs in the community. Several studies
have demonstrated the efficacy of early intervention,
but the challenge presented in educating the population
is enormous with regard to the number of people to
be trained, the efficacy of training, and the retention
levels of transmitted knowledge7. One option is to utilize
commercially available self-learning kits that are often
effective but may not achieve their objective because of low
levels of uptake of knowledge by the general population.
In Brazil in particular, the video format itself may be a
limiting factor due to local culture. For example, data
provided by the distributor of the kit used in the present
study show that 3.5 million units were sold in the United
States in 2011 as opposed to only 250 in Brazil. This may
be related to important cultural aspects of the Brazilian
society that need to be considered while planning future
training. Therefore, this study was undertaken to explore
the influence of socioeconomic and cultural aspects using
public and private schools.
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Arq Bras Cardiol. 2013;101(4):328-335
Prior levels of knowledge differed between the public
and private school students, with 8.74 and 9.65 correct
responses, respectively. This difference may be attributed
to the involvement in scouting, to having parents who are
health professionals, and to having access to the internet
and television as informally reported to the instructors by
the private school students. However, these background
differences did not limit the efficacy of the method.
Although the modification of parental habits is an important
outcome, it will be necessary to further assess these
differences in later studies.
Primary school students can be educated about
resuscitation from 11 years of age. By this age, they will
have achieved a certain level of maturity to understand the
importance of the topic and will have the necessary strength
to be perform chest compressions on adults8,9. Advantageous
aspects of training in this population are the possibility of
regular training sessions that can be included in the school
curriculum and the potential transfer of knowledge to
relatives. Children in the pre-teen age range can influence
their parents and motivate behavioral changes. The teaching
of CPR encourages the discussion of the risk factors for
cardiac arrest as well as how this can be avoided, resulting
in the questioning of parental habits2.
Medical students can be valuable collaborators in
establishing the “training tree” of CPR4. Their involvement
in teaching may be beneficial in reducing the anxiety
generated by years of basic learning that is often distant
from clinical reality. It also leads to questioning the efficacy
of teaching methods as well as an improved appreciation
of the cost, dedication, and work necessary for the
development of a teaching activity10. Similarly, considering
health professionals often show poor performance with
basic life support, the involvement in teaching activities
increases the time devoted to the topic and may improve
learning; therefore, this strategy may be beneficial to
the students themselves11. In addition, medical students
appeared to be identified as role models by middle school
students. In contrast, senior instructors may be less effective
in this role because of the greater age difference.
The retention of knowledge from basic life support courses
is difficult to assess. This is because of a myriad of factors
such as differences between populations, the nature of the
content taught, the assessment itself, and the delay between
the course and analysis12-14. In general, retention levels in the
general adult population are low, approximately 50%–60%,
with the possibility of reaching higher levels for specific
segments of content12. Courses that include practical training
tend to show improved retention13. Furthermore, there does
not appear to be a significant difference in retention levels
between children and adults14. When the analysis includes
more accurate methods of assessment, such as the volume
of air supplied by mouth-to-mouth respiration, the retention
levels are lower12,15. Only studies that include populations
receiving intensive and frequent training demonstrate
consistently better performance12-15, although the uptake of
re-training courses is low in the general adult population14.
Adaptations to the training methods that are already
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
Table 1 - Correct performance (mean ± SD) of the eighth grade students of public and private schools according to the domain assessed
in the questionnaire at the time of training (before and after). The comparison between public and private is shown in the p column; the
comparison between before and after was significant for all comparisons with a p value less them 0.05 (marked with an *)
Public school
(N = 81)
Variable
Total
General knowledge
Sequence of actions
Ventilation
Technical aspects
Chest compression
AED
Private school
(N = 121)
p
Before (N = 202)
8.74 (2.14)
9.65 (2.14)
< 0.01
After (N = 202)*
21.21 (2.14)
21.75 (3.34)
0.25
Difference
12.45 (3.44)
12.0 (3.98)
0.44
% increment
2.5 (0.68)
2.36 (0.68)
0.07
Before (N = 202)
3,04 (1,11)
3.46 (1.15)
0.01
After (N = 202)*
5.82 (1.15)
6.06 (1.13)
0.15
Difference
2.72 (1.39)
2.54 (1.51)
0.43
% increment
2.13 (0.94)
1.94 (0.94)
0.16
Before (N = 202)
2.20 (0,97)
2.39 (1.12)
0.25
After (N = 202)*
5.47 (1.59)
5.86 (1.43)
0.07
Difference
3.21 (1.91)
3.49 (1.71)
0.29
% increment
3.00 (1.80)
2.97 (1.69)
0.89
Before (N = 202)
3.53 (1.5)
3.80 (1.42)
0.22
After (N = 202)*
9.91 (1.13)
9.80 (1.56)
0.82
Difference
6.39 (1.76)
5.98 (2.02)
0.16
% increment
3.26 (1.52)
3.10 (2.02)
0.07
Before (N = 202)
1.51 (0.99)
1.63 (0.82)
0.37
After (N = 202)*
3.86 (0.38)
3.81 (0.61)
0.75
Difference
2.33 (1.02)
2.18 (1.06)
0.33
% increment
2.67 (1.15)
2.52 (1.09)
0.38
Before (N = 202)
1.14 (0.66)
1.13 (0.80)
0.86
After (N = 202)*
2.78 (0.56)
2.83 (0.48)
0.5
Difference
1.64 (0.38)
1.72 (0.92)
0.56
% increment
2.38 (0.80)
2.32 (0.85)
0.63
Before (N = 202)
0.87 (0.81)
1.05 (0.89)
0.15
After (N = 202)*
3.26 (0.76)
3.13 (0.85)
0.26
Difference
2.40 (1.06)
2.06 (1.17)
0.04
% increment
2.71 (1.09)
2.41 (1.04)
0.12
AED: automated external defibrillator
available do not seem to be effective16. Considering the data
as a whole, we can conclude that knowledge retention is
generally low and deteriorates with time regardless of either
the assessment performed or the target population. However,
the literature also suggests that knowledge retention is
favored by periodic courses that involve practical training.
The cause of lower knowledge retention in the
public schools may be socioeconomic factors. Students
with higher acquisitive power may be exposed to
situations that cause them to remember the knowledge
acquired. However, the difference mainly occurred
in questions regarding the sequence of actions and
breathing techniques, which involve greater complexity.
The modifications proposed by the 2010 guidelines of
AHA will probably have an impact on this context17.
Teaching of CPR in schools is an interesting strategy. This is
a population with a higher uptake rate that can be frequently
re-trained and that has comparable learning and retention
abilities to those of adults. The present study supports previous
reports, including differences in retention between content
domains. A similar strategy involving knowledge of trauma
has demonstrated positive effects18. However, similar to
other studies, the present investigation cannot recommend
an optimal training interval as only a 6-month interval was
measured. Future courses will be necessary to determine an
appropriate interval for re-training.
Arq Bras Cardiol. 2013;101(4):328-335
331
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
Table 2 - Results, in percentages, of the questionnaires given to the students of public and private schools after 6 months. Both the total
content and the content stratified by the learning domain are presented according to the profile of the schools (149 students)
Variable
Public school
Private school
p
Total
70.6 (23.0)
77.6 (15.7)
< 0.01
General knowledge
75.5 (28.0)
77.9 (24.8)
0.056
Sequence of actions
75.7 (58.0)
83.1 (38.7)
0.02
Technical aspects
71.0 (23.5)
77.7 (23.9)
0.09
Ventilation
67.9 (34.9)
85.6 (32.5)
0.001
Chest compression
75.4 (43.2)
68. (27.4)
0.69
AED
74.4 (29.0)
78.4 (43.3)
0.72
AED: automated external defibrillator
Table 3 - Qualitative analysis of the learning observed
Learning
Attention paid to the video by the students
There was a difference in the attention paid to the video and to the content transmitted by the instructors during the
training session. The students were more interested in the video, stopped talking and playing, and intently viewed the
images on the television.
Interest in performing the activity
They were initially frustrated about being unable to perform the activity in the first attempt; they asked for help and made an
effort to succeed. When they achieved their objective they would become enthusiastic; they had fun when they were able to
hear the “click” of the dummy or when the lungs filled with air and the chest rose.
Ability to perform the maneuvers
There was no difference in terms of gender, type of physique, or type of school.
Content not covered by the video
Several questions were asked that were not present in the teaching material chosen. These questions were mainly regarding
the unblocking of the airways, how to proceed with victims of drowning or trauma, and whether an in vivo click occurred
during chest compression.
Performance of the medical student as
an instructor
“In addition, it was interesting to be a teacher instead of a student in 12 classes. To perceive the difficulties of a tutor, it is
necessary not only to know the topic in depth but also to transmit it in a didactic as well as an easy-to-understand manner to
14-year-old students, using a language and a depth of knowledge of anatomy, physiology, and pathology differing from those
we habitually use. However, to perceive that they ask questions, are interested, and look for knowledge differing from what they
learn in their curriculum increasingly motivated us every day to continue the project, to give classes, to clarify doubts, and to
show other points that may generate doubts when the students did not ask.”
Table 4 - Qualitative analysis of the problems faced
Problems
Difference between public and private schools
332
The public school students were not tired of the repetitive and constructivist method of the instrument used. In contrast,
the students of the private school frequently complained about the repetition of the video and the excessive quantity of
similar exercises performed during the 60 min of practical class.
Ability to perform the maneuvers
In general, there was a greater difficulty with respiration compared with chest compression. We believe that this may
have been because of the difficulty in opening the airways of the manikin.
Content not covered in the video
Another interesting aspect is that the middle school students approached the medical students with other questions
about how the medical course is, how much the medical students must strive to achieve this objective, and explored
questions about the health of relatives. The medical student was seen as a reference point for the future objective of
entering university life and as a close and trustworthy person for discussing health topics that the middle school student
could not discuss with their parents or guardian.
Arq Bras Cardiol. 2013;101(4):328-335
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
Limitations
Acknowledgments
Knowledge was only assessed through a simple questionnaire.
Although knowledge retention is known to be universally low,
this loss is more marked when using assessment methods that
involve performance; therefore, the data obtained may not
provide a true reflection of the differences. The main goal of
the training in this study was the wider education of the general
population on the correct management of out-of-hospital
cardiac arrest. However, the dissemination and acquisition of
basic concepts must be provided before cardiac arrest can occur.
With respect to this, the evaluation used permits a comparison
of knowledge retention at two points in time and is sufficient
for the initial assessment. Because periodic training is proposed,
the complexity of training could be progressively increased,
which may have an impact on subsequent performance at
assessment19.
First, we would like to thank the four participating
schools: Colégio Marista, Colégio Oswaldo Cruz, E.E. Dom
Alberto José Gonçalves, and E.E. Alberto Santos Dumont.
Each school welcomed us and provided the opportunity to
conduct research with their students. We are grateful to the
Training Center for Life Support (FAEPA) that provided the
material necessary for the classes. We also thank Fundação
de Amparo à Pesquisa do Estado de São Paulo (FAPESP),
Conselho Nacional de Desenvolvimento Tecnológico
(CNPq/PBIC), and the Project Learning with Culture and
Extension–USP that permitted the execution of the project
with their three instructors.
The methodology employed is associated with inherent
difficulties, and these were encountered with regard to the
method, the population under study, and the continuity of the
project. First, this method requires audiovisual equipment as
well as a physical space that can accommodate 20 persons.
Thus, the schools must have at least one suitable room. It was
notable that private schools differed greatly in terms of the
availability of audiovisual resources. Therefore, classes were
dependent upon the availability of suitable rooms, and the
ability of the school to provide audiovisual equipment, which
was more difficult in public schools. A way of circumventing this
limitation would be the expansion of the material and instructors
available using mass training techniques.
Conclusion
This study has demonstrated that CPR training provided
by medical students using a commercially available training
kit (with a video and manikin) was effective in both the
immediate and late retention of knowledge. Greater
knowledge retention in private schools may have been
associated with cultural factors.
Author contributions
Conception and design of the research, Obtaining
funding, Writing of the manuscript and Critical revision
of the manuscript for intellectual content: Ribeiro LG,
Germano R, Menezes PL, Schmidt A, Pazin-Filho A;
Acquisition of data and Analysis and interpretation of the
data: Ribeiro LG, Germano R, Menezes PL, Pazin-Filho A;
Statistical analysis: Ribeiro LG, Schmidt A, Pazin-Filho A.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by FAPESP, PIBIC (CNPq),
Aprender com cultura e extensão, Centro de treinamento
em suporte a vida e FAEPA.
Study Association
This study is not associated with any post-graduation
program.
Arq Bras Cardiol. 2013;101(4):328-335
333
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
ENCLOSURE 1:
NAME: ___________________________________________________________
Date: _____/_____/20____
School: ___________________________________________________________
Check with an X the correct alternative for each question. Only one alternative
is correct.
SELF-EVALUATION:
Did you ever have a cardiopulmonary resuscitation (CPR) lesson in your life?
(
) Yes,
(
) No
01.
a)
b)
c)
d)
What is the importance of studying CPR?
Teaching my parents and siblings
Rescuing a drowning person
Being qualified to rescue somebody
It is of no importance to me
02. What is the first step that should be taken when you find somebody lying
unconscious on the ground?
a) Call for help
b) Check if the victim is breathing
c) Check if the victim responds when called
d) Leave the victim lying
03.
a)
b)
c)
d)
After taking the first step (above) what should you do?
Call for help
Check if the victim is breathing
Check if the victim responds when called
Leave the victim lying
04.
a)
b)
c)
d)
You already took two important steps; what is the last one?
Call for help
Check if the victim is breathing
Check if the victim responds when called
Leave the victim lying
05. Which number should you dial for help?
a)911
b)192
c)193
d) I call my parents
06.
a)
b)
c)
d)
What should you do when you call emergency?
Say “Somebody is unconscious,” and disconnect the call
Inform where you are and disconnect the call
Wait for the operator to ask and disconnect the call
Say “I need help”; keep the call on hold and return to the victim
07. You find a person unconscious on the ground and you are alone. What should
you do?
a) Look, listen, and feel
b) Begin performing ventilations and chest compression to avoid wasting time
c) Get the AED
d) Call emergency yourself
334
08.
a)
b)
c)
d)
How will you check if the victim is breathing?
Open his mouth and place a finger in his throat to “check” for any obstruction
Look, listen, and feel
See if the victim’s lips and fingers are turning purple
Check if the victim’s tongue is blocking the passage of air
09.
a)
b)
c)
d)
The person is not breathing; what will you do?
I will try to remove the obstruction in his throat
I will press his abdomen to make him cough (Valsalva maneuver)
I will apply two mouth-to-mouth ventilations
I will pull out the victim’s tongue to let air pass
Arq Bras Cardiol. 2013;101(4):328-335
10.
a)
b)
c)
d)
The person is not breathing; how would you open the victim’s airways?
I will hold his forehead and pull his chin up
I will push his chin forward
I will open his mouth while pushing the chin down
I will cover his nose and wait for him to open his mouth and breathe
11. How will you know if you should or should not perform chest compressions
in an unconscious person?
a) Check if the person has a pulse in the arm (radial artery)
b) Check if the person is breathing through the mouth
c) Check if the chest is moving; listen and feel if the person is breathing
d) Check if the person has a pulse in the neck (carotid artery)
12.
a)
b)
c)
d)
Where are chest compressions performed?
In the center of the chest
On the left side of the chest i.e., the side of the heart
On the right side of the chest to push the heart to the left
It is not performed on the chest
13.
a)
b)
c)
d)
How should chest compressions be applied?
Strongly but slowly
Weakly and slowly
Weakly and rapidly
Strongly and rapidly
14.
a)
b)
c)
d)
How many chest compressions should be applied between ventilations?
30 chest compressions
15 chest compressions
5 chest compressions
No ventilation is applied
15.
a)
b)
c)
d)
How many ventilations are applied in the intervals between chest compressions?
1 ventilation
2 ventilations
No ventilation
3 ventilations
16.
a)
b)
c)
d)
Regarding ventilation, how long should you blow into the victim’s mouth?
No ventilation is applied
Blow for approximately 1 s to fill the entire lung
Blow for approximately 5 s to permit enough air to enter the lungs
Blow rapidly several times to aid rapid air exchange
17.
a)
b)
c)
d)
What is the function of chest compression?
An attempt to wake up the victim
Permitting oxygen to reach the lungs
Cause the victim to have a pulse
Pump blood through the body
18. In an emergency situation, what is the correct sequence (full cycle)?
a) Checking respiration -> Checking if the victim responds when called ->
Ventilation and chest compression -> Calling for help
b) Ventilation and chest compression -> Checking if the victim responds when
called -> Calling for help -> Checking respiration
c) Calling for help -> Checking if the victim responds when called -> Ventilation
and chest compression> Checking respiration
d) Checking if the victim responds when called -> Calling for help-> Checking
respiration -> Ventilation and chest compression
19. After the CPR cycle, the victim does not breathe and his heart did not start
beating again but you have an automated external defibrillator (AED) on hand.
What should you do?
a) I don’t use it. Only adults can use it
b) I ask somebody to take it while I continue chest compressions
c) I go to the pharmacy to get it
20.
a)
b)
c)
d)
If you get the AED, how will you use it?
I follow the manual inside it
I first switch the instrument on
I place the paddles on the victim’s chest and I switch the instrument on
I don’t know what to do first, I only know that the instrument gives a shock to
the victim
Ribiero et al.
Medical students teaching CPR on a large scale
Original Article
21.
a)
b)
c)
d)
What is the first step for using the AED?
Plug the paddles into the instrument
Stick the paddles to the victim
Turning on the instrument
Press the shock button to see if it is working
22.
a)
b)
c)
d)
Where should you place the paddles?
Over each nipple
Over the right part of the chest and below the left part of the chest
Below the two parts of the chest
In the center of the chest, over the bone (sternum)
23. What should you do immediately before “switching on” the shock button?
a) Move everybody away from the victim, including myself
b) Hold the paddles in place to make sure that they will not detach
c)
d)
Ask somebody to hold the victim, so he will not jump
Check if the paddles are switched on
24.
a)
b)
c)
d)
After giving the shock, what should you do?
Follow the instructions of the instrument
Remove the paddles and start chest compression
Check the victim’s pulse and breathing
Wait for help
25.
a)
b)
c)
d)
Help has arrived. What should you do?
Help them with chest compressions
Make room for them to work
Continue with chest compressions even in their presence
Call emergency and tell them that the ambulance arrived
References
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the potential impact of highly accessible training in cardiopulmonary
resuscitation. J Cardiopulm Rehabil. 2006;26(6):346-54.
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programme - teaching basic life support in schools. Resuscitation.
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3. Done ML, Parr M. Teaching basic life support skills using self-directed
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in pairs. Resuscitation. 2002;52(3):287-91.
11. Breckwoldt J, Beetz D, Schnitzer L, Waskow C, Arntz HR, Weimann J.
Medical students teaching basic life support to school children as a required
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three different approaches to fifth year medical training in emergency
medicine. Resuscitation. 2007;74(1):158-65.
12. Einspruch EL, Lynch B, Aufderheide TP, Nichol G, Becker L. Retention
of CPR skills learned in a traditional AHA Heart Saver course versus 30min video self-training: a controlled randomized study. Resuscitation.
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13. Chamberlain D, Smith A, Woollard M, Colquhoun M, Handley AJ, Leaves
S, et al. Trials of teaching methods in basic life support (3): comparison of
simulated CPR performance after first training and at 6 months, with a note
on the value of re-training. Resuscitation. 2002;53(2):179-87.
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in children 3 months after basic life support training using a simple personal
resuscitation manikin. Resuscitation. 2007;74(2):296-302.
6. Pazin-Filho A, Scarpelini S, Schmidt A. Análise qualitativa da elaboração e
apresentação de aulas teóricas por alunos de pós-graduação da FMRP – USP.
Medicina (Ribeirão Preto). 2007;40(1):51-62.
15. Anderson GS, Gaetz M, Masse J. First aid skill retention of first responders
within the workplace. Scand J Trauma Resusc Emerg Med. 2011;19:11.
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et al. Education in cardiopulmonary resuscitation in Sweden and its clinical
consequences. Resuscitation. 2010;81(2):211-6.
8. Jones I, Whitfield R, Colquhoun M, Chamberlain D, Vetter N, Newcombe
R. At what age can schoolchildren provide effective chest compressions?
An observational study from the Heartstart UK schools training programme.
BMJ. 2007;334(7605):1201.
16. Garrido FD, Romano MM, Schmidt A, Pazin-Filho A. Can course format
influence the performance of students in an advanced cardiac life support
(ACLS) program? Braz J Med Biol Res. 2011;44(1):23-8.
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Arq Bras Cardiol. 2013;101(4):328-335
335
Back to the cover
Original Article
Pulmonary Arterial Hypertension: Use of Delayed Contrast-Enhanced
Cardiovascular Magnetic Resonance in Risk Assessment
Luiz Gustavo Pignataro Bessa, Flávia Pegado Junqueira, Marcelo Luiz da Silva Bandeira, Marcelo Iorio Garcia,
Sérgio Salles Xavier, Guilherme Lavall, Diego Torres, Daniel Waetge
Hospital Universitário Clementino Fraga Filho, Ilha do Fundão, RJ - Brazil
Abstract
Background: Pulmonary arterial hypertension is a severe and progressive disease. Its early diagnosis is the greatest
clinical challenge.
Objective: To evaluate the presence and extension of the delayed myocardial contrast-enhanced cardiovascular magnetic
resonance, as well as to verify if the percentage of the myocardial fibrosis mass is a severity predictor.
Methods: Cross-sectional study with 30 patients with pulmonary arterial hypertension of groups I and IV, subjected to
clinical, functional and hemodynamic evaluation, and to cardiac magnetic resonance.
Results: The mean age of patients was 52 years old, with female predominance (77%). Among the patients, 53% had right
ventricular failure at diagnosis, and 90% were in functional class II/III. The mean of the 6-minute walk test was 395m.
In hemodynamic study with right catheterism, the mean average pulmonary arterial pressure was 53.3mmHg, of the
cardiac index of 2.1L/ min.m2, and median right atrial pressure was 13.5 mmHg. Delayed myocardial contrast‑enhanced
cardiovascular magnetic resonance was found in 28 patients. The mean fibrosis mass was 9.9 g and the median percentage
of fibrosis mass was 6.17%. The presence of functional class IV, right ventricular failure at diagnosis, 6-minute walk test
< 300 meters and right atrial pressure ≥ 15 mmHg, with cardiac index < 2.0 L/ min.m2, there was a relevant association
with the increased percentage of myocardial fibrosis.
Conclusion: The percentage of the myocardial fibrosis mass indicates a non-invasive marker with promising perspectives in
identifying patients with high risk factors for pulmonary hypertension. (Arq Bras Cardiol. 2013;101(4):336-343)
Keywords: Hypertension, Pulmonary / diagnosis; Risk Assessment; Endomyocardial Fibrosis; Magnetic Resonance Imaging.
Introduction
Pulmonary Hypertension (PH) is a syndrome caused by
different conditions affecting pulmonary circulation. The causes
of PH that involve the pulmonary arterial bed include Pulmonary
Arterial Hypertension (PAH) and Chronic Thromboembolic
Pulmonary Hypertension (CTPH), known as group I and IV of
the current PH classification (Dana Point, 2008)1.
PAH is defined as a Mean Pulmonary Arterial Pressure
(mPAP) > 25mmHg at rest, in a situation of Pulmonary Artery
Wedge Pressure (PAWP) ≤ 15mmHg, with Pulmonary Vascular
Resistance (PVR) > 3 units Wood2. This condition has a poor
prognosis, with mortality of approximately 15% in 1 year for
those treated with modern therapy 3. Right Ventricular Failure
(RVF) is the main cause of death4.
Mailing Address: Luiz Gustavo Pignataro Bessa •
Rua Divino Salvador, 261, Piedade. Postal Code 20756-210,
Rio de Janeiro, RJ – Brazil
E-mail: [email protected], [email protected]
Manuscript received November 27, 2012; revised manuscript May 03, 2013;
accepted June 07, 2013.
DOI: 10.5935/abc.20130168
336
Efforts are made in order to obtain an early diagnosis.
Recently, prognostic factors that have an impact on survival
were reviewed 5. Mortality is higher for patients with
Functional Class (FC) III and IV6. The rapid progression of
symptoms, as well as signs of RVF at diagnosis, indicates
a worse prognosis. The result of the 6-Minute Walk
Test (6MWT) is an independent predictor of survival 7.
The presence of pericardial effusion, increased right atrium
and signs of right ventricular failure, at least moderate,
on transthoracic echocardiogram are consistent predictors
of mortality8. Patients with increased Right Atrial Pressure
(RAP) and decreased Cardiac Index (CI) had a higher
death risk9.
Study including 64 patients stated that Cardiac Magnetic
Resonance (CMR) imaging revealing an impaired function
of Right Ventricle (RV) – systolic volume ≤ 25mL/m 2,
end-diastolic volume of RV ≥ 84mL/m2 and end-diastolic
volume of Left Ventricle (LV) ≤ 40mL/m2 – are independent
predictors of mortality and therapeutic failure10.
The Delayed Myocardial Enhancement (DME) obtained
by CMR is a common finding in patients with PAH. Studies
have shown its relation with right ventricular function and
abnormalities in hemodynamics of pulmonary circulation11.
Bessa et al.
Delayed myocardial enhancement and risk assessment
Original Article
The objective of this study was to evaluate the presence
and extension of DME by CMR and verify if the percentage
of fibrosis mass is an indicator of severity in PAH.
Methods
Study design and patients screening
Cross-sectional study of patients in PAH outpatient clinic
at the Clementino Fraga Filho University Hospital (CFFUH),
who underwent CMR between May 2010 and April 2012.
This study selected and included 30 patients over 18 years
old, irrespective of gender, class, social group or ethnicity,
followed-up at the outpatient clinic of PH and CFFUH, and
patients with PAH from groups I and IV, who underwent clinical
evaluation and hemodynamics for starting a specific treatment.
These patients underwent all exams in the PH evaluation
protocol: specific laboratory, chest X-ray, pulmonary
function test, ventilation/perfusion (V/P) scintigraphy, chest
angiotomography, Right Catheterization (RC) and 6MWT.
Considering an interval of up to 72 hours from RC, these
patients were subjected to CMR, with a protocol specific for PH.
Patients with claustrophobia or any type of ferromagnetic
implants (pacemaker, orthopedic prosthesis, etc.),
patients who have renal dysfunction with creatinine
clearance < 30 mL / minute and contraindication
for RC due to increased risk of bleeding as a result of
severe blood dyscrasia (PTA < 60%, PTT rel > 2.0 and
platelets < 50,000cel/mm3).
All patients who participated in this study received an
informed consent, and the study was approved by the
Research Ethics Committee of CFFUH.
Hemodynamic evaluation by RC
RC was carried out in CFFUH hemodynamic laboratory
by an interventional cardiologist from the PH group,
inserting a Swan-Ganz catheter through the internal jugular
vein (model 131F7, Edwards Baxter, Irvine, CA, USA).
The catheter was positioned in West zone III. Confirmation
of its proper position was performed by scan and comparison
of the variation of Diastolic Pulmonary Artery Pressure (dPAP)
in relation to that of the Pulmonary Artery Occlusion Pressure
(PAOP) with respiratory cycle.
Monitoring of pressure, CO (Cardiac Output), and of
electrocardiographic tracing was performed with HewlletPackard device, model M1176-A (Hewlett-Packard, Walthan,
MA, EUA).
After the proper monitor calibration, we directly obtained
data from RAP, Systolic Pulmonary Artery Pressures (sPAP),
dPAP, mPAP, PAOP and Cardiac Frequency (CF). Blood samples
were collected, from the distal lumen of Swan-Ganz catheter,
for analyzing the Mixed Venous Oxygen Saturation (MVO2S).
CO measurement was performed by thermodilution
technique. Measurements with 10mL physiological saline
injection were carried out, at ambient temperature, in any
phase of the respiratory cycle, until we obtained three
measurements with <10% variation. The mean value was
then used in the study.
Using the CO result, we calculated PVR.
Hemodynamic evaluation by CMR
Exams were performed by a radiologist with 10 years
of experience, using a 1.5-T magnetic resonance device
(Siemens Magneton Avanto, Erlangen, Germany), operating
at 45mTm-1 maximum power gradient and 200Tm-1s-1 slew
rate, using six anterior canals and six posterior canals for data
collection. Patients were requested to exhale at maximum
and hold their breath during sequences. TRUE FISP (free
steady-state precession) cine resonance sequence was used
with ARGUS software, in order to evaluate cardiac function
and calculate right and left systolic function indexes (ejection
fraction through Simpson’s volumetric method), end-diastolic
and systolic volumes, ejective volume, cardiac output,
and ventricular mass in short axis and horizontal axis of
ventricles, with parallel acquisition technique (TR: 200ms;
FOV: 400mm; matrix: 128 x 88; flip angle: 15°; slice
thickness: 6mm). Moreover, 10 minutes after administrating
0.2mmoL/kg-1 gadodiamide (Dotaren TM, Gerbet, France),
and after requesting the patient to take a deep breath and
hold it, PSIR (phase-sensitive inversion recovery – TR: 700ms;
TE: 4.18ms; TI: 300ms; FOV: 340mm; matrix: 156 x 256;
flip angle 25°; slice thickness: 8mm) sequence, using same
position and number of cuts from TRUE FISP cine sequence
for evaluation of delayed myocardial enhancement.
Fibrosis volume was manually calculated based on the
outline of hypertensive myocardial areas obtained with CMR
after administrating gadolinium, in the short axis of the heart,
in each cut (Figure 1). Mass was obtained by multiplying total
fibrosis volume by 1.05 (myocardial density).
Functional evaluation
Each patient was evaluated by CFFUH physiotherapy
team with 6MWT performed in accordance with American
Thoracic Society12 guidelines. In this test, the patient is
requested to walk as fast as possible for 6 minutes, on a
30 m flat surface, and the distance is registered in meters.
In this test, the patient may reduce the intensity, stop and
rest, if necessary, without interrupting the timing process.
Running or jogging was not allowed.
FC was evaluated according to World Health Organization
(WHO). RVF clinical signs were defined as: jugular turgency,
increased RV at palpation, hepatomegaly, ascite and edema
on lower limbs.
Statistical analysis
Demographic, clinical, functional and hemodynamic
variables of CMR and RC were tested in order to verify the
type of distribution through histograms and Shapiro-Wilk test.
Variables that showed normal distribution were expressed in
mean ± standard or median deviation, with minimum and
maximum values in case of abnormal distribution.
Presence and extension of DME were evaluated in patients
with PAH subjected to CMR, and the percentage of myocardial
fibrosis was calculated based on data regarding fibrosis mass
and ventricular masses.
The relation between the percentage of myocardial
fibrosis to clinical (signs of RVF), functional (CF and 6MWT)
Arq Bras Cardiol. 2013;101(4):336-343
337
Bessa et al.
Delayed myocardial enhancement and risk assessment
Original Article
Figure 1 – Cardiac magnetic resonance in short axis, two chambers (heart mid section), after injecting gadolinium to evaluate the delayed myocardial
enhancement in a 26-year old patient with idiopathic pulmonary arterial hypertension at Clementino Fraga Filho University Hospital. It was observed a delayed
myocardial enhancement in the anterior and posterior portions of the interventricular septum, on the right ventricular insertion points (red arrows).
and hemodynamic parameters, through Mann-Whitney test,
performing an attempt to identify “high risk” patients according
to ROC curve, an optimal point (cutoff) of fibrosis percentage.
FC variable was categorized in FC IV (“high risk”) and
FC II/III (“low risk”). 6MWT variable was categorized
in distance walked <300m (“high risk”) and distance
walked >300m (“low risk”). Hemodynamic variable was
categorized in patients who had, at invasive hemodynamic
study: RAP ≥ 15mmHg and CI < 2.0L/min.m2 (“high risk”)
and RAP < 15mmHg and CI ≥ 2.0L/min.m2 (“low risk”).
Fifteen exams of CMR were randomized, then examined
by the same radiologist and another radiologist with
experience in cardiovascular medicine, in different
occasions. Examiners were blinded in relation to clinical,
functional and hemodynamical evaluation parameters.
Intraclass Correlation Coefficient (ICC) was applied to
evaluate the intra and interobserver reproducibility in DME
research and calculation of myocardial fibrosis percentage.
Statistical analysis was processed by the program Statistical
Package for Social Sciences (SPSS) 20.0 for MAC.
The criterion for significance determination was the
level of 5%.
Results
Study population was composed of 30 patients, of which
44% had idiopathic PAH. The remaining patients were
from Group I of Dana Point Classification, being composed
of collagenosis (5 patients), portopulmonary hypertension
(3 patients), schistosomiasis (1 patient) and HIV (1 patient).
Other 7 patients have CTEPH.
In relation to demographic and functional data (Table 1),
patients had a mean age of 52 years and most of them were
female (23%). The median onset period for symptoms at
diagnosis was 18 months. Among them, 53% had signs
of RVF at clinical exam during the diagnosis and most of
338
Arq Bras Cardiol. 2013;101(4):336-343
them had CF II or III (90%). The mean 6MWT was 395m
among the patients.
On Table 2 is shown the morphological and functional
data obtained from CMR. It is noted that the mean diameter
of RV was 76mm and of pulmonary artery was 38.5mm, and
the mean mass index of RV was 46.4g/m2 – all parameters
indicate increased resistance to blood flow and overload of RV.
Pericardial effusion (PE) was detected in nine patients (30%).
The mean ejection fraction of RV obtained in CMR was 31.8%,
as well as the mean of LV CI of 2.1L/min.m2, which presupposes
that most patients had right ventricular dysfunction at diagnosis.
On Table 3 is the shown hemodynamic data obtained
with RC. We noticed that mPAP was 53.3mmHg, PVR index
(PVRI) of 22.2 Woods Units (WU) and the RAP median was
of 13.5mmHg. The mean CI was 2.1L/min.m2, exactly the
same as that obtained with CMR.
DME was present in 28 patients (93%), distributed in the
anterior and inferior septal, and insertion areas of RV free-wall.
The mean fibrosis mass was 9.9g and the myocardial fibrosis
percentage was 6.17% (Table 2).
High risk factors, such as FC IV, RVF at diagnosis,
6MWT < 300 m, RAP ≥ 15 mmHg and CI < 2.0 L/min.m2 had
significant association with higher fibrosis percentage (Table 4).
Based on ROC curve analysis (Graph 1), it was observed
that a percentage of myocardial fibrosis > 5.99% is capable
of identifying patients with RVF (i.e., high risk) with 82%
Sensitivity (S), 92% Specificity (E), 99% Positive Predictive
Value (PPV) and 28% Negative Predictive Value (NPV).
A percentage of myocardial fibrosis > 6.67% is capable of
identifying the patient with a more advanced FC (FC IV, i.e.,
high risk) with 98% S, 75% E, 98% PPV and 73% NPV.
A percentage of myocardial fibrosis > 6.49% is capable
of identifying patients with a functional capacity of exercise
at 6MWT < 300m (i.e., high risk), with 71% S, 83% E, 98%
PPV and 18% NPV.
Percentage of myocardial fibrosis > 5.99% is capable
Bessa et al.
Delayed myocardial enhancement and risk assessment
Original Article
Table 1 – Demographic and functional evaluation data
Mean ± SD (%)
Age
Median (min.-max.)
52.5 ± 16.5
Gender (M/F)
P25
P75
Shapiro (p)
45
62
0.246
7 (23%)/23 (77%)
Weight (kg)
57
76
0.299
Height (meters)
65.5 ± 12.5
1.57 (1.49-1.82)
1.54
1.67
0.001
BSA (m /kg)
1.61 (1.36-2.04)
1.55
1.87
0.075
18 (6-36)
12
24
0.074
350
465
0.434
2
Time of symptoms onset (months)
Presence of RVF (Y/N)
16 (53%)/14 (47%)
FC WHO (II-III/IV)
27 (90%)/3 (10%)
6MWT (meters)
395.8 ± 109.8
Values stated in mean ± standard deviation (SD) or median, with minimum and maximum values with the respective percentiles 25 (P25) and 75% (P75), in Shapiro
normality test. Min.: minimum; max.: maximum; M: male; F: female; BSA: body mass area; RVF: right ventricular failure; S: yes; N: no; FC WHO: Functional Class of the
World Health Organization; 6MWT: 6-minute walk test.
Table 2 – Morphological and functional data, and information on mass/percentage of myocardial fibrosis by cardiac magnetic resonance
Mean ± SD (%)
RV long diam (mm)
P25
6.0 (3.0-8.0)
76.4 ± 10.9
RV thickness (mm)
PA trunk diam (mm)
RV massi (g/m2)
Median (min.-max.)
38.5 (27-72)
46.4 ± 10.0
LV massi (g/m2)
56.5 (46.5-80.4)
Pericardial effusion (Y/N)
P75
Shapiro (p)
70
84
0.842
5.0
6.0
0.011
36
42
0.01
36.8
51.3
0.208
51.7
62.1
0.088
9 (30%)/27 (90%)
CF (BPM)
76.2 ± 12.4
68
86
0.669
RV EF (%)
31.8 ± 12.2
24
38
0.609
RV EDVI (mL/m )
100.8 ± 26.7
80.2
122.7
0.676
RV ESVI (mL/m2)
70.7 ± 26.9
51
88.9
0.343
1.7
2.4
0.089
2
CI CMR (L/min.m )
2.1 (1.4-3.4)
2
LV EDVI (mL/m )
2
53.1 ± 12.8
LV ESVI (mL/m2)
LV SVI (mL/m )
2
Presence of fibrosis (Y/N)
28 (93%)/2 (7%)
Fibrosis on anterior septum (Y/N)
25 (83%)/5 (17%)
Fibrosis on inferior septum (Y/N)
28 (93%)/2 (7%)
Fibrosis mass (g)
Percentage of myocardial fibrosis (%)
43.4
60.2
0.731
19.7 (8.9-49.4)
15.6
32.1
0.037
28.2 (13.7-53.9)
25.5
36.1
0.025
9.9 (0-20.6)
8.1
12.8
0.095
6.17 (0-10.52)
4.79
7.10
0.14
Values stated in mean ± standard deviation (SD) or median, with minimum and maximum values with the respective percentiles 25 (P25) and 75% (P75), in Shapiro normality
test. Min.: minimum; max.: maximum; RV long diam: right ventricle longitudinal diameter; RV thickness: right ventricle thickness; PA trunk diam: pulmonary artery trunk
diameter; RV mass: right ventricle mass index; LV massi: left ventricle mass index; Y: yes; N: no; CF (BPM): cardiac frequency (beats per minute); RV EF: right ventricle
ejection fraction; RV EDVI: right ventricle end-diastolic volume index; RV ESVI: right ventricle end-systolic volume index; CI CMR: cardiac index by cardiac magnetic
resonance; LV EDVI: left ventricle end-diastolic volume index; LV ESVI: left ventricle end-systolic volume index; LV SVI: left ventricle systolic volume index.
Arq Bras Cardiol. 2013;101(4):336-343
339
Bessa et al.
Delayed myocardial enhancement and risk assessment
Original Article
Table 3 – Hemodynamic data by right catheterism
Mean ± SD (%)
CF R CAT (BPM)
Median (min.-max.)
P25
P75
Shapiro (p)
73.5 (53-108)
70
80
0.016
mPAP (mmHg)
53.3 ± 9
49
60
0.990
sPAP (mmHg)
85.4 ± 18.8
75
96
0.745
dPAP (mmHg)
32.4 ± 6.9
26
36
0.674
RAP (mmHg)
7
20
0.045
CI R CAT (L/min.m2)
2.14 ± 0.56
13.5 (3-24)
1.6
2.5
0.308
PVRi (WU)
22.2 ± 8.2
16.9
28.3
0.370
PCAP (mmHg)
10.3 ± 3.6
8
14
0.467
48.6
68
0.042
37
50
0.948
SVM O2 (%)
57.8 (42-77)
GT (mmHg)
43.2 ± 8.6
Values stated in mean ± standard deviation (SD) or median, with minimum and maximum values with the respective percentiles 25 (P25) and 75% (P75), in Shapiro normality
test. Min.: minimum; max.: maximum; CF R CAT (BPM): cardiac frequency by right catheterism (beats per minute); mPAP: mean pulmonary artery pressure; sPAP: systolic
pulmonary arterial pressure; dPAP: diastolic pulmonary arterial pressure; RAP: right atrium pressure; CI R CAT: cardiac index by right catheterism; PVRi: pulmonary vascular
resistance index; WU: Wood unit; PCAP: pulmonary capillary pressure; MVO2S: mixed venous oxygen saturation; TG: transpulmonary gradient.
Table 4 – Distribution of patients, according to risk factors, the clinical, functional and hemodynamical evaluations, and percentage of
myocardial fibrosis
Risk factors – percentage of myocardial fibrosis
RVF
Percentage of myocardial fibrosis
FV IV
Percentage of myocardial fibrosis
TC6M < 300m
Percentage of myocardial fibrosis
Hemodynamic (CI < 2.0L/min.m and RAP ≥ 15mmHg)
2
Percentage of myocardial fibrosis
p
None (n = 13)
Present (n = 17)
4.30 (3.93-5.55)
6.83 (6.28-7.19)
None (n = 27)
Present (n = 3)
5.54 (4.78-6.67)
7.51 (7.18-7.67)
None (n = 24)
Present (n = 6)
5.38 (4.62-6.78)
7.18 (6.58-8.16)
None (n = 17)
Present (n = 13)
5.12 (4.49-6.28)
6.55 (6.26-7.18)
< 0.0001
0.034
0.021
0.039
Values of the percentage of myocardial fibrosis stated in mean, with the respective percentiles 25 and 75 in parenthesis. RVF: right ventricular failure; FC: functional class;
6MWT: 6-minute walk test; CI: cardiac index; RAP: right atrium pressure.
of identifying patients with PAD ≥ 15mmHg and
IC < 2.0 L / min.m2 on RC (i.e., high risk), with 84% S,
81% E, 97% PPV and 18% NPV.
Intraobserver ICC for myocardial fibrosis mass was
0.984 (CI95% = 0.953-0.995) and interobserver of 0.966
(CI95% = 0.900-0.989).
Discussion
Right ventricular dysfunction is the main cause of
morbimortality in patients with PAH4. Several studies are
developed to find clinical and hemodynamical markers that
could be used in diagnosis and follow-up. Thus, it is possible
to characterize a high risk patient, who will be subjected to
early therapeutic interventions.
CMR is the gold standard for evaluating function, volume
and mass of the right ventricle13, which can be qualified
with excellent intra and interobserver14 variability and good
340
Arq Bras Cardiol. 2013;101(4):336-343
interstudy reproducibility15.
DME was initially described in dysfunctioning areas of
LV after gadolinium-based contrast agent administration in
patients undergoing CMR with previous infarction history
and fibrosis scarring16,17. Descriptions a posteriori have
shown the presence of DME in patients with hypertrophic
myocardiopathy and myocardiopathies with deposits
or inflammatory (viral myocarditis), each one with a
characteristic extension pattern18-22.
DME can be explained by the gadolinium capacity
of having a different pattern distribution in healthy and
unhealthy tissues. Contrast “removal” is more difficult in
the unhealthy tissue, creating a signal difference > 1.080%
in DME images. Consequently, areas of the unhealthy
myocardial tissue can be precisely identified, with high
accuracy and reproducibility23,24.
Even though there are several studies of DME evaluated
Bessa et al.
Delayed myocardial enhancement and risk assessment
Original Article
(A) RVF
(B) Functional class
(C) 6-minute walk test
(D) Hemodynamics
Graph 1 – ROC curve between clinical and hemodynamical severity stratifiers for patients with pulmonary arterial hypertension and percentage of myocardial fibrosis
obtained by cardiac magnetic resonance. A) right ventricular failure (RVD): area under a curve (AUC) of 0.864 (confidence interval of 95% - CI95% = 0.714 - 1.0).
The percentage of myocardial fibrosis > 5.99% was capable to identify the patient without signs of RVF (high risk) with 85% sensitivity (S), 92% specificity (E), 99%
positive predictive value (PPV) and 28% negative predictive value (NPV). B) Functional class: 0.877 (AUC) (CI95% = 0.753-1.0). The percentage of myocardial
fibrosis > 6.67% was capable to identify patients with functional class (FC) IV (high risk) with 98% S, 75% E, 98% PPV and 73% NPV. C) 6-minute walk test (6MWT):
0.806 AUC (CI95% = 0.647-0.965). The percentage of myocardial fibrosis > 6.49% was capable to identify patients who walk < 300 meters (high risk), with 71%
S, 83% E, 98% PPV and 18% NPV. D) Hemodynamics: 0.724 AUC (CI95% = 0.530-0.918). The percentage of myocardial fibrosis > 5.99% was capable to identify
patients with cardiac index (CI) < 2.0L/min.m2 and right atrium pressure (RAP) ≥ 15mmHg (high risk) with 84% S, 71% E, 97% PPV and 18% NPV.
by CMR in conditions that affect the LV, only three of
major importance evaluated this finding in patients with
PAH11,25,26.
In McCann et al 25 study, the presence of DMC was
noticed in insertion areas of the RV interventricular septum
in all 15 patients with PAH. The mean fibrosis mass was
3.1 ± 1.9g and there was no positive correlation with
any clinical or hemodynamical variable – only an inverse
correlation with right ventricular dysfunction measured
by CMR. Blyth et al11 noticed the presence of DME on
23 of 25 study patients, of 3.3g and there was a positive
correlation with several hemodynamic variables, primarily
patients with paradoxical interventricular septum deviation.
Junqueira et al26 demonstrated the presence of DME in 65%
of study patients and only found a positive correlation with
the duration of the disease at diagnosis.
Several speculations exist on the physiopathological
mechanism related to DME in patients with PAH. In MacCann
et al25 study, two patients who died were subjected to
autopsy, and fibrosis was present in the right ventricular
insertion point, suggesting that this was the DME mechanism
selected for these patients. It is speculated that myocardial
fibrosis results from an increased right ventricle afterload.
The hypertrophy and right cavity dilatation found in these
patients led to a mechanical stress in these points, with
subsequent hypoxia and ischemia27,28.
In this study, DME was present in 28 of the 30 study patients.
The median fibrosis mass was 9.9g (0-20.2g). Due to a large
variation of the ventricular mass related to age, gender, body
mass index and comorbities very prevalent in our environment,
such as systemic arterial hypertension, we chose to calculate
the percentage of myocardial fibrosis, which mean was 6.17%.
Apart from other studies, the percentage of myocardial
fibrosis has been able to identify patients with PH with high
risk factors, based on clinical (signs of RVF), functional (FC IV
and 6MWT < 300m) or hemodynamic (RAP ≥ 15mmHg and
CI < 2.0L/min.m2) evaluation.
This study had a few limitations. It was carried out
with a relatively small number of patients, which,
particularly, is reflected by the low prevalence of PAH in
the general population. No patient was subjected to cine
Arq Bras Cardiol. 2013;101(4):336-343
341
Bessa et al.
Delayed myocardial enhancement and risk assessment
Original Article
angiocoronariography to discard an ischemic heart disease,
which is an important cause of DME. However, the DME
pattern noticed in these patients is not a characteristic of
myocardial ischemic injury.
Conclusion
DME is present in most patients with PAH, and the
percentage of myocardial fibrosis evaluated by CMR has shown
a good non-invasive parameter for severity evaluation in this
group with 30 study patients.
These results are interesting, since the greatest clinical
challenge, in PH evaluation, is to identify patients who need
early interventions, due to the potential for high severity of the
disease. Longitudinal studies and with larger number of patients
need to be performed in order to assess the real prognostic role
of this evaluation parameter for patients with PAH.
Author contributions
Conception and design of the research: Bessa LGP,
Junqueira FP, Garcia MI, Xavier SS, Waetge D; Acquisition
of data: Bessa LGP, Junqueira FP, Bandeira MLS, Lavall G,
Torres D, Waetge D; Analysis and interpretation of the data:
Bessa LGP, Bandeira MLS, Garcia MI, Xavier SS; Statistical
analysis and Writing of the manuscript: Bessa LGP; Critical
revision of the manuscript for intellectual content: Bessa
LGP, Junqueira FP, Bandeira MLS, Garcia MI, Xavier SS,
Lavall G, Torres D.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is part of the thesis of master submitted by Luiz
Gustavo Pignataro Bessa, from Universidade Federal do Rio
de Janeiro.
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Back to the cover
Original Article
Big Endothelin-1 and Nitric Oxide in Hypertensive Elderly Patients
with and without Obstructive Sleep Apnea-Hypopnea Syndrome
Iara Felicio Anunciato, Rômulo Rebouças Lobo, Eduardo Barbosa Coelho, Waldiceu Aparecido Verri Jr., Alan Luiz Eckeli,
Paulo Roberto Barbosa Évora, Fernando Nobre, Júlio César Moriguti, Eduardo Ferriolli, Nereida Kilza da Costa Lima
Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP – Brazil
Abstract
Background: The role of oxidative stress in hypertensive elderly patients with obstructive sleep apnea-hypopnea
syndrome (OSAHS) is unknown.
Objective: The purpose was to evaluate the levels of big endothelin-1 (Big ET-1) and nitric oxide (NO) in elderly
hypertensive patients with and without moderate to severe OSAHS.
Methods: Volunteers were hospitalized for 24 h. We obtained the following data: body mass index (BMI);
24-ambulatory blood pressure monitoring; and current medication. Arterial blood was collected at 7pm and
7am for determining plasma NO and Big ET-1 levels. Pulse oximetry was performed during sleep. Pearson’s or
Spearman’s correlation and univariate analysis of variance were used for statistical analysis.
Results: We studied 25 subjects with OSAHS (group 1) and 12 without OSAHS (group 2) aged 67.0 ± 6.5 years and
67.8 ± 6.8 years, respectively. No significant differences were observed between the groups in BMI; number of
hours of sleep; 24-h systolic and diastolic BPs; awake BP, sleep BP and medications to control BP between groups.
No differences were detected in plasma Big ET-1 and NO levels at 19:00 h, but plasma Big ET-1 levels at 7:00 h
were higher in group 1 (p = 0.03). In group 1, a negative correlation was also observed between the mean arterial
oxyhemoglobin saturation level, 24-h systolic BP (p = 0.03, r = −0.44), and Big ET-1 (p = 0.04, r = −0.41).
Conclusions: On comparing elderly hypertensive patients with and without OSAHS having similar BP and BMI, we
observed higher Big ET-1 levels After sleep in the OSAHS group. NO levels did not differ between the hypertensive
patients with or without OSAHS. (Arq Bras Cardiol. 2013;101(4):344-351)
Keywords: Hypertension; Aged; Big endothelin-1; Obstructive sleep apnea-hypopnea syndrome.
Introduction
The endothelium plays a fundamental role in the regulation
of vascular tone and peripheral resistance through the synthesis
of numerous vasoactive compounds, i.e., vasodilators such as
nitric oxide (NO) and vasoconstrictors such as big endothelin-1
(Big ET-1), by endothelial cells1-3. Under pathological conditions
such as systemic arterial hypertension, there is a disequilibrium of
endothelium-derived factors with an attenuation of vasodilators
and a predominance of vasoconstrictors4. The elimination rate of
endothelin-1 (ET-1) is higher than that of its precursor Big ET-1.
In addition, plasma Big ET-1 levels of humans, rabbits, and rats
are higher than plasma ET-1 levels, with studies suggesting that the
precursor is a more appropriate indicator for the quantification
of release by endothelial cells5.
Mailing Address: Iara Felicio Anunciato •
Rua Natalicia Frederico de Vicenti, 30, JD Maria Imaculada I.
Postal Code 14340-000, Brodowski, SP - Brazil
E-mail: [email protected], [email protected]
Manuscript received October 11, 2012; revised November 29, 2012;
accepted March 15, 2013.
DOI: 10.5935/abc.20130179
344
NO has an important influence on the tone of peripheral
blood vessels, and it is released in response to the shear
stress produced by blood flow and by the activation of
various of receptors6. Because NO is released continuously,
systemic inhibition of its synthesis causes an elevation of
blood pressure (BP). On this basis, oxidative stress plays an
important role in hypertension pathogenesis7.
Oxidative stress is also considered to be involved in the
pathogenesis of arterial hypertension in obstructive sleep
apnea-hypopnea syndrome (OSAHS)8. OSAHS is defined as
a group of disorders characterized by periodic cessation of
breathing, with consequent hypoxia, frequent awakenings,
and sleep fragmentation during the night, triggering excessive
daytime somnolence9. This syndrome is more prevalent
among the elderly10. According to the apnea-hypopnea index
(AHI/h), OSAHS is classified as mild (AHI/h, 5–15 events/h);
moderate (AHI/h, 15– 30 events/h); and severe (AHI/h, >30
events/h) 11. Furthermore, mortality is significantly associated
with high rates of respiratory changes [awakenings and
microawakenings during sleep]; a body mass index (BMI) of
>30 kg/m2; and male sex12.
Few studies have assessed endothelial function
in OSAHS, and the role of oxidative stress in elderly
hypertensive patients with OSAHS is unknown.
Anunciato et al.
Big endothelin-1 and nitric oxide in OSAHS
Original Article
The objective of the present study was to evaluate Big ET-1
and NO before and after sleep in elderly hypertensive
patients with and without OSAHS.
Methods
The hypertensive patients were selected from the
outpatient services of the following centers of the Ribeirao
Preto School of Medicine, São Paulo University: the
Hypertension Center of the Clinical Hospital; the Geriatric
Clinic of the School Health Center; and the Center for
Family Health –V. All hypertensive volunteers with moderate
to severe OSAHS had previous diagnoses confirmed by
polysomnography; control hypertensive subjects were also
subjected to further examination to exclude OSAHS. The
hypertensive patients diagnosed with moderate or severe
OSAHS were diagnosed by the Laboratory of Clinical
Neurophysiology (Clinical Hospital – Ribeirao Preto School
of Medicine) and selected following the exclusion criteria
described below.
Exclusion criteria were based on the following factors
that could affect the evaluation of plasma Big ET-1 and
NO levels: age <60 years, diabetes mellitus, dyslipidemia,
heart and lung diseases, smoking, past history of smoking,
drinking , use of continuous positive pressure airway
ventilation, cardiac arrhythmia, and use of medications that
might interfere with sleep (anxiolytics, antidepressants, and
neuroleptics). Patients who did not consent to participate
were also excluded.
The volunteers were admitted to the Clinical Research
Unit of HCFMRP-USP. Upon admission, weight and height
were measured using a digital scale (Filizola), and the device
for the ambulatory blood pressure monitoring (ABPM) was
installed (SAPCELABS 90207, Redmond, USA. The ABPM
device was left in place for 24 h, divided into a probable
wakefulness period (7:00–23:00 h) and a probable sleep
period (23:00–7:00 h). The device was programmed to
take readings at 15 minute intervals during the probable
wakefulness period and at 20 minute intervals during the
probable sleep period. Before each blood collection for
the determination of Big ET-1 and plasma NO, three BP
measurements were made with the subject in the sitting
position, using a mercury column device (auscultatory
method) on the upper limb contralateral to that wearing
the cuff for ABPM.
A 4.5-ml arterial blood sample was collected at
19:00 h on the day of admission and 7:00 h the following
morning for the determination of plasma NO levels (µM).
Each sample was divided into three aliquots, and
1.5 ml arterial blood was stored in an Eppendorf tube
containing 0.08 ml heparin and centrifuged (Eppendorf
AG, model 5418R) for 10 min at 5000 rpm and a standard
temperature of 4°C. The supernatant (300 µl) of each
Eppendorf tube was removed and transferred to a new
tube, which was stored in a freezer at −70°C for later
determination by chemiluminescence (specificity of
93.9%). Each arterial blood sample was also processed
for the determination of plasma Big ET-1 levels (pg/ml).
The collected sample was immediately divided into three
aliquots in Eppendorf tubes. Each tube contained 0.1 ml
EDTA/1.5 ml blood and 0.1 ml aprotinin/1.5 ml blood
each. To reach this value, 0.39 mg EDTA was diluted in
350 ml 0.9% saline solution and 0.39 mg aprotinin was
diluted in 350 ml 0.9% saline solution. The sample was
then centrifuged in the same apparatus as that used for
the sample used for quantifying NO levels for 15 min but
at 1600 rpm and a temperature of 0°C. The supernatant
(300 ml) of each Eppendorf tube was then removed,
transferred to a new tube, and stored in a freezer at -70°C
for later determination by ELISA (sensitivity of 0.30 pg/ml
and specificity of 100%). The sensitivity for this kit was
determined using the guidelines provided by the National
Committee for Clinical Laboratory Standards (NCCLS)
Evaluation Protocols. (National Committee for Clinical
Laboratory Standards Evaluation Protocols, SC1, (1989)
Villanova, PA, USA: NCCLS).
Pulse oximetry (DIXTAL, model DX 2022) was recorded
from 7pm to 7am for all volunteers. A finger sensor placed
on the index finger contralateral to the arm used for BP
measurement by ABPM device was used in order to obtain
the level of arterial oxyhemoglobin saturation (O2 Sat).
The polysomnography study was performed in the
Clinical Neurophysiology Laboratory of HCFMRP-USP
using the Biologic Sleepscan Vision PSG Polygraph
(NatusBiologic Systems, San Carlos, CA, USA) to obtain
the AHI/h, as previously described, the total number of
apnea and hypopnea (NAH) episodes during sleep, and
the number of NAM.
The mean and standard deviation was calculated for data
with a normal distribution (parametric), and the median was
calculated for non-parametric data (those regarding Big ET-1
and NO). The SAS®9.0 software was used for these analyses.
Fisher’s exact test was used to describe the frequencies
according to gender. To determine possible correlations
between the variables, Pearson’s correlation coefficient was
calculated for parametric data and Spearman’s correlation
coefficient was calculated for non-parametric data using R
software. For the study of Big ET-1 and NO, we corrected
group comparison including BP, BMI and NAH in the analysis
since these are factors that may influence the final result
(univariate analysis of variance).The study was submitted to
the Ribeirao Preto School of Medicine’s Ethics Committee
and approved in accordance with protocol number 14103.
All participants received detailed information about the goals
and procedures of the study, and they signed an informed
consent form in compliance with Resolution 196/96 of the
National Health Council.
Results
Table 1 shows the participant characteristics obtained at the
initial clinical evaluation. No difference was observed between
the groups regarding the distribution of antihypertensive
medications used. Between group 1 and group 2, the
respective use was as follows: diuretics, 68% and 66.6%;
angiotensin-converting enzyme inhibitors or angiotensin
receptor antagonists, 68% and 58.3%; calcium channel
antagonists, 20% and 25%; and beta-blockers, 32% and 50%.
Arq Bras Cardiol. 2013;101(4):344-351
345
Anunciato et al.
Big endothelin-1 and nitric oxide in OSAHS
Original Article
Table 1 - Anthropometric and clinical characteristics of group 1 (hypertensive patients with obstructive sleep apnea-hypopnea syndrome) and
group 2 (hypertensive patients without obstructive sleep apnea-hypopnea syndrome)
Characteristics
Group 1 (25)
Group 2 (12)
Age
67.0 ± 6.5
67.8 ± 6.8
Weight (G)
78.8 ± 15.1
75.8 ± 13.1
Height (M)
1.60 ± 0.11
1.60 ± 0.09
BMI (kg/m )
30.3 ± 4.8
29.0 ± 5.0
Number of antihypertensive medications
1.9 ± 0.9
2.3 ± 0.9
Hours of sleep
5.3 ± 0.8
5.1 ± 1.6
2
Values are reported as mean ± standard deviation (unpaired Student t-test, p > 0.05); BMI: Body mass index
Table 2 lists the BP values obtained by ABPM and by the
auscultatory method.; no significant differences existed
between the groups (p > 0.05). The decrease in BP during
the sleep period compared with that during the wakefulness
period was as follows: 8.2 ± 9.5 mmHg for systolic BP
(SBP) and 7.4 ± 6.1 mmHg for diastolic BP (DBP) in
group 1 (percentage decrease: 6.6 ± 7.5% mmHg for SBP
and 9.8 ± 8.2% for DBP); 6.4 ± 9.5 mmHg for SBP and
5.8 ± 6.5 mmHg for DBP in group 2 (percentage decrease:
4.6 ± 7.8% for SBP and 6.7 ± 8.5% mmHg for DBP).
Evaluation of the BP measurements obtained for
the volunteers as a whole revealed a good statistical
correlation between the measurements obtained by
auscultation and 24-h ABPM (SBP: p < 0.001, r = 0.68;
DBP: p < 0.001, r = 0.61).
Table 3 presents the values of NAH, AHI, and NAM,
as well as the minimum and mean O2 saturation levels
recorded during the sleep period (p < 0.001).
Plasma NO levels determined at 19:00 h and 7:00 h
(Figure 1) did not differ between the groups (p > 0.05).
However, plasma Big ET-1 levels differed between the groups
at 7am only, when it increased in the OSAHS group following
sleep (Figure 2).
When group 1 and group 2 were analyzed jointly, no
correlations were found between BP and several variables,
including Big ET-1, NO, O2 saturation, AHI, and NAM.
However, a correlation was observed between BMI and the
mean O2 saturation level (r = −0.43, p = 0.008) and between
BMI and NAM (r = 0.51, p = 0.002) (Figure 3).
Today, sleep changes are highly prevalent in the general
population, in particular the elderly. Epidemiological
studies have pointed out that BP elevation is associated
with sleep disorders13,14 due to the high AHI9, resulting in
daytime hypersomnolence and cardiorespiratory changes14.
Furthermore, Mary et al8 stated that BP elevation occurs at
the end of each episode of obstructive apnea.
When evaluating BP by means of ABPM, we did not observe
differences in systolic (S) BP or diastolic (D) BP between
subjects with and without OSAHS during sleep, wakefulness
and during a 24-hour period. This result differs from that
reported by Martinez Garcia et al.9 who observed higher SBP
and DBP in patients with OSAHS, but agrees with the report of
Davies et al.15 who did not detect a difference in wakefulness
or 24-hour SBP between groups with and without OSAHS,
and also with an Oxford study cited by Davies et al.15 which,
when comparing SBP and DBP between the same groups,
did not detect a difference during sleep or wakefulness. In
our study, the BP decrease during the sleep period was the
same between the groups with and without OSAHS, and
both groups showed an attenuation of the decline in BP, with
values <10%. It is important to point out that the two groups
studied were composed of controlled hypertensive subjects
continuously taking antihypertensive medications, with no
differences in the number of medications taken. However,
the small number of volunteers may have limited the power
for detecting differences in BP between the groups.
The O2 saturation levels were negatively correlated with
Big ET-1 (r = −0.41, p = 0.04).
The result of conventional BP measurement performed
at 19:00 h and 7:00 h by auscultatory method by a trained
investigator correlated well with the 24-h BP obtained by ABPM.
This suggests that where skills exist, auscultatory method can be
used in clinical practice when ABPM is not readily available,
or at times when periodic reevaluation is necessary. However,
it is important to note that ABPM is the gold standard for BP
evaluation16, and that obtaining data in this manner allowed
the study to take be conducted during sleep and wakefulness.
Considering only the group without OSAHS, we
observed that sleep SBP recorded by ABPM was correlated
with NAH (r = 0.71 p = 0.01) and AHI (r = 0.67, p = 0.02).
Inverse correlation was observed between the O2 saturation
level and NAM (r = −0.61, p = 0.05) and the O2 saturation
level and BMI (r = −0.58, p = 0.05).
An important result of the present study was the difference
in minimum and mean O2 saturation levels observed during
sleep, with the OSAHS group showing significant hypoxemia,
as expected. Lima et al17 observed the same hypoxic effect in
patients with sleep apnea compared to healthy individuals,
and similar data were obtained by Peled et al12.
Considering only the group with OSAHS, we detected
significant correlations between auscultatory SBP and Big
ET-1 (r = 0.42, p = 0.04), 24-hour systolic ABPM and mean
O2 Sat (r = - 0.44, p= 0.03), and 24-hour DBP and NAM
(r = 0.50, p = 0.01).
346
Discussion
Arq Bras Cardiol. 2013;101(4):344-351
Anunciato et al.
Big endothelin-1 and nitric oxide in OSAHS
Original Article
Table 2 - Systolic blood pressure (SBP) and diastolic blood pressure (DBP) during ambulatory blood pressure monitoring (ABPM) and blood
pressure measurement by the auscultatory method in group 1 (hypertensive patients with sleep apnea-hypopnea syndrome) and group 2
(hypertensive patients without sleep apnea-hypopnea syndrome)
BP
ABPM
Mean
24-Hours
Sleep
Wakefulness
Auscultatory
At 19:00 Hours
At 7:00 Hours
BP
Group 1 (25)
Group 2 (12)
SBP
122 ± 12
127 ± 13
DBP
72 ± 11
74 ± 10
SBP
116 ± 15
122 ± 13
DBP
68 ± 12
70 ± 8
SBP
123 ± 13
127 ± 15
DBP
75 ± 10
76 ± 11
SBP
130 ± 22
132 ± 12
DBP
79 ± 13
78 ± 9
SBP
129 ± 17
144 ± 22
DBP
80 ± 11
85 ± 11
Values are reported as mean ± standard deviation (unpaired Student t-test, p > 0.05 group 1 vs. group 2). BP: Blood pressure.
Table 3 - Number of awakenings and microawakenings (NAM), number of apnea-hypopnea (NAH) episodes and apnea-hypopnea index (AHI)
obtained from polysomnography, and minimum oxygen saturation (min O2 saturation) and mean oxygen saturation (mean O2 saturation) in group 1
(hypertensive patients with sleep apnea-hypopnea syndrome) and group 2 (hypertensive patients without sleep apnea-hypopnea syndrome)
Variables
Group 1 (25)
Group 2 (12)
NAM
259.7 ± 133.9
140.2 ± 66.0*
NAH
140.2 ± 66.0
17.3 ± 11.0*
AHI
29.0 ± 13.7
3.1 ± 1.6*
Minimum O2 Saturation
80.7 ± 7.1
92.3 ± 4.5*
Mean O2 Saturation
91.1 ± 3.8
94.6 ± 2.4*
Values are reported as mean ± standard deviation (unpaired Student t-test, *p < 0.001 vs. group 1).
Figure 1 - Plasma levels of Nitric oxide (µM) in group 1 (OSAHS) and group 2 (no OSAHS).
Arq Bras Cardiol. 2013;101(4):344-351
347
Anunciato et al.
Big endothelin-1 and nitric oxide in OSAHS
Original Article
Figure 2 - Plasma levels of Big-Endothelin-1 (pg/ml) in group 1 (OSAHS) and group 2 (no OSAHS).
Figure 3 - Correlation between body mass index (BMI) and number of awakenings and microawakenings (NAM) in hypertensive patients with and without OSAHS
(Spearman, r = 0.51, p = 0.002).
348
Arq Bras Cardiol. 2013;101(4):344-351
Anunciato et al.
Big endothelin-1 and nitric oxide in OSAHS
Original Article
When we evaluated the respiratory events by
polysomnography we observed significant differences
between groups regarding NAM, NAH and AHI, in
agreement with published reports, since these are relevant
data for the characterization of individuals. These data agree
with those reported byr Lima et al17 and Ventura et al18.
The clinical importance of NO regarding BP has been well
defined since this powerful vasodilator directly affects the
tonus of peripheral blood vessels and its inhibition generates
hypertension 7. Basal NO activity is known to be reduced
in hypertensive patients19. Ip et al8 stated that endothelial
NO can also play an important role in BP regulation in
individuals with OSAHS. However, literature reports have
shown that NO deficiency can be reversed in hypertensive
individuals by the administration of antihypertensive
medications3,20. A study on hypertensive mice demonstrated
that, after the use of captopril, no inhibition of NO synthesis
was observed, with consequent BP regulation. Another
antihypertensive agent that results in BP attenuation and
improved NO-mediated vasodilation, is spironolactone20.
As already mentioned, basal NO levels in the present study
did not differ between the hypertensive individuals with
and without OSAHS. It should be pointed out that both
groups consisted of hypertensive subjects controlled with
antihypertensive medications with controlled BP. Based on
these data, we can suggest that NO activity is equilibrated
in cases of treated hypertension.
Studies conducted on elderly persons have demonstrated
an increase in plasma ET-1 levels compared with young
individuals4. Zamarron-Sanz et al21 confirmed a significant
increase in ET-1 levels in individuals with OSAHS compared
to healthy subjects. Jordan et al22 detected increased plasma
Big ET-1 levels in a group of patients with OSAHS not
receiving clinical or surgical treatment. In the present study
there was a higher Big ET-1 concentration in individuals
with OSAHS at 7am, after the sleep period.
In general, plasma ET-1 levels tend to be low and there is
no consensus on a definitive protocol that would facilitate
the reproducible determination of ET-1 or Big ET-1 levels
in different biological fluids. There are many variations in
the extraction protocols above basal values, ranging from
0.5 to 50 pg/ml, with comparison of the results obtained
often being difficult 23. In the present study, Big ET-1
determinations showed wide variability although identical
processing and storage techniques were used.
Evaluation of the variables in the OSAHS group revealed
a negative correlation between SBP and O2 saturation levels,
i.e., SBP increased with decreasing arterial oxygenation.
Moreover, increased Big ET-1 levels were correlated
with higher O2 saturation levels, and SBP was positively
correlated with Big ET-1 levels; thus, the greater the
vasoconstriction caused by Big ET-1, the higher the SBP.
Further, we observed a positive correlation between NAH,
AHI, and plasma Big ET-1 levels, suggesting a possible
increase in vasoconstriction associated with increasing NAH
episodes. No matter how small the number of awakenings
among individuals with the syndrome, an increase in
sympathetic tonus will occur, with a marked elevation not
only of BP, but also of heart rate. Depending on the intensity
of sleep apnea, this process may occur hundreds of times
during the night24. Thus, NAM during sleep contributes to
autonomic hyperactivity as one of the mechanisms that
explains hypertension associated with OSAHS25. In the
present study, a positive correlation was observed between
NAM and DBP (during sleep, wakefulness, and on 24-h
ABPM), with the increase in DBP being related to the
greater sleep fragmentation during the total sleep time.
We did not observe a significant correlation between NAM
and SBP (p > 0.05).
Martinez- Garcia et al 9 found a more significant
correlation between NAM and DBP (during sleep and
wakefulness). In contrast, Logan et al26 observed a greater
correlation between sleep fragmentation and SBP.
On comparing BMI with NAM, we observed that a higher
BMI was correlated with an increase in NAM, suggesting
that BMI may interfere with the sleep of individuals with
OSAHS. According to Ware, McBrayer and Scott, apnea
events are highly sensitive to changes in BMI, i.e., the
greater the weight, the higher the probability of apneic
events27. As described earlier, obesity is an established,
important pathogenic factor for OSAHS14.
Approximately 70% of individuals diagnosed with
sleep apnea are considered to be obese according to their
BMI, with this being the only significant risk factor that
is reversible10. In the present group without OSAHS, an
increased number of NAH and an increased AHI were
correlated with SBP elevation. Grote et al28 in studying the
influence of AHI on BP, observed that the probability of
uncontrolled hypertension increases by 2% with each unit
increase in AHI.
Antczak et al.29 reported that there is evidence that
obesity, even in the absence of respiratory sleep disorders,
negatively affects the quality of sleep, increasing daytime
somnolence. Furthermore, studies have observed that
obese patients without OSAHS had a higher frequency of
awakenings during sleep compared with patients of normal
weight30,31. On this basis, we believe that, regardless of
whether an individual has OSAHS or not, obesity is an
extremely important factor regarding the quality of sleep.
In the present study, groups did not differ in terms of the
prevalence of obesity.
In addition, we observed that obesity negatively
influences O 2 saturation levels, with an increased BMI
causing greater desaturation. When correlating NAM with
O2 saturation levels, we observed a decline in saturation
with increasing sleep fragmentation.
In conclusion, elderly hypertensive subjects with OSAHS
presented a greater Big-ET-1 level after the sleep period
regardless of BP, since their BP was controlled and similar
to the SBP of hypertensive elderly subjects without OSAHS.
In patients with OSAHS, a correlation was observed between
Big ET-1 and SBP; Big ET-1 and NAH; and O2 saturation
and SBP. In both groups, a higher BMI was correlated with
greater desaturation and NAM. NO levels did not differ
between the hypertensive patients with or without OSAHS.
It is noteworthy that both groups consisted of hypertensive
patients controlled with antihypertensive medications.
Arq Bras Cardiol. 2013;101(4):344-351
349
Anunciato et al.
Big endothelin-1 and nitric oxide in OSAHS
Original Article
Author contributions
Conception and design of the research: Anunciato IF,
Lima NKC; Acquisition of data: Anunciato IF, Lobo RR,
Verri Jr. WA, Eckeli AL, Évora PRB, Nobre F; Analysis and
interpretation of the data: Anunciato IF, Lobo RR, Eckeli
AL, Lima NKC; Statistical analysis: Coelho EB, Lima NKC;
Obtaining funding: Lima NKC; Writing of the manuscript:
Anunciato IF, Moriguti JC, Ferriolli E, Lima NKC; Critical
revision of the manuscript for intellectual content:
Anunciato IF, Coelho EB, Verri Jr. WA, Évora PRB, Nobre F,
Moriguti JC, Ferriolli E, Lima NKC.;
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was funded by FAEPA.
Study Association
This article is part of the thesis of master submitted by Iara Felício
Anunciato from Faculdade de Medicina de Ribeirão Preto - USP.
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Original Article
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Arq Bras Cardiol. 2013;101(4):344-351
351
Back to the cover
Original Article
Genetic Polymorphism G894T and the Prognosis of Heart Failure
Outpatients
Oziel Marcio Araujo Tardin1, Sabrina Bernardez Pereira1, Monica Wanderley Monçores Velloso1, Henrique Miller
Balieiro2, Bruno Costa1, Thiago Oliveira e Alves1, Camila Giro1, Leandro Pontes Pessoa1, Georgina Severo Ribeiro1,
Evandro Tinoco Mesquita1
Universidade Federal Fluminense1, Niterói, RJ; Escola de Medicina de Valença2, Valença, RJ – Brazil
Abstract
Background: Previous studies have analyzed the role of the genetic polymorphism of endothelial nitric oxide synthase
on heart failure prognosis. However, there are no studies relating the G894T and heart failure in Brazil.
Objective: To evaluate the association between G894T GP and the prognosis of a sample of Brazilian outpatients
with heart failure.
Methods: Cohort study included 145 patients with systolic heart failure, followed for up to 40 months (mean = 22),
at two university hospitals, in the State of Rio de Janeiro. We evaluated the relationship between G894T and the
following outcomes: reverse remodeling, improvement in functional class (NYHA), and mortality and hospitalization
rates. The diameters of the left atrium and ventricle, as well as the ejection fraction of the left ventricle, were evaluated
at baseline and at 6 months to assess reverse remodeling. The improvement in functional class was evaluated after
6 months, and mortality rate and hospitalization were evaluated during follow-up. Race was self-declared. G894T
polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism.
Results: The genotypic frequencies were GG (40%), GT (48.3%) and TT (11.7%). The allele frequency was guanine
(64.1%) and thiamine (35.8%). There were no differences between the genotype or allelic frequencies according to
self‑declared race, either as baseline characteristics. There was no relationship between genotype or allele frequency
and the outcome measures.
Conclusion: No association was observed between the G894T polymorphism (Glu298Asp) and prognosis in this sample
of Brazilian outpatients with systolic heart failure. (Arq Bras Cardiol. 2013;101(4):352-358)
Keywords: Heart Failure; Polymorphism, Genetic; Nitric Oxide; Ethnicity and Health.
Introduction
Heart failure patients’ evolution, prognosis and therapeutic
response are not uniform. The interpersonal variation
in disease behavior has multiple causes, genetic factors
among them1-7. Various genetic polymorphisms have been
implicated; among the most studied is G894T (Glu298Asp),
in which changing the nucleotide guanine (G) by thiamine
(T) at the position 894 of the exon 7 of the gene leads to
the substitution of aspartic acid (asp) for glutamic acid (Glu)
in the position 298 of the enzyme endothelial nitric oxide
synthase (eNOS), responsible for nitric oxide production
(NO) in endocardium and endothelium8-16.
Mailing Address: Oziel Marcio Araujo Tardin •
Rua Coronel Moreira Cesar, 63/501, Icaraí. Postal Code 24230-050,
Niterói, RJ – Brazil
E-mail: [email protected], [email protected]
Manuscript received December 18, 2012; revised manuscript April 10,
2013, accepted April 15, 2013.
DOI: 10.5935/abc.20130167
352
The study GRACE, whose population sample was
composed on European white, evaluated the impact
of Glu298Asp polymorphism of eNOS on heart failure
patients’ survival, and the Asp298 variant was associated
to the worst event-free survival, particularly in patients with
non-ischemic cardiomyopathy17.
In the A-HeFT study, Afro-American patients with systolic
heart failure showed a reduction in mortality and admission
rates in response to the combination isosorbide dinitrate
plus hydralazine (ISDN/HYD), which acted as a NO donor18.
The GRAHF study, a genetic sub study of A-HeFT, showed
that only patients homozygous for Glu298Glu achieved an
improvement in the compound score: admission, mortality
and better quality of life19.
Of note, these studies’ population samples show
strong ethnic predominance, and a genotype distribution
intimately related to skin color or self-declared race.
In a Brazilian study, Velloso et al20 evaluated samples of
heart failure patients and healthy controls and found no
difference in allelic frequency distribution (G/T) according
to self-declared skin color20
Tardin et al.
PG G894T and HF prognosis
Original Article
There are no studies associating G894T (Glu298Asp)
and heart failure in the Brazilian population, allowing us
to think that, maybe, the international studies’ results
may not be applicable directly to Brazil, with its heavily
miscigenated population.
The study was approved by the Ethics Committees of the
Institutions involved, in compliance with the Declaration of
Helsinki. All participants signed an informed consent document.
The present study aimed to evaluate the association of
G894T (Glu298Asp) polymorphism and prognosis in Brazilian
outpatients with systolic heart failure.
The Glu298Asp (G894T) polymorphism, caused by a
G-to-T transversion, located at the exon 7 of the eNOS
gene, was analyzed by polymerase chain reaction (PCR) and
restriction fragment length polymorphism (RFLP). The PCR
reaction was performed in a total blood volume of 25 mL,
using the following: 50 to 100 ng of genomic DNA, after
adjusting for concentration, 15 pmol of each oligonucleotide
sense 5’-AAGGCAGGAGACAGTGGATGG-3’ and antisense
5’-CCCAGTCAATCCCTTTGGTGCTCA-3’, 1 U of Taq DNA
polymerase, Fermentas reaction buffer (KCl 50 mM, MgCl2
1,5 mM, Tris-HCl 10 mM), 200mM of each desoxinucleotide
(dATP, dCTP, dGTP, dTTP). After denaturation at 94°C for
5 minutes, the samples were amplified in a program with
35 1-minute cycles at 94°C (denaturation) 1 minute at
58°C (annealing) and 1 minute at 72°C (elongation) in a
Progene Techne thermocycler. After that, the samples were
submitted to final elongation in a 7-minute cycle at 72°C.
The amplicons were evaluated in 2% agarose gel using a
100 base pair marker as length indicator.
Methods
Study population
This was an observational, multicenter, prospective
cohort study developed in the heart failure clinics of the
Antonio Pedro University Hospital of the Fluminense
Federal University (Universidade Federal Fluminense - UFF)
and the General Hospital of Valença Medical School, both in
Rio de Janeiro state, from December 2005 to March 2009.
The study included 145 outpatients with predominantly
systolic heart failure from the Unified Health System
(Sistema Único de Saúde - SUS). Convenience sample
The inclusion criteria were: age ≥ 18 years, history and
physical examination compatible with heart failure and
echocardiogram with left ventricle ejection fraction (LVEF)
≤ 50% (Simpson). The exclusion criteria were: active
myocarditis, myocardial infarction (MI) < 3 months, cardiac
resynchronization therapy (CRT), aborted sudden death
episode or implantable defibrillator, angioplasty or heart
surgery scheduled for the next 12 months.
Race was self-declared. Patients with past MI, confirmed
by electrocardiography, functional tests compatible with
ischemia or coronary angiography showing an epicardial
vessel with ≥ 50% stenosis were considered to have an
ischemic etiology.
After inclusion, patients had appointments scheduled
with cardiologists every 3 months or less, if the team
judged necessary, and were followed for 12 to 40 months
(mean = 22 months). Heart failure was treated according to
the II Guideline on Diagnosis and Treatment of Heart Failure
of the Brazilian Society of Cardiology21. On admission, blood
was sampled for lab exams (hemoglobin, glucose, creatinine
and sodium) and genetic analysis. Echocardiography was
performed on admission and after 6 months.
The following endpoints were analyzed: death during
follow-up, admission during follow-up, functional
class (NYHA) improvement after 6 months and reverse
remodeling after 6 months. Admission were counted
on subsequent clinical appointments, and deaths were
confirmed by calling relatives and/or patient record review.
Functional class (NYHA) was evaluated on admission and
after 6 months of follow-up. The 6-month echocardiograms
were compared to admission, and the presence of one or
more of the following parameters was considered evidence
of reverse remodeling (echocardiographic improvement):
(1) LVEF increase ≥ 20%; (2) LVEF increase ≥10%; or
(3) ≥ 5% reduction in left atrium (LA) diastolic diameter
and/or left ventricle diastolic diameter (LVDD).
eNOS gene polymorphism molecular analysis
The amplified 248 base pairs fragment was digested with the
restriction enzyme (RFLP) Ban II, which recognizes the G base
at codon 298, generating two fragments (with 163 and 85 base
pairs) in the presence of the amino acid Glu (E). The genotype
pattern defined in 2% agarose gel was: two fragments, with
163 and 85 bp, for the Glu298 homozygous, and one single
248 base-pair fragment identifying the Asp298 homozygous.
The heterozygous subjects were identified by the presence of
248-, 162- and 85-base pairs fragments.
Statistical analysis
The observed data were described in tables as
mean ± standard deviation (numerical variables) and
frequency and percent values (categorical variables).
For analyzing the echocardiographic variables, the Student
t-test (paired, for functional class - categorical data) and the
McNemar test were used.
The relationship among clinical, laboratorial and
echocardiographic variables and the genotype (GG, GT or TT)
was accessed by the Kruskal-Wallis univariate variance analysis
(non-parametric ANOVA).
The relationship among clinical, laboratorial and
echocardiographic variables, as well as survival and
event-free (admission) survival rates was accessed by the
following methods:
Chi-square or Fisher’s exact test was used for comparing
with categorical data;
Student t -test for independent samples or Mann-Whitney
test was used for comparing with numerical data; The Bartlet
test was used for analyzing subgroup variance homogeneity;
Logistic regression analysis was used for identifying
variables that could predict (or explain) the outcomes or
therapeutic responses.
Arq Bras Cardiol. 2013;101(4):352-358
353
Tardin et al.
PG G894T and HF prognosis
Original Article
Non-parametric methods were used for non-normal
variables due to data dispersion and rejection by the
Kolmogorov-Smirnov test. The criteria for determining
significance was 5%. The statistical analysis was performed by
the software SAS 6.11 (SAS Institute Inc., Cary, NC).
Results
General sample profile
T h e s t u d y p o p u l a t i o n w a s i n H a r d y -We i n b e r g
equilibrium (chi-square = 0.387; p = 0.53). The baseline
characteristics are summarized in Table 1.
Clinical and genotypic characteristics
There were no differences in genotypic distribution or
allelic frequency according to self-declared race. Also, no
differences were found regarding clinical, laboratorial or
echocardiographic characteristics on admission regarding
genotype (Table 2). Ischemic etiology tended to be more
frequent in TT patients.
Age (years)
58.8 ± 13.0
Left atrium (mm)
46.4 ± 7.8
LVDD (mm)
67.9 ± 9
LVEF (%)
35.5 ± 9.2
Body mass index(kg/m2)
25.8 ± 5.1
Hemoglobin (g/dL)
13.5 ± 1.8
Creatinine (mg/dL)
1.24 ± 0.73
Sodium (mEq/L)
139.2 ± 3.6
Male (%)
67.8
Self-declared race (%)
Non afro-Brazilian
50.7
Afro-Brazilian
49.3
Diabetes (%)
34.9
Atrial fibrillation (%)
15.8
Ischemic etiology (%)
46.6
Arterial hypertension (%)
74.0
Genotype and therapeutics
NYHA (%)
There were no differences regarding standard heart failure
therapy among the genotype subgroups. However, TT patients
were more frequently taking aspiring on admission (Table 3).
I
33.6
II
41.8
III
23.2
IV
1.4
Genotype and reverse remodeling
There was no relation between genotype and
echocardiographic features observed throughout the study.
Analyzing the variables simultaneously and using logistic
regression, we observed that larger LA (p = 0.0005) and
smaller LVDD (p = 0.009) on admission were associated to
LA diameter reduction ≥ 5%. Atrial fibrillation (p = 0.0002)
and smaller LA (p = 0.004) on admission were associated
to LA diameter reduction ≥ 5% after 6 months.
Functional class (NYHA) II (p = 0.006) and III/IV (p = 0.030),
as well as smaller LVEF (p = 0.023) on admission were associated
to a ≥ 10% LVEF increase after 6 months. Smaller LVEF
(p = 0.0001) and no hyponatremia (p = 0.02) on admission were
associated to a ≥ 20% LVEF increase after 6 months.
Genotype and HF improvement (NYHA)
HF improvement (NYHA) after 6 months was not related
to genotype or allelic frequency.
Genotype (%)
GG
40.0
GT
48.3
TT
11.7
Allele frequency (%)
G
T
64.1
35.8
LVDD: left ventricle diastolic diameter; LVEF: left ventricle ejection fraction; G:
guanine; T: thiamine.
After logistic regression, in only one occasion a higher
LVDD was independently related to death (p = 0.004), while
larger LA (p=0.02) and functional class III/IV (p = 0.004) on
admission were related to hospitalization.
Genotype impact on survival or admission
Mean LVDD was 75.6 ± 14.7 mm in the group who
died versus 67.1 ± 8.8 mm in the patients that survived
on follow-up (p = 0.017). Among the patients who were
hospitalized at least once, mean LVDD was 48.6 ± 8.6 mm
versus 45.6 ± 7.1 mm in the patients not admitted during
follow-up (p = 0.017).
Fifteen patients (10.3%) died during follow-up. Thirty-four
patients (23.4%) were admitted once; nine patients (6.2%)
were admitted twice and three patients (2.1%) were admitted
three times or more.
No statistically significant difference was observed
on survival or hospitalization rates regarding genotype
or allelic frequency (Kaplan-Meier curve, long-rank test)
(Graph 1).
HF improvement after 6 months was only associated to
creatinine levels > 1.5 mg/dL and functional class III/IV on
admission (p = 0.25 and 0.0001, respectively).
354
Table 1 - Baseline characteristics
Arq Bras Cardiol. 2013;101(4):352-358
Tardin et al.
PG G894T and HF prognosis
Original Article
Table 2 - Baseline characteristics versus genotype
GG
GT
TT
p value
56.0 ± 12.3
59.9 ± 13.7
63.4 ± 11.7
0.073
58.6
74.3
76.5
NS
Non afro-Brazilian
43.1
54.3
64.7
Afro-Brazilian
56.9
45.7
35.3
Ischemic etiology (%)
41.4
44.3
70.6
0.095
Diabetes (%)
39.7
28.6
41.2
NS
Atrial fibrillation (%)
13.8
15.7
23.5
NS
Arterial hypertension
75.9
70.0
82.4
NS
I
37.9
35.7
11.8
II
37.9
40.0
58.8
III/IV
24.2
24.3
29.4
Anemia (%)
30.4
34.8
29.4
NS
Creatinine > 1.5
14.0
21.4
5.9
NS
Age (years)
Male (%)
Self-declared race (%)
NS
NYHA (%)
Sodium < 135 (%)
NS
10.5
5.7
0.0
NS
Left atrium (mm ± SD)
47.3 ± 8.5
45.5 ± 7.2
47.5 ± 7.6
NS
LVDD (mm ± SD)
69.1 ± 9.7
67.6 ± 9.9
64.8 ± 9.2
NS
LVEF (% ± SD)
33.8 ± 9.4
36.3 ± 9.0
38.5 ± 8.7
NS
26.5 ± 5.4
25.6 ± 5.1
25.0 ± 3.7
NS
Body mass index (kg/m ± SD)
2
NS: non-significant; SD: standard deviation; LVDD: left ventricle diastolic diameter; LVEF: left ventricle ejection fraction.
Table 3 - Genotype and therapeutics
Admission
After 6 months
GG
GT
TT
p value
GG
GT
TT
p value
Angiotensin conversion enzyme inhibitor (%)
80.4
76.2
93.3
NS
76.5
66.7
73.3
NS
Angiotensin receptor blocker (%)
17.7
12.7
0.0
NS
23.5
27.0
20.0
NS
Betablocker (%)
76.5
65.1
73.3
NS
92.2
87.3
93.3
NS
Spironolactone (%)
66.7
50.8
60.0
NS
70.6
68.3
73.3
NS
Furosemide (%)
64.7
65.1
60.0
NS
62.8
63.5
66.7
NS
Hidralazine (%)
7.8
7.9
6.7
NS
13.7
11.1
13.3
NS
Nitrate (%)
35.3
25.4
53.3
NS
33.3
36.5
46.7
NS
Digoxin (%)
64.7
47.6
53.3
NS
54.9
52.4
40.0
NS
Amiodarone (%)
3.9
4.8
0.0
NS
3.9
4.8
0.0
NS
Thiazides (%)
19.6
25.4
40.0
NS
11.8
15.9
20.0
NS
Calcium channel blocker (%)
9.8
15.9
26.7
NS
9.8
15.9
26.7
NS
Aspirin (%)
37.3
54.0
73.3
0.031
47.1
61.9
73.3
NS
Statin (%)
41.2
38.1
66.7
NS
52.9
54.0
80.0
NS
Warfarin (%)
19.6
14.3
13.3
NS
17.7
11.1
20.0
NS
NS: non-significant.
Arq Bras Cardiol. 2013;101(4):352-358
355
Tardin et al.
PG G894T and HF prognosis
Original Article
A. Survival versus genotype
B. Survival versus allele frequency
C. Event-free survival versus genotype
D Event-free survival versus allele frequency
Graph 1 - Survival and event-free survival versus genotype and allele frequency.
Discussion
The present study population sample showed major
differences regarding previous studies involving eNOS
genetic polymorphism: the proportion of patients who
declared themselves white (50.7%) and Afro-Brazilians
(49.7%) was virtually the same, a fact that was not found
in previous studies such as GRACE17, with a 90.4% whites
and A-HeFT18 with 100% Afro-Americans. Still, different
to what was shown in previous studies, on which the G
allele was more prevalent among blacks and the T allele
was more prevalent among whites 17,19,22, no association
was observed between skin color or self-declared race and
genotypic distribution or allelic frequency. Besides, the
genotype distribution was 40% for Glu298Glu, 48.7% for
Glu298Asp e 11.7% for Asp298Asp, while in the A-HeFT
study population it was 9% for Glu298Glu, 20% for
356
Arq Bras Cardiol. 2013;101(4):352-358
Glu298Asp and 1% for Asp298Asp19 and, in GRACE, 67%
for Glu298Glu, 31% for Glu298Asp and 2% for Asp298Asp,
among the black patients, and 41% for Glu298Glu, 45%
for Glu298Asp and 14% for Asp298Asp, among whites17,18.
The great differences found on distribution according
to self-declared race, genotype distribution and frequency
between the present and previous studies’ samples
evaluating the G894T (Glu298Asp) polymorphism allow
us to think that the international studies’ results may not
be directly applicable to Brazilian heart failure patients.
After the results of the A-HeFT study, the FDA approved
BiDil® (ISDN/HYD) for black patients with systolic heart failure,
the first time a drug was approved for use in a specific race.
Heart failure has a huge social and economic impact in
Brazil23-25. Hydralazine and nitrate are low-cost drugs, and
their addition to standard therapy may potentially improve
Tardin et al.
PG G894T and HF prognosis
Original Article
the prognosis of systolic heart failure patients harboring the
Glu298Glu variant19. Thus, the proper quantification of
Glu298Asp genetic variability in the Brazilian population
and the potential impact of the ISDN/HYD association in
Brazilian heart failure patient is important, regardless of
the self-declared race.
Other significant finding is the higher tendency to ischemic
etiology (p = 0.09) found in TT patients, which also showed
a higher acetylsalicylic acid use rate (p = 0.03), matching the
findings in other studies17,26,27.
This study has some inherent limitations. The first one
is the sample, which is probably small for a genetic study
(n = 145). Besides, there was a low rate of hydralazine/
nitrate use, and a therapy based on NO donors (such as
hydralazine and nitrate) could exert some influence on
the relationship among the studied polymorphism and the
analyzed outcomes. Besides, currently, the genetic studies
are not based on the analysis of a single gene, but a set or
even thousands of related haplotypes simultaneously, such
as the Genome-Wide Association Studies (GWAS), which
uses data from HapMap28-30.
Conclusion
This study found no association between genotype or
allelic frequency of the G894T (Glu298Asp) eNOS genetic
polymorphism and the death, hospitalization, functional class
(NYHA) improvement and reverse remodeling in Brazilian
outpatients with systolic heart failure.
Author contributions
Conception and design of the research, Acquisition of
data and Analysis and interpretation of the data: Tardin
OMA, Pereira SB, Velloso MWM, Balieiro HM, Costa B, Alves
TO, Giro C, Pessoa LP, Ribeiro GS, Mesquita ET; Statistical
analysis and Critical revision of the manuscript for intellectual
content: Tardin OMA, Pereira SB, Mesquita ET; Writing of the
manuscript: Tardin OMA, Mesquita ET.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was funded by FAPERJ.
Study Association
This article is part of the thesis of master submitted by Oziel
Marcio Araujo Tardin from Universidade Federal Fluminense.
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23. Tavares LR, Victer H, Linhares JM, de Barros CM, Oliveira MV, Pacheco LC,
et al. Epidemiologia da Insuficiência Cardíaca Descompensada em Niterói
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26. Shimasaki Y, Yasue H, Yoshimura M, Nakayama M, Kugiyama K, Ogawa
H, et al. Association of missense Glu298Asp variant of the endothelial
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27. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, et al. A
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28. Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, et al.
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Back to the cover
Original Article
Features of the Onset of Takayasu’s Arteritis According to Gender
Andrea Rocha de Saboia Mont’Alverne, Luiz Eduardo de Paula, Samuel Katsuyuki Shinjo
Divisão de Reumatologia - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo – Brazil
Abstract
Background: Although there are various published epidemiological studies regarding Takayasu’s arteritis (TA), none have
analyzed the influence of gender on the clinical and laboratory manifestations or vascular alterations at disease onset.
Objectives: To analyze the influence of gender on clinical and laboratory manifestations and variations in vascular
imaging at TA onset.
Methods: A retrospective, unicentric cohort study that evaluated 55 consecutive TA patients between 1982 and 2012.
All available clinical data and laboratory test results related to the onset of the disease were analyzed. We included only
patients aged 12-35 years at diagnosis to exclude age-related factors.
Results: We analyzed 17 men and 38 women, mostly Caucasian, with a comparable mean age between genders. There was no
gender difference regarding the clinical or laboratory characteristics, comorbidities, or smoking habit, except for abdominal
pain, which was more common in men. Regarding vascular lesions, the presence of ascending aortic aneurysms was significantly
more frequent in males. Male gender represented an independent risk factor for the occurrence of abdominal pain and ascending
aortic aneurysms in TA patients.
Conclusion: Abdominal pain and ascending aortic aneurysms occurred more frequently in men with TA, suggesting a
more severe disease profile in males. (Arq Bras Cardiol. 2013;101(4):359-363)
Keywords: Takayasu Arteritis / epidemiology; Male; Female; Cohort Studies; Aortic Aneurysm, Abdominal; Abdominal Pain.
Introduction
Takayasu’s arteritis (TA) is a type of primary systemic
vasculitis that affects medium and large arteries, including the
aorta and its main branches, as well as the pulmonary and
coronary arteries1. The pathophysiology of TA is characterized
by vessel wall inflammation, leading to thickening, stenosis,
dilatation, and/or aneurysm formation of the affected vessels2.
The signs and symptoms that reflect the context of the systemic
inflammation or ischemia of an organ or limb include the
presence of claudication, angiodynia, peripheral pulselessness,
murmurs, severe systemic arterial hypertension, myocardium
infarction, and ischemic stroke, among others2,3.
In general, systemic autoimmune diseases affect more
women than men, by a ratio of 2–10:1. Systemic lupus
erythematosus and Sjogren's syndrome, for example, have
ratios of 7–10:1, whereas rheumatoid arthritis and systemic
sclerosis have ratios of 2–3:14, while TA also tends to affect
women more often, with a ratio of 1.2–29:13,5.
Mailing Address: Samuel Katsuyuki Shinjo •
Division of Rheumatology, Faculdade de Medicina da Universidade de São
Paulo - Av. Dr. Arnaldo, 455, 3º andar, sala 3150. Postal Code 01246-903,
São Paulo, Brazil
E-mail: [email protected]
Manuscript received December 10, 2012; revised December 22, 2012;
accepted March 28, 2013.
DOI: 10.5935/abc.20130180
359
Although there have been various epidemiological
studies regarding TA, none have reported the influence of
gender on the clinical and laboratory manifestations and
the vascular alterations at the onset of the TA. Although
Sharma and Jain6 studied a possible role of sex in the
distribution of the vascular lesions in TA and found a
tendency for greater involvement of the abdominal aorta in
men and the aortic arch and its branches in women, they
did not specify whether their findings were cumulative or
related to disease onset.
Thus, in the present study, we evaluated the initial clinical
manifestations and the vascular alterations at the onset of
TA according to gender.
Methods
We evaluated 55 consecutive TA patients (17 men and
38 women) treated at the vasculitis unit of our tertiary
facility between 1982 and 2012. We included only patients
who were aged between 12 and 35 years at TA diagnosis
and who met at least three of the six American College
of Rheumatology classification criteria (1990)7. The study
protocol was approved by our local ethics committee.
Demographic data, clinical manifestations, and vascular
images were obtained through a systematic review of the
patients’ medical records. The follow parameters were
analyzed: (A) clinical manifestations: constitutional symptoms
(weight loss, fever, fatigue), headache, dizziness, visual
Mont’Alverne et al.
Takayasu’s arteritis and gender
Original Article
impairment (blindness), seizures, carotidynia, claudication,
abdominal pain, chest pain, dyspnea, articular manifestations
(arthritis/arthralgia), and erythema nodosum; (B) laboratory
findings: C-reactive protein (CRP) (reference value: < 5 mg/L)
and erythrocyte sedimentation rate (ESR) (reference value:
< 19 mm/1st hour); (C) comorbidities: myocardium infarction,
ischemic stroke, systemic arterial hypertension, heart failure,
type 2 diabetes mellitus, and dyslipidemia; (D) habit: smoking;
and (E) echocardiography: aortic insufficiency.
The results were expressed as the means ± standard
deviation (SD) or as percentages. We used the Student’s t-test
to analyze the parametric data and the Mann-Whitney U-test
for the nonparametric data. The 95% confidence intervals
(95% CI) of the percentages were calculated by binomial
distribution. All calculations were performed using STATA ver.
7.0 statistical software (Stata Corp., College Station, TX, USA).
A p-value < 0.05 was considered statistically significant.
All vascular images were obtained via angiography
or computed tomography angiography, in which we
evaluated the following parameters: stenosis/occlusion,
aneurysm/vascular ectasia, and the anatomical location
of these lesions.
Results
We analyzed records of 17 men and 38 women with
TA, who were mostly Caucasian and had a comparable
mean age between genders (Table 1). The clinical and
Table 1 - Demographic, clinical, and laboratory characteristics of Takayasu’s arteritis according to gender
Features
Age at disease onset ± SD (years)
Ethnicity: white (%)
Male
(n = 17)
Female
(n = 38)
p
23.5 ± 7.6
25.3 ± 5.5
0.371
9 (52.9)
28 (73.7)
0.130
Clinical onset manifestations
Weight loss (%)
8 (47.1)
9 (23.7)
0.083
Fever (%)
7 (41.2)
10 (26.3)
0.270
Fatigue (%)
2 (11.8)
6 (15.8)
0.696
Headache (%)
1 (5.9)
6 (15.8)
0.308
Dizziness (%)
0
2 (5.3)
0.335
Visual disturbances (%)
1 (5.9)
2 (5.3)
0.926
Amaurosis (%)
1 (5.9)
0
0.131
Convulsions (%)
1 (5.9)
0
0.131
Carotidynia (%)
3 (17.6)
8 (21.1)
0.770
Upper limb claudication (%)
5 (29.4)
16 (42.1)
0.371
Lower limb claudication (%)
2 (11.8)
12 (31.6)
0.119
Abdominal pain (%)
6 (35.3)
2 (5.3)
0.004
0
6 (15.8)
0.083
Dyspnea (%)
1 (5.9)
6 (15.8)
0.308
Articular manifestations (%)
1 (5.9)
4 (10.5)
0.165
Chest pain (%)
Erythema (%)
1 (5.9)
4 (10.5)
0.580
Elevated ESR and/or CRP (%)
6 (35.3)
23 (60.5)
0.613
Aortic insufficiency (%)
3 (17.6)
6 (15.8)
0.863
Comorbidities
Ischemic stroke (%)
1 (5.9)
10 (26.3)
0.143
10 (58.8)
20 (52.6)
0.370
Cardiac insufficiency (%)
0
1 (2.6)
0.500
Myocardium infarction (%)
0
1 (2.6)
0.500
Diabetes mellitus (%)
0
2 (5.3)
0.335
Dyslipidemia (%)
2 (11.8)
12 (31.6)
0.119
Smokers (%)
2 (11.8)
4 (10.5)
0.892
Systemic arterial hypertension (%)
CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; SD: standard deviation.
Arq Bras Cardiol. 2013;101(4):359-363
360
Mont’Alverne et al.
Takayasu’s arteritis and gender
Original Article
laboratory characteristics and comorbidities of patients at
disease onset are shown in Table 1. There was no gender
difference regarding the distribution of signs and symptoms,
except for abdominal pain (35.3% vs. 5.3%, p = 0.004,
in men and women, respectively). The presence of aortic
insufficiency, elevation of ESR and CRP, comorbidities, and
habit (smoking) were also similar between genders.
Regarding vascular lesions found in the first imaging for
each patient, we observed that there was no gender difference
in the frequency or the location of the stenoses/occlusions,
which were more common in the carotid and subclavian
arteries in women than men (Table 2). However, the presence
of ascending aortic aneurysms was significantly more frequent
in men (35.3 vs. 10.5%, p = 0.028), although other aneurysm
locations did not differ between genders.
Multivariate analysis showed that male gender was a risk
factor for the occurrence of abdominal pain (OR, 18.75;
95% CI, 2.89–121.54) and aortic aneurysm (OR, 9.51;
95% CI, 1.94–46.70) (Table 3).
Discussion
To our knowledge, the present study is the first to analyze
the presentation of TA in terms of clinical manifestations and
vascular imaging alterations according to gender. Compared
to women, men had a higher prevalence of abdominal pain
and ascending aortic aneurysm at diagnosis of TA.
Despite the existence of various epidemiological series
regarding TA patients 3,8-19, none have compared disease
presentation between men and women. In this study, all
of the parameters refer clearly to the onset of symptoms
before any drug or surgical treatment is initiated.
Furthermore, we evaluated only patients aged between
12 and 35 years to exclude clinical manifestations,
comorbidities, or vascular changes that could be related
to advanced age rather than to TA alone.
Gender is likely a determinant in the prognosis
of several rheumatic diseases. For example, systemic
lupus erythematosus tends to have a worse prognosis
Table 2 - Angiographic characteristics of Takayasu’s arteritis according to gender
Vessels
Stenosis / Occlusion
Aneurysm /Ectasia
Male
Female
p
Male
Female
p
Left coronary (%)
0
1 (2.6)
1.000
0
0
1.000
Right coronary (%)
0
1 (2.6)
1.000
0
0
1.000
Left vertebral (%)
0
6 (15.8)
0.131
1 (5.9)
0
0.131
Right vertebral (%)
0
6 (15.8)
0.131
1 (5.9)
0
0.131
Left carotid (%)
7 (41.2)
20 (52.6)
0.487
0
0
1.000
Right carotid (%)
6 (35.3)
20 (52.6)
0.200
0
0
1.000
Left subclavian (%)
6 (35.3)
21 (55.3)
0.926
1 (5.9)
2 (5.3)
0.926
Right subclavian (%)
4 (23.5)
14 (36.8)
0.552
1 (5.9)
1 (2.6)
0.552
Brachiocephalic trunk (%)
1 (5.9)
5 (13.2)
0.391
2 (11.8)
2 (5.3)
0.391
0
1 (2.6)
0.500
0
1 (2.6)
0.500
Pulmonary trunk (%)
Aortic
361
Ascendant (%)
1 (5.9)
2 (5.3)
0.926
6 (35.3)
4 (10.5)
0.028
Cross (%)
1 (5.9)
4 (10.5)
0.168
2 (11.8)
1 (2.6)
0.168
Thoracic (%)
1 (5.9)
7 (18.4)
0.108
4 (23.5)
3 (7.9)
0.108
Abdominal (%)
2 (11.8)
7 (18.4)
0.552
1 (5.9)
1 (2.6)
0.552
Infrarenal (%)
2 (11.8)
8 (21.1)
0.131
1 (5.9)
0
0.131
Left renal (%)
7 (41.2)
5 (13.2)
0.500
0
0
0.500
Right renal (%)
6 (35.3)
5 (13.2)
0.131
1 (5.9)
1 (2.6)
0.131
Upper mesenteric (%)
3 (17.6)
7 (18.4)
0.945
0
0
1.000
Lower mesenteric (%)
2 (11.8)
3 (7.9)
0.645
0
0
1.000
Celiac trunk (%)
2 (11.8)
4 (10.5)
0.131
1 (5.9)
0
0.131
Left iliac (%)
1 (5.9)
6 (15.8)
0.308
0
0
1.000
Right iliac (%)
1 (5.9)
5 (13.2)
0.424
0
0
0.500
Arq Bras Cardiol. 2013;101(4):359-363
Mont’Alverne et al.
Takayasu’s arteritis and gender
Original Article
Table 3 - Multivariate analysis for gender
Variate
OR
95% CI
Age at disease onset
0.96
0.86–1.07
Abdominal pain
18.75
2.89–121.54
Ascendant aortic aneurysm
9.51
1.94–46.70
in men, although this view remains controversial 20-23.
In rheumatoid arthritis, female gender has been associated
with higher scores of disease activity24 and is an established
predictor of radiographic progression25. Furthermore, the
inflammatory response appears to be more severe in women
than in men as well as the presence of giant cell arteritis
and polymyalgia rheumatica 26. However, there are no
studies that have evaluated sex as a determining factor in TA
prognosis. Our results showed a strong association between
the presence of aortic aneurysm and male gender, thereby
correlating this gender to a poor prognostic factor.
true at the time of diagnosis, we do not know if they
accurately reflected manifestations at disease onset.
Other factors classically associated with poor prognosis
in TA include the following: retinopathy, hypertension,
severe aortic regurgitation, and the presence of aortic or
arterial aneurysm, as mentioned previously27. Subsequently,
the presence of severe functional disability and cardiac
involvement were reported as predictors of either death
or major events on follow-up28. Sharma and Jain6 reported
a trend toward a higher frequency of hypertension in men
with TA compared with women, but this was not observed
in the present study. Chugh et al29 studied renovascular
hypertension in Indians with AT and also found no
difference between genders. Aortic regurgitation was
also similar in both sexes in our series, in contrast to the
findings of Kobayashi and Numano30, who reported a higher
prevalence of aortic regurgitation in women.
Author contributions
Our study was limited by its retrospective nature and
complicated by typical problems of this type of cohort.
Furthermore, the collected data were dependent on the
medical records and even though all of the variables were
Conclusion
Abdominal pain and ascending aortic aneurysms occurred
more frequently in men with TA and the male gender was an
independent risk factor for such findings. Nonetheless, further
studies will be needed to confirm male gender as a predictor
of poor prognosis in TA.
Conception and design of the research and Statistical
analysis: Shinjo SK; Acquisition of data, Analysis and
interpretation of the data, Writing of the manuscript and
Critical revision of the manuscript for intellectual content:
MontAlverne ARS, Paula LE, Shinjo SK.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation
program.
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Back to the cover
Review Article
Renal Sympathetic Denervation for Resistant Hypertension
Treatment - Current Perspectives
Andréa Araujo Brandão, Erika Maria Gonçalves Campana, Maria Eliane Campos Magalhães, Esmeralci Ferreira
Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ - Brazil
Abstract
The authors review the concept of resistant hypertension
and the involvement of the sympathetic nervous system in
hypertension as a rational basis for the technique of renal
sympathetic denervation (RSD) performed percutaneously.
This revision is the result of an active search for scientific
articles with the term “renal denervation” in the Medline and
PubMed databases. The techniques and devices used in the
procedure are presented, as well as clinical outcomes at six,
12 and 24 months after the intervention with the Symplicity
catheter. Significant decreases and progressively higher
reductions of systolic and diastolic blood pressure were
observed after RSD. The complication rate was minimal.
New devices for RSD and its ongoing clinical studies
are cited. In conclusion, the RSD presents itself as an
effective and safe approach to resistant hypertension.
Results from ongoing studies and longer follow-up of these
patients are expected to confirm the initial results and put
into perspective the expansion of the procedure use in
hypertension approach.
Introduction
Blood pressure (BP) is directly related to the risk of death
and impairment of cardiovascular and cerebrovascular
systems, among others. According to IV Brazilian Guidelines
on Arterial Hypertension1, in Brazil this disease has high
prevalence, over 30%, and low control rates, below 20%1.
Despite the recommendation to carry out a strict and
effective control of tensional levels, frequently these goals
are not satisfactorily achieved, resulting in greater risk of
developing complications and increasing mortality. Many
reasons might be involved in obtaining these non-satisfactory
results, in a way that only a minority of hypertensive individuals
present a proper control of their BP. For these reasons, arterial
Keywords
Hypertension/therapy; Blood Pressure/innervation;
Sympathetic Nervous System; Renal Artery/innervation.
Mail Address: Andréa Araujo Brandão •
Rua General Tasso Fragoso, 24/503, Lagoa. CEP 22470-170, Rio de Janeiro,
RJ - Brazil
E-mail: [email protected]; [email protected]
Manuscript received March 15, 2013; revised manuscript July 2, 2013;
accepted July 3, 2013.
DOI: 10.5935/abc.20130187
364
hypertension (AH) that is difficult to control is a relevant public
health issue1. Included in this group are individuals with
resistant arterial hypertension (RAH). Different studies show
the RAH prevalence ranges between 3-30%1,2.
In this scenario, percutaneous approach for bilateral
renal sympathetic denervation (RSD) using radiofrequency
ablation procedure 3 has shown promise among new
available therapeutic strategies and is based on the
knowledge that, among the many physiopathological
mechanisms involved in refractoriness to AH control, the
excessive stimulation of renal sympathetic nervous system
is distinctive3.
Stimulated by new treatment for RAH, this study aims
at reviewing RAH concept, involvement of sympathetic
nervous system (SNS) in BP increase, and clinical results
with RSD.
Resistant arterial hypertension: definition and associated
conditions
Resistant arterial hypertension (RAH) diagnosis is confirmed
when there is maintenance of increased BP levels (above
adequate BP goals): ≥ 140/90 mmHg for hypertensive
individuals in general and > 130/80 mmHg for high risk
patients, such as diabetics), despite the use of three or more
antihypertensive drugs of different classes, including a diuretic
at optimal doses2.
Importantly, the diagnosis of true RAH requires the
exclusion of secondary causes of AH, in addition to any
other associated condition that may interfere in the proper
BP control, characterizing pseudo-resistance1,2.
Among the main conditions associated to RAH and
subject to specific approach are the inappropriate choice of
antihypertensive drugs and/or use of insufficient dosage, failure
to measure BP, adherence failure to prescribed medication
and/or changes in lifestyle, white-coat effect, AH resulted
from a non-identified and/or non-treated secondary cause,
and associated conditions that may complicate the BP control,
such as obesity, sleep apnea and the use of concomitant
medications that increase the BP1,2.
White-coat effect is a particularly important condition
and it must be removed through ambulatory blood pressure
monitoring (ABPM) before confirming the RAH diagnosis1,2.
More recently, it has been highlighted the association
between sleep disorders, including sleep obstructing apnea
(SOA), non-controlled AH and cardiovascular complications
in adults1. The prevalence of SOA in adult patients with RAH
has been estimated at 84%4.
Brandão et al
Renal sympathetic denervation and arterial hypertension
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The role of sympathetic nervous system in context of AH
Stimulation of the sympathetic nervous system (SNS)
increases BP in normotensive and hypertensive due to the
involvement of baroreceptors and chemoreceptors, through
peripheral and central mechanisms that have an effect on the
heart, kidneys and peripheral vasculature, leading to a cardiac
output, water retention, and increased peripheral vascular
resistance, which has a major role in AH physiopathology5,6.
SNS is involved in BP acute variations, in situations like
exercising and postural variation. However, the mechanisms
responsible for the presence of sympathetic hyperactivity
in chronic AH and its role in AH maintenance remain
unknown5-7. It is known that the increased sympathetic activity
and the consequent release of catecholamine by sympathetic
nerves, in addition to increasing vascular tone in resistance
vessels, in early stages of AH, could also be stimulating trophic
mechanisms and vascular hypertrophy in the long-term. It is
possible that trophic alterations on vessel walls are maintaining
BP increase in the chronic stage of AH5-7.
Noradrenaline serum levels are higher in hypertensive
individuals when compared to normotensive ones, primarily
in young people, in which sympathetic hyperactivity seems to
have a central role in the development of AH5,6.
Reflex mechanisms of the control of an autonomic activity
are suppressed in the context of AH. It is probable that the
minor baroreflex sensitivity observed in hypertensive patients
is the primary determinant of the BP variability observed and,
indirectly, of the injuries on associated target organs5,6.
SNS activity is related to increased cardiovascular morbidity
and mortality in the early morning hours. In this period, there
is an increase in alpha-sympathetic activity, with high BP, of the
heart rate and cardiac output present in many hypertensive
patients in this period of the day5-7.
Exposure to stress in known to increase the sympathetic
activity. This situation could be induced in laboratory animals,
developing AH by exposure to stress. In young individuals with
genetic predisposition to develop AH, it was observed higher
vasoconstrictor response to mental stress or physical exercise
tests and higher chance to develop AH5-7.
Plenty of evidence has pointed to the role of sympathetic
hyperactivity in the development and progression of
cardiovascular and metabolic complications related to
increased BP, such as left ventricular hypertrophy, vascular
hypertrophy, endothelial dysfunction, heart arrhythmia, and
insulin resistance5-7.
Renal sympathetic nervous system
The abundant adrenergic innervation in kidneys and renal
SNS appear to modulate the renin release via beta-adrenergic
receptors and control renal hemodynamics via alpha-adrenergic
receptors. Thus, the increased renal SNS activity could
contribute to AH physiopathology through many mechanisms:
increased tubular reabsorption of water and sodium, increased
secretion of renin and production of angiotensin II, increased
renal vascular resistance, and reduced glomerular filtration. In
fact, the increased renal SNS activity has been demonstrated
in several models of experimental AH5-7.
Sympathetic efferent innervation of the kidney is carried
out through a dense network of postganglionic neurons that
innervate the kidneys; axons of these neurons exit chest and
lumbar sympathetic trunk and reach the pre-paravertebral
sympathetic ganglia. They run throughout the artery and
renal hilum, subdividing itself and penetrating the cortex and
juxtaglomerular area. Stimulating the renal sympathetic nerve
increases the production and release of noradrenaline, while
interrupting the sympathetic nervous stimulation results in
reducing its production and release. When renal sympathetic
nerves are stimulated, beta-1 receptors increase renin
secretion and alpha-1 receptors increase renal reabsorption of
sodium and fluids, promote renal vasoconstriction and reduce
renal blood flow3,5-7.
Triggering afferent renal sympathetic nerves results in signals
that reach the cardiovascular and renal regulation centers
in the central nervous system. Thus, afferent sympathetic
fibers appear to strongly contribute in the regulation of the
systemic vascular resistance and BP control3,5-7 and, therefore,
antihypertensive treatment must consider the effective
inhibition of sympathetic activity5.
Thus, mechanisms through which RSD reduces BP are
fascinating, although not yet completely understood. Probably
there is a reduction of efferent sympathetic nervous fibers and
an additional reduction of afferent sensory fibers. Evidence
suggests the possibility that sensory afferent sympathetic
nervous fibers also participate in AH genesis and its
denervation has therapeutic effects3,5-7.
Renal sympathetic denervation
Interventional methods more recently implemented, such
as baroreflex stimulation or renal sympathetic denervation3,
have been pointed out as new strategies to treat RAH3,8.
Technique and devices
Invasive procedures for the treatment of AH had already
been tried before. Lumbar sympathectomy performed six
decades ago9 in 1,266 hypertensive patients with malign
AH resulted in relevant and effective decrease of BP, but
the increased incidence of complications, such as postural
hypotension, syncope and impotence, limited the use of this
technique in clinical practice. The development of effective
antihypertensive medications also contributed to stop using
this technique.
Recently, efforts have been directed to conduct a bilateral
approach of renal nerves, initially through a percutaneous
interventional technique using a catheter embedded to a
radiofrequency device. Radiofrequency pulses are fired on
the arterial wall in several points, from the distal part to the
proximal part of both arteries, in spiral. The procedure can be
conducted in renal arteries with ≥ 4 mm diameter and at least
20 mm length, before any bifurcation of the main branches3,10,11.
Pre-clinical studies demonstrated that this technique is
safe, efficient and minimally invasive, associated with little
incidence of side effects and short recovery time3,10. In pigs,
the radiofrequency application causes acute transmural lesion
with coagulation, loss of endothelial surface and thrombus
Arq Bras Cardiol. 2013;101(4):364-371
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Brandão et al
Renal sympathetic denervation and arterial hypertension
Review Article
formation, but without impairment of the renal perfusion.
In 10 days, it was observed a reendothelization of arterial
luminal surface12. Histopathological evaluation of pigs, six
months after the procedure, primarily revealed renal nerves
fibrosis. Findings for renal artery have shown 10-25% fibrosis
of medial and adventitial layer with mild ruptures of the
external elastic lamina, without changes on smooth muscular
layer, without thrombosis or arterial stenosis. No changes on
kidneys or bladder were found13.
To date, clinical results are very positive and encouraging.
Systematic review, including 19 studies and 683 individuals,
concluded that RSD promoted decreases of systolic BP (SBP)
which varied between 18-36 mmHg and diastolic BP (DBP)
ranging between 9-15 mmHg. In five studies, it was observed a
BP-lowering effect sustained in 12 months of follow-up. There
was no worsening of renal function and there were very few
side effects related to the procedure, such as pseudo-aneurysm
of renal artery, hypotension and bradicardia14.
Several devices have been developed to conduct RSD8.
What presents clinical results with larger number of patients
and longer follow-up period is the Symplicity (Medtronic
Inc., Minneapolis, Minnesota) catheter system, which fires
radiofrequency pulses. Radiofrequency RSD is also possible
with other devices, in ongoing development, some have
already been tried in human beings and approved for use
in Europe, such as the catheters EnligHTN (St. Jude Medical
Inc., St. Paul, Minnesota), Vessix V2 (Vessix Vascular Inc.,
Laguna Hills, California), and One Shot (Maya Medical
Inc.,Campbell, California) catheter. The radiofrequency
catheters Thermocool (Biosense Webster Inc., Diamond
Bar, California) and Chilli II (Boston Scientific Inc., San
Jose, California) are being used for human beings, but have
not been approved for use yet. New technology involving
ultrasound ablation is also available with Paradise (ReCor
Medical Inc., Ronkonkoma, New York) catheter, already in
experimental clinical use8.
Simplicity studies: results and limitations
RSD technique was initially tested in an open-label
pilot clinical study, Symplicity HTN-111, conducted with 45
patients with RAH, with preserved renal function. Patients
administrated, in average, 4.7 antihypertensive drugs and
had mean baseline BP of 177/101 mmHg. Primary outcomes
of the study were procedure safety and decrease of casual
BP. Secondary outcomes were procedure effects on the
production of renal noradrenaline (spillover) and renal
function. Patients’ follow-up occurred with one, three, six,
nine and twelve months, without adjusting the quantity of
antihypertensive medications, unless necessary11.
BP decreases were significant in all periods of the
follow-up. Thus, with one month of follow-up, the observed
SBP and DBP decrease was of −14/−10 mmHg, respectively,
reaching −27/−17 mmHg with 12 months after procedure.
Six of the 45 patients (13%) had SBP reduction < 10 mmHg,
being considered as non-responsive, while the five patients
with RAH who were not subjected to the procedure (control
group) had BP increased in subsequent evaluations. Twelve
months after the procedure, 38% of patients had BP controlled
366
Arq Bras Cardiol. 2013;101(4):364-371
(SBP < 140 mmHg) and 28% had BP partially controlled (SBP
140-159 mmHg)11 - Table 1.
In this pilot, the presence of intercurrences was minimal,
such as the occurrence of periprocedural diffuse abdominal
pain, relieved with analgesics. The procedure proved to be
safe and free from complications in 43 of the 45 patients
(one patient had renal artery dissection that was treated and
resolved by interrupting the RSD procedure and another patient
had pseudo-aneurysm at the injection site and was treated
conservatively). Angiographies conducted after the procedure
in 18 patients have not demonstrated any abnormality of renal
arteries; thus, magnetic resonance conducted after six months
in 14 patients had not demonstrated complications related to
the procedure11.
The efficiency of the RSD procedure was also evaluated by
the decreased noradrenaline release (spillover): in 10 study
patients, this decrease was of 47%, and these patients had
a decreased mean BP after six months of −22/−12 mmHg,
similar to the group as a whole. Heart rate remained unaltered
at all moments11.
Positive results of this initial pilot study stimulated
the proposal for a new study: the Symplicity HTN-215,
randomized, prospective, multicenter study. In this study,
106 patients with RAH were randomized for RSD (n = 52,
initial mean BP of 178/96 mmHg) or maintenance of
the previous drug therapy (n = 54, initial mean BP of
178/97 mmHg), having as main outcome the modification
of casual BP in six months and as secondary outcomes the
procedure safety, occurrence of cardiovascular outcomes, and
additional measures of BP after six months.
At the end of the sixth month of follow-up, casual BP in
the RSD group was reduced in -32/-12 mmHg in relation
to baseline. In the control group, BP had no decrease
(+1/0 mmHg). Thus, the difference of BP between RSD and
control groups after six months was of 33/11 mmHg. Significant
decreases were also observed in residential measurement and
ABPM and BP at six months, although smaller in absolute
numbers to decreased casual BP observed15 (Table 1).
Ten patients (20%) reduced the number of medications
administered in the group subjected to intervention against
three (6%) in the control group. Four patients (8%) increased
the number of drugs used in the RSD group against six (12%)
in the control group15.
At the end of six months, 41 patients (84%) who were
subjected to RSD showed a decreased SBP ≥ 10 mmHg and
were considered responsive, against only 18 patients (35%)
in the control group. The procedure had not complications
or side effects 15. The patients who, during the first six
months, continued administering medications and had an
unsatisfactory control of BP, were submitted to RSD, and the
follow-up was extended to one year, with BP results similar
to those who underwent the intervention at baseline16.
One-year results of the follow-up of patients who underwent
RSD in Symplicity HTN-2 study showed decrease maintenance
of SBP (−28.1 mmHg), value similar to that observed with six
months of follow-up (−31.7 mmHg)16 - Table 1.
However, in Symplicity HTN-111 and Symplicity HTN-2
(HR11)15 studies, we observed important limitations that
Brandão et al
Renal sympathetic denervation and arterial hypertension
Review Article
Table 1 − Main characteristics and results of Simplicity HTN-1 e HTN-2 studies11,15,16
Study
Characteristics
Main results
Simplicity HTN-1
Open-label, non-randomized study
N = 45
Mean age 58±9 years; 56% male; 31% diabetics
Initial BP: 177/101 mmHg
Outcomes: decreased casual BP at 12 months and procedure safety
↓ casual BP at 12 months: -27/-17 mmHg
12 months: 38% SBP < 140 mmHg; 28% SBP 140-159
mmHg and 13% decreases < 10 mmHg (non-responsive)
Procedure free from complications
Simplicity HTN-215
Randomized, nonblinded study
N = 106
Mean age 58±12 years; 58% male; 67% diabetics
Initial BP: 178/97 mmHg (intervention) and 178/98 mmHg (control)
Outcomes: decreased casual BP at 6 months and procedure safety
↓ casual BP at 6 months: -32/-12 mmHg
↓BP ABPM* at 6 months: -11/-7 mmHg
6 months after the procedure: 84% decrease of SBP < 10
mmHg; 10% had no decreases SBP (non-responsive)
Procedure free from complications
Simplicity HTN-2
Extension to 1 year’16
Patients in Simplicity HTN-2 control group who maintained the
unsatisfactory control of BP (SBP > 160 mmHg) underwent the RSD
procedure with 6 months of follow-up
Follow-up extended to 1 year
↓casual SBP at 12 months (for group early treated with
RSD): −28.1 mmHg
↓casual SBP at 12 months (for group late treated with RSD):
-23.7 mmHg
Procedure free from complications
11
*ABPM was conducted in only 20 patients of the procedure group.RSD: renal sympathetic denervation; ABPM: ambulatory blood pressure monitoring; BP: blood
pressure; SBP: systolic arterial pressure..
need to be considered: a) possible mechanisms responsible
for reducing BP at RSD were not investigated in any of the
studies6,11,15,17,18; b) there was no control group for Symplicity
HTN-111, reducing the relevance of its results; c) at Symplicity
HTN-215, due to the complexity of the tested procedure
(invasive intervention), the study could not be blind, thus
creating a possible evaluation bias6,11,15,17,18; d) in both studies,
patients were not properly evaluated for the possibility of
secondary AH (it is known that up to 10% of patients with
RAH have primary aldosteronism and, in these patients,
RAH invasive treatment could be considered; e) only a small
number of patients was administering the appropriate clinical
therapy for RAH treatment, such as the restriction of salt in diet
and use of spironolactone, raising the question whether these
patients were really treatment-resistant. Thus, it is believed
that more rigorous inclusion and exclusion criteria must be
applied in future studies in order to test this RAH treatment
technique6,11,15,17,18.
Still with limitations, in both studies some patients had their
medication changed during the follow-up, reducing the impact
of the procedure on BP decrease6,11,15,17,18. Another aspect was
the wide variability of hypotensive response observed at the
end of six months with different methods of BP measurement
used in both studies, making the efficacy analysis of the
procedure quite heterogeneous6,11,15,17,18. It is worth noting
that in both studies, only part of the patients was subjected
to ABPM, and this supplemental method is crucial to remove
the white-coat effect. In this cohort, BP decrease in ABPM
was of approximately 1/3 from that obtained for casual BP,
suggesting the RSD effects may not be as significant as they
initially appeared6,11,15,17,18.
A concern with this technique is related to safety and
durability of hypotensive effect in the long-term, due to the
regenerative ability of the nervous tissue6,11,15,17,18. However,
the follow-up of 24 months after the procedure of 153
patients with RAH in the study Symplicity HTN-119 showed
progressively greater decreases of casual BP after procedure,
reaching −32/−14 mmHg at 24 months. The authors
concluded that RSD resulted in substantial decrease and
sustained of BP with two-year follow-up, without significant
adverse events.
It is worth noting that about 20% of patients initially
selected for the procedure did not participate in the study
Symplicity HTN-215 for difficulties in renal anatomy that
prevented the procedure from being carried out, which could
limit the clinical use of this therapy on a large scale6,11,15,17,18.
Ultimately, not all patients subjected to the procedure
managed to reduce the BP. If we consider that RSD had
a mean decrease of SBP of 20-25 mmHg and DBP of
10-15 mmHg, at the end of 12 months of follow-up, similar
decreases in SBP and DBP were also observed in patients
administering spironolactone as the fourth drug in RAH treatment.
For this reason, it is important to try to identify factors
that may predict the therapeutic success of the intervention.
Univariate analysis in Symplicity HTN-111 did not identify any
pre-procedure condition capable of predicting RSD success,
while in Symplicity HTN-215 the highest SBP values and use
of central sympatholytic agents were capable of predicting the
procedure success6,11,15,17,18.
Due to the nature of the procedure, a more detailed
analysis on renal function of patients undergoing RSD is
mandatory 17. Extended results of Symplicity HTN-1 for
24 months of follow‑up19 observed a significant decrease of TGF
(‑16 ml / min/1,73 m²) in 10 patients; smaller decrease, but also
significant (‑7,8 ml / min/1,73 m²) was observed in five patients
who were not administering spironolactone or any other diuretic
in the first year after procedure. It is worth noting that, even with
TGF decrease, no patient showed increase in serum creatinine
or evolution to renal insufficiency or need for dialysis, and this
TGF decrease was also lower than that estimated if patients had
maintained BP unchanged from the protocol start19.
Arq Bras Cardiol. 2013;101(4):364-371
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Clinical studies with other devices
EnligHTN is a multi-electrode catheter with a basket and,
when it opens inside the renal artery, it allows energy release
simultaneously in four points of the arterial endoluminal surface.
It was the catheter used in ARSENAL study, which preliminary
results were presented in 2012, reporting a BP decrease of
−28/−10 mmHg, one month after the intervention, with
78% of patients showing a decreased systolic BP > 10 mmHg.
Adverse events occurred in very few cases (n = 6): bruising
on the arterial puncture site, vasovagal response on sheath
withdrawal and bradycardia after procedure. Study final results
will be recognized in 2013, after the six months follow-up of 47
patients treated with RSD using EnligHTN8 catheter.
Vessix V2 system of DSR has a catheter with a low-pressure
balloon, with bipolar radiofrequency electrodes on the
balloon surface, and it is being tested in the REDUCE-HTN
study, with closure of results scheduled for August, 2014.
Preliminary results in 10 patients showed BP decreases of
−30/−11 mmHg8.
The first experience in human beings with One Shot system
was reported. It is a catheter with an irrigated balloon and
electrodes mounted helically, in a way that radiofrequency
pulse can to be conducted only once, making the procedure
faster and more accurate, without the need of handling the
catheter. BP decreases observed one month after intervention
were similar to those observed in the Symplicity20 study.
ThermoCool catheter is being used in SWAN HT study
and intends to include 800 hypertensive patients. Pilot study
results with 10 patients have shown decreases in BP and in
markers of sympathetic activity. This same catheter and Chilli II
system are being implemented in SAVE study, which also aims
at including a relevant number of individuals - 500 patients8.
Paradise catheter is being tested in REALISE study.
Preliminary results of 15 patients have shown BP decrease of
−32/−16 mmHg with three months of follow-up and were
presented in congress in 20128.
Clinical studies that conduced RSD with irrigated
radiofrequency ablation catheters, generally used for ablation
in heart tissue, have also demonstrated positive results.
Ten patients subjected to RSD with this type of device were
followed-up for six months. Mean BP decreases observed
were significant (−21/−11 mmHg) and all patients reduced
their BP in 10 mmHg or more by the end of this observation
period. There were no complications on renal artery, such
as aneurysms or stenoses, and there were no renal function
impairments21.
Another experiment with this type of catheter confirmed
the effect on BP, evidencing decreases in mean BP of 24h on
ABPM of −24/−14 mmHg, three months after the procedure,
without changes on renal function or albuminuria and without
vascular complications22.
RSD effects besides the decreased peripheral arterial
pressure
RSD positive impact on the central hemodynamics and
arterial rigidity was recently reported. Evaluation of 110 patients
who underwent RSD showed a decrease in central aortic BP
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Arq Bras Cardiol. 2013;101(4):364-371
from 167/92 mmHg at baseline to 141/85 mmHg in six months.
In this same period, the augmentation index presented a decrease
of 5.3% and the carotid-femoral pulse wave velocity decreased
from 11.6 ± 3.2 m/s to 9.6 ± 3.1 m/s. Improvements in central
hemodynamics and arterial rigidity may be important prognostic
implications, particularly in patients with cardiovascular high-risk,
such as patients with RAH23.
RSD was also capable of reducing the sympathetic activity
measured through muscle sympathetic nerve activity (MSNA)
after three months from procedure, with mechanisms not
yet elucidated. RSD results were more evident for single
sympathetic vasoconstrictor fibers, demonstrating substantial
and rapid decrease of its acitivity24.
The association between increased renal sympathetic
activity and components of metabolic syndrome (MS) was
already demonstrated. A group of 50 patients was evaluated25,
with 37 being subjected to RSD and 13 maintained under
conservative treatment. Initial mean BP in both groups was
of 178/96 mmHg. After three months of procedure, we
observed significant decreases in BP (−32/−12 mmHg),
fasting blood glucose (from 118 mg/dl to 108 mg/dL), of insulin
levels (from 20.8 UI/ml to 9.3 UI/ml) and levels of C-peptide
(from 5.3 ng/ml to 3.0 ng/ml). Authors also tested the impact
on insulin sensitivity, calculated through homeostasis model
assessment-insulin resistance (HOMA-IR), and observed the
decreased level of insulin resistance with RSD (from 6 to 2.4).
Glucose, after two hours of stimulation, also improved after the
procedure, with a decrease of 27 mg/dl compared to baseline.
There were no changes on BP and metabolic parameters in
the control group25.
RSD impact on renal hemodynamics and urinary excretion
of albumin was assessed in a study with 100 patients: 88 were
subjected to RSD and 12 constituted the control group. There
was a decrease in resistivity index with three and six months
of procedure, but there was no change in urinary excretion
of albumin or C-cystatin values. However, the number of
individuals with microalbuminuria or macroalbuminuria was
reduced with RSD. There were no changes in these parameters
in the control group26.
Another study27 evaluated the role of RSD in 10 patients
with RAH and sleep apnea. At the end of six months, it
was observed a decrease in BP (−34/−13 mmHg) and
improvement in sleep apnea (from 16.3 to 4.5 events/hour).
Another interesting evidence related to RSD was recently
published, demonstrating the capacity of this technique
to reduce left ventricular hypertrophy (LVH) and improve
ventricular systolic and diastolic functions in patients with RAH.
The study28 included 46 patients who underwent RSD and
echocardiogram in three stages (baseline, one month and six
months after the procedure), with 18 patients comprising the
control group. There was decrease in BP (−22.5/−7.2 mmHg
after one month and −27.8/−8.8 mmHg after six months
from procedure) and LVH parameters: reduction of the width
of interventricular septum, left ventricular mass index from
53.9 ± 15.6 g/m2,7 (112.4 ± 33.9 g/m2) to 47.0 ± 14.2 g/m2,7
(103.6 ± 30.5g/m2) and 44.7 ± 14.9g/m2,7 (94.9 ± 29.8 g/m2) in
one and six months, respectively. The improvement of systolic
and diastolic functions was evidenced by the reduction of
Brandão et al
Renal sympathetic denervation and arterial hypertension
Review Article
E/E¢ mitral scale and for the increase in ejection fraction from
63.1 ± 8.1% to 70.1 ± 11.5% at the end of six months28.
RSD has also shown a relevant improvement in scores
evaluating the quality of life three months after procedure.
In the study, the subjective evaluation on the quality of life
of resistant hypertensive patients before the procedure, was
quite negative. It is worth noting that the improvement in the
quality of life was not directly associated with the magnitude
of BP decrease29.
Cost-effectiveness studies and estimates on clinical
benefits in the long-term
Based on the results of the study Symplicity HTN-215, it was
carried out an analysis of RSD cost-effectiveness and its clinical
impact in the long-term. Compared to conventional treatment,
RSD reduced the probability of cardiovascular and renal
outcomes (relative risk - RR - in 10 years/lifetime: 0.70/0.83
for CVA; 0.68/0.85 for AMI; 0.78/0.90 for all coronary
events; 0.79/0.92 for heart insufficiency and 0.72/0.81 for
renal disease in the final stage). Estimated mean survival in
RSD group was of 18.4 years and in conventional treatment
group was of 17.1 years. The ratio of discounted incremental
cost-effectiveness was of U$3,071 per quality-adjusted
life-year (QALY), and was, therefore considered a cost-effective
strategy for RAH30.
Another analysis revealed the cost-effectiveness in men and
women of different ages, and RSD resulted in a gain of 0.98
QALYs for men and 0.88 QALYs in women aged 60, with an
additional cost of €2,589 and €2,044, respectively, compared
to drug therapy. The younger the patient, the greater the gain
in QALYs and the lower the cost. This study pointed out that
RSD would be cost-effective until 78 years old for men and
76 years old for women31.
Study limitations
This review is a result of an active research of scientific
articles named “renal denervation” at Medline e PubMed
databases, considering a limited number of published original
articles and ongoing clinical trials. It represents an exploratory
phase of this new intervention method and, therefore, a
knowledge theme still in construction.
Bullfrog micro-infusion catheter8 are still being tested for
clinical use. Using non-specific catheters, used in ablation
techniques for heart arrhythmias, may represent lower cost
to RSD procedure, however, it has not yet been validated
for its full scientific use22,23. Among future challenges, is the
possibility of performing a non-invasive denervation treatment,
using Doppler pointed at renal artery.
Another demand for the future concerns the development
of indicators for immediate evaluation of the success of RSD
procedure.
Conducting robust, randomized, blinded studies in centers
specialized in AH is required to evaluate the long-term
efficacy and safety and the possible impact on the reduction
of morbidity and mortality. Simplicity HTN-334 ongoing study
must contribute this matter.
Development of knowledge with the use of RSD for
RAH could suggest potential use in other conditions
concurrent with sympathetic hyperactivity, such as: isolated
systolic hypertension, diabetes, chronic renal disease, heart
insufficiency, heart arrhythmias, sleep apnea and cirrhosis6.
On the basis of limitations of clinical study results with RSD
up to this moment and the absence of more comprehensive
studies on cost-effectiveness of the procedure, its application
in large scale is not yet to be recommended; currently, it must
be indicated only for true resistant hypertensive patients,
group of very high cardiovascular risk35. It is worth noting
that, regardless of a positive clinical result of RSD for RAH,
the medical treatment must be based on the combination
of continued administration of medications, weight loss and
change of lifestyle for all patients1,2.
Author contributions
Conception and design of the research, Acquisition of
data, Analysis and interpretation of the data, Writing of
the manuscript and Critical revision of the manuscript for
intellectual content: Brandão AA, Campana EMG, Magalhães
MEC, Ferreira E.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Future perspectives with RSD
The initial success of RSD technique on RAH, using
radiofrequency stimulated the appearance of other types of
device, with very promising proposals and more simplified
handling and with a more homogeneous performance
of RSD 8,32. Other interesting techniques, such as renal
intra-arterial infusion of guanethidine, or renal periarterial
infusion of ethanol33, or periarterial vincristine injection with
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation
program.
Arq Bras Cardiol. 2013;101(4):364-371
369
Brandão et al
Renal sympathetic denervation and arterial hypertension
Review Article
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5. Consolim-Colombo FM, Irigoyen MC, Krieger EM. Papel dos principais
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al. Substantial reduction in single sympathetic nerve firing after renal
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7. Papademetriou V, Doumas M, Tsioufis K. Renal sympathetic denervation
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25. Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et
al. Effect of renal sympathetic denervation on glucose metabolism in patients
with resistant hypertension: a pilot study. Circulation. 2011;123(18):1940-6.
8. Bunte MC, Infante de Oliveira E, Shishehbor MH. Endovascular treatment
of resistant and uncontrolled hypertension: therapies on the horizon. JACC
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27. Witkowski A, Prejbisz A, Florczak E, Kadziela J, Sliwinski P, Bielen P, et al.
Effects of renal sympathetic denervation on blood pressure, sleep apnea
course, and glycemic control in patients with resistant hypertension and
sleep apnea. Hypertension. 2011,58(4):559-65.
11. Krum H, Schlaich M, Whitbourn R. Catheter-based renal sympathetic
denervation for resistant hypertension: a multicentre safety and proof-ofprinciple cohort study. Lancet.2009;373(9671):1275-81.
28. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M,et al.
Renal sympathetic denervation reduces left ventricular hypertrophy and
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12. Steigerwald K, Titova A, Malle C, Kennerknecht E, Jilek C, Hausleiter J, et al.
Morphological assessment of renal arteries after radiofrequency catheter-based
sympathetic denervation in a porcine model. J Hypertens. 2012;30(11):2230-9.
29. Lambert GW, Hering D, Esler MD, Marusic P, Lambert EA, Tanamas SK,
et al. Health-related quality of life after renal denervation in patients with
treatment-resistant hypertension. Hypertension. 2012;60(6):1479-84.
13. Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins CK. Catheterbased renal sympathetic denervation: chronic preclinical evidence for renal
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30. Geisler BP, Egan BM, Cohen JT, Garner AM, Akehurst RL, Esler MD, et al. Costeffectiveness and clinical effectiveness of catheter-based renal denervation
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LH, et al. Potential lifetime cost-effectiveness of catheter-based renal
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15. Esler MD, Krum H, Sobotka PA, Schiaichi MP, Schmieder RF, Bohm M. Renal
sympathetic denervation in patients with treatment-resistant hypertension
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of the Symplicity HTN-2 Investigators. Renal sympathetic denervation for
treatment of drug-resistant hypertension: One-year results from the Symplicity
HTN-2 randomized, controlled trial. Circulation. 2012;126(25):2976-82.
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Effects of renal sympathetic denervation on arterial stiffness and central
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33. Streitparth F, Walter A, Stolzenburg N, Heckmann L, Breinl J, Rinnenthal
JL et al. MR-guided periarterial ethanol injection for renal sympathetic
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18. Bunte MC. Renal sympathetic denervation for refractory hypertension.
Lancet. 2011;377(9771):1074-5.
34. Kandzari DE, Bhatt DL, Sobotka PA, O’Neill WW, Esler M, Flack JM,
et al. Catheter-based renal denervation for resistant hypertension:
rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol.
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19. Azizi M, Steichen O, Frank M, Bobrie G, Plouin PF, Sapoval M. Catheterbased radiofrequency renal-nerve ablation in patients with resistant
hypertension. Eur J Vasc Endovasc Surg. 2012;43(3):293-9.
35. Schimieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K, et
al. ESH position paper: renal denervation ¾ an interventional therapy of
resistant hypertension. J Hypertens. 2012;30(5):837-41.
Arq Bras Cardiol. 2013;101(4):364-371
Brandão et al
Renal sympathetic denervation and arterial hypertension
Review Article
Arq Bras Cardiol. 2013;101(4):364-371
371
Back to the cover
Letter to the Editor
Impact on Hypertension Reclassification by Ambulatory Blood
Pressure Monitoring (ABPM) according to the V Brazilian Guidelines
on ABPM
Guilherme Brasil Grezzana, Airton Tetelbon Stein, Lúcia Campos Pellanda
Fundação Universitária de Cardiologia do Rio Grande do Sul, Porto Alegre, RS - Brazil
Dear Editor,
We would like to draw attention to the importance to publish
the manuscript Impact on Hypertension Reclassification by
Ambulatory Blood Pressure Monitoring (ABPM) according
to the V Brazilian Guidelines on ABPM, which addresses
the subject of making decisions regarding the thresholds
of normality of blood pressure1. We have found that the
population studied presents similarities relating to the sample
of patients receiving antihypertensive treatment, in keeping
with the database of IDACO2. However, notwithstanding
the fact that three out of four cities in this database are
European cities, the guidelines of the European Society of
Cardiology (ESC) keep as thresholds of blood pressure, to
define hypertension by ABPM of 24 hours, the amounts of
125 to 130 mmHg, for systolic blood pressure, and 80 mmHg
for diastolic blood pressure3. On account of that, we kindly
request that the authors express their opinions about two
issues: firstly, the applicability and importance of these more
aggressive thresholds for hypertensive patients under treatment
and, secondly, we wonder if the authors have diagnostic
accuracy data for this sample regarding the conventional
measurements of blood pressure and the consequent
prevalence of the white‑coat effect and masked hypertension.
Keywords
Hypertension; Blood Pressure Monitoring, Ambulatory /
methods, Practice Guidelines as Topic.
Mailing Address: Guilherme Brasil Grezzana •
Oswaldo Hampe, 258, Centro. Postal Code 95250-000, Antônio Prado,
RS – Brazil
Email: [email protected], [email protected]
Manuscript received April 12, 2013; revised manuscript April 16, 2013;
accepted June 11, 2013.
DOI: 10.5935/abc.20130197
References
1.
Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão,
Sociedade Brasileira de Nefrologia. V Diretrizes Brasileiras de
Monitorização Ambulatorial da Pressão Arterial (MAPA) e III Diretrizes
Brasileiras de Monitorização Residencial de Pressão Arterial (MRPA). Arq
Bras Cardiol. 2011;97(3 supl.3):1-24.
2. Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T,
Ohkubo T, et al: IDACO investigators. Diagnostic thresholds for ambulatory
blood pressure monitoring based on 10-year cardiovascular risk. Blood
Press Monit. 2007;12(6):393-5.
372
3. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et
al; European Association for Cardiovascular Prevention & Rehabilitation
(EACPR); ESC Committee for Practice Guidelines (CPG). European
Guidelines on cardiovascular disease prevention in clinical practice (version
2012). The Fifth Joint Task Force of the European Society of Cardiology and
Other Societies on Cardiovascular Disease Prevention in Clinical Practice
(constituted by representatives of nine societies and by invited experts. Eur
Heart J. 2012;33(13):1635-1701.
Back to the cover
Letter to the Editor
Prognostic Factors in Patients with Acute Coronary Syndrome
without ST-segment Elevation
Sinan İşcen
Diyarbakır Military Hospital, Yenısehır, Dıyarbakır
Dear Editor,
We read the article, “Prognostic factors in patients with
acute coronary syndrome without ST-segment elevation”
written by Santos JC 1. The authors concluded that the
assessment of renal function and lymphocyte count
provide potentially useful information for the prognostic
stratification of patients with non-ST elevation ACS.
We know that patients with end-stage renal disease have
a higher risk for and a worse outcome after myocardial
infarction. However, lesser degrees of renal dysfunction
also predict an adverse prognosis in patients with acute MI.
Several studies have shown the magnitude of this effect2.
We also know that patients with a higher white blood
cell (WBC) count – which is a marker of inflammation, have
an increased risk for adverse events, in-hospital mortality,
and short- and long-term mortality after a non-ST elevation
ACS, as well as for acute ST-elevation MI3. The value of
the baseline WBC in patients with non-ST-elevation MI
or unstable angina was evaluated in the TACTICS-TIMI
18 trial4, which concluded that higher WBC was associated
with significantly lower TIMI flow grades, myocardial
perfusion grades and more extensive coronary disease.
This was found in relation to WBC but not to lymphocytes,
because many factors in the ICU environment may lead to
lymphocytopenia (trauma, hemorrhage, viral infections,
etc.). Therefore, in order to establish a relationship between
lymphocyte count and prognosis, further evaluation and
objective evidence are needed.
Keywords
Acute Coronary Syndrome; Inflammation; Myocardial
Infarction, Prognosis, Lymphopenia.
Mailing Address: Sinan İşcen •
Diyarbakır Military Hospital, Yenısehır. Postal Code 34100, Dıyarbakır
E-mail: [email protected]
Manuscript received 04/15/13; revised manuscript received 04/17/13;
accepted 06/20/13.
DOI: 10.5935/abc.20130198
References
373
1. Santos JC, Rocha Mde S, Araújo Mda S. Prognostic factors in patients with
acute coronary syndrome without ST segment elevation. Arq Bras Cardiol.
2013;100(5):412-21.
3. Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and
coronary heart disease: implications for risk assessment. J Am Coll Cardiol.
2004;44(10):1945-56.
2.
4. Sabatine MS, Morrow DA, Cannon CP, Murphy SA, Demopoulos LA,
DiBattiste PM, et al. Relationship between baseline white blood cell count
and degree of coronary artery disease and mortality in patients with acute
coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat
and determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction 18 trial)substudy. J Am Coll Cardiol.
2002;40(10):1761-8.
Al Suwaidi J, Reddan DN, Williams K, Pieper KS, Harrington RA, Califf RM,
et al; GUSTO-IIb, GUSTO-III, PURSUIT. Global Use of Strategies to Open
Occluded Coronary Arteries. Platelet Glycoprotein IIb/IIIa in Unstable
Angina: Receptor Suppression Using Integrilin Therapy; PARAGON-A
Investigators. Platelet IIb/IIIa Antagonism for the Reduction of Acute
coronary syndrome events in a Global Organization Network. Prognostic
implications of abnormalities in renal function in patients with acute
coronary syndromes. Circulation. 2002;106(8):974-80.
İşcen
Is lymphocytopenia a prognostic marker?
Letter to the Editor
Reply
As regards Dr. İşcen’s comments, we have some points
to consider.
All patients diagnosed with unstable angina (UA)
or non‑ST segment elevation (STE) acute myocardial
infarction (AMI) admitted to our hospital from Janurary to
December 2010 were included in our study. In an attempt
to eliminate possible confounders, patients presenting with
malignant neoplasias, infectious diseases, autoimmune
diseases, and those who had recently suffered a trauma
or undergone surgery – conditions which could lead to
leukocytosis, neutrophilia or lymphopenia, were excluded.
The inclusion and exclusion criteria were described in the
respective article1.
We verified that complete white blood cell and neutrophil
counts in our sample were not able to discriminate patients
at a higher risk for adverse events (7781 ± 3252 /mm³ vs.
8140 ± 2835 /mm³, p = 0.5; and 5653 ± 3058 /mm³ vs.
5220 ± 2496 /mm³, p = 0.4, respectively). However, the
logistic regression analysis showed an independent and
significant relationship between lymphocyte count and
combined events (OR: 1.02; 95%CI: 1.01-1.04; p = 0.03).
Some studies have suggested that the count of leukocytes and
their subpopulations may predict fatal and non-fatal outcomes
in patients with non-STE acute coronary syndrome 2,3.
Cannon et al4 and Núñez et al5 demonstrated that the
relationship between leukocytosis, neutrophilia and a worse
prognosis is valid for patients with AMI, but not for those with
UA. Lloyd‑Jones et al6 and Zouridakis et al7 found that only
lymphopenia, among the subpopulations of white blood cells,
was associated with future cardiac events in these patients.
Since, in our article¹, two thirds of our sample was comprised
of patients with UA, we suggested that the lymphocyte count
in this population probably provides a better identification of
patients with a worse prognosis.
Sincerely,
Jessica C M D’Almeida Santos
Mário de Seixas Rocha
Marcos da Silva Araújo
References
1. Santos JC, Rocha Mde S, Araújo Mda S. Prognostic factors in patients with
acute coronary syndrome without ST segment elevation. Arq Bras Cardiol.
2013;100(5):412-21.
2.
Barron HV, Cannon CP, Murphy SA, Braunwald E, Gibson CM. Association
between white blood cell count, epicardial blood flow, myocardial perfusion,
and clinical outcomes in the setting of acute myocardial infarction: a thrombolysis
in myocardial infarction 10 substudy. Circulation. 2000;102(19):2329-34.
3.
Furman MI, Gore JM, Anderson FA, Budaj A, Goodman SG, Avezum A, et al.
Elevated leukocyte count and adverse hospital events in patients with acute
coronary syndromes: findings from the Global Registry of Acute Coronary
Events (GRACE). Am Heart J. 2004;147(1):42-8.
4.
Cannon CP, McCabe CH, Wilcox RG, Bentley JH, Braunwald E. Association
of white blood cell count with increased mortality in acute myocardial
infarction and unstable angina pectoris. OPUS-TIMI 16 Investigators. Am J
Cardiol. 2001; 87(5):636-9.
5.
Núñez J, Sanchis J, Bodí V, Nunez E, Mainar L, Heatta AM, et al. Relationship
between low lymphocyte count and major cardiac events in patients with
acute chest pain, a non-diagnostic electrocardiogram and normal troponin
levels. Atherosclerosis. 2009;206(1):251-7.
6. Lloyd-Jones DM, Camargo CA Jr, Giugliano RP, O’Donnell CJ. Effect of
leukocytosis at initial examination on prognosis in patients with primary
unstable angina. Am Heart J. 2000;139(5):867-73.
7. Zouridakis EG, Garcia-Moll X, Kaski JC. Usefulness of the blood lymphocyte
count in predicting recurrent instability and death in patients with unstable
angina pectoris. Am J Cardiol. 2000;86(4):449-51.
Arq Bras Cardiol. 2013;101(4):373-374
374
Back to the cover
Clinicoradiological Session
Case 5/2013 - A Four-Year-Old Boy with a Rhabdomyoma-Type
Cardiac Tumor in Both Ventricles and Repeated Ventricular
Tachycardia
Edmar Atik
Clínica privada do Dr. Edmar Atik, São Paulo, SP – Brazil
Clinical data: Chest radiography performed during
upper respiratory tract infection at 5 months of age
suggested heart disease because of a deformity observed
in the ventricular arch. At that time, echocardiography
confirmed the presence of two tumor masses in both
ventricles. At nine months of age, the patient started
to present with episodes of paroxysmal ventricular
tachycardia, with a heart rate of approximately 200 bpm,
accompanied by diaphoresis and paleness, all reverted
after electrical cardioversion. The episodes recurred for
five times, despite the systematic use of antiarrhythmic
medication comprising propranolol and amiodarone.
Physical examination: Active, eupneic, mucous membranes
pink, normal pulses. Weight: 17 kg . Height: 97 cm.
BP: 90/52‑61 mmHg. HR: 100 bpm. Aorta non‑palpable in
the suprasternal notch area.
No deformities were observed in the precordium; the
apical impulse was not palpable and there were no systolic
impulses. The heart sounds were normal with no murmurs.
The liver was not palpable.
Laboratory tests
Electrocardiogram (Figure 1) showed normal sinus
rhythm and signs of left ventricular overload. QR complex in
aVL with negative T wave in aVL and isoelectric in D1 were
observed, thus characterizing the diagnosis of electrical
ischemia of the high lateral wall. AP: +60o. AQRS: +80o.
AT: +90o. During an episode of tachycardia, ECG showed
complete right bundle branch block, with a ventricular
rate of 210 bpm.
Chest radiography showed normal cardiac silhouette and
pulmonary vascular network, and a deformity characterized
by a mild bulging located in the middle of the left ventricular
arch (Figure 1).
Palavras-chave
Heart Neoplasms; Rhabdomyoma; Tachycardia, Ventricular.
Mailing Address: Edmar Atik •
Rua Dona Adma Jafet 74 , cj 73 01308-050 São Paulo, SP - Brazil
E-mail: [email protected]
DOI: 10.5935/abc.20130193
e74
Ecocardiogram (Figure 2) showed two homogeneous
and echodense images with well-defined round contours.
The smallest was located in the right ventricular free
wall and its diameters were 39 x 21 mm, with an area of
6.9 cm 2; the largest, in the left ventricular anterior wall,
was 51 x 37 mm, with an area of 12.5 cm2. Both masses
showed a cleavage plane with the contiguous ventricular
walls and did not cause obstruction in the ventricular
inflow and outflow tracts. Function of both ventricles
was normal.
Tomography of the thoracic aorta (Figure 2) showed the
same pattern, with the larger mass protruding from the left
ventricle, however without causing obstruction to the flow.
Clinical diagnosis: Biventricular cardiac tumors
without obstruction in the inflow and outflow tracts, no
heart failure, but with repeated paroxysmal ventricular
tachycardia. The tumors were classified as rhabdomyomas
because of their multiple locations, well- defined
cleavage plane with the myocardium, and for not causing
obstruction to the flow.
Clinical reasoning: The clinical elements were consistent
with a normal cardiovascular system, except for the
electrocardiogram and chest radiography, which showed
electrical ischemia of the high lateral wall and protrusion of
the ventricular arch, respectively. These findings suggested
the presence of a “mass” corresponding to the region
described, presumably in the pericardium, myocardium
or endocardium. Other imaging tests were decisive to find
the ventricular intracavitary mass which projected itself in
the left ventricular anterolateral wall, and was responsible
for the abnormalities described. The other mass found in
the free wall of the right ventricle was smaller and lacked
clinical relevance.
Differential diagnosis: The abnormal findings observed
in the electrocardiogram and chest radiography could also
be present in pericardial processes such as cysts and tumors,
or even in myocardial processes such as fibroma or other
benign tumors.
Management: Because of the paroxysmal manifestation
of the cardiac arrhythmia of left ventricular origin, of the
right bundle branch block found on the electrocardiogram
during a tachycardia episode, the dose of antiarrhythmic
drugs was increased. If an adequate clinical response is
not observed, surgical removal of the tumor becomes a
priority, since the electrophysiological study was unable to
demonstrate possible foci of arrhythmia.
Atik
Biventricular rhabdomyoma, ventricular tachycardia
Clinicoradiological Session
Figure 1 - Electrocardiogram showing electrical ischemia of the high lateral wall with characteristic abnormalities in D1 and aVL. Chest radiography shows a protrusion
in the ventricular arch corresponding to the intracavitary left ventricular mass.
Comments: The clinical manifestations of benign
tumors of the heart commonly include heart failure,
supraventricular and ventricular arrhythmias, and sudden
events such as syncope and low cardiac output, whether or
not accompanied by cerebral symptoms. They are usually
diagnosed during an episode of infection, convulsion or
fainting. In the present case, chest radiography was the first
test to raise the diagnostic hypothesis of a cardiac tumor
because of the bulging observed in the ventricular arch.
The electrical ischemia found in the electrocardiogram
may characterize the exact location of the abnormality,
and the diagnostic imaging tests – echocardiography
and MRI, confirmed the diagnosis. Today, arrhythmias
in general may be better treated by means of more
appropriate medications, of ablation after the triggering
electrophysiological mechanism has been established, or
even of surgical resection of the tumor mass that is causing
the arrhythmia. All are valid and adequate options. A more
conservative approach, with the use of antiarrhythmic
drugs, should be the first option. Over time, other steps
may be necessary to achieve the clinical control of the
ventricular arrhythmia.
Arq Bras Cardiol. 2013;101(4):e74-e76
e75
Atik
Biventricular rhabdomyoma, ventricular tachycardia
Clinicoradiological Session
Figure 2 - Echocardiogram, in cross-sectional view, showing the diagnostic elements of the biventricular intracavitary mass not causing obstruction to the flow (A).
Tomography shows that the tumor on the left side fills the ventricular cavity more than does the tumor on the right side (B).
e76
Arq Bras Cardiol. 2013;101(4):e74-e76
Back to the cover
Case Report
Renal Denervation by Ablation with Innovative Technique in
Resistant Hypertension
Luiz Aparecido Bortolotto, Thiago Midlej-Brito, Cristiano Pisani, Valéria Costa-Hong, Maurício Scanavacca
INCOR - Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil
Introduction
Case report
Hypertension is the cause of thousands of deaths annually ,
and half of the patients treated present controlled blood
pressure (BP)2. Resistant hypertension (RH)is defined when
the BP remains above the recommended targets with the
use of three antihypertensive drugs with synergistic actions at
maximum doses recommended and tolerated, preferably one
being a diuretic, or when in use of four or more anti‑hypertensive
drugs, even with controlled BP3. It is estimated that 12%-15% of
persons with hypertension are considered resistant, with high
risk of cardiovascular morbidity and mortality4.
1
The pathogenesis of hypertension is multifactorial, but
the sympathetic activity plays an important role, especially in
patients with resistant hypertension2. Efferent renal sympathetic
activity stimulates renin release, increases sodium reabsorption
and reduces renal blood flow and may be a mechanism for
the development and maintenance of hypertension2. Genetic,
behavioral and environmental factors influence increased
sympathetic activity in persons with hypertension5.
New therapies aiming to reduce sympathetic activity have
been developed. Renal Sympathetic Denervation (RSD)
by radiofrequency catheter ablation of renal arteries has
been shown to control BP in resistant hypertension6,7 and
in associated clinical conditions such as sleep destructive
apnea8 and insulin resistance9.
The main RSD clinical studies used a specific catheter
not yet available in Brazil, but the radiofrequency ablation
of arrhythmias is a procedure that has been performed by
electrophysiologists through appropriate catheters for years
in our country. Experimental studies of RSD with catheters
used for ablation of arrhythmias indicated the possibility of
using these to replace those used in international studies,
considering the unavailability of those in our reality. Based
on this, for the procedure to be reported, the model used for
ablation in children (4 mm tip and 5F), which was proven to
be more appropriate, was chosen. The objective of the report
is to show the result of the first RSD in our community, with
the aid of technology used in cardiac arrhythmias.
Keywords
Denervation; Hypertension; Catheter Ablation; Sympathetic
Nervous System.
Mailing Address: Thiago Midlej-Brito •
Rua Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César. Postal Code 05403-000,
São Paulo - SP - Brazil
E-mail: [email protected], [email protected]
Manuscript received October 04, 2012; manuscript revised December 19,
2012; manuscript accepted March 08, 2013.
DOI: 10.5935/abc.20130194
e77
39-year-old woman was admitted to our institution
with a history of hypertension since age 17. At age 29, the
patient began to experience episodes of hypertensive crisis
associated with tachycardia, pallor, sweating and dry mouth,
and pheochromocytoma was ruled out. After three years, the
patient presented Cerebrovascular Accident (CVA) without
neurological sequelae. Since then, it was harder to control
hypertension and the patient has to use multiple antihypertensive
drugs, while maintaining high levels of BP. In the last year, the
patient was hospitalized due to hypertensive crises, reaching
BP of 230/130 mmHg. On admission, she was using seven
antihypertensive drugs at maximum dose (amlodipine, valsartan,
furosemide, spironolactone, clonidine, hydralazine and atenolol).
She denied the use of illegal drugs or other medications that
would worsen hypertension. Her mother was hypertensive,
died at age 40 from CVA, and two brothers were hypertensive.
Physical examination revealed BP 180/110 mmHg
(lying position), 182/112 mmHg (standing position) and
heart rate 120 bpm. Cardiovascular examination revealed no
abnormalities and the remainder of the physical examination
was normal. Investigation of secondary hypertension ruled out
all probable causes. Doppler echocardiography showed no
abnormalities and 24-hour Holter showed no arrhythmias.
As the patient presented hypertension resistant to several
medications, the medical staff suggested RSD by ablation
and the patient accepted after explanation of risks and
benefits. The patient read and signed the Informed Consent
Form, since it was the first procedure in Brazil.
The RSD procedure was conducted on August 25, 2011
by the Electrophysiology team. Access to the renal artery
was through the femoral artery and anatomy eligible for the
procedure was confirmed by angiography after selective
catheterization. For renal ablation, a 5F catheter was used
(Mariner Series AblationCatheters, Medtronics) and positioned
in the aorta, retrograde in the renal artery, guided by radioscopy
and connected to a radiofrequency (RF) generator. An
electroanatomic map (EnSite System, StJude Medical) of the
aorta and the renal arteries was constructed (Figure 1) and
four RF applications in each renal artery were planned, distal
to proximal, separated longitudinally and in rotation (helical),
with markings on the map (white dots in Figure 1). After that,
the catheter was introduced into each renal artery and four
RF applications were made (8W, 60 oC, 120s) per artery in the
regions previously marked (red dots in Figure 1). The patient
was under general anesthesia, with BP monitored during the
procedure, which occurred without complications. At the end,
the patient was awakened from anesthesia reporting mild lower
back discomfort that improved after administration of painkiller.
A new selective angiography showed no abnormalities.
Bortolotto et al.
Denervation of renal artery by catheter ablation
Case Report
Ablation
Ablation
Figure 1 – Electroanatomic map of the aorta and renal arteries with markings for ablation. The white dots show areas manually marked where application of RF was
planned, and the red dots show the areas where RF application was done. On the left, anteroposterior view and on the right, posteroanterior view.
Table 1 – Office and 24-h ABPM blood pressure, and arterial function parameters before and after renal denervation
Variables
Pre
6 months
1 year
Office BP (mmHg)
180/110
160/100
150/100
Daytime BP (mmHg)
190 / 121
162 / 107
146 / 100
Nighttime BP (mmHg)
170 / 117
120 / 77
111 / 75
Carotid distension (%)
4,65
6,95
-
APWV (m/s)
15,3
13,2
-
APWV: aortic pulse wave velocity; BP: blood pressure.
Six months after the procedure, the patient had lower
office and ABPM BP, in use of four classes of antihypertensive
drugs (Table 1). After one year, the patient remained little
symptomatic, with improved quality of life, without any serious
hypertensive crisis. Evolutionary office and ABPM BP data, as
well as the arterial properties are shown in Table 1. After six
months, angiography of renal arteries showed no stenosis.
Discussion
This is the first experience of RSD held in Brazil with
catheter ablation used for arrhythmias in children. The results
showed the safety of the procedure, and satisfactory BP control
and quality of life results.
The first study using this technique demonstrated safety
and significant BP reduction in 58 patients with resistant
hypertension10. Average reduction in systolic and diastolic BP,
respectively, was 22/11 mmHg in six months, and 27/17 mmHg
in twelve months.
In 2010, an international multicenter trial studied
106 patients, 52 assigned to intervention and 54 assigned to
clinical treatment. After six months, there was a decrease in
office BP of 33/11 mmHg in those undergoing the procedure
compared to the medical group. Among patients undergoing
denervation, 20% reduced antihypertensive drugs and in
84% BP decreased 10 mmHg or more2. There were no
serious complications related to the procedure.
All studies show high success rate after RSD in patients
with resistant hypertension, with significant reduction in BP,
decreased dose and/or number of drugs, without causing
damage to the renal artery or impaired renal function1,9,10.
Regarding the case reported, RSD using conventional
electrophysiology catheter for ablation in children (5F) is safe and
effective. Adding electroanatomic mapping, we can accurately
assess renal artery sites where the applications were made, since
the strategy used in the denervation procedures is based on the
anatomy without immediate functional evaluations.
In the evolution, we observed improvement in 24-h, daytime
and especially nighttime BP (Table 1). Increased sympathetic
activity is one of the most important mechanisms of the absence
of nocturnal blood pressure falls during sleep, which could explain
the effect of a significant reduction in nocturnal BP in our patient.
We also assessed arterial properties through measurements
of pulse wave velocity and carotid distension. These rates are
markers of arterial function, whose changes may be involved
in the mechanisms of difficulty in controlling BP. Increased
sympathetic activity can increase arterial stiffness in patients with
resistant hypertension and improvement of these parameters in
the patient after denervation reinforces this interaction.
Ablation RSD is a safe and promising approach in
reducing blood pressure, and improves quality of life in
patients with resistant hypertension, even with catheters
used in cardiac electrophysiology.
Arq Bras Cardiol. 2013;101(4):e77-e79
e78
Bortolotto et al.
Denervation of renal artery by catheter ablation
Case Report
Author contributions
Conception and design of the research: Bortolotto LA,
Midlej-Brito T, Scanavacca M; Acquisition of data and
Analysis and interpretation of the data: Bortolotto LA,
Midlej-Brito T, Pisani C, Costa-Hong V, Scanavacca M;
Statistical analysis: Bortolotto LA, Midlej-Brito T; Writing
of the manuscript and Critical revision of the manuscript
for intellectual content: Bortolotto LA, Midlej-Brito T,
Pisani C, Scanavacca M.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation program.
References
1. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic
denervation for resistant hypertension: durability of blood pressure
reduction out to 24 months. Hypertension. 2011;57(5):911-7.
2. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M;
Symplicity HTN-2 Investigators Renal sympathetic denervation in patients
with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a
randomised controlled trial. Lancet. 2010;376(9756):1903-9.
3.
de Souza WS, Alessi A, Cordeiro A, da Rocha Nogueira A, Feitosa A, Amodeo
C, et al. First Brazilian position on resistant hypertension. Arq Bras Cardiol.
2012;99(1):576-85.
4.
Pimenta E, Calhoun DA. Resistant hypertension: incidence, prevalence, and
prognosis. Circulation. 2012;125(13):1594-6.
5. Esler M. The sympathetic system and hypertension. Am J Hypertens.
2000;13(6 Pt 2):99S-105S.
e79
Arq Bras Cardiol. 2013;101(4):e77-e79
6. DiBona GF. The sympathetic nervous system and hypertension: recent
developments. Hypertension. 2004;43(2):147-50.
7. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev.
1997;77(1):75-197.
8.
Baguet JP, Barone-Rochette G, Pépin JL. Hypertension and obstructive sleep
apnoea syndrome: current perspectives. J Hum Hypertens. 2009;23(7):431-43.
9. Witkowski A, Prejbisz A, Florczak E, Kądziela J, Śliwiński P, Bieleń P, et al.
Effects of renal sympathetic denervation on blood pressure, sleep apnea
course, and glycemic control in patients with resistant hypertension and
sleep apnea. Hypertension. 2011;58(4)559-65.
10. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus
K, et al. Catheter-based renal sympathetic denervation for resistant
hypertension: a multicentre safety and proof-of-principle cohort study.
Lancet. 2009;373(9671):1275-81.
Back to the cover
Case Report
Exuberant Pattern of Late Gadolinium Enhancement in Hypertrophic
Cardiomyopathy
Elsa Fernandes, Gabriel C. Camargo, Maria Eduarda Derenne, Tamara Rothstein, Ilan Gottlieb
CDPI - Clínica de Diagnóstico por Imagem, Rio de Janeiro, RJ - Brazil
Introduction
Hypertrophic cardiomyopathy (HCM) is the most common
form of genetic heart disease, with an incidence of 1: 500
individuals in the general population, being the most frequent
cause of sudden death in athletes and young adults in the
United States1,2.
Cardiac magnetic resonance imaging (CMRI) is a
noninvasive imaging method that allows the accurate
identification of various forms of hypertrophy, quantification
of ventricular volume and mass and characterization of
myocardial fibrosis through the late enhancement technique3.
The presence of myocardial fibrosis in CMRI is associated
with the risk of sudden death, ventricular tachycardia and
systolic dysfunction4. The presence of late enhancement is the
strongest predictor of worse prognosis, even after adjustment
for other factors such as maximum thickness and myocardial
mass, obstruction of the LV outflow tract and clinical variable5,6.
The purpose of this study is to report the case of a
patient with HCM, asymptomatic, with extensive/exuberant
myocardial fibrosis detected by CMRI and to discuss a potential
therapeutic implication.
Case Report
Patient aged 42, Caucasian, asymptomatic, with family
history of HCM and diagnosis of the same cardiomyopathy
22 years ago. The 24-h Holter heart rhythm monitoring
(April 5, 2012) showed sinus rhythm, rare atrial ectopic
beats, presence of 2,970 isolated ventricular extrasystoles
and five outbreaks of non-sustained ventricular tachycardia
(NSVT), the longest one presenting 13 QRS complexes. Given
the Holter results, the patient was referred by the assistant
physician to cardiac magnetic resonance imaging for a better
phenotypic characterization of the myocardium.
CMRI was performed on a 3T-Verio scanner (Siemens,
Germany) on May 9, 2012 and Cine SSFP (steady-state
free precession) sequences and were used for functional
Keywords
Cardiomyopathy, Hypertrophic; Endomyocardial Fibrosis;
Ventricular Dysfunction; Tachycardia Ventricular.
Mailing Address: Tamara Rothstein •
Rua Ataulfo de Paiva, 669, Leblon. Postal Code 22430-210,
Rio de Janeiro, RJ - Brazil
E-mail: [email protected]
Manuscript received October 18, 2012; manuscript revised October 23,
2012; manuscript accepted February 26, 2013.
DOI: 10.5935/abc.20130195
e80
assessment and Inversion Recovery-GRE (gradient echo)
for the late enhancement. The following observations
were made: severe asymmetric hypertrophy, where the
point of greatest thickness was measured at 2.4 cm on
the mid inferoseptal wall; normal left ventricular mass;
outbreaks of hypointense signal on all sequences in
the septal and anterior mid-apical LV walls, which may
represent calcifications; LV of normal cavity volumes with
mild global systolic dysfunction at the expense of segmental
hypokinesis of the anterior and septal walls; severe muscular
thickening of the RV apical region; late enhancement on
contrast media in hypertrophied LV and RV segments of
predominantly mesocardial distribution (nonischemic
pattern). Figures 1 and 2 illustrate some of these findings.
The patient underwent implantation of cardioverter on
June 2, 2012 and remains asymptomatic to date.
Discussion
The patient under discussion has had longtime
hypertrophic cardiomyopathy (for 22 years) with biventricular
involvement, severe myocardial fibrosis and mild systolic
dysfunction. There were no classical markers of high risk
for sudden death, such as myocardial thickness ≥ 30 mm,
family history of sudden death, syncope, ventricular
tachycardia (VT) or obstruction of the LV outflow tract or
abnormal behavior of blood pressure during exercise testing.
The markers that suggested that this patient was at higher risk
for sudden death were non-sustained ventricular tachycardia
and the presence of severe late enhancement on MRI.
Although sustained VT is clearly associated with sudden
death, the association with non-sustained VT is less
robust. However, a recent study showed no association of
non‑sustained VT with death in multivariate analysis7.
The detection of myocardial fibrosis in HCM by CMRI
using the late enhancement technique has an incidence
of 50-80% of cases of hypertrophic cardiomyopathy and is
believed to be the anatomical substrate for the occurrence
of malign ventricular tachyarrhythmias8,9.
The late enhancement pattern most often described is the
heterogeneous and mesocardial pattern, preferably located
in hypertrophied segments and at the points of insertion
of the right ventricle with the interventricular septum4,9.
In the clinical case reported, only the anterolateral and
inferolateral segments (both basal and mid) and lower
basal were free of late enhancement, which characterizes
a pattern of an unusual presentation.
In the patient reported, the late enhancement area
measured using five standard deviations of the remote area
is 46.9% of the left ventricular mass. There is no consensus
Fernandes et al.
Presence of late enhancement in hypertrophic cardiomyopathy
Case Report
Figure 1 – 4-chamber long axis image. Septal hypertrophy and hypertrophy of the apical portion of the RV and a potential calcification in the apical septum (hypointense
signal area — arrow).
Figure 2 - Images of late enhancement in 4-chamber (A), 3-chamber (B) and 2-chamber (C) long-axis and short-axis (D). Presence of diffuse enhancement, including
in the RV middle-apical region (A and D).
Arq Bras Cardiol. 2013;101(4):e80-e82
e81
Fernandes et al.
Presence of late enhancement in hypertrophic cardiomyopathy
Case Report
on what percentage value should be considered higher risk
for adverse events, but 46.9% is certainly considered a high
percentage. Some studies show that the presence of late
enhancement above 5% of the LV mass is associated with
increased risk of sudden death, appropriate therapy by
implantable defibrillator and ventricular tachyarrhythmia5,10.
The right ventricular involvement has been reported in
approximately 18% of patients with HCM, affecting the
middle and apical region also found in the clinical case
reported4. These patients may have maximum wall thickness
greater than 8 mm, as well as increased right ventricular
mass8. The presence of severe late enhancement in the right
ventricle in this patient is another atypical characteristic.
The apparent discrepancy between the maximum
myocardial thickness and the severe late enhancement
may result from burnt out hypertrophic cardiomyopathy,
i.e., fibrosis and ventricular thinning due to disease
duration. Myocardial calcifications may corroborate this
long aggression on the cardiac muscle11.
The importance of late enhancement in patients with
hypertrophic cardiomyopathy was investigated in two recent
studies, and both demonstrated that the enhancement is not
only an independent predictor of cardiovascular events in
multivariate analysis, but also the best predictor compared
to the usual predictors, such as maximum myocardial
thickness, obstruction of the LV outflow tract, clinical
factors and family history of sudden death5,6. However, we
recognize that the presence of late enhancement has a low
positive predictive value for sudden death as mentioned in
the guidelines of the ACC/AHA of 20112, and confirmed
in a meta-analysis in which the presence of enhancement
was significantly associated with cardiovascular outcomes,
but not with mortality from arrhythmia12.
The patient has no classical markers of high risk for sudden
death, and the decision to implant ICD was made based on the
presence of NSVT on 24-h Holter, severe myocardial fibrosis
on MRI after discussion of risks and benefits with the patient
and the family. The presence of late enhancement by CMRI is
an emerging marker of prognosis, but its role in directing the
therapy is still controversial.
Author contributions
Conception and design of the research and Analysis and
interpretation of the data: Gottlieb I ; Acquisition of data:
Fernandes E, Camargo GC, Rothstein T, Gottlieb I; Writing of
the manuscript: Fernandes E, Gottlieb I; Critical revision of the
manuscript for intellectual content: Camargo GC, Derenne
ME, Rothstein T, Gottlieb I.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation program.
References
1. Maron BJ. Hypertrophic cardiomyophaty: a systematic review. JAMA.
2002;287(10):1308-20.
2. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et
al; American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines; American Association
for Thoracic Surgery; American Society of Echocardiography; American
Society of Nuclear Cardiology; Heart Failure Society of America;
Heart Rhythm Society; Society for Cardiovascular Angiography
and Interventions; Society of Thoracic Surgeons. 2011 ACCF/
AHA Guideline for the Diagnosis and Treatment of Hypertrophic
Cardiomyopathy: A Report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines. Circulation. 2011;124(24):e783-831.
3. Shiozaki AA, Raymond JK, Parga JR, Tassi EM, Arteaga E, Rochitte CE.
Ressonância magnética cardiovascular na cardiomiopatia hipertrófica. Arq
Bras Cardiol. 2007;88(2):243-8.
4. Noureldin RA, Liu S, Nacif M, Judge D, Halushka M, Abraham T, et al. The
diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic
resonance. J Cardiovasc Magn Reson. 2012;14:17.
5. O´Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R,
et al: Prognostic significance of myocardial fibrosis in hypertrophic
cardiomyopathy. J Am Coll Cardiol. 2010;56(11):867-74.
e82
Arq Bras Cardiol. 2013;101(4):e80-e82
6. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, et al.
Myocardial scar visualized by cardiovascular magnetic resonance imaging
predicts major adverse in patients with hypertrophic cardiomyopathy. J Am
Coll Cardiol. 2010;56(11):875-87.
7. Elliott PM, Gimeno JR, Tomé MT, Shah J, Ward D, Thaman R, et al. Left
ventricular outflow tract obstruction and sudden death risk in patients with
hypertrophic cardiomyopathy. Eur Heart J. 2006;27(16):1933-41.
8. Maron MS. Clinical utility of cardiovascular magnetic resonance in
hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2012;14:13.
9. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson
CM, et al: Occurrence and frequency of arrhythmias in hypertrophic
cardiomyopathy in rElation to delayed enhancement on cardiovascular
resonance. J Am Coll Cardiol 2008, 51: 1369-1374.
10. Fluechter S et al: extent of late gadolinium enhancement detected by
cardiovascular magnetic resonance correlates with the inducibility of
ventricular tachyarrhythmia in hypertrophic cardiomyopathy. journal of
cardivascular magnetic resonance 2010, 12:2-8
11. Hughes SE, Mckenna WJ: New insights into the pathology of inherited
cardiomyopathy. Heart 2005, 91(2): 257-264.
12. Green JJ, Berger JS, Kramer CM, Salermo M: Prognostic value of late
gadolinium enhancement in clinical outcomes for hypertrophic
cardiomyopathy. J Am Coll Cardiol Imaging 2012, 5 (4): 370-377.
Back to the cover
Viewpoint
Paternalism, Autonomy and Ontology
Max Grinberg and Antonio Sergio de Santis Andrade Lopes
InCor – HCFMUSP, São Paulo, SP – Brazil
The bond with the patient, in the asymptomatic phase of
natural history of the rheumatic heart valve disease (RHVD),
provided certain lessons for the communication physicianpatient that respects both beneficent paternalism of Medicine
(guidelines, for example), and values and preferences of the
human being (principle of autonomy).
Alliance among nature and medicine
As said by Aristotle (384 BC-322 B.C.), Nature favors
utilities and, therefore, when a RHVD occurs, it is the
natural heart plasticity, held as Adaptation for Beneficial Cardiac Ontological Remodeling (AB-COR), or simply heart
remodeling1, that sustains the preservation of good ejection
performance.
Medicine validates AB-COR "therapeutic" effect and advises
against interruption with the use of drugs, plastic surgeries, and
valvular prosthesis while the patient remains asymptomatic,
i.e. myocardium is then signaled 2 and is under active
surveillance. It is known the participation of this "therapeutic
of Nature" in algorithms of guidelines on valvopathy3 using
intersection Symptoms?
But such "therapeutic" of Nature has an expiry date and,
when AB-COR utility is over4, surviving RHVD requires the
administration of technoscience of Medicine.
Naturism and heart
The natural adaptive capacity of myocardium has universal
laws "promulgated" by remarkable people such as Otto Frank
(1865-1944), Ernest Starling (1866-1927), Pierre Simon,
Marquês de Laplace (1749-1827), and Jean-Louis-Marie
Poiseuille (1797-1869). But Thomas Wilkinson King (18091847)5 noticed in an isolated heart that tricuspid valve opens
at a certain pressure with certain volume of fluid, which does
not happen to mitral valve, presuming Nature made the
tricuspid valve a safety valve. The volume overload determined
by "tricuspidization" means, therefore, a help of Nature in
Keywords
Cardiomyopathies; Heart Valve Diseases; Rheumatic Heart
Disease; Paternalism.
Mailing Address: Max Grinberg •
Rua Manoel Antonio Pinto, 04, apto. 21A, Paraisópolis. Postal Code 05663-020,
São Paulo, SP - Brazil
E-mail: [email protected], [email protected]
Manuscript received March 11, 2013, revised manuscript April 26, 2013;
accepted May 03, 2013.
DOI: 10.5935/abc.20130196
e83
view of the limitation of right ventricle in order to withstand
pressure overloads.
Remodeled myocardium and insufficient tricuspid
valve are, therefore, natural utilities of human survival,
comprehensible, either based on Edward Stone's (1702-1768)
rational theology, that the Nature places the medicine along
with the disease - he found in a swamp, place of fevers, that
the willow bark has acetylsalicylic acid - or by evolutionism.
Consent
Activation of "therapeutic” plasticity6 of AB-COR happens
naturally, such as wound healing, coagulation, and bone callus.
It is self, and the organic freedom of happening discards the
patient's consent and specially rationale on the potential of
adversities, as a future systolic myocardial failure – such as a
wound healing may result in keloid, coagulation may result in
mass effect, and bone callus may perpetuate misalignments.
Therefore, there is a similarity of the exposed and the
deontological denial of autonomy to the human whose life
is at imminent risk.
It should be noted that the Nature "therapeutic" under
active surveillance represents the replacement of the patient's
unconscious submission by consent form to disclosure by the
physician. And when the "prescriptive endorsement" of self
acting for life quality maintenance by the patient is no longer
valid, technoscience administration should be granted to the
physician, i.e. it requires from a human (physician) - and not
Nature - a noncoercion certificate. The emphasis of autonomy
in Medicine emerged from violence between human beings
which could not be perceived as natural.
Physician-patient communication
For supporting a usually long term asymptomatic phase
of RHDV, AB-COR provides frequent physician-patient
conversations, from one medical appointment to another,
in which, gradually, more realistic expectations are molded,
and giving clarity on future consent situations. These are
opportunities where the use of narrative competence7 helps
to improve the absorption, interpretation, and response of
the patient regarding explanations on medical resources,
contributing to aggregate empathy, professionalism, and trust.
Thus, when the patient needs to perform the surgery, this
decision becomes less stressful, because the prior moments
developed the basis for this consent. This avoids the large
amount of "new" information for an immediate response and,
therefore, according to hot-cold empathy gap8, concerning
emotions on decision making, this reduces the probability of
poor future analysis (patient prioritizes getting rid of diseases
Grinberg & Lopes
Paternalism, autonomy and ontology
Viewpoint
at that moment and does not assess future consequences of
the method) and sub-treatment (patient rejects the medical
recommendation due to an excessive impact of possible
adversities).
Moreover, having the perception that Nature provides the
benefit of AB-COR without anticipating inherent negative
consequences, proves that communication considering a future
consent term in order to obtain a benefit must be more emphatic
than the possible adversities, avoiding early frustrations.
Time for a conversation, time for critical analysis, and time to
use good common sense are situations that benefit the freedom
of speech, elucidate opposite opinions between what medical
knowledge justifies and the consent of a patient's individuality.
So, remembering Pitágoras de Samos (580 B.C.-497 B.C.),
who realized that the combination of organization and time is
enough to do anything and do it right, and Sigismund Schlomo
Freud (1856-1939), who knew intuitively that countless
unconscious processes have an impact on a conscious
attitude, the time spent on physician-patient intersubjectivity
contributes to the ethical value of integrating deliberation,
system availability, and effective deployment of diagnostic
and therapeutic processes.
Lesson on paternalism/autonomy
The great lesson on AB-COR "therapeutic of nature" in
Bioethics is the inconvenience of a radical negative view
of paternalism. The Manichaeism (Manes, 3rd century),
paternalism is bad and autonomy is good, can restrict the
physician when understanding that it is essential to be more
persuasive with a particular hesitating patient, as this is a
more acceptable behavior in response to the clinical need.
Not settling for being a Poncio Pilatos means to make good
use of the professional tension9 supported by cautiousness
and diligence that enhances the perception on reconciliation
between the singularities of medical evidence and diversity of
patient behaviors - often on opposite sides. Thus, the physician is
able to make more adequate adaptations in order to match the
practice of two sequential articles of the Code of Medical Ethics
from 2010, with the main section the physician is not allowed
to: art. 31 - Disregard the patient's right to freely decide on the
use of diagnostic or therapeutic practices; art 32 - Not employ
every available diagnostic and treatment measures, scientifically
renown and at the physician's reach, to benefit the patient.
The physician's effort to obtain the consent for a justifiable
technoscience for a particular case does not make the patient
feel unsure of the decision, because there is no pretense in
suppressing free thought, the purpose is merely the choice
rationality. Trying to convince10 is a cooperation morally
acceptable to whom sought you to lead, it is an encouragement
to inertia reaction, a sound argument in favor of survival, it is
understanding human hesitations about the drop (in relation to
animals) of instinctive efficiency. Overall, when facing emotional
situations too strong to be rationalized, it is contributing to make
the patient aware that the denial may represent a negative
progress of the clinical condition, resulting in carrying out what
is being proposed under worse prognosis. This is not about
brainwash, simply because the physician would accept the
recommendation himself.
The structure of a communication on technoscience which
is fed-back by a desirable compassion that goes beyond the
informative-clarifying, which sounds like a theory class, is
characterized by what Erich Fromm (1900-1980) called benign
narcissism, i.e. a glimpse of a scientific reality reflected by the
case which, however, it does not shut its eyes for a different
point of view, perhaps considered by the patient. Authority
without authoritarianism.
Longevity of the asymptomatic phase of valvular disease
(AB-COR-dependent) that provides time-facilitation for good
physician-patient intersubjectivity practices legitimately paves
the way to deliberation on surveillance, which has a start
point in paternalism (physician's proposal) and guidance to
autonomy (patient's adaptation), with several exits along the
route, each accordingly appropriate to the specific realities of
each physician-patient relationship.
Absolute paternalism or autonomy is a chimera that in an
elective surgery causes resentment, which does not comply with
the articles of the Code of Medical Ethics. Nature temporality
serves as a guide for the cautiousness of a communication based
on "pencil and rubber." Through drawing, fences become
bridges that connect the good according to the physician and
patient. The pencil tip is strengthened by rational medicine
comprehended by the patient and the rubber would become
softer as the physician understands how the patient expresses
his needs and desires.
Basically, a continuous and structured physician-patient
communication can reduce asymmetries between what is
shown by Medicine and the irrefutable patient's feelings
and, then, give shape and spontaneity to decision makings.
Subsequently, paternalism slides towards autonomy, pari
passu, looking for the most appropriate point of equilibrium
in between.
Finally, AB-COR acronym represents the modeling of
physician-patient relationship that seeks a consent and
legitimate Medicine in addition to technicism, each letter
with a double meaning: Autonomy/Acceptance, Beneficence/
Brazilianness, Communication/Compassion, Organization/
Optimism, and Respect/Realism.
Author contributions
Conception and design of the research, Writing of the
manuscript and Critical revision of the manuscript for
intellectual content: Grinberg M, Lopes ASSA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation
program.
Arq Bras Cardiol. 2013;101(4):e83-e85
e84
Grinberg & Lopes
Paternalism, autonomy and ontology
Viewpoint
References
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2. Frangogiannis NG. Matricellular proteins in cardiac adaptation and
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7. Sutrop M. Viewpoint: how to avoid a dichotomy between autonomy and
beneficence: from liberalism to communitarianism and beyond. J Intern
Med. 2011;269(4):375-9.
3. Tarasoutchi F, Montera MW, Grinberg M, Barbosa MR, Piñeiro DJ,
Sánchez CR, et al; Sociedade Brasileira de Cardiologia. Diretriz Brasileira
de Valvopatias - SBC 2011 / I Diretriz Interamericana de Valvopatias SIAC 2011. Arq Bras Cardiol. 2011;97(5 supl. 3):1-67.
8. Charon R. The patient-physician relationship. Narrative medicine:
a model for empathy, reflection, profession, and trust. JAMA.
2001;286(15):1897-902.
4. Ferreira JC, Boer BP, Grinberg M, Brum PC, Mochly-Rosen D. Protein
quality control disruption by PKCbii in heart failure; rescue by the
selective PKCbii inhinitor, bIIV5-3. PLoS One. 2012;7(3):e33175.
9. Grinberg M. Prudência na conduta em valvopatia. Arq Bras Cardiol.
2013;100:e38-e40.
5. King TW. An essay safety-valve function in the right ventricle of the human
heart and the gradations of this function in the circulation of warmedblooded animals. London: S. Highley; 1837.
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10. Loewenstein G. Hot-cold empathy gaps and medical decision making.
Health Psychol. 2005;24(4 Suppl):S49-56.