Original Article - Arquivos Brasileiros de Cardiologia

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www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 106, Nº 4, April 2016
Figure 1 – Page 349
Original Article
Review Article
Potential Utility of the SYNTAX Score 2 in Patients Undergoing Left
Network Meta-analysis to Synthesize Evidence for Decision Making in
Main Angioplasty
Cardiovascular Research
Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose
Viewpoint
Associated with Ezetimibe
Protective Effect of Aortic Stenosis on the Coronary Arteries.
Risk Prediction of Cardiovascular Complications in Pregnant Women
Hypothetic Considerations to an Old Enigma
With Heart Disease
Clinicoradiological Session
Cardiac Autonomic Adjustments During Baroreflex Test in Obese and
Case 3/2016 – 36-Year-Old Man with Anomalous Origin of the Right
Non-Obese Preadolescents
Coronary Artery in the Left Sinus of Valsalva and Interarterial Course
Serial High-Sensitivity Troponin T in Post-Primary Angioplasty Exercise Test
Case Report
Aerobic Training after Myocardial Infarction: Remodeling Evaluated by
Platypnea-Orthodeoxia Syndrome Due to Venovenous Malformation
Cardiac Magnetic Resonance
Image
Correlation of Insulin Resistance with Anthropometric Measures and
Congenital Muscular Interventricular Septal Malformation with
Blood Pressure in Adolescents
Complex Anatomical Features
Assessment of Intima-Media Thickness in Healthy Children Aged 1 to
Letter To the Editor
15 Years
Circulatory Support as a Bridge to Pediatric Heart Transplantation
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Original Articles
Coronary Angioplasty with and without Stent
Potential Utility of the SYNTAX Score 2 in Patients Undergoing Left Main Angioplasty
Sérgio Madeira, Luís Raposo, João Brito, Ricardo Rodrigues, Pedro Gonçalves, Rui Teles, Henrique Gabriel,
Francisco Machado, Manuel Almeida, Miguel Mendes
.....................................................................................................................................................................page 270
Atherosclerosis/Endothelium/Vascular
Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe
Maristela Magnavita Oliveira Garcia, Carolina Garcez Varela, Patricia Fontes Silva, Paulo Roberto Passos Lima,
Paulo Meira Góes, Marilia Galeffi Rodrigues, Maria de Lourdes Lima Souza e Silva, Ana Marice Teixeira Ladeia,
Armênio Costa Guimarães, Luis Claudio Lemos Correia
.....................................................................................................................................................................page 279
Heart disease and pregnancy
Risk Prediction of Cardiovascular Complications in Pregnant Women With Heart Disease
Luciana Carvalho Martins, Claudia Maria Vilas Freire, Carolina Andrade Bragança Capuruçu, Maria do Carmo
Pereira Nunes, Cezar Alencar de Lima Rezende
.....................................................................................................................................................................page 289
Pediatric Cardiology
Cardiac Autonomic Adjustments During Baroreflex Test in Obese and Non-Obese Preadolescents
Mário Augusto Paschoal, Aline Carnio Brunelli, Gabriela Midori Tamaki, Sofia Serafim Magela
.....................................................................................................................................................................page 297
Exercise Stress Testing
Serial High-Sensitivity Troponin T in Post-Primary Angioplasty Exercise Test
Humberto Andres Vaz, Ana Paula Vanz, Iran Castro
.....................................................................................................................................................................page 304
Ventricular Function / Cardiac Remodeling
Aerobic Training after Myocardial Infarction: Remodeling Evaluated by Cardiac Magnetic Resonance
Nataly Lino Izeli, Aurélia Juliana dos Santos, Júlio César Crescêncio, Ana Clara Campagnolo Real Gonçalves,
Valéria Papa, Fabiana Marques, Antônio Pazin-Filho, Lourenço Gallo-Júnior, André Schmidt
.....................................................................................................................................................................page 311
Arquivos Brasileiros de Cardiologia - Volume 106, Nº 4, April 2016
Hypertension
Correlation of Insulin Resistance with Anthropometric Measures and Blood Pressure in Adolescents
Polyana Resende Silva de Morais, Ana Luiza Lima Sousa, Thiago de Souza Veiga Jardim, Flávia Miquetichuc
Nogueira Nascente, Karla Lorena Mendonça, Thaís Inácio Rolim Povoa, Carolina de Souza Carneiro, Vanessa
Roriz Ferreira, Weimar Kunz Sebba Barroso de Souza, Paulo César Brandão Veiga Jardim
.....................................................................................................................................................................page 319
Vascular Ultrasonography
Assessment of Intima-Media Thickness in Healthy Children Aged 1 to 15 Years
Liz Andréa Villela Baroncini, Lucimary de Castro Sylvestre, Roberto Pecoits Filho
.....................................................................................................................................................................page 327
Review Article
Network Meta-analysis to Synthesize Evidence for Decision Making in Cardiovascular Research
Leonardo Roever e Giuseppe Biondi-Zoccai
.....................................................................................................................................................................page 333
Viewpoint
Protective Effect of Aortic Stenosis on the Coronary Arteries. Hypothetic Considerations to an
Old Enigma
Paulo Roberto Barbosa Evora, Livia Arcêncio, Alfredo José Rodrigues, André Schmidt
.....................................................................................................................................................................page 338
Case 3/2016 – 36-Year-Old Man with Anomalous Origin of the Right Coronary Artery in the Left
Sinus of Valsalva and Interarterial Course
Edmar Atik, Roberto Kalil Filho, Marcelo Jatene
.....................................................................................................................................................................page 342
Case Report
Meng-Luen Lee and Ing-Sh Chiu
.....................................................................................................................................................................page 345
Image
Congenital Muscular Interventricular Septal Malformation with Complex Anatomical Features
Zafer ışılak, Mehmet Uzun, Ejder Kardeşoğlu, Ömer Uz, Uğur Küçük
.....................................................................................................................................................................page 349
Letter To the Editor
Fernando A. Atik
.....................................................................................................................................................................page 350
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
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Back to The Cover
Original Article
Potential Utility of the SYNTAX Score 2 in Patients Undergoing Left
Main Angioplasty
Sérgio Madeira1, Luís Raposo1, João Brito1, Ricardo Rodrigues1, Pedro Gonçalves1, Rui Teles1, Henrique Gabriel1,
Francisco Machado2, Manuel Almeida1, Miguel Mendes1
UNICARV – Serviço de Cardiologia - Hospital de Santa Cruz - Centro Hospitalar de Lisboa Ocidental1, Carnaxide – Portugal; Hospital da Luz –
Luz Saúde2, Lisboa – Portugal
Abstract
Background: The revascularization strategy of the left main disease is determinant for clinical outcomes.
Objective: We sought to 1) validate and compare the performance of the SYNTAX Score 1 and 2 for predicting major
cardiovascular events at 4 years in patients who underwent unprotected left main angioplasty and 2) evaluate the
long‑term outcome according to the SYNTAX score 2-recommended revascularization strategy. Methods: We retrospectively studied 132 patients from a single-centre registry who underwent unprotected left main
angioplasty between March 1999 and December 2010. Discrimination and calibration of both models were assessed by
ROC curve analysis, calibration curves and the Hosmer-Lemeshow test.
Results: Total event rate was 26.5% at 4 years. The AUC for the SYNTAX Score 1 and SYNTAX Score 2 for percutaneous
coronary intervention, was 0.61 (95% CI: 0.49-0.73) and 0.67 (95% CI: 0.57-0.78), respectively. Despite a good overall
adjustment for both models, the SYNTAX Score 2 tended to underpredict risk. In the 47 patients (36%) who should
have undergone surgery according to the SYNTAX Score 2, event rate was numerically higher (30% vs. 25%; p = 0.54),
and for those with a higher difference between the two SYNTAX Score 2 scores (Percutaneous coronary intervention vs.
Coronary artery by-pass graft risk estimation greater than 5.7%), event rate was almost double (40% vs. 22%; p = 0.2).
Conclusion: The SYNTAX Score 2 may allow a better and individualized risk stratification of patients who need
revascularization of an unprotected left main coronary artery. Prospective studies are needed for further validation.
(Arq Bras Cardiol. 2016; 106(4):270-278)
Keywords: Angioplasty Balloon Coronary / adverse effects; Coronary Artery Bypass / adverse effects; Myocardial
Revascularization; Coronary Artery Disease / surgery; Risk Assessment; Risk Factors.
Introduction
Unprotected left main coronary artery disease (ULMD)
is associated with poor prognosis when medically treated.1
Large-scale trials and meta-analysis support that survival is at
least similar for both coronary artery by-pass graft (CABG) and
percutaneous coronary intervention (PCI) up to 5 years.2-4
This consistent non-inferiority has been reflected in the
current European revascularization guidelines with PCI of
the ULMD being upgraded to a class I and IIa for patients
with a low and intermediate SYNTAX (Synergy Between
PCI with Taxus and Cardiac Surgery) score, respectively.5,6
Nonetheless, selecting the optimal revascularization strategy
remains challenging. Despite the inherent strengths and
limitations, risk stratification tools are useful as adjuncts for
decision-making particularly in the Heart Team setting.7-10
Mailing Address: Sérgio Lourenço Madeira •
Hospital de Santa Cruz. Avenida Prof. Reinaldo dos Santos, 2790-134,
Carnaxide. Postal Code 2700, Lisboa – Portugal
Manuscript received May 20, 2015; revised manuscript January 04, 2016;
accepted January 06, 2016.
DOI: 10.5935/abc.20160038
270
The SYNTAX Score 1 (SS1) was created as part of the
SYNTAX trial9,11 in order to objectively characterize the severity
of coronary artery disease (CAD), stratifying patients into low
(SS1 < 22), intermediate (SS1 23-32) and high (SS1 > 33)
risk tertiles.12 Within this population, the 5-year follow-up
supports PCI as an acceptable alternative in patients with
ULMD and a low or intermediate risk SS1.13 In addition,
the prognostic value and usefulness of the SS1 has been
extensively studied and substantiated ULMD PCI patients.14-18
However some limitations have been pointed out, namely
the absence of clinical variables, the lack of a personalised
approach to decision-making and the lack of predictive ability
in the CABG subset of patients.8,19-21
The SYNTAX Score 2 (SS2) emerged to overcome those
limitations, by incorporating prognostically important clinical
variables and by making an individualised estimate of mortality
risk associated with each revascularization strategy.8 By applying
the SS2 in the all-comers population of the SYNTAX trial it was
shown that subsets of patients existed in all tertiles of SS1 in
which both CABG and PCI would confer mortality benefit.8
We sought to validate and compare the performances of the
SS1 and the SS2 as predictors of major cardiovascular events
(MACE) at 4 years in patients who underwent ULMD PCI.
Madeira et al.
Clinical Syntax Score in left main disease
Original Article
Furthermore, we aimed to evaluate the long-term outcome
according to the SS2 recommended revascularization in a
ULMD PCI population.
Methods
Patient population and data collection
This was a single-centre, retrospective, observational
study that included 132 patients who underwent ULMD
PCI between March 1999 and December 2010 with at
least one stent implanted in the left main coronary artery.
The interventional strategy was left to the discretion of the treating
operator. Acceptance of the patient for ULMD stenting required
consensus of the Heart Team in the elective cases. All data
concerning demographic, clinical, angiographic and procedural
characteristics were prospectively entered in our institutional
cath lab-based and dedicated database. Post-discharge clinical
follow‑up was performed during scheduled outpatient visits
or telephone interviews. All angiograms were retrospectively
analyzed, by two operators blinded for clinical outcomes, for
assessment of the angiographic variables necessary for the
calculation of the SS1. The SS1 was calculated using the online
calculator. The SS2 was estimated manually in each patient
for both revascularization strategies (SS2 for PCI and SS2 for
CABG) by matching the sum of points of both clinical (age, sex,
chronic obstructive pulmonary disease, creatinine clearance,
left ventricular ejection fraction and peripheral artery disease)
and angiographic variables (SS1 and left main disease) with the
corresponding prediction, using the published nomogram.8
Definitions
The left main stem was defined as unprotected if there
was no patent bypass graft to the left anterior descending
artery or the circumflex artery. Acute myocardial infarction
during follow-up was defined according to the 2012 third
universal definition of myocardial infarction,22 applied
retrospectively. Target vessel revascularization and target
lesion revascularization were defined as any revascularization
procedure of the target vessel or target lesion (from 5 mm distal
to the stent up to 5 mm proximal to the stent), respectively.
Cardiovascular death was defined as death due to a
demonstrable cardiovascular cause or any unexplained death.
Stroke was defined as new neurological defect adjudicated
by a neurologist based on clinical and imaging features.
The primary endpoint (MACE) was defined as the composite
outcome of death, nonfatal myocardial infarction, target-vessel
revascularization and stroke.
Statistical analysis
Continuous variables were expressed as means and
standard deviation when normally distributed, and as medians
and interquartile range when not normally distributed.
Normality was tested with the Kolmogorov-Smirnov test
and/or Q-Q Plot visual assessment. Discrete variables were
expressed as frequencies and percentages. Event-free survival
was computed using Kaplan-Meyer estimates.
The performance of the SYNTAX models was analyzed
focusing on discriminative power and calibration.
Discrimination indicates the extent to which the model
distinguishes between patients who will or will not have
MACE. It was evaluated by constructing receiver operating
characteristic (ROC) curves for each model. The comparison
between curves was assessed with the method described by
DeLong et al.23 Calibration refers to the agreement between
observed outcomes and predictions, and was evaluated
by using calibration curves and the Hosmer-Lemeshow
goodness-of-fit test. Calibration curves were constructed by
plotting predictions in the X-axis and the observed outcome
in the Y-axis (by decile of the score-derived predictions).
Subsequently a linear regression was applied to the plot
and a trend line was inferred. The resulting plots allow for a
visual comparison between the predicted and the observed
probability of the outcome and are characterized by an
intercept, which indicates the extent to which predictions
are systematically low or high, and a calibration slope, which
should be zero in the ideal scenario. The perfectly calibrated
predictions stay on the 45-degree line, while a curve below
or above the diagonal, respectively, reflects over- and
under‑prediction, respectively. Furthermore, calibration was
tested with the Hosmer–Lemeshow goodness-of-fit test.
The comparison of baseline characteristics and MACE
occurrence between patients in whom SS2 favored CABG
versus those in whom it favored PCI was performed using the
chi-square test or Fisher’s exact test, when appropriate, for
categorical variables, and the Student t test or the Satterthwaite
test for continuous variables.
Additionally, the best discriminative value of the difference
between SS2 PCI and SS2 CABG for MACE prediction at four
years in patients in whom SS2 favoured CABG was determined
by c-statistics.
All tests were two-sided and differences were considered
statistically significant at a p-value of 0.05. Statistical analysis
was performed with SPSS 20.0 software (SPSS Inc., Chicago,
IL, USA) and MedCalc version 9.3.8.0 (MedCalc Software,
Acacialaan Ostend, Belgium).
Results
Baseline clinical, angiographic and procedural variables
The overall baseline clinical, angiographic, and procedural
characteristics in the whole population are shown in Table 1.
The median [interquartile range] SS1, SS2 for PCI and
SS2 for CABG were 22 [13.3−31.8], 7.2 [3.5−17.7] and 8.5
[4.6−18.8], respectively. Forty-seven patients (36%) had a SS2
for PCI greater than SS2 for CABG and therefore, theoretically,
should preferably have undergone CABG instead of PCI,
according to the SS2 recommendation (Table 2).
Patients in whom SS2 for PCI was higher than SS2 for CABG
(thus favoring CABG) were more likely to be females, smokers,
have depressed left ventricular ejection fraction, history of
previous PCI, three-vessel disease and presented more often
with an acute coronary syndrome (Table 1).
Arq Bras Cardiol. 2016; 106(4):270-278
271
Madeira et al.
Original Article
Table 1 – Population baseline characteristics
Total
(n = 132)
SS2_PCI > SS2_CABG
(n = 47)
SS2_PCI < SS2_CABG
(n = 85)
p value
66 ± 12
63 ± 14
67 ± 10
0.06
105 (79.5%)
25 (53%)
80 (94%)
< 0.001
Creatinin clearance (ml/min) (mean ± SD)
74 ± 33
69 ± 33
77 ± 32
0.2
Pulmonary chronic obstructive disease
6 (5%)
0
6 (7%)
0.08
20 (15%)
6 (13%)
14 (16.5%)
0.6
Baseline characteristics
SYNTAX Score 2 clinical features
Age (mean ± SD)
Male sex
Peripheral artery disease
Ejection fraction > 50%
93 (70%)
25 (53%)
68 (85%)
< 0.001
26 [24-28.6]
26 [23-29]
26 [24-28]
0.87
Diabetes
35 (27%)
12 (25%)
23 (27%)
1
Dyslipidaemia or statin treatment
92 (70%)
36 (77%)
56 (66%)
0.2
Hypertension on drug therapy
95 (72%)
34 (72%)
61 (71%)
1
BMI
Family history of cardiovascular disease
15 (11%)
5 (11%)
10 (12%)
0.54
Smoking (current)
23 (17%)
13 (28%)
10 (12%)
0.03
Previous PCI
43 (33%)
9 (19%)
34 (40%)
0.02
Stable CAD
70 (53%)
18 (38%)
52 (61%)
0.02
Acute coronary syndrome
61 (46%)
29 (62%)
32 (38%)
0.01
Unstable angina
16 (12%)
8 (17%)
8 (9%)
0.3
Non-ST elevation myocardial infarction
28 (21%)
13 (28%)
15 (18%)
0.2
ST-elevation myocardial infarction
17 (13%)
8 (17%)
9 (11%)
0.3
Clinical setting
Cardiogenic shock
9 (7%)
6 (7%)
3 (4%)
0.07
Multi-vessel CAD
62 (47%)
26 (55%)
36 (42%)
0.2
Three-vessel disease
19 (14%)
13 (28%)
6 (7%)
0.003
22 [13.3−32]
29 [18-38.5]
18 [13-26]
< 0.001
Glycoprotein IIb/IIIa inhibitors
52 (44%)
21 (48%)
31 (42%)
0.6
Drug-eluting stent implantation
95 (72%)
35 (74%)
60 (70%)
0.3
SYNTAX Score
Procedure-related characteristics
Other vessel PCI
71 (64%)
26 (59%)
45 (61%)
1
Complete revascularization
90 (76%)
26 (66%)
61 (82%)
0.04
SS2: SYNTAX Score 2; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; BMI: body mass index; CAD: coronary artery disease.
Table 2 – SYNTAX Score results
Score
22 [13.3 − 31.8]
SYNTAX 2 PCI
7.2 [3.5 − 17.7]
SYNTAX 2 CABG
8.5 [4.6 − 18.8]
SYNTAX 2 PCI – SYNTAX 2 CABG
-1.1 [-4.3 − 1.4]
SYNTAX 2 PCI > SYNTAX 2 CABG [n (%)]
PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; IQR: interquartile range.
272
Median (IQR)
SYNTAX 1
Arq Bras Cardiol. 2016; 106(4):270-278
47 (36%)
Madeira et al.
Original Article
Four-year outcomes
During the post-procedure 4-year interval, 35 MACE
occurred: 13 deaths, 14 repeated revascularization
procedures (7 percutaneous interventions and 7 CABG),
4 nonfatal myocardial infarction, and 4 strokes.
The median [interquartile range] time to first event
was 117 [25-200] days, with most events (n = 28; 80%)
occurring during the first year after the index procedure.
The cumulative annualized MACE rate was 21%, 26%, 27%
and 28% for the first, second, third and fourth years after
the intervention, respectively (Figure 1).
Performance of the SYNTAX 2 models
Because this is a cohort of patients that underwent PCI,
we only compared the SS1 with the SS2 for PCI.
Discriminative Power
With respect to 4-year MACE, the area under the ROC
curve (AUC) for the SS1 was 0.61 (95% CI, 0.49-0.73) and
0.67 (95% CI, 0.57-0.78) for the SS2 for PCI (Figure 2).
Despite being numerically superior for the SS2, the difference
was not statistically significant (DeLong test p = 0.08), but
there was a relevant trend towards better performance.
Concerning 4-year mortality, the AUC for the SS1 was 0.62
(95% CI, 0.46-0.78) and 0.69 (95% CI, 0.59-0.79) for the
SS2 for PCI (DeLong test p = 0.1).
Calibration
The pattern of calibration was different between the
two scores (Figure 3): the SS1 tended to underpredict risk
in patients at lower risk and to overpredict it in those at
high risk. On the other hand, the SS2 for PCI seemed to
underpredict risk across almost all risk spectrum, however
it gradually approaches the optimal calibration curve as
risk increases.
The calibration curve slope and intercept for SS1 and
SS2 for PCI are summarized on Table 3. Both scores had
nonsignificant p-values (p = 0.31 for SS1, and p = 0.27
for SS2) for the Hosmer-Lemeshow test indicating that they
would provide accurate probabilities.
Outcome of patients in whom SS2 would have
recommended a different revascularization strategy
Total MACE rate was numerically but nonsignificantly
higher in patients in whom the SS2 would have favoured
CABG (30% vs 25%; p=0.54) (Table 4).
To further explore what could be the difference in
the scores (SS2 PCI vs. SS2 CABG) that may be clinically
relevant, we used the best discriminative value for MACE
at 4 years of the difference between SS2 for PCI and SS2
for CABG in the 47 patient subgroup in whom SS2 would
have favoured CABG (Figure 4). When the difference was
greater than 5.7% (the cut-off value found by ROC curve
analysis), MACE rate was almost double (22% vs. 40%);
however this difference did not reach statistical significance
(p = 0.2) (Figure 4).
Discussion
The main findings of our study were: 1) both scoring
systems had a modest performance; 2) overall, the SS2
improved only slightly the performance of the purely
anatomic SS1; 3) MACE was nonsignificantly higher in those
patients that would have had a different revascularization
strategy according to the SS2; and 4) a difference between
SS2 PCI and CABG estimates greater than 5.7% may be
clinically relevant.
In general, these findings are in line with prior studies
assessing the association between the SS1 and clinical
outcomes, at different time points,14-17,21,24-26 indicating that
anatomical complexity alone may be rather insufficient
to warrant reliable risk stratification. Although in most
of the analysis the overall rate of ischemic events has
been systematically higher in patients in the highest risk
tertiles,15,17,24,26 the discriminative power for mortality and
MACE, in both PCI and especially in CABG-treated patients,
has been inconsistent. In a population of 949 UMLD cases
(400 PCI and 549 CABG), the AUCs of SS1 for 2-year
mortality were 0.73 and 0.56 for PCI- and CABG-treated
patients, respectively.19 In another ULMD cohort (n = 1580),
the SS1 showed only modest 3-year MACE prediction in
patients treated with drug-eluting stents (AUC 0.60), was
even worse for patients treated with bare metal stents and
CABG (0.48 and 0.51, respectively).21 In our study, the AUC
of the SS1 for 4-year MACE was 0.61, which is comparable
to that shown in other cohorts of ULMD PCI with shorter
follow‑up (AUCs for SS1 between 0.53 and 0.64).14,15,21,27
As in our dataset, others have also shown a poorer
discrimination of SS1 for overall composite MACE than for
cardiac mortality alone in patients undergoing PCI.8,14,15,19
Scarce data exists on the additional value of the SS2.
It has been externally validated for long-term mortality in
the Drug Eluting stent of left main coronary artery disease
(DELTA) registry,8 and in a large single-centre registry by Xu
et al.28 that included 1,528 patients with ULMD submitted
to PCI. In these cohorts, the SS2 showed an AUC for 4-year
mortality of 0.72 and 0.69, respectively, similar to that shown
in the original SYNTAX trial population (AUC of 0.73), clearly
outperforming the SS1 (AUCs of 0.57, 0.61 and 0.59, in
the SYNTAX, DELTA and Xu populations, respectively).8,28
Our results concerning mortality also compared favorably
to the ones obtained in these larger cohorts: the AUC of
the SS1 for 4-year mortality was 0.62 (which is similar to
the DELTA registry) and the c-statistic for the SS2-PCI was
0.69 (equal to the reported by the Xu registry28 and only
slightly lower than the observations in the DELTA registry
validation sets). These small differences may be due to a
smaller sample size, differences in the rate of the primary
endpoint and to the overfitting of the predictive score to
its derivation cohort. Recently, the SS2 was prospectively
applied to patients included in the Evaluation of the Xience
Everolimus Eluting Stent vs. Coronary Artery Bypas Surgery
for Effectiveness of Left Main Revascularization (EXCEL) trial.
It indicated equipoise for long-term mortality between CABG
and PCI in subjects with ULMD and intermediate anatomical
complexity, and strengthened the notion that both clinical
and anatomical features influence mortality predictions.29
Arq Bras Cardiol. 2016; 106(4):270-278
273
Madeira et al.
Original Article
1.0
Survival free of events
0.8
0.6
0.4
0.2
0.0
0
150
300
450
600
750
Days
750
1050
1200
1350
1500
Figure 1 – Major cardiovascular event (MACE)-free survival.
ROC curve analysis 4-year Mace
ROC curve analysis 4-year Mortality
1.0
0.8
0.8
0.6
0.6
Sensitivity
Sensitivity
1.0
0.4
0.2
0.4
0.2
Syntax
Syntax II_PCI
Syntax
Syntax II_PCI
0.0
0.0
0.2
0.4
0.6
1 - Specificity
0.8
1.0
0.0
0.0
0.2
0.4
0.6
1 - Specificity
0.8
1.0
Figure 2 – 1) SS1 and SS2 ROC curves for major cardiovascular events. (MACE) prediction at 4 years. 2) SS1 and SS2 ROC curves for mortality prediction
at 4 years.
274
Arq Bras Cardiol. 2016; 106(4):270-278
Madeira et al.
Original Article
Calibration Curve of SYNTAX II PCI
MACE at 4 years
Under prediction
Over prediction
MACE at 4 years
Calibration Curve of SYNTAX I
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
9
14
19
24
29
34
39
44
49
54
Predicted MACE at 4 years
Calibration Curve of SYNTAX I
59
64
69
74
Optimal calibration
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
1
6
11
16
21
26
31
36
41
46
51
56
Predicted MACE at 4 years
Calibration Curve of SYNTAX II
61
66
71
76
Optimal calibration
Figure 3 – SS1 and SS2 for PCI calibration curves. MACE: major cardiovascular events
Table 3 – Calibration parameters
SYNTAX 1
SYNTAX 2 PCI
Slope
0.59
0.75
Intercept
12.3
15.7
p-value
0.31
0,27
Chi-square
9.4
9.9
0.059
0.079
Calibration curve
Hosmer-Lemeshow test
Nagelkerke R
2
PCI: percutaneous coronary intervention.
The Hosmer-Lemeshow test p-value indicated an
overall acceptable calibration for both scoring systems;
moreover, the SS1 demonstrated a comparable p-value
to other registries. 15,27 The SS1 behaved differently
for low- and high-risk patients, underpredicting it in
the former and overpredicting in the latter (Figure 3).
This kind of performance can theoretically lead to an
unrealistic optimism in patients with less risk and at a
preposterous concern in those at highest risk. On the other
hand, the SS2 tends to underestimate risk progressively less
along the spectrum, with the worst performance for low-risk
patients and better for high-risk patients. For practical and
clinical purposes, the SS2 seems to have a more predictable
behavior and therefore should be better suitable for assisting
decision-making concerning the optimal revascularization
strategy. Overall, as previously outlined, the SS2 performed
better (although nonsignificantly) than the SS1 for predicting
MACE at 4 years (p = 0.08 for the comparison between
ROC curves).
It was expected that patients, who should have had
CABG instead of PCI according to the SS2 estimates,
might have had a higher MACE rate when undergoing PCI.
However, despite actually being numerically higher (30%
vs. 25%), the difference was not statistically significant.
In the Xu et al28 registry, which included nearly 10 times as
many patients as we did, there was no significant difference
in MACE rate between patients that would have had other
revascularization strategy according to SS2 (21.6% vs.
24.8%; p = NS).28 Still, in all cases it is not known whether
patients in either cohort would have had any less MACE
if they had undergone CABG instead in the first place.
On the other hand, in a pooled analysis of a heterogeneous
low-risk profile for a PCI cohort of 5,433 patients enrolled
in contemporary coronary stent trials, patients who should
have had CABG (less than 1% of all population) according
to the SS2 had higher 3-year mortality.30 However, in that
population, the difference in CAD complexity (assessed
by SS1) between the recommended treatment groups was
higher than in our cohort. This fact may in part explain the
difference found in outcome.
Conceptually, the SS2 would direct the decision
between either CABG or PCI on the basis of the estimated
risk for each revascularization strategy. The choice would
than theoretically “fall” for the strategy associated with
the lowest risk. Although this seems to be an intuitive
and rational policy, there is no established clinically
relevant threshold for the difference between SS2-PCI
and SS2‑CABG that should mandate a change in strategy.
Small and intermediate differences will remain controversial
and only large differences will be categorical when deciding
the optimal revascularization strategy.
In our cohort of patients undergoing PCI who would
have been reclassified for CABG by the SS2, the threshold
of the difference between SS2-PCI and SS2-CABG for
prediction of MACE was 5.7%. The MACE rate was
almost double in those patients with a difference greater
than 5.7% (40% vs. 22%). Despite not being statistically
significant (analysis of only 47 patients), this finding may be
clinically relevant, is surely hypothesis generating, should
be explored in larger cohorts including patients submitted
to both CABG and PCI, and, if confirmed, validated
prospectively in a clinical trial.
Arq Bras Cardiol. 2016; 106(4):270-278
275
Madeira et al.
Original Article
Table 4 – Outcomes according to SYNTAX Score 2 recommended revascularization strategy
Total
(n = 132)
SS2_PCI > SS2_CABG
(n = 47)
SS2_PCI < SS2_CABG
(n = 85)
p value
Total MACE
35 (28%)
14 (30%)
21 (25%)
0.5
Death
13 (10%)
6 (13%)
7 (8%)
0.5
CABG
7 (5%)
2 (4%)
5 (6%)
1
PCI
7 (5%)
3 (6%)
4 (5%)
0.7
Myocardial infarction
4 (3%)
2 (4%)
2 (2%)
0.6
Stroke
4 (3%)
1 (2%)
3 (4%)
1
Repeat revascularization
SS2: SYNTAX Score 2; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; MACE: major cardiovascular events.
A
B
Difference between SS2 for PCI and SS2 for CABG
45
* p = 0.21
50%
40
35
30
25
40%*
25%
20
15
22%*
>5.7%
10
5
0
<5.7%
0
10
20
30
Observed Mortality
40
50
60
<5.7%
>5.7%
Figure 4 - A) Relationship between the absolute difference between the SS2 for PCI and SS2 for CABG with the observed mortality by decile of the difference, in patients
in whom SS2 favoured CABG (n=47); B) 4-year MACE in patients in whom SS2 favoured CABG (n=47), stratified according to the ROC-defined best cut-off of the
difference between SS2-PCI and SS2-CABG. * p value for the comparison between the values of each column.
Limitations
Some important limitations should be pointed out in
our study. First, the inherent limitations of a single-centre
retrospective study. Second, the limited number of patients may
have limited the power of the statistical analysis and the ability
to find statistical significance for many of the comparisons.
Third, the long time span of the registry (~10 years) renders
the group highly heterogeneous, especially considering that a
significant number of patients treated with bare metal stents
was included. This goes against contemporary practice in
ULMD PCI and is in marked contrast with the original SYNTAX
trial cohort, in which TAXUS stents were used, and from which
the original scores have been derived. Fourth, our analysis did
not take into account the location of the lesions in the left main
276
Arq Bras Cardiol. 2016; 106(4):270-278
coronary artery and the different stenting techniques for distal
and bifurcation lesions. Not only have there been variations
in the stenting strategies throughout the study period, but
these also play a role in defining the complexity and success
of the procedure and would help to interpret our results.
However, in our cohort of ULMD patients, lesion location
within the left main coronary artery was not an independent
predictor of 5-year MACE,31 and Capodano et al.18 have not
found a prognostic impact of the stenting technique, regardless
of the baseline SS1. Fifth, it is not possible to ascertain the
extent to which confounders inherent to specific selection
criteria for left main stenting have influenced MACE rates and
thus the predictive ability of the scores, especially if we bear
in mind that a large part of this population was included at a
Madeira et al.
Original Article
period when CABG would be regarded as a more common
choice. Finally, true validation of SS2 would require random
assignment to either CABG or PCI in a prospective study.
Conclusions
The SYNTAX Score 2, by combining and weighting clinical
and anatomical features, may allow a better and individualized
risk stratification of patients who need revascularization of an
unprotected left main coronary artery. A difference greater than
5.7% between SYNTAX Score 2 estimates for PCI versus CABG
may be clinically relevant in selecting the optimal revascularization
strategy. Prospective studies are needed for further validation.
Author contributions
Conception and design of the research: Madeira S,
Raposo L, Brito J; Acquisition of data: Madeira S, Rodrigues
R, Gonçalves P, Teles R, Gabriel H, Machado F, Almeida M;
Analysis and interpretation of the data: Madeira S, Raposo L,
Brito J, Rodrigues R; Statistical analysis: Madeira S, Raposo
L, Brito J, Rodrigues R; Writing of the manuscript: Madeira
S; Critical revision of the manuscript for intellectual content:
Raposo L, Brito J, Rodrigues R, Gonçalves P, Teles R, Gabriel
H, Machado F, Almeida M, Mendes 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 thesis or dissertation work.
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Associated with Ezetimibe
Maristela Magnavita Oliveira Garcia, Carolina Garcez Varela, Patricia Fontes Silva, Paulo Roberto Passos Lima,
Paulo Meira Góes, Marilia Galeffi Rodrigues, Maria de Lourdes Lima Souza e Silva, Ana Marice Teixeira Ladeia,
Armênio Costa Guimarães, Luis Claudio Lemos Correia
Escola Bahiana de Medicina e Saúde Pública (EBMSP)- FBDC, Salvador, BA – Brazil
Abstract
Background: The effect of statins on the endothelial function in humans remains under discussion. Particularly, it
is still unclear if the improvement in endothelial function is due to a reduction in LDL-cholesterol or to an arterial
pleiotropic effect.
Objective: To test the hypothesis that modulation of the endothelial function promoted by statins is primarily mediated
by the degree of reduction in LDL-cholesterol, independent of the dose of statin administered.
Methods: Randomized clinical trial with two groups of lipid-lowering treatment (16 patients/each) and one placebo group
(14 patients). The two active groups were designed to promote a similar degree of reduction in LDL-cholesterol: the first
used statin at a high dose (80 mg, simvastatin 80 group) and the second used statin at a low dose (10 mg) associated
with ezetimibe (10 mg, simvastatin 10/ezetimibe group) to optimize the hypolipidemic effect. The endothelial function
was assessed by flow-mediated vasodilation (FMV) before and 8 weeks after treatment.
Results: The decrease in LDL-cholesterol was similar between the groups simvastatin 80 and simvastatin 10/ezetimibe
(27% ± 31% and 30% ± 29%, respectively, p = 0.75). The simvastatin 80 group presented an increase in FMV from
8.4% ± 4.3% at baseline to 11% ± 4.2% after 8 weeks (p = 0.02). Similarly, the group simvastatin 10/ezetimibe showed
improvement in FMV from 7.3% ± 3.9% to 12% ± 4.4% (p = 0.001). The placebo group showed no variation in
LDL‑cholesterol level or endothelial function.
Conclusion: The improvement in endothelial function with statin seems to depend more on a reduction in LDL‑cholesterol
levels, independent of the dose of statin administered, than on pleiotropic mechanisms. (Arq Bras Cardiol. 2016;
106(4):279-288)
Keywords: Endothelium / physiology; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use;
Ezetimibe; Anticholesterolemic Agents.
Introduction
The cardiovascular benefits of cholesterol-reducing
statin therapy have been demonstrated in primary 1 and
secondary2 prevention scenarios, and the improvement in
endothelial function is one of the involved mechanisms.
This mechanism is credited to the lipid-lowering effect
of the statins, supported by the association between the
magnitude of the reduction in cholesterol and a reduction
in cardiovascular risk.3 On the other hand, some authors
suggest that the improvement in endothelial function
is also mediated by pleiotropic actions4,5 independent
of cholesterol: anti-inflammatory, antioxidant, and
antithrombotic effects.6-8
Mailing Address: Luis C. L. Correia •
Av. Princesa Leopoldina, 19/402. Postal Code 40.150-080, Salvador, BA – Brazil
Manuscript received December 31, 2014; manuscript revised November 10,
2015; accepted November 24, 2015.
DOI: 10.5935/abc.20160048
279
These observations are based on in vitro studies.
However, clinical confirmation has been limited by the
challenge of isolating the theoretical pleiotropic effect of
the statins from their lipid-lowering effect. The emergence
of ezetimibe as a drug to treat hypercholesterolemia
offers a scientific model suitable to test the pleiotropic
hypothesis, since it allows a similar degree of reduction
in LDL-cholesterol with a lower statin dose.9 For a similar
reduction in cholesterol, higher doses of statin promoting
greater endothelial benefit than smaller doses would
represent clinical evidence in favor of a pleiotropic action.
This model is based on the fact that ezetimibe does not
interfere in the mevalonate pathway, and its effect is only
mediated by the intestinal absorption of cholesterol.10
We conducted this randomized clinical trial to test the
hypothesis that the factor influencing the endothelial function
is the decrease in LDL-cholesterol, regardless of the dose of
statin administered. In this study, the outcome of the statin
effect on the endothelial function was evaluated by comparing
the degree of arterial flow-mediated vasodilation (FMV) in
individuals randomized to a high dose of simvastatin versus a
low dose of simvastatin associated with ezetimibe.
Garcia et al.
Endothelial effect of statins
Original Article
Methods
Study Design
Clinical randomized, double-blind, placebo-controlled
trial, registered at ClinicalTrials.gov with the identifier
NCT01241097, carried out at the Obesity Outpatient Clinic of
Escola Bahiana de Medicina e Saúde Pública in Salvador, Bahia,
Brazil. The study was approved by the Ethics Committee of
the institution under the protocol number 157/2009, and all
participants signed a free and informed consent form.
Cohort Selection
Women attending the clinic were consecutively selected
based on the following inclusion criteria: age above 18 years,
body mass index (BMI) > 25 kg/m², and LDL-cholesterol
> 100 mg/dL. We defined the following as exclusion criteria:
use of statin, ezetimibe, fibrate, or hormone replacement
therapy within the previous 3 months; triglyceride level
> 400 mg/dL; serum creatinine above 2.0 mg/dL; hepatic
enzymes levels at least 1.5 times above the normal reference
limit; serum creatine kinase (CPK) level higher than three
times the upper normal limit; pregnancy or lactation; and
occurrence of cardiac insufficiency, collagenosis, acute
inflammatory conditions, or psychiatric disease. We also
excluded patients who had started beta-blockers, angiotensinconversion inhibitors, or calcium-channel blockers within the
prior 4 weeks and those with a brachial artery diameter below
2.5 mm, since the measurement of the degree of dilation is
compromised in these cases.
Study Protocol
After enrollment, the participants were randomized
in blocks of three to the following treatment modalities:
1) simvastatin 80 mg, 2) simvastatin 10 mg plus ezetimibe
10 mg, and 3) placebo (Figure 1). We used the following
criteria for early therapy interruption: medication intolerance,
increase in liver enzymes levels three times above the upper
normal level, or isolated measurement of CPK exceeding
10 times the upper normal level.
We performed three sequential evaluations to analyze
the endothelial function and collect laboratory data: the first
was before the beginning of the treatment, the second was
after 4 weeks of treatment, and the third was after 8 weeks of
treatment and represented the final assessment. During these
evaluations, we recorded possible adverse events, which we
rated as major (rhabdomyolysis, liver failure, renal failure,
pancreatitis, obstructive jaundice, and death), intermediate
(myalgia, diarrhea, and vomiting, among others), and minor
(constipation, nausea and flatulence, among others).
Biochemical Analysis
We collected blood after 12 hours of fasting following
the techniques and methods standardized by the Sociedade
Brasileira de Patologia Clínica (Brazilian Society of Clinical
Pathology). We determined C-reactive protein levels with
a commercially available high-sensitivity nephelometric
method11 (Dade Behring Inc., Newark, DE, USA). Plasma
concentrations of total cholesterol, HDL-cholesterol, and
triglycerides were determined with a biochemical enzyme
method (Dade Behring Inc., Newark, DE, USA).
Brachial Artery Flow-Mediated Vasodilation
All participants were previously instructed to fast, not
perform physical activity, drink coffee, use medications,
or smoke on the day of the test. The adherence to these
instructions was checked before the procedure.
We used ultrasonography with high-resolution color
Doppler (Vivid 3, GE). The evaluation was performed
according to a previously published guideline,12 and the
volunteers were evaluated after fasting for 4 hours and resting
while lying down for 10 minutes in a room with controlled
temperature (22° to 24° C). The tests were performed by a
single examiner who was blinded to the participants’ data.
Simultaneous electrocardiographic monitoring, coupled to the
ultrasound system, allowed synchronization with the cardiac
cycle. The brachial artery was identified in the longitudinal axis
at 3 centimeters above the antecubital fossa and demarcated
in the skin with a brush to prevent its position to change or tilt.
A longitudinal image of 6 to 8 centimeters was obtained as a
baseline reference. We then assessed the flow and estimated
the average speed of a sample volume in the center of the
artery, with a 60° vessel angulation. After that, we positioned
the cuff of a sphygmomanometer in the forearm and inflated
the cuff to at least 50 mmHg above the baseline systolic
pressure during 5 minutes to occlude the artery. We then
deflated the cuff, inducing a brief status of increased flow or
reactive hyperemia, and 1 minute later obtained the image
of the FMV, which represents the endothelium-dependent
dilatation that occurs due to nitric oxide production caused
by shear stress. We digitalized images during movement,
starting 30 seconds before cuff deflation until 2 minutes later.
An image corresponding to the second rest phase was acquired
15 minutes later. We then obtained again the Doppler flow
of the brachial artery after releasing the cuff and 15 seconds
before deflation, registering the flow speed during hyperemia.
Finally, we measured the endothelium-independent
vasodilation by calculating the vasodilation response 4 minutes
after administration of sublingual isosorbide dinitrate 5 mg.
We digitalized all steps of the FMV assessments to analyze
later the correlations between the arterial diameter at
baseline and the maximum arterial diameters after dilation,
as well as the FMV percentages. This analysis was conducted
with 22% of the cohort, and the intraobserver correlations for
these measurements were 0.99, 0.98, and 0.88, respectively,
whereas the interobserver correlations were 0.98, 0.91,
and 0.82, respectively. We did not perform evaluations at
different moments, i.e. new FMV acquisitions specifically for
this type of analysis.
Data Analysis
The sample size was estimated a priori to achieve a statistical
power of 90% ( = 5%) to detect an absolute difference of 20%
in FMV variation between the treatment groups (simvastatin
80 and simvastatin 10/ezetimibe; intergroup comparison).
We used the pessimistic premise that the standard deviation
Arq Bras Cardiol. 2016; 106(4):279-288
280
Garcia et al.
Original Article
Recruitment
Eligible patients (n = 72)
Excluded (n = 26)
Psychiatric disorders (n = 2), Inflammatory
condition (n = 5), Recent statin use (n = 3), Refuse
to participate (n = 5), Other reasons (n = 11)
Randomized (n = 46)
Allocation
Allocated to the simvastatin
80 group(n = 16)
Allocated to the simvastatin 10 mg +
ezetimibe 10 mg group
(n = 16)
Allocated to the placebo
group (n = 14)
Follow-up
Loss to follow-up
(n = 0)
Loss to follow-up
(n = 0)
Loss to follow-up - Fail to show up
(n = 2)
Analyzed (n = 16)
Analyzed (n = 12)
Analysis
Analyzed (n = 16)
Figure 1 – Flowchart of the study protocol.
of the delta in each group would be around 15%, resulting in
the requirement of 13 patients in each group.
The FMV was calculated as the percentage variation in
artery diameter after hyperemia. The effect of the treatment
on the endothelial function was measured primarily by the
percentage change in FMV between baseline and after
8 weeks of treatment. This variable was compared between
the two treatment groups with the Mann-Whitney test.
In the intragroup analysis, FMV measurements were
compared separately in each group before and after
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Arq Bras Cardiol. 2016; 106(4):279-288
treatment with the Wilcoxon signed-rank test. For paired
comparison of FMV at all three moments (baseline, 4 weeks,
and 8 weeks) we used ANOVA for repeated measures. This
analysis was also used to compare the treatment effects
considering all three moments through an interaction
between group and moment. In addition, to assess during
follow-up the occurrence of possible clinical differences
between the groups that could constitute confusion biases,
we performed ANOVA for comparison of the clinical
characteristics among the three groups.
Garcia et al.
Original Article
Secondarily, we compared using the Mann-Whitney test
the percentage variation in FMV between baseline and the
8th week in the active treatment groups with those in the
placebo group. In this case, we opted for not comparing
simultaneously the three groups (ANOVA), since this was
considered a complementary analysis that did not concern
the main hypothesis of the study. For group comparison at the
intermediate analysis (4th week), the treatment was carried
out in a similar way, since this was a complementary analysis.
We tested the linear association between the changes in
LDL-cholesterol and FMV results with Spearman’s correlation
coefficient. We used analysis of covariance (ANCOVA) to
adjust the treatment effect for age. We considered twotailed probability values < 0.05 as statistically significant.
The results are presented as mean ± standard deviation
for continuous variables and as percentage for categorical
variables. Variables not following a normal distribution are
expressed as median and interquartile range (IQR). For
statistical analyses, we used the software Statistical Package
for Social Sciences, version 20 for Windows (SPSS Inc,
Chicago, IL, USA).
Results
the simvastatin 10/ezetimibe group), and vomiting (one case
in the simvastatin 10/ezetimibe group).
After 8 weeks of active treatment, there was a significant
reduction in LDL-cholesterol levels, which was similar between
the groups simvastatin 80 (27% ± 31%) and simvastatin
10/ezetimibe (30% ± 29%, p = 0.75). The absolute
reduction was 36 ± 45 mg/dL in the simvastatin 80 group
and 45 ± 36 mg/dL in the simvastatin 10/ezetimibe group
(p = 0.57). There was no reduction in LDL-cholesterol levels
in the placebo group (Table 3 and Figure 2).
The reduction in LDL-cholesterol level was already present
in the assessment performed at 4 weeks of treatment, which did
not differ from that performed at the 8th week in the simvastatin
80 group (p = 0.15) or in the simvastatin 10/ezetimibe group
(p = 0.90).
There was no significant variation in plasma levels of
HDL‑cholesterol or triglycerides in any of the three treatment
groups, except for a reduction in triglyceride levels in the
simvastatin 80 group. Similarly, blood glucose levels remained
unchanged. Liver enzymes, C-reactive protein, CPK, and weight
did not change significantly during treatment. Exceptions to that
were increases in CPK level in the simvastatin 80 group, which
occurred without clinical complaints or values considered of
risk, and ALT in the simvastatin 10/ezetimibe group (Table 4).
Characteristics of the Cohort
The cohort was characterized by young adult women
(43 ± 10 years) with excess weight, evidenced by a BMI
of 35 ± 5.8 kg/m2. Mean plasma LDL-cholesterol levels
were slightly elevated (137 ± 31 mg/dL), while the median
C-reactive protein level (3.6 mg/L, IQR = 1.7 – 6.7 mg/L)
indicated an exacerbated inflammatory status. As for the
endothelial function, the mean FMV was 8.5% ± 4.3%,
including reduced and normal FMV values (healthy patients
are considered to have an FMV above 7%).13 A diagnosis
of diabetes was present in 8.7% of the participants, who
were all taking metformin. Also, 41% of the participants had
hypertension and were on antihypertensive drugs. None of
the participants had hepatic or renal dysfunction.
Following randomization, 16 women were allocated to
the simvastatin 80 group, 16 to the simvastatin 10/ezetimibe
group, and 14 to the placebo group. There were no significant
differences among the treatment groups regarding clinical
and laboratory characteristics or class of antihypertensive
drugs (Table 1). During follow-up, the clinical characteristics
remained similar among the groups (Table 2). The mean
FMV results were similar between the groups simvastatin
80 (8.4% ± 4.3%), simvastatin 10/ezetimibe (7.6% ± 3.9%),
and placebo (9.8% ± 4.5%, p = 0.31).
Antilipidemic Effect of the Treatments
During the 8 weeks of the study, there were no treatment
interruptions, and the adherence was complete and identical
in all three groups. No side effects requiring treatment
suspension were recorded. There were minor symptoms,
of which the most frequent was headache (one case in the
simvastatin 80 group, one case in the simvastatin 10/ezetimibe
group, and three cases in the placebo group), followed by leg
pain (one case in the simvastatin 80 group and one case in
Effect of the Treatments on Arterial Flow-Mediated
Vasodilation
The simvastatin 80 group presented an increase in FMV
from 8.4% ± 4.3% to 11% ± 4.2% after 8 weeks of treatment
(p = 0.02). Similarly, the simvastatin 10/ezetimibe group
showed improvement in vasodilation, from 7.3% ± 3.9%
to 12% ± 4.4% (p = 0.001). In relative terms, the variation
in arterial vasodilation had a median of +39% (IQR = 2.2%
to 105%) in the simvastatin 80 group, which was similar to
+41% (IQR = 13% to 227%) in the simvastatin 10/ezetimibe
group (p = 0.36). This comparison remained nonsignificant
after adjustment for the difference in age between these two
groups (ANCOVA, p = 0.30). The placebo group presented
a minimal variation in arterial vasodilation, with a median of
+6.2% (IQR = - 6.6% to 56%), without statistical significance
in the comparison between the baseline measurement and
that performed at the 8th week (p = 0.28; Figure 3 and
Table 5). When we performed a paired comparison of the
three moments of evaluation (baseline, 4 weeks, and 8 weeks)
with ANOVA for repeated measures, the simvastatin 80
(p = 0.045) and simvastatin 10/ezetimibe (p = 0.001) groups
showed significant variations, which was different from the
placebo group (p = 0.25). In this analysis, there was no
interaction between group and moment when only the active
treatments were considered (p = 0.30), indicating a similar
variation between these two groups.
The active groups showed no differences in the variation in
endothelium-independent vasodilation mediated by nitrate.
Unlike the effect on LDL-cholesterol, 4 weeks of treatment
were not sufficient to obtain an impact on the arterial FMV
comparable to that obtained at the end of 8 weeks, although
a trend of improvement in vasodilation was already observed
in this interim assessment. This improvement was represented
Arq Bras Cardiol. 2016; 106(4):279-288
282
Garcia et al.
Original Article
Table 1 - Comparison of clinical and laboratory characteristics among the treatment groups
Simvastatin 80
Sample
Age (years)
Simvastatin 10/Ezetimibe
Placebo
p
16
16
14
41 ± 8.6
48 ± 8.1
40 ± 12
0.05
BMI (kg/m²)
35 ± 4.3
36 ± 4.4
36 ± 8.6
0.90
Waist circumference (cm)
107 ± 7.6
108 ± 9.9
107 ±17
0.94
0.92 ± 0.71
0.92 ± 0.67
0.91 ± 0.56
0.84
133 ± 15
132 ± 18
130 ± 18
0.86
Waist/hip
SBP (mmHg)
DBP (mmHg)
Total cholesterol (mg/dL)
85 ± 9
86 ± 13
81 ± 14
0.52
205 ± 29
225 ± 47
206 ± 33
0.26
HDL-cholesterol (mg/dL)
49 ± 11
52 ± 12
49 ± 11
0.75
LDL-cholesterol (mg/dL)
133 ± 26
149 ± 43
136 ± 27
0.50
Triglycerides (mg/dL)
125 ± 51
121 ± 67
115 ± 41
0.46
3.9 (2.1 – 8.1)
3.0 (1.8 – 5.1)
3.3 (1.2 – 7.2)
0.70
Blood glucose (mg/dL)
96 ± 12
103 ± 24
94 ± 19
0.39
Urea (mg/dL)
29 ± 7.3
29 ± 8.3
26 ± 6
0.42
0.83 ± 0.11
0.79 ± 0.12
0.85 ± 0.18
0.55
18 ± 5.1
20 ± 4.6
20 ± 11
0.71
CRP (mg/dL)
Creatinine (mg/dL)
AST (U/L)
ALT (U/L)
18 ± 5.1
20 ± 4.6
20 ± 11
0.71
GGT (U/L)
32 ± 11.74
42 ± 22.99
42 ± 23.70
0.27
CPK (mg/dL)
123 ± 60
168 ± 88
109 ± 62
0.07
Hypertension
5 (31%)
6 (38%)
8 (57%)
0.33
ACEi
2 (13%)
0 (0%)
4 (29%)
0.07
ARB
1 (6.3%)
2 (13%)
2 (14%)
0.75
Menopause
1 (6.3%)
4 (25%)
2 (14%)
0.33
Smoking
0 (6.3%)
1 (6.3%)
0 (0%)
0.38
Sedentary lifestyle
11 (69%)
8 (50%)
8 (57%)
0.55
Low-calorie diet
6 (38%)
7 (44%)
6 (43%)
0.93
Diabetes
Coffee consumption
FMV
0 (0%)
1 (6.3%)
3 (21%)
0.10
14 (88%)
14 (88%)
12 (86%)
0.99
8.4% ± 4.3%
7.6% ± 3.9%
9.8% ± 4.5%
0.31
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HDL: High-density lipoprotein; LDL: low-density lipoprotein; CRP: C-reactive protein;
AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: Gamma glutamyltransferase; CPK: creatine phosphokinase; ACEi: angiotensin‑converting
enzyme inhibitor; ARB: angiotensin receptor blocker; FMV: flow-mediated vasodilation.
by a median of +27% (IQR = - 13% to 63%, p = 0.09) in
the simvastatin 80 group and +25% (IQR = - 4% to 92%,
p = 0.03) in the simvastatin 10/ezetimibe group.
There was a correlation (r = - 0.33, p = 0.03) between the
variations in LDL-cholesterol and FMV in a combined analysis
of the studied population.
Discussion
The present study suggests that the improvement in
endothelial function promoted by statin therapy depends
primarily on the drug’s hypolipidemic effect, without evidence
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Arq Bras Cardiol. 2016; 106(4):279-288
of a pleiotropic action. The pleiotropic hypothesis was tested
with different doses of simvastatin (80 mg versus 10 mg) under
the assumption that a dose-response gradient would occur if
this mechanism were present. In order to avoid the degree
of reduction in LDL-cholesterol as a confounding factor,
ezetimibe was associated to simvastatin in the low simvastatin
dose group, providing the same lipid-lowering effect as the
high-dose group. When we observed that both therapies had
the same benefit on the endothelial function, we inferred that
the dose-response gradient was absent.
In addition to the main result, some secondary findings
deserve further discussion. First, the presence of a placebo
Garcia et al.
Original Article
Table 2 – Comparison of the clinical characteristics in the three groups during follow-up
Characteristics
Follow-up (weeks)
Treatment groups
Simvastatin 80
Placebo
p
BMI (kg/m²)
4
8
35 ± 4.3
34 ± 4.4
35 ± 4.4
35 ± 4.3
35 ± 6.6
36 ± 9.3
0.87
0.77
SBP (mmHg)
4
8
133 ± 13.5
133 ± 14.5
132 ± 15.3
133 ± 15.5
130 ± 15.7
132 ± 15.1
0.84
0.82
DBP (mmHg)
4
8
86 ± 7.3
84 ± 9.4
83 ± 9.3
84 ± 9.4
81 ± 12
81 ± 12
0.39
0.49
4
8
49 ± 9.8
51 ± 12
53 ± 14
52 ± 13
52 ± 14
50 ± 8
0.76
0.89
4
8
91 ± 29
99 ± 39
124 ± 60
122 ± 73
132 ± 38
127 ± 52
0.30
0.34
4
8
93 ± 11
95 ± 10
102 ± 22
102 ± 18
111 ± 54
103 ± 32
0.28
0.32
Urea (mg/dL)
4
8
31 ± 5.0
29 ± 6.3
28 ± 4.7
28 ± 6.4
28 ± 4.7
27 ± 5.3
0.30
0.43
Creatinine (mg/dL)
4
8
0.84 ± 0.14
0.82 ± 0.12
0.85 ± 0.15
0.80 ± 0.12
0.78 ± 0.12
0.87 ± 0.19
0.42
0.37
AST (U/L)
4
8
17 ± 4
19 ± 5
22 ± 9
23 ± 10
17 ± 7
18 ± 5
0.17
0.17
ALT (U/L)
4
8
17 ± 6
21 ± 8
26 ± 15
25 ± 12
17 ± 10
18 ± 10
0.12
0.17
GGT (U/L)
4
8
31 ± 9.3
32 ± 11.1
41 ± 18.8
38 ± 15.3
44 ± 30.8
42 ± 33.1
0.32
0.53
CPK (mg/dL)
4
8
136 ±64
155 ± 84
185 ± 127
195 ± 118
103 ± 60
120 ± 67
0.12
0.10
CRP (mg/dL)
4
8
3.3 (2.1 – 6.4)
2.9 (1.9 – 8.3)
2.0 (1.7 – 4.2)
2.0 (1.6 – 4.2)
4.0 (2.4 – 8.2)
4.4 (2.7 – 8.3)
0.19
0.43
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HDL: high-density lipoprotein; AST: aspartate aminotransferase; ALT: alanine
aminotransferase; GGT: gamma glutamyltransferase; CPK: Creatine phosphokinase; CRP: C-reactive protein.
group in which the endothelial function remained unchanged
assures us that the improvement observed with the active
treatment in both groups was not due to a phenomenon of
regression to the mean. Second, the negative correlation
between the reduction in LDL-cholesterol and the
improvement in endothelial function represents additional
information in favor of the lipid-lowering mechanism, even
though it was a weak correlation and that this analysis, as it
is well known, is mainly of exploratory nature and does not
show causality. Third, we observed that the positive influence
on the endothelial function occurs progressively with the
length of exposure, since the late results (8 weeks) were
better than the early results (4 weeks), despite the fact that
the nadir in LDL-cholesterol levels was achieved at 4 weeks
of treatment. Regarding the anti-inflammatory mechanism,
the treatments were unable to promote a reduction in
C-reactive protein levels in any of the groups, which makes
it less likely to be an additional mechanism of improvement
in endothelial function.
The lack of differences in clinical characteristics
among the groups, both at baseline (promoted by the
randomization process), and during follow-up (confirmed
by intergroup comparisons at 4 and 8 weeks) assured the
control of possible confounding variables that could have
influenced the comparative results of the outcome variable.
The methodological care adopted in this study, especially that
regarding the FMV analysis, also contributed to the internal
validation process.
The recent study of Westerink et al.14 is in line with our
results. In this study, the authors demonstrated a similar
impact on the endothelium of simvastatin at a high dose
versus low dose associated with ezetimibe in subjects with
metabolic syndrome, as previously reported by Settergren
et al.15 as well in patients with diabetes or coronary disease.
In contrast, Liu et al.16 only obtained improvement in FMV
with a higher dose of simvastatin and suggested the occurrence
of pleiotropic benefits of the statins based on results obtained
at 4 weeks. Their option to only observe for a short period of
time may have precluded the observation of effects requiring
longer treatment duration.
Some limitations of this study deserve recognition.
The method to measure FMV followed all the steps of
the protocol recommended by the International Brachial
Artery Reactivity Task Force12. However, the method has an
Arq Bras Cardiol. 2016; 106(4):279-288
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Original Article
Table 3 – Effect of the treatments on lipid and metabolic profiles in the three groups at 4 and 8 weeks
Baseline
8 Weeks
p
4 Weeks
p (4 versus 8 weeks)
Simvastatin 80
133 ± 26
95 ± 44
0.006
72 ± 23
0.15
205 ± 29
166 ± 48
0.007
141 ± 26
0.12
49 ± 11
51 ± 12
0.48
49 ± 9.8
0.97
125 ± 51
99 ± 39
0.01
91 ± 29
0.26
96 ± 12
95 ± 10
0.88
93 ± 11
0.28
149 ± 43
100 ± 45
< 0.001
97 ± 49
0.90
226 ± 51
176 ± 54
< 0.001
169 ± 52
0.83
54 ± 12
52 ± 13
0.98
53 ± 14
0.39
121 ± 67
122 ± 73
0.08
124 ± 60
0.52
103 ± 24
102 ± 18
0.28
102 ± 22
0.65
136 ± 27
137 ± 29
0.80
123 ± 30
0.21
206 ± 33
212 ± 31
0.79
201 ± 35
0.32
49 ± 11
50 ± 8
0.39
52 ± 14
0.50
115 ± 41
127 ± 52
0.27
132 ± 38
0.48
94 ± 19
103 ± 32
0.06
111 ± 54
0.40
Placebo
LDL: low-density lipoprotein; HDL: high-density lipoprotein.
180
160
Placebo
140
120
Simvastatin 10
Ezetimibe 10
100
80
Simvastatin 80
60
40
Baseline
4 weeks
8 weeks
Figure 2 – Effect of the treatments on LDL-cholesterol, showing a significant reduction of this lipoprotein in the active groups.
285
Arq Bras Cardiol. 2016; 106(4):279-288
Garcia et al.
Original Article
Table 4 – Effect of the treatments on weight and biochemical characteristics
Baseline
4 Weeks
p
8 Weeks
p
Body mass index (kg/m²)
35 ± 4.3
35 ± 4.3
0.51
34 ± 4.4
0.19
Aspartate aminotransferase (U/L)
18 ± 5.1
17 ± 4
0.73
19 ± 5
0.50
Alanine aminotransferase (U/L)
18 ± 5.1
17 ± 6
0.90
21 ± 8
0.05
Creatine phosphokinase (mg/dL)
123 ± 60
136 ±64
0.04
155 ± 84
0.03
3.9 (2.1 - 8.1)
3.3 (2.1 - 6.4)
0.14
2.9 (1.9 - 8.3)
0.65
36 ± 4.4
35 ± 4.4
0.63
35 ± 4.3
0.27
20 ± 4.6
22 ± 9
0.42
23 ± 10
0.22
0.03
Simvastatin 80
CRP (mg/dL)
20 ± 4.6
26 ± 15
0.21
25 ± 12
168 ± 88
185 ± 127
0.30
195 ± 118
0.11
3.0 (1.8 – 5.1)
2.0 (1.7 – 4.2)
0.55
2.0 (1.6 – 4.2)
0.66
36 ± 8.6
35 ± 6.6
0.23
36 ± 9.4
0.81
20 ± 11
17 ± 7
0.59
18 ± 5
0.24
20 ± 11
17 ± 10
0.20
18 ± 10
0.12
109 ± 62
103 ± 60
0.17
120 ± 67
0.25
3.3 (1.2 – 7.2)
4.0 (2.4 – 8.2)
0.43
4.4 (2.7 – 8.3)
0.11
CRP (mg/dL)
Placebo
CRP (mg/dL)
CRP: C-reactive protein (median and interquartile range).
Panel A
Panel B
12%
10%
6%
Placebo
Placebo
Flow-mediated vasodilation
Flow-mediated vasodilation
14%
Simvastatin 10/Ezetimibe 10
Simvastatin 80
4%
2%
0%
Baseline
4 weeks
8 weeks
0
Simvastatin 80
Simvastatin 10/Ezetimibe10
10
20
30
40
50
Figure 3 – Variation in flow-mediated vasodilation, indicating an increase in the two active groups. Panel A: Line graph showing the variation in vasodilation at 4 and
8 weeks of treatment; Panel B: Bar graph showing the percentage of variation in vasodilation from baseline to the 8th week.
inherent large variability of measurements influenced by
several external factors. This variability may be a limiting
factor to reproduce the FMV findings and, consequently,
their interpretation. The wider circumferences of the arms
of obese women could have led to technical challenges in
the measurements. However, this was not an interfering
factor in this study since the cuff of the sphygmomanometer
was positioned in the forearm, which has a shorter
circumference than the arm, leaving a larger area for
identification of the brachial artery when the transducer was
positioned on the arm. Although the automated technique
is more robust and accurate,17 the manual technique used in
this study is also reliable and considered feasible to diagnose
and monitor the endothelial function.18
Arq Bras Cardiol. 2016; 106(4):279-288
286
Garcia et al.
Original Article
Table 5 – Effect of the three treatments on flow-mediated vasodilation
Baseline
8 Weeks
p
4 Weeks
p
8.4 ± 4.3
11 ± 4.2
0.02
8.6 ± 3.6
0.03
+ 27% (-13% – 63%)
0.09
9.1 ± 4.3
0.03
Simvastatin 80
FMV (%)
FMV variation
+ 39% (2.2% – 105%)
FMV (%)
7.3 ± 3.9
FMV variation
0.001
12 ± 4.4
+ 41% (13% – 227%)
+ 25% (-4% – 92%)
Placebo
FMV (%)
FMV variation
9.8 ± 4.5
10 ± 4
0.28
+ 9% (-6.6% – 56%)
11 ± 2.2
0.93
+13% (-8% – 31%)
Parentheses - 95% confidence interval. FMV: brachial artery flow-mediated vasodilation.
The study was performed with a small sample, which only
consisted of women with excess weight from a single outpatient
clinic. However, since this is a small study, it justifies the option
for homogenizing the sample and including only women.
The selection of women with excess weight had the purpose
of including a group more predisposed to impaired endothelial
function,19 favoring the possibility to observe a corrective effect
of the therapy. Although the choice of this type of population is
justifiable, we must recognize that it reduces the generalization
of the study to the overall population. We must also remember
that this study has a surrogate outcome (purely mechanistic
objective) that should not be interpreted as evidence that the
clinical effect of the two therapies is similar. Another limitation
is related to the low statistical power and refers to the fact
that to avoid detecting differences among the variables we
would need a very large sample, which would make the study
unfeasible. Regarding the analyzes of the deltas in the general
variations (including FMV and LDL-cholesterol), we found no
difference among the treatments. These findings may have
been influenced by a large measurement variability, hindering
the statistical analysis.
Conclusion
In conclusion, the present randomized clinical study
showed that the most probable mechanism of improvement
in endothelial function obtained with statins is the decrease in
LDL-cholesterol, independent of the dose of statin used. In this
context, the pleiotropic effects of statins have lower relevance.
was reported.
Sources of Funding
This study was funded by FAPESB.
Study Association
This article is part of the thesis of Doctoral submitted by
Maristela Magnavita Oliveira Garcia , from Escola Bahiana de
Medicina e Saúde Pública.
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Arq Bras Cardiol. 2016; 106(4):279-288
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Back to The Cover
Original Article
Risk Prediction of Cardiovascular Complications in Pregnant Women
With Heart Disease
Luciana Carvalho Martins1,2, Claudia Maria Vilas Freire1,2, Carolina Andrade Bragança Capuruçu1, Maria do Carmo
Pereira Nunes1, Cezar Alencar de Lima Rezende1
Universidade Federal de Minas Gerais – UFMG1; Maternidade Odete Valadares - Fundação Hospitalar do Estado de Minas Gerais2, Belo
Horizonte, MG – Brazil
Abstract
Background: Heart disease in pregnancy is the leading cause of non- obstetric maternal death. Few Brazilian studies have
assessed the impact of heart disease during pregnancy.
Objective: To determine the risk factors associated with cardiovascular and neonatal complications.
Methods: We evaluated 132 pregnant women with heart disease at a High-Risk Pregnancy outpatient clinic, from January
2005 to July 2010. Variables that could influence the maternal-fetal outcome were selected: age, parity, smoking,
etiology and severity of the disease, previous cardiac complications, cyanosis, New York Heart Association (NYHA)
functional class > II, left ventricular dysfunction/obstruction, arrhythmia, drug treatment change, time of prenatal care
beginning and number of prenatal visits. The maternal-fetal risk index, Cardiac Disease in Pregnancy (CARPREG), was
retrospectively calculated at the beginning of prenatal care, and patients were stratified in its three risk categories.
Results: Rheumatic heart disease was the most prevalent (62.12%). The most frequent complications were heart failure
(11.36%) and arrhythmias (6.82%). Factors associated with cardiovascular complications on multivariate analysis were:
drug treatment change (p = 0.009), previous cardiac complications (p = 0.013) and NYHA class III on the first prenatal
visit (p = 0.041). The cardiovascular complication rates were 15.22% in CARPREG 0, 16.42% in CARPREG 1, and 42.11%
in CARPREG > 1, differing from those estimated by the original index: 5%, 27% and 75%, respectively. This sample had
26.36% of prematurity.
Conclusion: The cardiovascular complication risk factors in this population were drug treatment change, previous
cardiac complications and NYHA class III at the beginning of prenatal care. The CARPREG index used in this sample
composed mainly of patients with rheumatic heart disease overestimated the number of events in pregnant women
classified as CARPREG 1 and > 1, and underestimated it in low-risk patients (CARPREG 0). (Arq Bras Cardiol. 2016;
106(4):289-296)
Keywords: Cardiovascular Diseases / complications; Pregnant Women; Risk Factors; Heart Failure; Arrhythmias, Cardiac;
Rheumatic Heart Disease.
Introduction
Maternal mortality is still very high in Brazil. According to
the Brazilian Unified Health System data bank (DATASUS),
in 2007 the maternal mortality in Brazil was 77 per 100,000
live births. Heart disease in pregnancy is the first cause
of non-obstetric maternal death and the fourth cause of
maternal death in general.1 Diagnosing heart disease before
or at the beginning of pregnancy is fundamental to assess
the maternal-fetal risk, and has an impact on the patients’
Mailing Address: Claudia Maria Vilas Freire •
Universidade Federal de Minas Gerais – UFMG. Rua Ivai 96, Serra. Postal
Code 30210-520, Belo Horizonte, MG – Brazil
Manuscript received March 30, 2015; revised manuscript October 26, 2015;
accepted November 06, 2015
DOI: 10.5935/abc.20160028
289
approach and therapeutic strategy. The other causes of
maternal death are inherent to the condition, and, unlike
heart disease, are usually unpredictable.2,3
Several studies have investigated the risk factors for adverse
outcomes and cardiac complications during pregnancy in
women with heart diseases.4-6 However, only a few Brazilian
studies have assessed them.7 The present study had the
following objectives: to establish the prevalence and etiology
of heart diseases in pregnant women cared for at our referral
center; to identify the most frequent maternal complications
and their repercussions on maternal and perinatal outcomes;
and to assess the risk predictors of cardiac complications that
may influence maternal-fetal outcomes.
In addition, this study assessed the maternal Cardiac
Disease in Pregnancy (CARPREG) risk score, developed by Siu
et al.,4 aiming at classifying the risk of pregnant women with
heart disease and at observing the predictors of cardiac and
neonatal complications in that population with characteristics
Martins et al.
Cardiovascular Complications in Pregnant Women With Heart Disease
Original Article
different from those of the population studied by the authors
of that risk score.
Methods
This study included pregnant women with heart disease
followed up from prenatal care up to delivery and puerperium
by the team of the High-Risk Pregnancy Care Sector, from
January 2005 to July 2010. A total of 153 women were cared
for at that sector during that period. This study was approved
by the Committee on Ethics in Research, and all patients
provided written informed consent.
All pregnant women were examined by the same
cardiologist and underwent tests to confirm the diagnosis and
to classify and assess the severity of the heart disease, such as
Doppler echocardiography, electrocardiography and 24-hour
Holter monitoring.
To analyze the risk predictors of maternal cardiac
complications from this historical cohort, this study included
only patients with complete information. Those with the
following characteristics were excluded: miscarriage (fetal
loss before the 20th week); delivery at other institutions; twin
pregnancies; and peripartum cardiomyopathy developed in
the puerperium period. Thus, 132 of 153 pregnant women
with heart disease followed up at the sector were included.
Variables assessed
The possible risk predictors of maternal cardiovascular
complications assessed were as follows: age; parity;
number of visits to the high-risk prenatal care (HRPC);
HRPC beginning on the third trimester; maternal smoking;
previous cardiac complications and previous surgical or
clinical heart treatments; need to begin or change cardiac
medication during pregnancy for patients who changed,
at the most, one functional class during follow-up, or
dose adjustment to abide by a follow-up protocol; valve
prosthesis; New York Heart Association (NYHA) functional
class ≥ III at the beginning of HRPC; left ventricular (LV)
systolic dysfunction; associated preeclampsia or systemic
arterial hypertension (SAH); left heart obstruction (LHO);
and calculated CARPREG risk score. The following
disorders were grouped as LHO: mitral stenosis with valve
area < 2.0 cm2; aortic stenosis with valve area < 1.5 cm2;
and LV outflow tract gradient > 30 mm Hg.
The following variables relating to the ongoing pregnancy
were assessed: gestational age at the beginning of prenatal
care and number of consultations; cardiac complications
during pregnancy; invasive procedures required during
prenatal care; NYHA functional classification; comorbidities;
delivery type; hospital length of stay; and obstetric
complications. The neonatal variables assessed were
gestational age at the time of delivery and birth weight.
The prediction index of risk for complications associated
with pregnancy in women with heart disease (CARPREG
risk score) was retrospectively calculated for each patient.
The variables associated with cardiovascular complications
according to the CARPREG risk score are defined in Chart 1.
Pregnant women are classified as CARPREG 0, 1 or > 1 in
the presence of none, one, or more than one defined risk
factor.4 The patients in this study were distributed into three
groups: CARPREG 0, CARPREG 1 and CARPREG > 1, and
the percentage of complications occurring in each group
was compared to that predicted according to the original
score: 5%, 27% and 75%, respectively.
Definition of outcomes
The cardiac complications were described according
to the definitions proposed by Siu et al.4 The following
cardiac complications were considered: death due to
heart disease; heart failure with acute pulmonary edema
(documented on chest X-ray or bilateral pulmonary rales
on posterior chest auscultation on physical examination);
acute myocardial infarction; sustained symptomatic
tachyarrhythmia or bradyarrhythmia requiring treatment;
worsening of at least 2 NYHA functional classes as
compared to baseline; and need for emergency invasive
procedures during pregnancy.
The Statistical Package for the Social Sciences (SPSS
17, Inc., Chicago, IL, USA) software was used for statistical
analysis. The continuous variables were presented as mean
± standard deviation, and the categorical ones, as frequency
and percentage.
The variables assessed were compared between the
pregnant women with cardiovascular complications in
pregnancy and those with favorable outcomes by use of the
chi-square test (categorical variables) or non-paired Student t
test (continuous variables with normal distribution).
Univariate analysis and multivariate logistic regression
were performed to identify the variables associated with
cardiovascular complications in pregnancy. The criterion used
to select the variables to the multivariate model was clinical
relevance or p < 0.20 on univariate analysis. A p value < 0.05
was considered statistically significant.
Predictors of cardiovascular events
Points
Prior cardiac event (heart failure, transient ischemic attack, infarction prior to pregnancy) or arrhythmias
1
NYHA functional class at baseline > II or cyanosis
1
Left heart obstruction (mitral valve area < 2.0 cm2; aortic valve area < 1.5 cm2; and LV outflow tract gradient > 30 mm Hg)
1
Reduced systolic ventricular function (ejection fraction < 40%)
1
Chart 1 - CARPREG (Cardiac Disease in Pregnancy) risk score. NYHA: New York Heart Association.
Arq Bras Cardiol. 2016; 106(4):289-296
290
Martins et al.
Cardiovascular complications in pregnant women with heart disease
Original Article
Results
The maternal age ranged from 16 to 45 years (mean:
27.59 ± 7.17). Regarding the number of gestations, 50 patients
(37.88%) were on their first gestation, 38 (28.79%) were on their
second gestation, and 44 (33.33%) had at least three gestations
[15 (11.36%) were on their fifth pregnancy or more].
Only 34 patients (25.75%) initiated their HRPC follow-up
on the first gestational trimester. Most patients (79; 59.85%)
initiated their HRPC follow-up on the second trimester, while
19 patients (14.40%), on the third trimester.
The major heart disease diagnoses in the study population
were: rheumatic heart diseases, 82 patients (62.12%);
congenital heart diseases, 18 (13.65%); arrhythmias,
15 (11.36%); and mitral valve prolapse, 6 (4.54%).
Cardiomyopathies of different causes and other cardiac
diseases added up to 11 patients (8.33%).
Of the 82 pregnant women with rheumatic heart disease,
19 (23.17%) had valve prosthesis, of whom, 14 (73.68%) had
normal functioning prostheses and 5 had residual dysfunction
or associated lesion in other valves. The mitral biological
prosthesis was the most frequently found (13; 68.42%),
followed by mitral mechanical prosthesis (3; 15.79%). Two
patients had mitral-aortic mechanical prostheses, and only
one had an aortic mechanical prosthesis.
Of the 18 patients with congenital heart disease, 9 (50%)
had a shunt defect (ventricular septal defect; atrial septal
defect; atrioventricular septal defect; and patent ductus
arteriosus), 50% of which had been surgically repaired before
pregnancy. Regarding the LHO, one pregnant woman had a
bicuspid aortic valve, and another had coarctation of the aorta
and bicuspid aortic valve. None of those lesions was surgically
corrected before pregnancy. Diseases of the pulmonary
valve (pulmonary valve stenosis or double lesion) added up
to 3 patients (16.7%). Regarding cyanotic heart diseases,
3 patients were followed up, 2 of whom had uncorrected
Ebstein’s anomaly and 1 had corrected tetralogy of Fallot.
One patient with severe tricuspid regurgitation was observed.
Fifteen patients (11.36%) had arrhythmic heart disease,
8 of whom (53.33%) had supraventricular tachyarrhythmias
(paroxysmal supraventricular tachycardia, atrial flutter or
fibrillation). Four patients (26.67%) had bradyarrhythmia
(atrioventricular block and bundle branch blocks), and 3 had
other arrhythmias.
Twenty patients (15.15%) smoked 5 to 40 cigarettes
per day (mean of 8.63 ± 8.95), of whom 31.5% smoked
more than 10 cigarettes per day. Regarding the associated
comorbidities, 23 patients (17.42%) had one as follows: type
I diabetes, 2 patients; chronic obstructive pulmonary disease/
asthma, 11; thyroid diseases, 4; nephropathy, 1; epilepsy, 3;
dermatomyositis, 1; and megaesophagus, 1.
Of 132 pregnancies, 57 (43.18%) had cardiovascular
complications prior to the ongoing pregnancy. Cardiac
decompensation followed by arrhythmias was the most
frequent complication.
Forty-six patients (34.85%) had LHO, 44 of whom (95.65%)
had rheumatic mitral stenosis, with a mean valve area of
1.60 cm², which was considered severe in 11 (25%).
291
Arq Bras Cardiol. 2016; 106(4):289-296
On the first prenatal visit, only 4 patients (3.3%) were
classified as NYHA functional class III, 3 of which (75%) had
moderate or severe mitral stenosis associated with moderate
mitral regurgitation. One patient had dilated cardiomyopathy.
At baseline, 2 patients had LV ejection fraction lower than
40%, 18 (13.63%) had it between 40% and 60%, and the
remaining had it normal (≥ 60%).
Adverse outcomes
Cardiovascular complications occurred in 30 (22.72%)
pregnant women. Cardiac decompensation, diagnosed as a
two-level worsening in NYHA functional class or worsening
in patients with functional class III at baseline, was the most
frequent complication: 15 cases (11.36%). Cardiac arrhythmias
occurred in 9 (6.82%) patients. Four patients (3.03%) required
invasive procedures during the pregnancy as follows: one stent
implantation in aortic coarctation and 3 percutaneous balloon
mitral valvoplasties for severe mitral stenosis. One patient with
severe mitral and aortic regurgitation and nephrotic syndrome
died suddenly in the post-delivery period (Table 1).
According to the CARPREG risk score, our population had
the following percentages of complications: CARPREG 0, 46
patients (34.85%); CARPREG 1, 67 (57.76%); and CARPREG
> 1, 19 (14.39%). The pregnant women classified as CARPREG
> 1 had a significantly higher number of complications during
pregnancy than those classified as the other CARPREG classes
(p = 0.0013) (Table 2). The percentages of cardiovascular
complications in the population studied, according to the
CARPREG classes, were compared with those expected
according to the original CARPREG risk score (Figure 1).
Of the 132 pregnancies assessed to analyze risk predictors,
the following were not cardiovascular complication predictors
in pregnancy: maternal age (p = 0.071); number of visits
to the HRPC (p = 0.344); maternal smoking (p = 0.327);
SAH (p = 0.295); preeclampsia (p = 0.450); prenatal care
beginning on the third trimester (p = 0.379); and valve
prosthesis (p = 0.542). In addition, the non-cardiovascular
diseases associated were not predictors of complication.
On univariate analysis, the following factors were identified as
risk predictors: need to initiate or change cardiac medication
during pregnancy (p = 0.001); LHO (p = 0.018); cardiac
complications prior to pregnancy (p = 0.002); ejection fraction
<40% (p = 0.038); and NYHA functional class III on the first
visit to the HRPC (p = 0.011) (Table 3).
On multivariate analysis, the following factors were
independent risk predictors of cardiovascular complications
that can influence maternal-fetal outcomes: need to initiate
or change cardiac medication during pregnancy [p = 0.009;
95% confidence interval (95%CI): 0.058-0.408]; previous
cardiac complications (p = 0.013; 95%CI: 0.401-0.342);
and functional class III on the first prenatal visit (p=0.041;
95%CI: 0.032-0.134).
The perinatal outcomes assessed in 129 pregnancies were
as follows: 13 (10.07%) small for gestational age newborns and
34 (26.36%) premature babies (4 aged less than 30 weeks,
14 between 32 and 34 weeks, and 16 between 35 and
37 weeks). No association was found between those results
and risk factors for maternal cardiovascular complications.
Martins et al.
Original Article
Table 1 – Distribution of the pregnant women according to the occurrence of cardiovascular complications
Cardiovascular complications
n (%)
Arrhythmias
8 (26.67)
Stroke
2 (6.67)
Cardiac decompensation
15 (50.00)
APE
0
IE
0
Sudden death*
1 (3.33)
Need for invasive procedure
4 (13.33)
BMV
3 (75)
Ao stent
1 (25)
*Severe mitral regurgitation. APE: acute pulmonary edema; IE: infectious endocarditis; BMV: balloon mitral valvoplasty; Ao: aorta.
Table 2 – Distribution of the gestations according to the occurrence of cardiovascular complications, as classified by the Cardiac Disease in
Pregnancy (CARPREG) risk score
Risk categories
CARPREG 0
Cardiovascular complications
Present
Absent
15.2
84.8
CARPREG 1
16.4
83.6
CARPREG >1
42.1
57.9
p value
0.013
Figure 1 – Percentage of complications expected during pregnancy according to the CARPREG risk score versus those found.
Arq Bras Cardiol. 2016; 106(4):289-296
292
Martins et al.
Original Article
Table 3 – Univariate analysis of risk predictors of cardiovascular complications
Variables*
Cardiovascular complication
Present (%)
Absent (%)
OR
95%CI
p value
Drug treatment
35.4
65.6
4.57
1.84-11.35
0.001
Maternal smoking
29.4
70.6
1.86
0.59-5.86
0.327
SAH
13.0
87.0
0.56
0.15-2.05
0.295
Preeclampsia
08.3
91.7
0.34
0.43-2.80
0.450
LHO
60.9
39.1
3.04
1.35-6.86
0.018
Previous cardiac complications
38.6
61.4
3.65
1.59-8.41
0.002
EF > 60%
18.5
81.5
2.38
1.34-5.42
0.038
NYHA class III
25.0
75.0
3.89
1.23-7.69
0.011
HRPC initiated on the 3rd trimester
15.4
84.6
1.34
0.50-3.57
0.379
Valve prosthesis
21.1
79.0
1.10
0.33-3.65
0.542
*Need to initiate/change cardiac medication. OR: odds ratio; 95%CI: 95% confidence interval; SAH: systemic arterial hypertension; LHO: left-heart obstruction;
EF: ejection fraction; HRPC: high-risk prenatal care; CARPREG: Cardiac Disease in Pregnancy.
Discussion
The present study describes the profile of a population
of pregnant women with heart disease, mainly rheumatic
lesions, which are usual in the Brazilian population.
A 22.72% prevalence of cardiovascular complications in
pregnancy was found, a rate close to those found in this
same institution in 19977 and at the Instituto do Coração
(Incor) of the Medical School of the São Paulo University,8
23.9% and 23.5%, respectively. The most recent international
studies have revealed a lower number of complications: a
Canadian study has reported 13% of complications;4 the
ZAHARA I study, conducted in Holland in 2010,5 reported
a 7.6% incidence; and, even more recently, in 2013, an
European collaborative study reported 10% of cardiovascular
complications.9 That difference in the complication rates as
compared to international data can be partially explained
by the difference in the characteristics of the populations
studied. In addition, pregnant women with heart disease
in developed countries are more likely to have earlier and
easier access to prenatal follow‑up, which did not happen
in 75% of this study population.
This study shows that the population of pregnant women
with heart disease cared for at our institution did not change
much in the past 17 years regarding etiology. Over half of this
population (62%) had rheumatic heart disease, a percentage
similar to that obtained by Bacha et al.7 (56.8%) from 1990 to
1995. That percentage was also close to the one reported by
Ávila et al.8 when following 1,000 patients up at Incor during
a similar period.
Of the assessments for risk prediction of cardiovascular
complications during pregnancy, only Siu et al.4 and Tanous
et al.10 have included both congenital and acquired cardiac
diseases, but with a greater prevalence of congenital heart
diseases (74% in both studies). In other studies, all populations
analyzed consisted of pregnant women with only congenital
heart diseases.6,10-12 Of the complications presented by our
293
Arq Bras Cardiol. 2016; 106(4):289-296
patients, the most frequent was cardiac decompensation
(11.36%), a diagnosis that can be inaccurate, because, during
pregnancy, the distinction between the physiological changes
inherent in pregnancy and the signs of heart disease is difficult.
The criteria used to consider cardiac decompensation, as
discussed in the ZAHARA study,5 need to be better defined and
can explain the elevated percentage of complications in our
study population as compared to that of other publications.2,6
Comparison with the CARPREG risk score
Although the total frequency of complications was greater
in our patients, when assessing the incidence of cardiovascular
complications by using the CARPREG risk score, risk
overestimation was observed in the pregnant women classified
as CARPREG 1 and > 1. Our patients classified as CARPREG
1 had a 16.42% rate of complications as compared to the
27% proposed by the study by Siu et al.4 Those classified
as CARPREG > 1 had a 42.11% rate of complications as
compared to the 75% expected according to the same index.
This can be due to the apparent lower severity of the heart
diseases in our population of pregnant women.
Similarly, the LHO in our population less often progressed
to cardiac decompensation or other complications. While
the mean mitral valve area in our group of patients was
1.62 cm² and that of the aortic valve was 1.4 cm², those of
the pregnant women followed up in the CARPREG study4
were smaller, 1.3 and 0.9 cm², respectively.
The congenital diseases of the patients in this study,
in addition to being less frequent, were less complex,
reflecting the reduced number of patients with ventricular
dysfunction and complex congenital heart diseases who
reach the fertile age in the Brazilian population.
Although the patients classified as CARPREG 1 and > 1
had a lower percentage of complications than expected, the
CARPREG 0 group had twice more complications than that
expected according to the CARPREG risk score2 (11.36%).
Martins et al.
Original Article
This risk underestimation can reflect a late diagnosis of heart
diseases in young women, pregnancy being the moment
of the first diagnosis.
Other studies conducted with other populations have
also reported an overestimation of the risk for complications
by the CARPREG risk score. The authors of the ZAHARA I
study5 have attributed that overestimation by the CARPREG
risk score to the possibility that patients with acquired heart
diseases had more severe lesions in the CARPREG study
than in other studies and also to the criteria used to define
cardiac decompensation. Tanous et al.10 and Curtis et al.13
have also observed overestimation by the CARPREG risk
score when using it in their patients, and have suggested
that population differences would account for that.
The ZAHARA II study6 has considered that CARPREG
has a high prediction power for cardiac events in patients
at moderate and high risk, but that it could underestimate
the risk in patients classified as low risk.
Regarding the presence of advanced functional class
at the beginning of pregnancy, all studies, regardless of
the population studied, indicate that variable as a risk
predictor, similarly to that observed in our population.
Since the studies by Bacha et al., 7 that association of
maternal complications has been reported in the presence
of a baseline NYHA classification III or IV at the beginning
of the prenatal care or when the pregnant woman has
pulmonary hipertension.2,4,8,12
Maternal smoking did not prove to be an independent
risk factor for maternal complications, which is in
accordance with the observation of other authors.4,6 Khairy
et al.,11 however, have found an association of maternal
smoking with maternal complications, indicating that a
more careful interpretation is required regarding that habit.
The variables identified on multivariate analysis as
predictors of complication in that population are very
evident on clinical practice. The need to initiate or change
maternal medications during pregnancy was associated with
maternal complications (odds ratio of 4.57), and can be
interpreted as an equivalent to the need for intervention
due to NYHA functional class worsening during the
pregnancy-puerperal cycle.8,12
Other risk factors proposed in the CARPREG study,
such as LHO, ventricular dysfunction and previous cardiac
complications, were associated with maternal complications
on univariate analysis, but were not considered significant
in the logistic regression model13. The reduced number
of patients with that condition in our study could explain
that difference. This analysis suggests that, in populations
in which rheumatic acquired heart diseases prevail, the
LHO conditions, which actually predict cardiovascular
complications in pregnancy, are those with mitral stenosis,
mainly in the presence of severe valve area reduction.
Regarding perinatal outcomes, approximately one
quarter of the newborns were premature and/or small
for the gestational age, which is usually the most direct
complication of severe maternal complications, which lead
to premature interruptions of pregnancy and a reduction
in placental nutrition. However, of that population, only
4 newborns were extremely premature, and, probably
because of that small number, we could not find the
expected association with maternal outcomes.14
Study limitations
The obstetric factors were not controlled, which can
have influenced the results of the present study.
Siu et al. 4 have reported that, even in the presence
of LHO, cyanosis and advanced NYHA functional class,
women with heart disease and no other obstetric risk factor
had a minimally increased risk of neonatal complications.
In addition, no patient had cyanosis, and the number of
women with advanced functional class was relatively small.
Clinical implications
The present study emphasizes the need for the early
assessment of heart disease in pregnancy, that is, in
young women. Our patients’ mean age was 27 years, in
accordance with the mean age described in almost all
international studies. However, most of our patients arrive
at the HRPC outpatient clinic from the second trimester
on, and 40%, after the 20th gestational week. Those data
show that our patients are referred to the reference center
later. Regarding the quality of the patients’ follow-up
care and of the family planning offered, it is worth noting
that most women were between their second and fifth
pregnancy, and almost 12% of them were at least on their
fifth pregnancy. Comparison with studies from developed
countries, such as that by Siu et al.,4 in which only 1%
of the women were on their fifth pregnancy and most
(58%) of them were on their first pregnancy, evidences
the great difference between developed and developing
countries regarding the prevention of cardiovascular
complications based on effective prenatal counseling and
family planning. Our patients most likely do not have a
regular follow-up with a cardiologist, and, thus, receive
poor information on the risks of pregnancy regarding
their cardiac problems. Ideally, pregnancy should be
fully planned to occur on an occasion of disease stability,
and the obstetric follow-up should be initiated on the
first trimester. 13,15
Most severe rheumatic diseases should be treated,
usually with invasive procedures, before pregnancy.
This would reduce the need to use those procedures
during pregnancy itself, diminishing maternal-fetal
morbidity and mortality. 16,17 Other patients with more
severe forms and no possibility of effective treatment
should be oriented to avoid pregnancy and should receive
effective contraceptive counseling.15,18
The intermediate- and long-term prospective follow‑up
of a significant number of patients with severe heart
diseases can provide a more adequate analysis of the near
miss situations. In addition, it will enable the assessment
of the disease impact on the quality of life, sexual and
reproductive health, and long-term consequences of the
overload pregnancy imposes on patients with impaired
cardiac function. It will also contribute to the appearance
of health policies aimed at that group of patients.
Arq Bras Cardiol. 2016; 106(4):289-296
294
Martins et al.
Original Article
Conclusion
In this study on pregnant women with heart disease,
mostly rheumatic heart disease, the following independent
risk factors for cardiovascular complications during pregnancy
stood out: beginning or changing cardiac medication during
pregnancy; cardiac complications prior to the gestational
period; and NYHA functional class III at the beginning of
prenatal follow-up. In addition, the use of CARPREG risk
score in that population tended to underestimate the risk of
patients classified as low risk and to overestimate the risk of
those classified as moderate or high risk.
Capuruçu CAB, Nunes MCP; Statistical analysis: Martins LC, Freire
CMV, Capuruçu CAB, Nunes MCP; Writing of the manuscript:
Rezende CAL; Critical revision of the manuscript for intellectual
content: Martins LC, Freire CMV, Nunes MCP, Rezende CAL.
was reported.
Sources of Funding
Conception and design of the research: Martins LC, Freire
CMV, Rezende CAL; Acquisition of data: Martins LC, Freire CMV;
Analysis and interpretation of the data: Martins LC, Freire CMV,
Study Association
This article is part of the thesis of master submitted by
Luciana Carvalho Martins, from UFMG.
References
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Ministério da Saúde. Indicadores de dados. Datasus. Brasilia; 2009. [Acesso em
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Confidential Enquiry into Maternal and Child Health (CEMACH). Saving
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Obstet Med. 2008;1(1):54.
Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al;
Cardiac Disease in Pregnancy (CARPREG) Investigators. Prospective multicenter
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12. Song YB, Park SW, Kim JH, Shin DH, Cho SW, Choi JO, et al. Outcomes
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13. Curtis SL, Marsden-Williams J, Sullivan C, Sellers SM, Trinder J, Scrutton
M, et al. Current trends in the management of heart disease in pregnancy.
Int J Cardiol. 2009;133(1):62-9
14. Rezende CA, Freire CM, Bacha CA. Cardiopatia e gravidez. In: Corrêa
MD, Correa Jr MD, Aguiar RA, Melo VH. 14ª. ed. Noções práticas de
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al. Aderse neonatal and cardiac outcomes are more common in pregnant
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6. Balci A, Sollie KW, Mulder BJM, Ross-Hesselink JW, Van Dijk APJ, Vliegen HW,
et al. Prospective assessment of pregnancy risk estimation model in women with
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al. Diretrizes brasileiras para diagnóstico, tratamento e prevenção da
febre reumática da Sociedade Brasileira de Cardiologia, da Sociedade
Brasileira de Pediatria e da Sociedade Brasileira de Reumatologia. Arq
Bras Cardiol. 2009;93(3 supl.4):1-18.
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Bacha C, Rezende CA, Cury GC. Avaliação dos fatores de risco para
desenvolvimento de complicações clínicas secundárias à cardiopatia na
gestante. J Bras Gynec. 1997;107(9):315-22.
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Ávila WS, Rossi EG, Ramires JA, Grinberg M, Bortolotto MR, Zugaib M, et al.
Pregnancy in patients with heart disease: experience with 1,000 cases. Clin
Cardiol. 2003;26(3):135-42.
9. Roos-Hesselink JW, Ruys TP, Stein JI, Thilen U, Webb GD, Niwa K, et al. Outcome
of pregnancy in patients with structural or ischaemic heart disease: results of a
registry of the European Society of Cardiology. Eur Heart J. 2013;34(9):657-65.
10. Tanous D, Siu SC, Mason J, Greutmann M, Wald RM, Parker JD, et al.
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Original Article
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Back to The Cover
Original Article
Cardiac Autonomic Adjustments During Baroreflex Test in Obese
and Non-Obese Preadolescents
Mário Augusto Paschoal, Aline Carnio Brunelli, Gabriela Midori Tamaki, Sofia Serafim Magela
Pontifícia Universidade Católica de Campinas, PUC-Campinas, Campinas, SP – Brazil
Abstract
Background: Recent studies have shown changes in cardiac autonomic control of obese preadolescents.
Objective: To assess the heart rate responses and cardiac autonomic modulation of obese preadolescents during
constant expiratory effort.
Methods: This study assessed 10 obese and 10 non-obese preadolescents aged 9 to 12 years. The body mass index of the
obese group was between the 95th and 97th percentiles of the CDC National Center for Health Statistics growth charts, while
that of the non-obese group, between the 5th and 85th percentiles. Initially, they underwent anthropometric and clinical
assessment, and their maximum expiratory pressures were obtained. Then, the preadolescents underwent a constant
expiratory effort of 70% of their maximum expiratory pressure for 20 seconds, with heart rate measurement 5 minutes
before, during and 5 minutes after it. Heart rate variability (HRV) and heart rate values were analyzed by use of a software.
Results: The HRV did not differ when compared before and after the constant expiratory effort intra- and intergroup.
The heart rate values differed (p < 0.05) during the effort, being the total variation in non-obese preadolescents of
18.5 ± 1.5 bpm, and in obese, of 12.2 ± 1.3 bpm.
Conclusion: The cardiac autonomic modulation did not differ between the groups when comparing before and after
the constant expiratory effort. However, the obese group showed lower cardiovascular response to baroreceptor stimuli
during the effort, suggesting lower autonomic baroreflex sensitivity. (Arq Bras Cardiol. 2016; 106(4):297-303)
Keywords: Heart Rate/physiology; Autonomic Nervous System/physiopathology; Obesity; Barorreflex; Physical
Exertion; Adolescents.
Introduction
Expiratory efforts maintained for a certain time against a
constant pressure can simulate the autonomic function test,
known as Valsalva maneuver.
The Valsalva maneuver was named after Antônio Maria
Valsalva, who described it for the first time in 1704, and
used it to expel mucopurulent secretion from the middle ear
to the nasopharynx. Many years later, it was shown to cause
autonomic cardiac and vascular oscillations intermediated by
the baroreceptor system.1,2
Since then, that maneuver began to be used as a non‑invasive
autonomic cardiac function test, being standardized as an
expiratory effort equivalent to 40 cmH2O, maintained for
15 to 20 seconds.3 That test usually assesses heart rate (HR)
and systemic blood pressure (BP) behavior in response to
Mailing Address: Mario Augusto Paschoal •
PUC – Campinas. Av. John Boyd Dunlop s/n, Jd. Ipaussurama.
Postal Code 13090-950, Campinas, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received March 23, 2015; revised manuscript November 29,
DOI: 10.5935/abc.20160040
297
a stimulus that sensitizes baroreceptors, chemoreceptors
and cardiopulmonary receptors, through overload of the
cardiovascular system caused by the Valsalva maneuver.4
The Valsalva maneuver can be applied to assess baroreflexdependent cardiocirculatory responses in several situations,
such as in ill and healthy individuals, in pre- and post-physical
training periods, or in comparative studies of autonomic
cardiac modulation between groups of athletes and
sedentary individuals.5,6
However, it is rarely applied to children and preadolescents,
because, according to some authors, the expiratory pressure
exerted can be excessive. That population is believed to
have difficulty correctly exerting the expiratory pressures
and maintaining them for the established time, therefore
encouraging the development of studies on that issue.1
Several studies have suggested the existence of cardiac
dysautonomia in obese children and preadolescents,7,8 mainly
the morbid obese ones. This study aimed at assessing the
HR responses and cardiac autonomic modulation of obese
preadolescents during a constant expiratory effort.
The tested hypothesis was that such functional test,
by provoking an autonomic cardiorespiratory reflex
response, could also reveal the presence of dysautonomia in
obese children.
Paschoal et al.
Baroreflex in obese preadolescents
Original Article
Methods
This cross-sectional study was approved by the Ethics
Committee of Research in Human Beings of the Life Sciences
Center of the Pontifícia Universidade Católica of Campinas
(protocol 0298/11).
Study sample
This study selected 20 preadolescents aged 9
to 12 years, who were divided into two groups of
10 individuals each, as follows: obese sedentary (OB);
and non-obese (NO). This sample was selected by using
the convenience sampling technique.
The inclusion criteria were as follows: no regular physical
activity practice; no medication that interfered on the
data studied; and no changes on clinical examination.
In addition, the 10 obese preadolescents had to have body
mass index (BMI) values between the 95th and 97th percentiles
of the CDC National Center for Health Statistics growth
charts,9 while the 10 non-obese ones, between the 5th and
85th percentiles.
Anthropometric assessment
The anthropometric data assessed were body weight,
height, BMI, perimeters of body segments (arm, forearm,
thigh, leg and abdomen) and local fat (subscapular, suprailiac,
triceps and abdominal).
To measure body weight, individuals should be barefoot
and positioned on a pre-calibrated Filizola® scale graded in
100-g units. Height was taken on that same device, using a
metallic rod graded in centimeters, with the volunteer in the
standing position, facing back the metallic rod, which should
be positioned above the head.
In addition, the body perimeters were measured by
using a flexible measuring tape, and the skinfolds, by using
a scientific caliper (Premier Cescorf®, Porto Alegre, RS, Brazil)
graded in millimeters.
Clinical assessment
The clinical assessment consisted of a brief anamnesis
to confirm the sedentary lifestyle. Heart rate and BP
were recorded. For BP measurement, a standard aneroid
sphygmomanometer (Wan Med®, São Paulo, SP, Brazil)
was used, with cuffs adequate for the participants’
arm circumference.
In addition, cardiac and pulmonary auscultations were
performed in all participants with a stethoscope (Littmann
Classic II®, USA), according to the techniques widely described
in the literature.
Obtaining maximal expiratory pressure
Aiming at selecting the expiratory pressure to be used to
assess expiratory resistance to stimulate the baroreceptor
reflex, the maximal expiratory pressure (PEmax) of each
participant was obtained. For that, an M-120 analogical
manovacuometer (Global Med®, Minas Gerais, Brazil),
graded in cmH 2O, was used. Before that assessment,
all participants were instructed on the maneuver to
be performed.
The participants were then asked to sit, using a nose clip
to prevent air from escaping. They were then instructed
to inspire deeply through the mouth, and, right after,
to suddenly expire as strongly as possible against the
manovacuometer’s resistance.
That maneuver was performed three times, at 1-minute
intervals. At the end, the nose clip was withdrawn, and
the participant rested for 5 minutes. The highest measure
of the three interventions (PEmax) was selected to serve
as basis for calculating the effort the participant would
have to perform for the expiratory resistance maneuver.
That effort should correspond to 70% of the participant’s
PEmax. That percentage was based on previous calculations
performed in pilot studies showing that, at that expiratory
effort intensity, cardiocirculatory responses are not impaired,
and participants can maintain the expiratory pressure with
low oscillation for the 20 seconds of the test.
Participants began to be prepared for the expiratory
effort test 5 minutes after the last PEmax measurement,
when a belt was fixed to their chest to register their
heartbeats with a frequency meter (Polar S180®, Kempele,
Finland). That device has a belt with an elastic system tied
to the back and a wristwatch, with which heartbeats can
be measured. Later, the heartbeats recorded were entered
to a computer, with an IR interface, and by use of the Polar
Precision Performance® software (Kempele, Finland), the
HR values analyzed during the maneuver, as well as the HR
variability (HRV) index, could be calculated.
Expiratory effort test performance and baroreceptor
reflex stimulus
After the 5-minute rest, the participant initiated the
expiratory effort test, using a nose clip. The participant
inspired deeply through the mouth, and then performed
the predetermined expiratory effort (70% of PEmax),
which should be continuous for 20 seconds, maintaining
the expiratory pressure. During the effort, to facilitate
its control, the participant was instructed to read on the
manovacuometer display the pressure value, highlighted
in red, that should be achieved and maintained.
The tests were considered valid when the highest
pressure oscillation during 20 seconds was 5 cmH2O.
It is worth noting that data were collected under
controlled conditions (temperature of 23°C and at the
same day times) to avoid the circadian influences of HR
on autonomic modulation.
Later, participants remained in the dorsal decubitus
position for 5 minutes more, resting , to record the
heartbeats of the post-test condition.
Data collection for HR variability analysis
Before and after the expiratory maneuver, heartbeats
were recorded for 5 minutes, so that the autonomic balance
would be compared on those two moments. The objective
was to know whether, after performing the expiratory
Arq Bras Cardiol. 2016; 106(4):297-303
298
Paschoal et al.
Original Article
effort, the OB group would have more difficulty than the
NO group to return to the cardiac autonomic modulation
pattern of before the effort.
response to the autonomic nervous system stimulus resulting
from the expiratory maneuver.
The HRV analysis involved the time and frequency
domains. For the time domain, the following indices were
selected according to the Task Force:10
Data analysis and statistical approach
• iRR: RR intervals between each normal heartbeat;
• pNN50: percentage of adjacent iRR values greater than
50ms. It represents the parasympathetic influences
on the iRR, because the actions controlled by the
parasympathetic nervous system are faster than those
modulated by the sympathetic nervous system; when
greater than 50ms and frequent, they can mean greater
vagal interference in heart functioning;
• rMSSD: square root of the sum of the square of the
differences between iRR. Similarly to pNN50, rMSSD
expresses interferences of the parasympathetic nervous
system in the heart, and the higher its value, the greater
the vagal action on the heart.
For HRV analysis in the frequency domain, the following
indices were selected:
• LF NU: low frequency component (0.04 to 0.15 Hz),
whose values express cardiac sympathetic tonus,
although some authors report a certain vagal
influence on those values. In the present study, that
HRV parameter was normalized (normalized units –
NU), according to the Task Force, 10 and presented
as percentages. The values therefore calculated
express the percentage influence of the sympathetic
component on cardiac autonomic modulation on
the occasion of heartbeat recording, considering the
total potency of the spectrum after eliminating the
influence of the values of the very low frequency (VLF)
component, because they have less influence on
short‑term records;
• HF NU: high frequency component (0.15 to 0.4 Hz),
whose values express cardiac parasympathetic tonus.
Those values were also normalized according to the
Task Force.10
Collection of HR values and calculation of the delta
HR 0 to 10 seconds and 10 to 20 seconds during
forced expiration
The HR values were recorded during the expiratory
maneuver at an intensity of 70% of the PEmax and analyzed
in the computer. The Polar Precision Performance ®
software (Kempele, Finland) presented graphically all
the HR behavior before, during and after the maneuver.
The value immediately before beginning the expiratory
maneuver was recorded and compared with those of the
times 0-10 seconds and 10-20 seconds of the maneuver.
From those values, all HR variations were calculated.
The period of 20 seconds refers to the exact duration of
the expiratory effort during the maneuver and represents,
through HR elevation in the period, the interference of the
baroreceptor reflex. Greater HR elevations may suggest
greater sensitivity to the baroreflex, and, thus, good heart
299
Arq Bras Cardiol. 2016; 106(4):297-303
Statistical analysis was performed with the Graph Pad
Prism 4.0® (San Diego, USA) software. The anthropometric
and clinical data were shown in tables as means and
standard deviations. The Shapiro-Wilk test was used
to assess data normality, and, because of their normal
distribution, Student t test was used to show the differences
(p < 0.05) between the groups.
The Shapiro-Wilk test was used to assess the distribution
of HRV data, and, because of their non-normal distribution,
the nonparametric Mann-Whitney test was used to compare
the indices before and after the expiratory maneuver.
To compare the HR values (pretest vs. 10 seconds and
10 seconds vs. 20 seconds during the maneuver), the
Kruskal-Wallis test and Dunn’s post-test were used.
The significance level adopted was p < 0.05.
Results
Table 1 shows the anthropometric data of all participants,
while Table 2, their clinical data. The weigh and BMI values
were higher in the OB group, which was expected and is
part of the study’s inclusion criteria.
All body segments and skinfolds assessed differed
significantly (p < 0.05) between groups, and the OB group
had always the greatest values.
Despite obesity, no clinical differences in HR and
systolic and diastolic BP were observed between the
groups. In addition, the clinical parameters were within the
normal range.
Similarly to the clinical data, the HRV indices did not
differ in the pre- and post-expiratory maneuver conditions
(Table 3). This shows that, after the effort, the HRV values
expressing the cardiac autonomic modulation returned to
their pre-effort values.
Figure 1 shows, as boxplots, the median values of the first
and third quartiles, and the extreme HR values obtained in
the NO group before and during the expiratory effort (10 and
20 seconds). The HR showed a trend towards elevation
from the beginning to the end of the expiratory effort,
characterizing the normal HR response to the baroreceptor
reflex in the NO group.
Under the same conditions, the OB group did not show
the same HR behavior (Figure 2). The HR value increased up
to the 10th second of the expiratory effort (HR pre compared
to HR at 10 seconds); however, the HR value did not increase
from the 10th to the 20th second of the expiratory effort.
Discussion
In addition to showing that the expiratory pressure to be
applied during the expiratory effort similar to the Valsalva
maneuver can be individually calculated, the present
study aimed at assessing whether the magnitude of the
cardiovascular response to the baroreceptor reflex stimulus
Paschoal et al.
Original Article
of obese preadolescents would differ from that of the
healthy control group.
The major findings of the present study were: an
expiratory effort calculated as 70% of the PEmax and
maintained for 20 seconds, although slightly greater than
that proposed in other studies,1 can be applied in functional
tests to assess cardiovascular responses to stimuli promoted
by baroreceptors; the cardiac autonomic modulation, which
was similar in the OB and NO groups before the expiratory
effort, returned rapidly to its characteristic after the effort;
the OB group did not show the same magnitude of the HR
response stimulated by baroreceptors, unlike that of the
NO group, this being the most relevant finding of this study.
A reduction in the baroreflex response has also been
reported in children and preadolescents by Dangardt et al.11
and Lazarova et al.12 The analysis of the baroreceptor reflex
is important to assess the cardiac baroreflex activity, because
it incorporates both the sympathetic and parasympathetic
afferent and efferent branches; therefore, its assessment
could be more sensitive than HRV to identify cardiac
autonomic dysfunction in children.11,13
The analysis began with anthropometric and clinical
data, which could raise questions whether they could have
interfered in the above results, and showed that the mean
values of the body segments and skinfolds of the OB group
were significantly greater, as expected.
Those values certainly contributed to the higher body
weight of the obese individuals and their inclusion in this
study. It is worth noting that the greater abdominal perimeter
was confirmed in the obese individuals. That body region
measure has clinical relevance because it correlates with
an increased risk for cardiovascular diseases, such as
Table 1 – Anthropometric data
Non-obese
(n = 10)
Obese
(n = 10)
p value
9.6 ± 0.5
9.5 ± 0.5
> 0.99
Weight, kg
38.8 ± 4.9
51.8 ± 4.8
0.0002
Height, m
1.4 ± 0.07
1.4 ± 0.06
0.74
Anthropometric data
Age, years
18.5 ± 1.9
24.5 ± 2.0
< 0.0001
Arm, cm
22.3 ± 1.6
26.9 ± 1.5
0.0001
BMI, kg/m
2
Forearm, cm
19.1 ± 1.2
21.8 ± 1.0
0.0002
Thigh, cm
41.5 ± 3.8
47.2 ± 4.4
0.015
Leg, cm
28.8 ± 1.3
33.3 ± 2.5
0.0004
Abdomen, cm
65.5 ± 6.4
77.7 ± 6.1
0.0021
Skinfolds, mm
Subscapular
15.5 ± 7.3
24.4 ± 7.6
0.0362
Triceps
21.1 ± 8.2
31.1 ± 6.0
0.0098
Abdominal
27.1 ± 10.0
41.6 ± 7.0
0.0055
Suprailiac
34.0 ± 15.8
51.6 ± 8.6
0.0066
Data presented as mean ± standard deviation. BMI: body mass index.
coronary artery disease,14 acute myocardial infarction,15
and diabetes, 16 and can even interfere with cardiac
autonomic modulation.17-20
The values of systolic and diastolic BP and of HR did not
differ between the groups, suggesting that obesity has no effect
on them, as reported by some studies.15,17 However, that is a
controversial issue, because some studies14,21 have reported
higher BP and HR values in obese preadolescents, including
increased vascular stiffness of their carotid artery.22
Briefly, it seems that the significant effect of obesity on
those clinical data is not simple, and some factors, such as
genetic inheritance, obesity duration and presence or absence
of sedentary lifestyle, have been suggested to be related and
require further investigation.
In addition, the PEmax values did not differ between the
groups. It is worth noting that, if they did differ, they could
account for the difference in the HR data obtained during
the expiratory effort, as shown in another study conducted
by our team.1
Regarding the HRV indices in the time and frequency
domains, no significant difference was identified between
the groups (before or after the expiratory effort, when the
heartbeats were recorded).
However, unlike our results, some studies7,17 have shown
differences in the cardiac autonomic modulation between
obese and non-obese preadolescents, tending towards a
reduction in vagal activity and an increase of the cardiac
sympathetic tonus in the obese ones. Other authors have
suggested that, in that population, dysautonomia relates to a
decrease in the sympathetic and parasympathetic activity.23
The lack of difference in the HRV indices obtained in this
study, in addition to suggesting normality of the autonomic
nervous system at rest in both groups, contributes to prevent
that possible changes in the OB group could be held
responsible for the differences in HR responses, which were
documented during the baroreceptor reflex stimulation.
The most important finding of this study occurred during
the expiratory effort, which triggered the baroreceptor reflex.
Analyzing the HR behavior on the occasions of pre-effort
rest and at the 10th and 20th seconds of the expiratory test,
the OB group did not show the same HR response pattern
of the NO group, suggesting cardiac autonomic dysfunction
in that group.
Table 2 – Clinical data
Clinical data
Non-obese
(n = 10)
Obese
(n = 10)
p value
HR, bpm
Systolic BP, mm Hg
93.4 ± 13.5
86.4 ± 9.6
0.42
106.6 ± 8.6
100.0 ± 7.2
0.65
Diastolic BP, mm Hg
56.6 ± 5.0
60.0± 7.0
0.07
PEmax, cmH2O
80.7 ± 20.5
77.3 ± 15.9
0.43
70% PEmax, cmH2O
56.4 ± 14.1
54.1 ± 11.1
0.43
Data presented as mean ± standard deviation. HR: heart rate; BP: blood
pressure; PEmax: maximal expiratory pressure.
Arq Bras Cardiol. 2016; 106(4):297-303
300
Paschoal et al.
Original Article
Table 3 – Mean values of heart rate variability (HRV) indices before and after the expiratory maneuver
Before
HRV Indices
After
Non-obese
(n = 10)
Obese
(n = 10)
p value
Non-obese
(n = 10)
Obese
(n = 10)
p value
664.0
655.0
0.73
673.0
678.0
0.5
RR intervals, ms
pNN50, %
6.6
9.5
0.79
6.9
11.9
0.4
rMSSD, ms
40.5
52.8
0.66
43.0
50.0
0.2
LF, NU
58.2
37.2
0.38
59.9
47.7
0.2
HF, NU
41.7
62.7
0.38
40.0
52.2
0.2
pNN50: percentage of adjacent RR intervals greater than 50ms; rMSSD: square root of the sum of the square of the differences between RR intervals; LF:
low frequency component; HF: high frequency component; NU: normalized unit.
160
150
p < 0.05
140
HR (bpm)
130
120
110
100
90
80
70
HR pre
HR 10s
HR 20s
Figure 1 - Median values, first and third quartiles, and extreme heart rate (HR) values obtained right before the beginning of the expiratory effort (HR pre), after 10 seconds
from the beginning of the expiratory effort (HR 10s) and on the 20th second of the expiratory effort (HR 20s), with 70% of the maximal expiratory pressure, obtained in
the non-obese preadolescent group. Kruskall-Wallis test. p = 0.0432 – significant difference.
140
130
HR (bpm)
120
110
100
90
80
70
HR pre
HR 10s
HR 20s
Figure 2 - Median values, first and third quartiles, and extreme heart rate (HR) values obtained right before the beginning of the expiratory effort (HR pre), after 10 seconds
from the beginning of the expiratory effort (HR 10s) and on the 20th second of the expiratory effort (HR 20s), with 70% of the maximal expiratory pressure, obtained in
the obese preadolescent group. Kruskall-Wallis test; p = 0.1332 – no significant difference.
301
Arq Bras Cardiol. 2016; 106(4):297-303
Paschoal et al.
Original Article
During expiratory efforts sustained for a certain time, HR
elevation usually occurs, as reported in studies using the
Valsalva maneuver. In those studies, the HR elevation that
occurs from time 0 (beginning of effort) to 10 seconds of the
effort is vagus-dependent, that is, there is vagal release, which
determines a rapid HR elevation; the HR elevation in the
final 10 seconds occurs in response to arteriolar sympathetic
activation.1,3,8 However, some authors consider it difficult,
from the methodological viewpoint, to separate the HR
response during the baroreflex stimulus promoted by the
expiratory effort into times (from 0 to 10 seconds, and from
10 to 20 seconds).24
Thus, the OB group, with similar values to those of the NO
group at rest, cannot have the same cardiovascular performance
when stimulated by use of the baroreceptor reflex.
However, when analyzing HR values obtained during the
expiratory effort in adults, because parameters in adolescents
are scarce, the HR differences from the beginning of the
expiratory effort to the end of the 20th second showed
that obese individuals had a mean 12.2-beat elevation
while non‑obese had an 18.5-beat elevation. According to
Hohnloser and Klingenheben,3 that would represent normal
cardiac response of non-obese individuals, and borderline
(upper limit of normality) response of the obese ones.
In addition, according to Hohnloser and Klingenheben,3
delta HR values ≥ 15 bpm indicate proper cardiac autonomic
response, while delta HR values between 11 and 14 bpm are
considered borderline. When delta HR values ≤ 10 bpm, such
as those usually found in heart failure, diabetes, post-acute
myocardial infarction, and mitral stenosis, the response is
considered abnormal.
It is difficult to explain why the OB group did not have the
same performance of the NO group, although some studies,
such as that by Wieling et al.,25 have reported that the functional
changes in the reflex loop, responsible for the chronotropic
activity regulation that results in insufficient HR elevation during
provocative stimuli, could suggest autonomic dysfunction.
control of HR, as evidenced in the present study, and these
results are in accordance with those by Dangardt et al.11
The small sample size is a limitation of this study. Therefore,
further investigation involving a higher number of participants
should be conducted to confirm the lower baroreflex
responsiveness detected in the OB group.
Conclusion
The Valsalva maneuver applying a resistance equivalent
to 70% of the PEmax can be used in a population of
preadolescents to assess the cardiovascular response to the
baroreceptor system stimulus.
This study most important finding was that obese
preadolescents had lower autonomic baroreflex responsiveness
than non-obese ones, because they had lower total HR
response during the expiratory effort used to stimulate the
baroreceptor reflex.
Conception and design of the research: Paschoal MA;
Acquisition of data: Brunelli AC, Tamaki GM, Magela
SS; Analysis and interpretation of the data: Paschoal
MA, Brunelli AC, Tamaki GM, Magela SS; Writing of
the manuscript: Paschoal MA, Brunelli AC, Magela SS;
Critical revision of the manuscript for intellectual content:
Paschoal MA, Tamaki GM.
was reported.
Sources of Funding
Study Association
According to Rabbia et al.,8 obese preadolescents tend to
have sympathovagal dysfunction, which hinders the baroreflex
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Back to The Cover
Original Article
Serial High-Sensitivity Troponin T in Post-Primary Angioplasty
Exercise Test
Humberto Andres Vaz, Ana Paula Vanz, Iran Castro
Instituto de Cardiologia - Fundação Universitária de Cardiologia, Porto Alegre, RS - Brazil
Abstract
Background: The kinetics of high-sensitivity troponin T (hscTnT) release should be studied in different situations,
including functional tests with transient ischemic abnormalities.
Objective: To evaluate the release of hscTnT by serial measurements after exercise testing (ET), and to correlate hscTnT
elevations with abnormalities suggestive of ischemia.
Methods: Patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary angioplasty were
referred for ET 3 months after infarction. Blood samples were collected to measure basal hscTnT immediately before
(TnT0h), 2 (TnT2h), 5 (TnT5h), and 8 hours (TnT8h) after ET. The outcomes were peak hscTnT, TnT5h/TnT0h ratio, and the
area under the blood concentration-time curve (AUC) for hscTnT levels. Log-transformation was performed on hscTnT
values, and comparisons were assessed with the geometric mean ratio, along with their 95% confidence intervals.
Statistical significance was assessed by analysis of covariance with no adjustment, and then, adjusted for TnT0h, age and
sex, followed by additional variables (metabolic equivalents, maximum heart rate achieved, anterior wall STEMI, and
creatinine clearance).
Results: This study included 95 patients. The highest geometric means were observed at 5 hours (TnT5h).
After adjustments, peak hscTnT, TnT5h/TnT0h and AUC were 59% (p = 0.002), 59% (p = 0.003) and 45% (p = 0.003)
higher, respectively, in patients with an abnormal ET as compared to those with normal tests.
Conclusion: Higher elevations of hscTnT may occur after an abnormal ET as compared to a normal ET in patients with
STEMI. (Arq Bras Cardiol. 2016; 106(4):304-310)
Keywords: Troponin T; Ischemia; Myocardial Infarction; Exercise Test; Angioplasty.
Introduction
Cardiac troponins (cTn) are highly sensitive and specific
biomarkers for the detection of myocardial necrosis. They are
an essential complement to the clinical and electrocardiographic
criteria for the diagnosis of acute myocardial infarction (AMI)
according to the guidelines developed by the European Society
of Cardiology (ESC), American College of Chest Physicians
(ACCF), American Heart Association (AHA) and World Heart
Federation (WHF).1 The cTn not only added agility to diagnostic
confirmation,2,3 but proved to be very useful in choosing between
different therapeutic strategies4-9 and in identifying patients at
higher risk for future cardiovascular events.10,11
Recent advances have yielded greater accuracy for those
tests. They are now called high-sensitivity troponins, because
they have the ability to be detected at small concentrations
Mailing Address: Humberto Andres Vaz •
Instituto de Cardiologia do Rio Grande Do Sul. Avenida Princesa Isabel 395,
bairro Santana, Postal Code 90620-000, Porto Alegre, RS – Brazil
E-mail: [email protected]; [email protected]
Manuscript received May 26, 2015; revised manuscript November 23, 2015;
accepted November 24, 2015.
DOI: 10.5935/abc.20160029
304
with higher accuracy, including in individuals apparently free
from cardiovascular disease.2 Consequently, their kinetics has
been the focus of several studies in cardiology. One important
topic is their elevation in transient ischemia during physical or
pharmacological stress tests.12-16 The present study was aimed at
assessing the kinetics of high-sensitivity troponin T (hscTnT) by use
of serial measurements after an exercise test (ET) performed in
ST-segment elevation myocardial infarction (STEMI) patients, and
at comparing the changes in that biomarker levels on abnormal
versus normal tests.
Methods
Cross-sectional study performed from December 2010 to
August 2012 at the Institute of Cardiology/Fundação Universitária
de Cardiologia (IC/FUC), Rio Grande do Sul state, Brazil.
The inclusion criteria were patients aged at least 18 years,
diagnosed with STEMI, undergoing anticoagulant therapy and
adjuvant antiplatelet therapy during follow-up at a coronary care
unit, according to the ACCF/AHA guideline for the management
of STEMI, 2013,17 and primary angioplasty with conventional
stents with the following angiographic conditions: final TIMI
III flow in the affected vessel and complete revascularization,
defined as no stenosis ≥ 50% in another epicardial coronary
artery. The exclusion criteria were as follows: patients without
Vaz et al.
Post-Exercise Test Troponin T
Original Article
full conditions to exercise on a treadmill and presence of left
bundle-branch block or left ventricular overload with ST-segment
depression ≥ 1 mm on baseline electrocardiogram. The presence
of lesions in the left main coronary artery or equivalent, unstable
clinical findings, planned coronary artery bypass grafting, and
impossibility to follow the research protocol and/or refusal to
participate in the study were also considered exclusion criteria.
Of the 104 patients recruited, 9 did not undergo initial
assessment, one underwent coronary artery bypass grafting,
7 withdraw the study before undergoing ET, and one could not
exercise on a treadmill due to orthopedic problems, leaving
95 participants to be included in this study sample.
The following data were collected: anthropometric data;
laboratory data; medical history; and relevant data on primary
angioplasty and coronary angiography. Patients were invited to
participate in the study before hospital discharge. When eligible,
they provided written informed consent (WIC) after being
instructed on the ET and the research protocol.
Exercise testing was recommended 3 months after STEMI, but,
because of logistic factors and issues related to scheduling and
participants’ displacement, that period varied, the median being
108 days (interquartile interval: 93-145). The blood collections
for hscTnT measurement were as follows: immediately before
the ET, and after 2 hours (mean, 2.7 ± 0.6 hours), 5 hours (mean,
5 ± 0.6 hours) and 8 hours (mean, 8.6 ± 0.6 hours).
The study was approved by the Research Ethics Committee
(protocol nº 4391/09) and abided by the Helsinki declaration.
All participants provided the WIC before undergoing any
intervention.
Exercise test protocol
The stress test adopted was the symptom-limited ET on
treadmill according to the Bruce protocol.18 It was scheduled
within approximately 3 months after the STEMI, maintaining
the complete treatment, including beta-blockers and nitrates.
Valid tests were those with 12-lead electrocardiographic tracing
in the sitting and standing up position, at rest and during exercise,
with stable baseline and no interferences.
Blood pressure and continuous heart rate measurements
were taken, and the maximum load was calculated in METS.
The ET would be immediately interrupted in case of sustained
ventricular tachycardia, blood pressure drop during exertion, STsegment depression ≥ 2mm and progressive chest pain during
the procedure. The ET was conducted by a cardiologist with no
knowledge on baseline hscTnT (TnT0h) or any of the following
measurements. The abnormality criteria considered for the ET
were: on electrocardiogram, horizontal/descending ST depression
≥ 1mm at 0.08s after the J point and complex ventricular
arrhythmias; and symptoms or clinical findings characteristic of
myocardial ischemia during exertion.
hscTnT collections
Peripheral blood samples were obtained according to the
manufacturer’s instructions. They were collected before the ET
(TnT0h), and after 2 hours (TnT2h), 5 hours (TnT5h) and 8 hours
(TnT8h). All patients had a meal before the baseline collection
and ET, and remained on the hospital premises with no physical
activity until the next venous puncture. Blood was collected at
the same place of exercise testing. To ensure rest, the participants
remained sitting for 30 minutes before the collection. The
blood samples were always processed by the same professional
immediately after collection. Troponin T STAT (Short Turn Around
Time) assay was analyzed by using the commercially available
Elecsys 2010 analyzer (Roche Diagnostics, batches nº 153401,
157120, 160197, 163704), which uses the chemiluminescence
method (analysis of two monoclonal antibodies specifically
directed against human troponin T). The limits of the blank,
of detection and maximum are 3ng/L, 5ng/L and 10,000ng/L,
respectively. The limit of test quantification was 13ng/L (functional
sensitivity), corresponding to the lowest concentration that can be
measured in a reproducible way with coefficient of variation (CV)
≤ 10%. The 99th percentile detected in a reference population
was 14ng/L.19 The information for calibration of each assay is
specifically established according to each batch used. Each batch
was adapted to the analyzer by using the Elecsys Troponin T
STAT CalSet calibrator no later than 24 hours after registering
the reagent kit. New calibrations were performed as needed,
according to the manufacturer.
The normal distribution of the continuous variables in this
sample was assessed by using the Kolmogorov–Smirnov test.
The continuous variables were presented as mean and standard
deviation, and, in case of asymmetrical distribution, as median
(interquartile interval: p25-p75). Categorical variables were
presented as absolute count and percentages. To compare
between different categories of hscTnT changes and the presence
of normal or abnormal ET, Fisher exact test was used. To compare
hscTnT values between two groups, Mann-Whitney U test was
used. In addition, Spearman coefficient was adopted to assess
the correlation between age and hscTnT values, and between
creatinine clearance and hscTnT values. Due to the asymmetrical
distribution of hscTnT values, logarithmic transformation was
used. To assess hscTnT changes between the groups with
normal and abnormal ET, the following outcomes were used:
post-ET peak troponin (peak TnT); ratio between troponins
collected in the fifth hour and at baseline (TnT5h/TnT0h); and
area under the blood concentration-time curve. Due to the
logarithmic transformation, the hscTnT values were presented
as geometric means, and the comparisons between the groups
were summarized by using the geometric mean ratio with their
respective confidence intervals. The statistical significance of those
comparisons was assessed in a model of analysis of covariance
(ANCOVA), initially without adjustments, and then adjusting for
TnT0h, age, sex and additional variables (METS, percentage of
the maximum heart rate achieved, anterior left ventricular wall
STEMI, and creatinine clearance estimated with the CockcroftGault formula). A p value <0.05 was considered statistically
significant, and the entire analysis was elaborated by using the
Statistical Package for the Social Sciences (SPSS) software, version
21.0 (SPSS Inc., Chicago, IL, USA).
Results
This study included 95 patients diagnosed with STEMI, treated
with primary angioplasty and submitted to ET 3 months after the
initial event. The mean age of this sample was 54.25 ± 11 years,
with a higher prevalence of the male sex (81%).
Arq Bras Cardiol. 2016; 106(4):304-310
305
Vaz et al.
Original Article
The right coronary artery was affected in 46% of the
cases, followed by the anterior descending (43%) and the
circumflex (8%) arteries. On coronary angiography, threevessel disease was detected in only 4% of the patients,
no lesion being detected in the left main coronary artery.
Only 5% of the patients underwent stent implantation in
a second epicardial vessel, right after treating the affected
coronary artery. Whenever anatomically possible, the
patients underwent complete revascularization, defined as
residual lesions smaller than 50%. Table 1 shows the baseline
characteristics of this sample.
abnormal
ET
(n=13)
normal
ET
(n=82)
Age (years)
59 ± 12
54 ± 10
Male sex n (%)
12 (92)
65 (79)
BMI (kg/m )
28 ± 3
27 ± 5
Current or previous smoking
9 (70)
53 (65)
Systemic arterial hypertension
9 (70)
65 (80)
Family history of CAD
2 (15)
30 (37)
Characteristics
Anthropometric
2
Regarding medication, most patients used a combination
of acetylsalicylic acid (97%), clopidogrel (92%), statins (96%),
beta-blockers (92%) and angiotensin-converting-enzyme
inhibitors (94%) at the time of the ET. A smaller proportion
(4%) of patients used oral or sublingual nitrates to relieve
anginal symptoms before the ET.
Risk factors (%)
Diabetes
1 (8)
13 (15)
Of the total sample, 13 patients were classified as
having an abnormal ET. Of those, 11 (84%) had persistent
ST‑segment depression ≥ 1 mm during the test, one patient
(8%) had non-sustained ventricular tachycardia associated
with clinical signs of coronary artery disease (CAD), and
another (8%) had progressive angina pectoris, requiring the
interruption of the procedure.
Dyslipidemia
7 (54)
62 (76)
Time until treatment (hours)
5 (2 - 6)
4 (2 - 5)
Anterior wall location n (%)
3 (23)
44 (53)
1
8 (61)
64 (78)
≥2
5 (38)
18 (22)
9 (70)
68 (80)
2
4 (30)
14 (17)
1st stent length (mm)
27 ± 8
21 ± 7
2nd stent length (mm)
19 ± 10
18 ± 8
% of maximum HR achieved
79 ± 12
80 ± 12
Double product (x10 )
22 ± 5
22 ± 6
METS
8±2
8±2
90 ± 25
100 ± 30
6.7 (4.7 - 7.4)
5.4 (3 - 9.5)
The values of creatinine clearance and ET performance
were similar in the groups with normal and abnormal ET.
The frequencies of the traditional risk factors for CAD and
of anterior left ventricular wall STEMI were similar in both
groups. There was a trend towards the use of longer stents
(p = 0.06) in the group with abnormal ET as compared to
that with normal ET.
In 35 (37%) patients, TnT0h was undetectable. Smoking
(p = 0.03) and age (p < 0.001), directly, and creatinine
clearance (p < 0.01), indirectly, were associated with higher.
TnT0h values. Ten patients (19%) reached or exceeded the
clinical decision level (14 ng/L), and that finding was more
frequent in the abnormal ET than in the normal ET group,
46.2% versus 14.6%, respectively (p = 0.015).
Higher hscTnT geometric means were identified at the
time of the third collection (TnT5h) in patients with abnormal
ET than in those with normal ET, as well as a decrease in
those values in the fourth collection (TnT8h). The ANCOVA
showed a 71% greater peak TnT in patients with abnormal
ET as compared with those with normal tests, 54% greater
with adjustments for TnT0h, sex and age (p = 0.003), and 59%
greater after adjustment for additional factors (p = 0.002),
as shown in Table 2.
When comparing the groups with normal and abnormal
ET, the analysis of the area under the blood concentrationtime curve of the hscTnT values showed statistical significance
(p = 0.003) after adjustments (Figure 1).
Discussion
Using a high-sensitivity troponin T assay, we demonstrated that
elevations in that marker, adjusted for the baseline levels, are greater
in ET with changes suggestive of transient ischemia as compared
to normal tests of STEMI patients treated with primary angioplasty.
306
Table 1 – Characteristics of the patients according to abnormal or
normal exercise tests (ET)
Arq Bras Cardiol. 2016; 106(4):304-310
Acute myocardial infarction
Number of vessels affected n (%)
Stents n (%)
1
ET: additional parameters
3
Biochemistry
Creatinine clearance (mL/min)
TnT0h
Data presented as mean ± standard deviation (SD), n (percentages)
and median (p25 - p75); ET: exercise test; BMI: body mass index; CAD:
coronary artery disease; HR: heart rate; METS: metabolic equivalents;
TnT0h: baseline troponin T.
The ET changes defined in this study were associated with hscTnT
increments, especially after the fifth hour, even with adjustments for
additional variables, such as load, percentage of maximum heart
rate achieved and creatinine clearance. The cTn released into
blood stream seems to originate initially from the cytosol content,
and later from the cardiomyocyte structural content. The latter
would account for the sustained curve of cTn known in AMI, and
would translate an irreversible injury to the sarcomere proteins.
That difference is the basis for the questions related to the transient
troponin increase in the absence of myocardial necrosis.20
Vaz et al.
Original Article
Table 2 – Non-adjusted and adjusted comparisons between the groups with abnormal exercise test (ET) versus normal ET for
selected outcomes
Adjusted analysis for TnT0h,
age and sex
Non-adjusted analysis
Analysis with additional
adjustment†
Abnormal ET*
(n = 13)
Normal ET*
(n = 82)
geometric mean
ratio (95% CI)
p
geometric mean
ratio (95% CI)
p
geometric mean
ratio (95% CI)
p
13.15
7.69
1.71
(1.07 - 2.73)
0.025
1.54
(1.14 - 2.07)
0.003
1.59
(1.17 - 2.15)
0.002
TnT5h/TnT0h
1.90
1.22
1.56
(1.16 - 2.10)
0.004
1.51
(1.11 - 2.04)
0.008
1.59
(1.17 - 2.15)
0.003
AUC (ng/L)2
84.3
55.0
1.54
(0.98 - 2.39)
0.058
1.39
(1.10 - 1.77)
0.007
1.45
(1.14 - 1.85)
0.003
Outcome
Primary
peak TnT (ng/L)
Secondary
*Data are presented as geometric means; CI: confidence interval; p: statistical significance; ET: treadmill exercise test; TnT: high-sensitivity troponin T; AUC: area
under the curve; †additional adjustment for baseline troponin T (TnT0h), metabolic equivalent, percentage of maximum heart rate reached, anterior wall infarction and
creatinine clearance (Cockcroft-Gault method).
20
Abnormal exercise test
Normal exercise test
High-sensitivity Troponin T (ng/l)
18
16
14
12
10
8
6
4
p = 0.003
2
0
0
1
2
3
4
Time (hours)
5
6
7
8
Figure 1 – Variation of hscTnT over time in the groups of normal and abnormal exercise tests, presenting the geometrical means, their respective confidence intervals
and significance for the area under the curve analysis (AUC).
Hessel et al., in a study inducing cardiomyocytes to
metabolic inhibition, have concluded that the release of
troponin T (cTnT) and I (cTnI), in their both intact and
degradation product forms, occurs simultaneously and
only after necrosis.21 However, hypothetical mechanisms
for the transient release are as follows: apoptosis; 22
normal cardiomyocyte turnover;23 passage of degradation
fragments through the intact cell membrane; 24 and
formation and passage of vesicles with cytosol content to
the extracellular space.20
In previous studies with fourth-generation cTn assays
performed after stress testing, the results remained undetectable,
below the CV limit of 10%, or not associated with ischemia
induction.25-29 Another study using high-sensitivity cTnI (hscTnI),
however, has found changes proportional to the intensity of
the ischemia (mild and moderate-to-severe) estimated on
myocardial perfusion imaging, when the sample was collected
2 and 4 hours after the stress test. In that same study, changes in
troponin levels in patients with different ischemic categories were
indistinguishable using conventional troponin assays.12
Arq Bras Cardiol. 2016; 106(4):304-310
307
Vaz et al.
Original Article
The present study assessed a specific population of patients
with a sequela of STEMI, and measuring those markers at
baseline and after ET in individuals with structural heart disease
is particularly important. In a previous study with 118 patients,
measuring cTnI before Bruce protocol symptom-limited ET, and
then 8-12 and 24 hours after, no correlation of the elevation
in biomarker levels with the presence of multiarterial disease
and ET changes was found. However, on multivariate analysis,
ejection fraction ≤ 50% was an independent variable for
cTnI elevations above the 99th percentile.30 Another study
has assessed serial hscTnT and hscTnI after myocardial
perfusion imaging stress testing, and none of those markers
could identify patients with reversible ischemia. A significant
increase in hscTnI was comparable to hscTnT levels at all
collection times in the presence of previous AMI, but without
reversible ischemia (p < 0.001 versus baseline collection).
The baseline cTn concentrations in that study seemed to
be influenced by variables related to myocardial structural
changes.13 Another study using hscTnT after magnetic resonance
imaging has detected small amounts 1 and 3 hours after nonpharmacological stress, not fulfilling criteria for AMI, but the
levels were related to the intensity of the ischemia found. History
of diabetes, CAD, lower creatinine clearance and ejection
fraction were more frequently found in patients with moderateto-severe ischemia.16 Other studies demonstrating cTnI release
in individuals with heart failure31 submitted to exercise or in
marathon runners with exercise-induced high blood pressure32
could also indicate a role for the presence of those markers in
different left ventricular overload situations.
In the present study, a late ET was performed 3 months after
AMI to avoid the detection of TnT0h levels in the descending
curve because of the primary tissue injury caused by AMI.
Our study found that higher TnT0h levels correlate with
smoking, older age and lower creatinine clearance. The last
two findings are similar to those studies using hscTnT33 and
hscTnT and hscTnI.13
We believe that the values found were not actually related
to new coronary events, because of the small variations and
the early descent, but rather to cases with imbalance between
oxygen offer and demand, based on the significantly lower
levels of high-sensitivity troponins found in that situation.34
Lower values found on the initial assessment of patients for acute
coronary syndrome seemed not related to type I AMI (ischemia
due to atherosclerotic plaque rupture, thrombus formation,
fissure and spontaneous dissection),35 and regardless of the
cause of hscTnT release in circulation, increases in the marker
can be related to higher mortality. Data from the SWEDEHEART
Registry have shown that patients suspected of having acute
coronary syndrome and hscTnT levels greater than 14 ng/L had
higher adjusted mortality rates; however, only 18.2% of them
actually had had an AMI.36 We could infer that, even without
knowing the exact mechanism of hscTnT release, increases
in that marker, especially from the 99th percentile on, could
indicate other changes related to the post-STEMI period, which
should, from now on, be studied.
The use of that marker in association with the traditional
risk parameters in ET could indicate one more risk criterion.
308
Arq Bras Cardiol. 2016; 106(4):304-310
However, this cross-sectional study assessed the kinetics of that
marker in a limited population. The meaning of those changes
in association with ET should be assessed in large prospective
studies. The use of high-sensitivity assays will not often identify
patients at risk without high hscTnT levels, above the clinical
decision limits, or with small transient changes. The clinical
setting should be valued when considering the circumstances
under which low hscTnT levels can be detected in circulation.
Conclusion
Serial hscTnT elevations after ET were demonstrated.
In abnormal tests, after determining the baseline values,
the hscTnT levels are significantly higher as compared to
normal ET in STEMI patients. In transient abnormalities
suggestive of myocardial ischemia in ET, hscTnT shows
a pattern of elevation followed by an early descent.
Higher baseline values are related to smoking, older age and
lower creatinine clearance levels. In that population, elevated
levels, especially from the 99th percentile, can indicate a
higher risk or myocardial structural injury.
Limitations
Exercise testing without the addition of imaging tests has
limitations. Thus, the presence of hscTnT changes cannot be
considered a manifestation of residual ischemia. In addition,
there were neither a control group nor echocardiographic data
to correlate left ventricular structural changes with the hscTnT
kinetics. The pathway to the knowledge of the real meaning
of those changes regarding the increment of prognostic data
should be delineated in prospective studies with a larger
number of participants.
Acknowledgments
We thank all professionals who collaborated in the care
provided to this study participants, and in data interpretation
and analysis, and to the IC/FUC Research Unit.
Conception and design of the research, Acquisition of
data, Analysis and interpretation of the data, Statistical
analysis, Writing of the manuscript and Critical revision of the
manuscript for intellectual content: Vaz HA, Vanz AP, Castro I.
was reported.
Sources of Funding
Study Association
This article is part of the thesis of master submitted by Humberto
Andres Vaz, from Fundação Universitária de Cardiologia.
Vaz et al.
Original Article
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Arq Bras Cardiol. 2016; 106(4):304-310
Back to The Cover
Original Article
Aerobic Training after Myocardial Infarction: Remodeling Evaluated
by Cardiac Magnetic Resonance
Nataly Lino Izeli1, Aurélia Juliana dos Santos1, Júlio César Crescêncio1, Ana Clara Campagnolo Real Gonçalves1,
Valéria Papa1, Fabiana Marques1, Antônio Pazin-Filho2, Lourenço Gallo-Júnior1, André Schmidt1
Divisão de Cardiologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto – USP1; Divisão de Emergência da Faculdade de
Medicina de Ribeirão Preto – USP2, Ribeirão Preto, SP - Brazil
Abstract
Background: Numerous studies show the benefits of exercise training after myocardial infarction (MI). Nevertheless, the
effects on function and remodeling are still controversial.
Objectives: To evaluate, in patients after (MI), the effects of aerobic exercise of moderate intensity on ventricular
remodeling by cardiac magnetic resonance imaging (CMR).
Methods: 26 male patients, 52.9 ± 7.9 years, after a first MI, were assigned to groups: trained group (TG), 18; and
control group (CG), 8. The TG performed supervised aerobic exercise on treadmill twice a week, and unsupervised
sessions on 2 additional days per week, for at least 3 months. Laboratory tests, anthropometric measurements, resting
heart rate (HR), exercise test, and CMR were conducted at baseline and follow-up.
Results: The TG showed a 10.8% reduction in fasting blood glucose (p = 0.01), and a 7.3-bpm reduction in resting HR
in both sitting and supine positions (p < 0.0001). There was an increase in oxygen uptake only in the TG (35.4 ± 8.1 to
49.1 ± 9.6 mL/kg/min, p < 0.0001). There was a statistically significant decrease in the TG left ventricular mass (LVmass)
(128.7 ± 38.9 to 117.2 ± 27.2 g, p = 0.0032). There were no statistically significant changes in the values of left ventricular
end-diastolic volume (LVEDV) and ejection fraction in the groups. The LVmass/EDV ratio demonstrated a statistically
significant positive remodeling in the TG (p = 0.015).
Conclusions: Aerobic exercise of moderate intensity improved physical capacity and other cardiovascular variables.
A positive remodeling was identified in the TG, where a left ventricular diastolic dimension increase was associated
with LVmass reduction. (Arq Bras Cardiol. 2016; 106(4):311-318)
Keywords: Exercise; Rehabilitation; Myocardial Infarction; Magnetic Resonance Spectroscopy.
Introduction
Left ventricular (LV) remodeling after myocardial infarction
(MI) is a complex and multifactorial process with prognostic
and therapeutic implications.1 Minimizing LV remodeling with
medications improved survival and quality of life.2-4
Exercise training has been shown to improve exercise
capacity and reduce mortality, amplifying potential therapeutic
interventions. 5 In addition, aerobic exercise reduces
cardiovascular risk factors, which makes it further appealing
as an adjuvant treatment.6,7
The benefits of exercise training in increasing aerobic
capacity, as well as other hemodynamic changes, are well
documented. Nevertheless, the effects of exercise on
Mailing Address: André Schmidt •
Divisão de Cardiologia do Hospital das Clínicas - Faculdade de Medicina de
Ribeirão Preto – Universidade de São Paulo. Av. Bandeirantes 3900, Monte
Alegre. Postal Code 14048-900 – Ribeirão Preto, SP – Brazil
Manuscript received September 14, 2015; revised manuscript November 18,
DOI: 10.5935/abc.20160031
311
myocardial function and LV remodeling after MI are still
controversial. Some studies have suggested that exercise after
MI further deteriorates cardiac function due to additional stress
over the infarcted area, infarct expansion, aneurysm formation,
or ejection fraction (EF) reduction.8-10 Numerous studies have
failed to confirm these findings and suggested that exercise
does not alter ventricular parameters even in different training
intensities.11-14 Other studies have shown that after a recent
acute MI with systolic dysfunction, exercise can attenuate
ventricular remodeling and even reverse this process.15-18
Heterogeneity related to patient sampling, intensity of training,
measurement techniques, or even a combination of these
factors could be potential explanations for that divergence.19
We sought to evaluate the effects of aerobic exercise of
moderate intensity, performed in patients after MI on cardiac
function through cardiac magnetic resonance (CMR), a
well‑recognized gold standard technique for the quantification
of ventricular volumes, EF and myocardial mass.20
Methods
Male patients were selected according to strict inclusion
criteria during an 18-month period. All patients presented
Izeli et al.
LV remodeling evaluated by magnetic resonance
Original Article
an acute MI with ST elevation. Patients enrolled should be
younger than 70 years, clinically stable, on sinus rhythm
and not previously included in any cardiac rehabilitation
program. It must also be no later than 6 months after their
first MI. Exclusion criteria included unstable coronary artery
disease, uncontrolled hypertension, malignant ventricular
arrhythmia and ventricular failure during exercise, Chagas
disease, untreated thyroid function disorders, neurological
or orthopedic inability to perform physical exercises on a
treadmill, and general debility. Since cardiac rehabilitation
was offered to all patients as part of our institution standard of
care, patients with inclusion criteria but not willing to engage
in the program, who accepted to perform the exams of the
protocol, were included as controls.
The study was approved by the local ethical committee.
Written informed consent was obtained from all patients.
Study Design
Initially, all patients were evaluated by a cardiologist to
provide a clinical history and undergo physical examination with
anthropometric measurements. When necessary, medications
were optimized. Patients in both groups underwent laboratory
tests that included complete blood count, lipid profile, and
fasting glucose. A functional evaluation was performed at
baseline and after at least 3 months of aerobic exercise training,
including resting heart rate (HR), exercise testing and CMR.
The first two were always performed in the morning, and no
medication was withdrawn. The intervention period (IP) for the
trained group (TG) was defined as the time between the first
exercise training session and the final CMR and clinical and
laboratorial evaluations. The IP for the control group (CG) was
the period between the two CMR exams.
Resting HR
The resting HR was obtained beat-by-beat, using a modified
MC5 electrocardiogram lead, in the morning, and on currently
prescribed medications. The volunteers remained at rest in
the supine position for 15 minutes, and in the sitting position
for 8 minutes. Patients were instructed to maintain a relaxed
posture without moving arms and legs, talking or sleeping.
To obtain the mean HR, the first ten beats were discarded and
arithmetic mean was performed with the other values.
Exercise Testing
Patients performed a symptom-limited treadmill exercise
test with electrocardiographic monitoring of three leads
(MC5, D2M, and V2M), using the Micromed Ergo PC software
(São Paulo, Brazil). They were instructed not to consume
stimulating food substances, and not to perform strenuous
activities before the test. They underwent the modified
Balke protocol, with increments in treadmill speed and
inclination every minute, selected according to the physical
capacity expected for each patient. The electrocardiogram
was monitored continuously. Blood pressure, HR, and signs
and symptoms were obtained every minute during exercise,
and throughout the recovery period. The following variables
were obtained at peak exercise: HR, blood pressure, oxygen
uptake, metabolic equivalent, treadmill load, and rating of
perceived exertion (Borg CR10 scale).21 The peak oxygen
uptake was obtained indirectly, using the treadmill speed
and inclination at peak exercise.
MRI
All imaging was performed using a 1.5T unit (Magneton
Vision, Siemens, Erlängen, Germany). After initial scout
imaging, breath-hold steady-state free precession cine
MR images were acquired along the vertical long axis
(2- and 4-chamber view) and a short axis stack (contiguous
8-mm-thick slices) covering the ventricle extension.
The later sequence was used to assess the LV mass (LVmass),
LV dimensions and EF. All images were blindly analyzed by a
single operator (A.S.) using Image J.22 LV end-systolic volume
and LV end-diastolic volume (LVEDV) were calculated using
Simpson’s rule. The LVmass was determined by the sum
of the myocardial area (LV epicardial contour minus LV
endocardial contour) times slice thickness, and multiplied
by the specific myocardial gravity (1.05g/mL). The LVEF
was calculated as the difference between LVEDV and LV
end-systolic volume, divided by LVEDV and multiplied by
100. No gadolinium infusion was used.
Exercise Training Protocol
The aerobic exercise training was prescribed based on
the peak HR or HR in the ischemic threshold obtained
during exercise testing. Exercise intensity was determined at
50‑70% of HR reserve (Karvonen’s equation). The TG patients
participated in a supervised 30-minute treadmill session,
twice a week in the morning period, for at least 3 months.
Each session was preceded by a 5-minute warm-up and
followed by a 5-minute cooling-down period. During each
supervised session, intensity of exercise (treadmill speed and
inclination), HR, blood pressure, and rating of perceived
exertion (Borg CR10 scale) were recorded. Patients were
instructed to undergo more two unsupervised sessions each
week, adjusting the speed of walking by counting the radial
pulse or using a pulse HR monitor. Data from outside walking
were registered in a dairy, in which the patient reported
the resting HR, exercise time, and HR during walking and
after 5 minutes of recovery. During training sessions, the TG
patients received information regarding lifestyle modification
strategies, regular physical activity, healthy diet, importance
of weight control, and stress reduction. The CG underwent
the usual clinical follow-up and was subsequently contacted
to perform the final exams. The volunteers’ medications were
not modified during the IP.
Statistical Analysis
Continuous variables were expressed as mean ±
standard deviation. Categorical variables were presented
as percentages. The distribution of the data was analyzed
with the Shapiro-Wilk test. Categorical data were compared
with the chi-square and Fisher exact tests. Continuous data
were assessed by the Wilcoxon nonparametric rank-sum
test (intragroup analysis) and Mann-Whitney nonparametric
test (intergroup analysis), with a significance level of 5%.
Statistical analysis was performed using the SPSS for Windows
software (version 10.0, SPSS Inc., Chicago Illinois, USA).
Arq Bras Cardiol. 2016; 106(4):311-318
312
Izeli et al.
Original Article
Results
A total of 26 male patients (52.9 ± 7.9 years) were
enrolled in the study after fulfilling the inclusion criteria
and presenting no exclusion criteria. Since 8 of them
were not willing to participate in the rehabilitation
program, but agreed to undergo the tests needed, they
constituted the CG. The other 18 patients were the TG.
Seventeen patients received fibrinolytics on MI admission
(TG = 10 and CG = 7; p = 0.29). The TG had a lower
prevalence of smoking and sedentary lifestyle than the CG.
Baseline clinical data of the two groups are summarized
in Table 1. The IP was 136.7 ± 26.2 days for the TG, and
150.5 ± 44.5 days for the CG (p = 0.87). The TG performed
a mean of 27.5 ± 5.6 supervised training sessions. None of
the groups had clinical complications during the IP.
Anthropometric measurements and laboratory tests
Baseline anthropometric measurements were similar
between the two groups. At the end of the IP, the TG showed
a decrease of 1.28 kg in weight and of 0.47 kg/m2 in body
mass index (BMI), with no statistical difference (p = 0.17
and p = 0.15, respectively). We observed a statistically
significant increase in weight (3.8kg) and BMI (1.27 kg/m2)
in the CG (p = 0.04 for both).
There were no differences between the groups for baseline
measures of total cholesterol (p = 0.64), triglycerides (p = 0.19),
high-density-lipoprotein cholesterol (HDL-c) (p = 0.4530),
low-density-lipoprotein cholesterol (LDL-c) (p = 0.53) and
fasting glucose (p = 0.52) (Table 2). The TG showed changes
in lipids and glucose levels at the end of the exercise training
protocol. Fasting glucose decreased significantly (106.0 ± 26.4
to 94.5 ± 14.8 mg/dL, p = 0.01). The lipid profile showed
improvement without statistical significance. Total cholesterol
was reduced by 6% (p = 0.08). There was a mean reduction
of 16.9% in triglycerides (p = 0.14). HDL-c increased 5.1%
(p = 0.42), LDL-c decreased 6.1% (p = 0.32). In CG there was
a trend to increase in total cholesterol (p = 0.46), triglycerides
(p = 0.11) and fasting glucose (p = 0.47).
Resting HR
No statistically significant difference was found at baseline
between groups in resting HR. The resting HR in TG in
the sitting position showed a decrease from 62.4 ± 9.1 to
55.1 ± 5.9 bpm (p < 0.0001). In the supine position, HR
decreased from 61.6 ± 9.7 to 54.3 ± 6.5 bpm (p < 0.0001).
No changes were observed in the CG.
Exercise testing
Chest pain was the reason for interruption in 3 participants
of the TG at baseline, and 2 had it again in the second
exercise test. No CG participant had chest pain in the
baseline exam, but it was the reason for interruption of one
participant in the second test. Data from the exercise tests
are summarized in Table 3. No differences were observed
within or between groups in maximal HR or systolic blood
pressure at baseline and follow-up. The TG demonstrated
313
Arq Bras Cardiol. 2016; 106(4):311-318
a 38.7% increase in maximal oxygen uptake (p < 0.0001).
At the end of the training protocol, a statistically significant
increase in the maximum treadmill load, expressed by values
of speed and inclination in the TG, was noted. No changes
occurred in the CG.
MRI
Table 4 shows the LVEDV, LVmass, EF values, and LVmass/
EDV ratio in both groups. Baseline LV parameters were similar
in the two groups, except for ventricular mass (p = 0.0225)
and indexed LVmass (p = 0.0429), which were higher
in the CG. The LVEDV increased slightly in both groups,
without significant differences. The EF showed no significant
modification in the groups during the study.
The LV mass showed a statistically significant 8.9%
reduction in the TG (128.7 ± 38.9 g to 117.2 ± 27.2 g;
p = 0.0032). Indexed LVmass (g/m2) showed a statistically
significant reduction in the TG (p = 0.0032). An opposite
trend occurred in the CG, but without statistical significance.
Also, a similar LVmass/EDV ratio was present at baseline
(TG = 1.29 ± 0.36 g/mL, and CG = 1.36 ± 0.48 g/mL;
p = 0.63). At the end of the protocol, we observed a
statistically significant reduction in the LVmass/EDV ratio
in the TG (p = 0.015), with a value of 1.05 ± 0.22 g/mL.
In the CG, the LVmass/EDV ratio had a final value of
1.30 ± 0.37 g/mL (p > 0.99).
Discussion
The present study demonstrated that aerobic exercise
training provided a positive LV remodeling, as evaluated by
CMR, and modification of cardiovascular risk factors in a
sample of male individuals after a first acute MI. The exercise
training protocol was tailored to patients’ needs after optimized
pharmacological treatment to allow a widespread application,
even to patients with residual ischemia, reproducing what
happens in the “real world”, where patients present inherent
difficulties to adhere to a cardiac rehabilitation program.
Aerobic capacity
There was a statistically significant increase of 38.7%
in the peak oxygen uptake in the TG. This increase was
associated with an increase in the peak power during
exercise, as shown by the higher values of treadmill
speed and inclination reached after the training period.
Several studies have documented an increase in the peak
oxygen uptake, from 10% to 46%, in post-MI patients
undergoing a cardiac rehabilitation program,12,14,15,17,19,23-25
depending on the training intensity. There was also a
statistically significant reduction in resting HR in the TG,
an expression of the positive adaptation of the sinus node.
It is also important to emphasize that the reduction in resting
HR decreases the risk of cardiovascular events.26 Also, during
aerobic exercise, it enables the increase of HR reserve from
rest to maximum physical exercise.27,28 No favorable changes
were found in the CG, reinforcing the favorable effects of
the aerobic training protocol despite the use of ß-blockers.
Izeli et al.
Original Article
Table 1 – Baseline characteristics of the trained and control groups (TG and CG, respectively)
TG n = 16
Age (years)
Time from MI (days)
Killip class, I/II/III (n)
Weight (kg)
CG n = 8
p value
54.1 ± 7.0
50.3 ± 9.7
0.87
145.0 ± 104.7
117.5 ± 91.1
0.99
10/8/0
4/3/1
0.31
80.0 ± 14.8
90.5 ± 12.4
0.08
Body mass index (kg/m )
28.1 ± 3.9
30.2 ± 3.1
0.34
EF (%)
45.1 ± 11.8
44.9 ± 11.0
0.80
66.6
50.0
2
Culprit lesion artery (%)
Left anterior descending
0.60
Left circumflex coronary
16.7
37.5
Right coronary artery
16.7
12.5
PTCA
14
5
CABG surgery
1
0
61.1
75.0
Revascularization procedures (n)
0.44
Cardiovascular risk factors (%)
Hypertension
0.67
Dyslipidemia
66.7
37.5
0.22
Diabetes mellitus
22.2
37.5
0.64
Family history
44.4
37.5
1.00
0
50.0
0.0047
Current smokers
Sedentary
50.0
100
0.0098
Overweight
72.2
100
0.10
Medical therapy (%)
Antithrombotic agent
100
100
1.00
β-blocker
100
100
1.00
ACEI or ARB
88.8
87.5
1.00
Statin
100
100
1.00
Diuretics
22.2
25.0
1.00
MI: myocardial infarction; EF: ejection fraction; PTCA: percutaneous transluminal coronary angioplasty; CABG: coronary artery bypass grafting; ACEI: angiotensin‑convertingenzyme inhibitors; ARB: angiotensin-receptor blockers.
Left ventricular function, volume and mass
To control or inhibit cardiac remodeling is a treatment target
for patients after MI. Many studies have shown that drugs
like angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, β-blockers and aldosterone antagonists
present anti-remodeling properties.29 However, the achieved
results are so far unsatisfactory.
Research continues in pharmacological and nonpharmacological interventions that can reverse and/or inhibit
this process. A recent meta-analysis has demonstrated that
even the time after a MI influences the results obtained.30
CMR has been extensively validated as a precise tool to
measure volumes and masses in normal and pathological
scenarios.31 It has also been demonstrated that small samples
can be used to accurately determine mass and volume
modifications following an intervention. 32 No change in
LVEF or LVEDV could be demonstrated in both groups after
aerobic exercise training, which could reflect optimized
pharmacological treatment.
In addition, LVmass decreased in TG and slightly
increased in CG. Since both groups were similar regarding
MI characteristics, it seems reasonable to raise the hypothesis
that this opposite pattern could be attributed to the aerobic
exercise intervention.
The same opposite pattern was demonstrated regarding
LVmass/EDV, with better proportionality in the TG than in
the CG, which developed eccentric remodeling. An evidence
has demonstrated that LVmass/EDV ratio is close to 1 in
children and adolescents.33,34 Our results suggest a trend
toward reestablishment of a normal LVmass/EDV ratio in the
Arq Bras Cardiol. 2016; 106(4):311-318
314
Izeli et al.
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Table 2 – Lipid profile and fasting glucose values (mean ± SD) in the trained and control groups (TG and CG, respectively) at baseline and follow-up
Laboratory tests
TG
Baseline
CG
Follow-up
Baseline
Follow-up
157.4 ± 43.8
147.9 ± 47.9
170.1 ± 44.8
178.1 ± 44.5
168.5 ± 76.7
140.1 ± 66.4
226.0 ± 112.9
319.1 ± 194.1
HDL-c (mg/dL)
37.4 ± 7.1
39.3 ± 10.0
39.8 ± 4.1
40.4 ± 5.7
LDL-c (mg/dL)
86.3 ± 36.8
81.0 ± 34.8
73.8 ± 12.2
73.2 ± 27.3
Fasting glucose (mg/dL)
106.0 ± 26.4
94.5 ± 14.8*
114.8 ± 42.5
122.4 ± 38.8
p = 0.011.
*
Table 3 – Data from exercise tests (mean ± SD) from the trained and control groups (TG and CG, respectively) at baseline and follow-up
Exercise tests
Peak HR (bpm)
Peak systolic blood pressure (mmHg)
TG
CG
Baseline
Follow-up
Baseline
Follow-up
132.0 ± 20.2
140.2 ± 20.1
127.0 ± 21.0
125.4 ± 26.5
178.3 ± 24.6
181.1 ± 22.1
183.8 ± 16.0
193.8 ± 23.4
23598.6 ± 5093.5
25540.8 ± 5640.0
23612.5 ± 6353.0
24312.5 ± 5997.9
Metabolic equivalent (MET)
10.1 ± 2.3
14.0 ± 2.8*
8.7 ± 2.7
8.6 ± 2.5
Peak oxygen uptake (mL/kg/min)
35.4 ± 8.1
49.1 ± 9.6*
30.3 ± 9.5
30.2 ± 8.9
Speed (mph)
3.07 ± 0.5
3.8 ± 0.7*
2.9 ± 0.3
2.9 ± 0.5
Ramp inclination (%)
15.9 ± 3.6
19.1 ± 3.0#
13.5 ± 4.9
13.0 ± 3.5
Peak HR-pressure product (bpm.mmHg)
HR: heart rate. *p < 0.0001; #p = 0.0026.
Table 4 – Cardiac magnetic resonance (CMR) measurements (mean ± SD) from the trained and control groups (TG and CG, respectively) at
baseline and follow-up
CMR
TG
CG
Baseline
Follow-Up
Baseline
Follow-Up
EDV (mL)
110.7 ± 43.5
116.8 ± 38.2
126.3 ± 39.4
134.3 ± 42.2
Indexed EDV (mL/m2)
38.5 ± 14.1
40.6 ± 12.3
42.2 ± 12.5
44.4 ± 11.9
EF (%)
45.1 ± 11.8
46.8 ± 10.0
44.9 ± 11.0
42.6 ± 11.6
LVmass (g)
128.7 ± 38.9
117.2 ± 27.2*
159.6 ± 29.3#
167.8 ± 49.7
Indexed LVmass (g/m2)
44.9 ± 12.5
40.9 ± 8.6*
53.6 ± 10.4φ
55.9 ± 14.0
LVmass/EDV ratio (g/mL)
1.29 ± 0.36
1.36 ± 0.48
1.05 ± 0.22
1.30 ± 0.37
§
EDV: end-diastolic volume; EF: ejection fraction; LV: left ventricular. *p = 0.0032; #p = 0.0225 between baseline values of the two groups; φp = 0.0429 between
baseline values of the two groups; §p = 0.015.
315
TG. Another published study has identified different patterns
of ventricular hypertrophy as indicators of worse prognosis in
patients after MI in a 2-year follow-up.35
reduced preload, adjustment in autonomic system, reduction
in HR and blood pressure at rest and in submaximal loads, and
reduction in the LV wall stress.15,17,18,23,36
Our results do not confirm the negative effect of exercise on
cardiac remodeling as observed by others.8-10 There is evidence in
the literature that the benefits of exercise on cardiac function and
remodeling after MI are due to distinct mechanisms: improved
endothelial function, reduced systemic vascular resistance,
Direct comparisons may be difficult because
echocardiographic measurements for mass and function
were done with 2D echocardiographic techniques, based
on formulas and assumptions of the LV geometric shape.37
Fewer studies have used CMR for mass and function quantitation.
Arq Bras Cardiol. 2016; 106(4):311-318
Izeli et al.
Original Article
Dubach et al.19 have studied 25 patients after MI with reduced
LVEF (32.3 ± 6%). Twelve patients were randomized to
perform high-intensity physical activity in a rehabilitation
center. Patients in both groups underwent CMR evaluations
initially and after 2 months. They observed a nonsignificant
increase in LV end-systolic volume and LVEDV (2.5% and
4.8%, respectively) in TG, and no changes occurred in LVmass
and EF in the groups. These same patients were followed up
for 1 year, one group with vigorous physical activity, with
a weekly energy expenditure of approximately 2,100 Kcal
more than the CG. The cardiac volumes, mass and function
measurements showed no significant difference, indicating
that no deleterious effect of cardiac rehabilitation could
be detected.38 Schmid et al.39 have evaluated 38 post‑MI
patients with an EF of 50.4 ± 12.7%, assigned either to
combined endurance training and resistance training or
to endurance training alone for 12 weeks. By CMR at the
end of the training period, EF, stroke volume, LVEDV and
end-systolic volume increased slightly in both groups.
No deleterious effect on remodeling was observed.39
Only male patients were included in our sample. This may
have reduced the sample size, but may have assured that no
gender related influence on the remodeling process would
be present.40
The peak oxygen uptake was obtained indirectly through
equations. Cardiopulmonary exercise analysis should be
more appropriate for obtaining this variable. However, all TG
patients showed an increase in treadmill speed and inclination.
The study showed the benefits of aerobic exercise
training on functional capacity and cardiac function of
patients after MI. However, the physiological mechanisms
responsible for these changes were not evaluated.
Conclusions
Finally, the medications were maintained during the IP in
the present study, eliminating the possibility that the results
may have been influenced by changes in medication doses.
The present study showed a positive remodeling in the
TG, as indicated by the slight increase in diastolic LV size
associated with a reduction in LVmass. This was obtained
with a moderate-intensity aerobic training that was effective
in improving peak oxygen uptake and promoted benefic
cardiovascular adaptations associated with a reduction in
cardiovascular risk factors.
Study limitations
Our study has several limitations. The volunteers were not
randomly assigned. For ethical reasons cardiac rehabilitation
is offered to all MI patients in our institution as a standard
of care. The CG participants did not accept to enroll in the
rehabilitation program, but accepted to undergo the tests.
This may be more close to the “real world” and allowed
the completion of the protocol by all patients in the TG.
On the other hand, we observed that the baseline LVmass was
significantly different between the study groups. One possible
explanation may be our selection method, but no other
suitable way was available. Sample size is always a concern
when dealing with continuous variables such as volumes and
mass, but using CMR to quantify them seems to be appropriate
because of its high reproducibility and accuracy.28 In addition,
previous studies have indicated that, even in small samples,
modifications due to interventions in structural and functional
parameters can be detected.29
No specific infarct location was selected in order to provide a
variety of conditions close to what is seen in clinical practice. Also,
for logistical reasons, we have not performed images to quantify
the extent of the scar area through the late enhancement on
CMR. Such information could be useful in attempting to explain
individual behavior in both groups.
Conception and design of the research: Izeli NL, Santos AJ,
Gonçalves ACCR, Gallo-Júnior L, Schmidt A; Acquisition of data:
Izeli NL, Santos AJ, Crescêncio JC, Gonçalves ACCR, Gallo-Júnior
L, Schmidt A; Analysis and interpretation of the data: Izeli NL,
Crescêncio JC, Gallo-Júnior L, Schmidt A; Statistical analysis and
Writing of the manuscript: Izeli NL, Schmidt A; Critical revision
of the manuscript for intellectual content: Papa V, Marques F,
Pazin-Filho A, Gallo-Júnior L, Schmidt A.
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
Study Association
Nataly Lino Izeli, from Faculdade de Medicina de Ribeirão
Preto da Universidade de São Paulo.
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magnetic resonance. J Cardiovasc Magn Reson. 2000;2(4):271-8.
33. Poutanen T, Jokinen E. Left ventricular mass in 169 healthy children and young
adults assessed by three-dimensional echocardiography. Pediatr Cardiol.
2007;28(3):201-7.
34. Fratz S, Chung T, Greil GF, Samyn MM, Taylor AM, Buechel ER, et al. Guidelines
and protocols for cardiovascular magnetic resonance in children and adults
with congenital heart disease: SCMR expert consensus group on congenital
heart disease. J Cardiovasc Magn Reson. 2013;15(1):51.
35. Verma A, Meris A, Skali H, Ghali JK, Arnold JM, Bourgoun M, et al. Prognostic
implications of left ventricular mass and geometry following myocardial
infarction: the VALIANT (VALsartan In Acute myocardial iNfarcTion)
Echocardiographic Study. JACC Cardiovasc Imaging. 2008;1(5):582-91.
36. Zheng H, Luo M, Shen Y, Ma Y, Kang W. Effects of 6 months exercise training
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37. Myerson SG, Montgomery HE, World MJ, Pennell DJ. Left ventricular mass:
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Hypertension. 2002;40(5):673-8.
38. Myers J. Effects of exercise training on abnormal ventilatory responses
to exercise in patients with chronic heart failure. Congest Heart Fail.
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40. Piro M, Della Bona R, Abbate A, Biasucci LM, Crea F. Sex-related differences
in myocardial remodeling. J Am Coll Cardiol. 2010;55(11):1057-65.
Arq Bras Cardiol. 2016; 106(4):311-318
318
Back to The Cover
Original Article
Correlation of Insulin Resistance with Anthropometric Measures and
Blood Pressure in Adolescents
Polyana Resende Silva de Morais, Ana Luiza Lima Sousa, Thiago de Souza Veiga Jardim, Flávia Miquetichuc Nogueira
Nascente, Karla Lorena Mendonça, Thaís Inácio Rolim Povoa, Carolina de Souza Carneiro, Vanessa Roriz Ferreira,
Weimar Kunz Sebba Barroso de Souza, Paulo César Brandão Veiga Jardim
Liga de Hipertensão Arterial/Hospital das Clínicas da Universidade Federal de Goiás (UFG), GO – Brazil
Abstract
Background: Blood pressure is directly related to body mass index, and individuals with increased waist circumference
have higher risk of developing hypertension, insulin resistance, and other metabolic changes, since adolescence.
Objective: to evaluate the correlation of blood pressure with insulin resistance, waist circumference and body mass
index in adolescents.
Methods: Cross-section study on a representative sample of adolescent students. One group of adolescents with altered
blood pressure detected by casual blood pressure and/or home blood pressure monitoring (blood pressure > 90th percentile)
and one group of normotensive adolescents were studied. Body mass index, waist circumference were measured, and
fasting glucose and plasma insulin levels were determined, using the HOMA-IR index to identify insulin resistance.
Results: A total of 162 adolescents (35 with normal blood pressure and 127 with altered blood pressure) were studied;
61% (n = 99) of them were boys and the mean age was 14.9 ± 1.62 years. Thirty-eight (23.5%) adolescents had altered
HOMA-IR. The group with altered blood pressure had higher values of waist circumference, body mass index and
HOMA-IR (p<0.05). Waist circumference was higher among boys in both groups (p<0.05) and girls with altered blood
pressure had higher HOMA-IR than boys (p<0.05). There was a significant moderate correlation between body mass
index and HOMA-IR in the group with altered blood pressure (ρ = 0.394; p < 0.001), and such correlation was stronger
than in the normotensive group. There was also a significant moderate correlation between waist circumference and
HOMA-IR in both groups (ρ = 0.345; p < 0.05). Logistic regression showed that HOMA-IR was as predictor of altered
blood pressure (odds ratio − OR = 2.0; p = 0.001).
Conclusion: There was a significant association of insulin resistance with blood pressure and the impact of insulin
resistance on blood pressure since childhood. The correlation and association between markers of cardiovascular
diseases was more pronounced in adolescents with altered blood pressure, suggesting that primary prevention strategies
for cardiovascular risk factors should be early implemented in childhood and adolescence. (Arq Bras Cardiol. 2016;
106(4):319-326)
Keywords: Blood Pressure; Body Mass Index; Insulin Resistance; Anthropometry; Adolescent.
Introduction
Hypertension is one of the main risk factors for cardiovascular
diseases, which are the main cause of deaths in Brazil and
in the world.1-3 In the last decade, high blood pressure levels
have been identified in children and adolescents.1,4-6
in blood volume homeostasis to changes in left ventricular
function. It is also indicated as a potential causal link between
hypertension and insulin resistance (IR), among other metabolic
changes.8,10 It is estimated that 20%-30% of overweight / obese
children and adolescents have hypertension.11,12
Obesity is highlighted as one of the important risk factors
for hypertension, and it reaches epidemic proportions in many
parts of the world.7-9 Body fat mass is associated with profound
changes in physiological functions, including from alterations
Body composition is one of the main determinants of
high blood pressure in childhood and adolescence. There is
a direct relationship between weight, body mass index (BMI)
and hypertension, particularly in the second decade of life.13
Mailing Address: Paulo César Brandão Veiga Jardim •
Rua 115F 135 Setor Sul Goiânia - GO. Postal Code 74085-300. Liga de
Hipertensão Arterial/HC/UFG, Goiânia, GO – Brazil
Manuscript received August 17, 2015; revised manuscript November 11, 2015;
accepted November 19, 2015
The strong association between high blood pressure and
excessive weight has led to an increase in the prevalence
of hypertension among children and adolescents. 8
Waist circumference (WC) has a good predictive value for
abdominal obesity-related diseases in adolescents, and
increased WC values have been considered as a significant
risk factor for IR and cardiovascular diseases.14
DOI: 10.5935/abc.20160041
319
Morais et al.
Metabolism and blood pressure in adolescents
Original Article
IR is also considered a risk marker for cardiovascular
disease, and is associated with several metabolic changes
related to, but not exclusively associated with obesity or type
2 diabetes.15,16 For decades, abdominal fat has been associated
with hyperinsulinemia, which is a predictor of hypertension
and dyslipidemias.9,17
Adolescents and caregivers were instructed in the use
of HBPM, to take four blood pressure measures, two in the
morning (between 7h and 9h) and two in the afternoon
(between 18h and 19h), with a 3-5 min-interval between
them. One week later, participants returned the monitors,
totaling 6 days of measurements.
The homeostasis model assessment as an index of IR
(HOMA-IR) is a rapid, easy, low-cost method, which has been
used as an alternative approach for IR diagnosis.19
The diagnosis of altered blood pressure (casual or
HBPM) was determined according to international
guidelines. Normal blood pressure was defined as having
systolic pressure below the 90th percentile and blood
pressure readings below 120/80 mmHg, and altered blood
pressure was defined as systolic pressure greater than the
90th percentile.
There are no studies in Brazil correlating IR and blood
pressure in adolescents aged over 12 years, and few
studies have evaluated the correlation between IR and
anthropometric variables in this population. The aim of
this study was to evaluate the correlation between IR, WC,
BMI and blood pressure in adolescents, and the behavior
of these variables by sex.
Methods
This was a cross-sectional study, part of the original project
CorAdo (Coração de Adolescente, Adolescent’s heart).
The study was approved by the local Ethics Committee
(protocol: 017/2010), and conducted in a capital city of
Brazil in 2012. The sample was representative of adolescent
students, enrolled in the city’s (public or private) schools.
In the initial sample of 1,025 adolescents, stratified
by sex, anthropometric measurements were performed,
as well as casual blood pressure and home blood pressure
monitoring (HBPM).
WC was measured using a non-elastic measurement tape
(200 cm). The cut-off points were adjusted by sex and age, and
the 90th percentile was set as indicator of metabolic changes.20
Body weight was measured to the nearest 0.1 kg using
an electronic, portable scale (Kratos®, 150 kg capacity),
calibrated by the National Institute of Metrology, Quality
and Technology (Inmetro). Height was measured to the
nearest 0.1 cm using a wall-mounted stadiometer (Secca®).
All measurements were performed following the World
Health Organization guidelines (WHO).21
BMI was calculated by dividing body weight (kilograms)
by the square of the height (meters).22 The adolescents were
classified into obese or overweight based on WHO BMI
cut-off points for age and sex (WHO).23
Casual blood pressure and HBPM were measured
using Omron HEM-705CP semi-automatic blood pressure
monitors and different sizes of cuffs, in accordance to the
4th Task Force’s recommendations.24
Four measures of casual blood pressure were taken,
the first two measures when the blood pressure monitor
was handed to patients, and the other two when patients
returned the monitors one week later. There was a 3-min
interval between measurements. The mean of the second
readings was used for analysis. Blood pressure percentile
was calculated using the formulas proposed by the 4th Task
Force, using the MeDCal 3000 software.
Since there are no validated criteria for HBPM, we used the
criteria proposed by the 4th Task Force in the study by Stergiou
et al.,25 which suggests that both casual and HBPM measures
should be similar in adolescents aged greater than 12 years.
Of the initial sample (n = 1,025), 198 (19.3%)
adolescents had altered systolic and/or diastolic blood
pressure in the casual measurement and/or HBPM, and
composed the potential group for phase 2.
For sample size calculation, an error of 5% and power of
80% were fixed, considering the number of subjects with
altered blood pressure (n= 198) identified from the initial
sample during phase 1 of the CorAdo study. A minimum
of 127 adolescents were required, and we also included
35 adolescents with normal blood pressure (controls),
who were invited to the phase 2 of the study. A total of
162 adolescents completed the study (Figure 1).
Participants’ parents or caregivers signed the informed
consent form before participating in the phase 2 of
the study. Adolescents who met the inclusion criteria
answered a questionnaire and had their blood collected.
Sexual maturation was assessed by self-assessment, using
Tanner’s photographs of five sexual maturation stages.26
Children classified as prepubertal (Tanner stage I) were
withdrawn from the study.
Inclusion criteria were adolescents aged from 12
to 18 years (to be completed), enrolled in public and
private schools, with altered blood pressure (by casual
measurement and/or HBPM), and Tanner stage ≥ 2
(pubertal stage).
Exclusion criteria included patients with physical
disabilities that hinder blood pressure measurement,
self-reported chronic disease, diabetes mellitus, kidney
disease or heart disease, pregnancy, and chronic use
of medications that may affect blood pressure, such as
antihypertensive drugs, corticosteroids, antidepressants,
anxiolytics, anti-inflammatories, and oral contraceptives.
Serum glucose and plasma insulin levels were
determined. The HOMA-IR index (insulin µu/mL x glycemia
mmol/L/22.5) was used to quantify IR, whose threshold set
for adolescents is ≥ 3.16;27 values of glycemia (mg/dL) were
multiplied by 0.05551.28,29
Arq Bras Cardiol. 2016; 106(4):319-326
320
Morais et al.
Original Article
Results
Statistical analysis was performed using the Statistical
Package for Social Science (SPSS) software version 20 (IBM,
Chicago, IL, USA) and Epi-Info™. The Kolmogorov-Smirnov
test was used to test the normality of the continuous variables
and the Mann-Whitney U test to compare the means of the
variables. Values were expressed as mean, median, standard
deviation and confidence interval. A descriptive analysis
of data was performed; associations between categorical
variables were tested by the chi-square test, and the Spearman
correlation was used to assess the association between blood
pressure and BMI, WC, and HOMA-IR.
A total of 162 adolescents participated in the phase 2 of the
study, 127 with altered blood pressure and 35 controls. Mean age
of participants was 14.9 ± 1.62 years, and 61.1% were male.
Thirty-eight adolescents (23.5%) had altered HOMA-IR,
74 (45.7%) were overweight/obese, and 17 (10.5%) had
increased WC (Table 1).
Mean values of HOMA-IR, BMI and WC were significantly
higher in the group with altered blood pressure than in
controls (Table 2).
When variables were categorized considering the normality
criteria, a significant association was found only between blood
pressure and BMI (p < 0.022), with 50.4% of participants
with altered blood pressure and excessive weight, and no
difference in sex distribution.
Stepwise regression was conducted, considering changes in
blood pressure as dependent variable. In the bivariate analysis,
variables with a p-value < 0.20 were considered predictors.
The level of significance was set at p< 0.05.
1,025 adolescents (Phase 1)
Normal blood pressure
(827 adolescents)
Altered blood pressure (casual and/or HBPM)
(198 adolescents)
35 adolescents
(normal blood pressure group)
127 adolescents
(altered blood pressure group)
Study group (Phase 2): 162 adolescents
Figure 1 – Fluxogram of sample composition for the phase 2 of the study.
Table 1 – Anthropometric and biochemical characteristics of the study group (n = 162)
Variables
n (%)
Waist circumference
0.005
Normal
145 (89.5)
Increased
17 (10.5)
Body mass index
< 0.001
Normal
88 (54.3)
Overweight
39 (24.1)
Obese
35 (21.6)
HOMA-IR
< 0.001
Normal
124 (76.5)
Altered
38 (23.5)
*Chi-square test. HOMA-IR: Homeostasis Model Assessment – Insulin Resistance.
321
Arq Bras Cardiol. 2016; 106(4):319-326
p value*
Morais et al.
Original Article
HOMA-IR index and BMI were similar between sexes.
Mean WC was higher among male adolescents in both
groups (altered blood pressure and normotensive) (p < 0.05)
(Tables 3 and 4). In the group of adolescents with altered
blood pressure group, HOMA-IR indexes were higher in
female than in male adolescents (p < 0.05) (Table 4).
and a statistically significant but weak correlation between
blood pressure and BMI, and between blood pressure and
WC (ρ = 0.254; p = 0.001; e ρ = 0.258; p = 0.001).
In the group analysis, stronger correlations between
variables were detected, especially between BMI and
HOMA‑IR in the group of altered blood pressure (ρ = 0.394;
p < 0.001). Similar correlations between WC and HOMA-IR
were found in both groups (ρ = 0.345; p < 0.05) (Table 5).
There was a direct, moderate correlation between
blood pressure and HOMA-IR (ρ = 0.323; p < 0.001),
Table 2 – Blood pressure, Homeostasis Model Assessment – Insulin Resistance (HOMA-IR) index, waist circumference (WC) and body
mass index (BMI) (n = 162)
Blood pressure
Variables
Normal (n = 35)
Altered (n = 127)
p value*
Mean
SD
Mean
SD
HOMA-IR
1.8
± 1.1
2.8
± 1.7
≤ 0.001
WC, cm
71.0
± 10.0
76.5
± 11.0
0.001
BMI, kg/m2
21.1
± 3.7
23.8
± 4.8
0.001
*Mann-Whitney U test. SD: standard deviation.
Table 3 – Relationship between Homeostasis Model Assessment – Insulin Resistance (HOMA-IR), waist circumference (WC) and body mass
index (BMI) in normotensive adolescents (n = 35)
Sex
Male (n = 99)
Variables
Female (n = 63)
p value*
Mean
Mean
SD
95% CI
Mean
Median
SD
95%CI
HOMA-IR
1.9
1.5
1.3
0.65-6.12
1.7
1.5
0.7
0.7-3.4
0.960
WC, cm
74.2
70.6
11.2
61-107
65.8
65.3
4.4
58.5-75.0
0.009
BMI, kg/m2
21.5
20.6
4.0
17.0-30.7
20.4
19.6
3.1
16.8-26.3
0.511
*Mann-Whitney U test. SD: standard deviation; 95%CI: 95% confidence interval.
Table 4 – Relationship between Homeostasis Model Assessment – Insulin Resistance (HOMA-IR), waist circumference (WC) and body mass
index (BMI) in adolescents with altered blood pressure (n = 127)
Sex
Male (n = 99)
Variables
Female (n = 63)
p value*
Mean
Median
SD
95%CI
Mean
Median
SD
95%CI
HOMA-IR
2.7
2.2
1.7
0.53-8.39
3.1
2.7
1.7
0.61-8.57
0.036
WC, cm
78.1
76.2
10.9
61-120
74.1
70.7
10.7
56-107
0.035
BMI, kg/m2
23.8
23.4
4.1
15.9-35.0
23.7
22.5
5.7
16.1-42.5
0.248
*Mann-Whitney U test. SD: standard deviation; 95%CI: 95% confidence interval.
Arq Bras Cardiol. 2016; 106(4):319-326
322
Morais et al.
Original Article
Table 5 – Correlation of Homeostasis Model Assessment – Insulin Resistance (HOMA-IR) index, with body mass index (BMI) and waist
circumference (WC) in adolescents with normotensive adolescents (n = 35) and altered blood pressure (n=127)
Variables
Normal blood pressure (n = 35)
Spearman
Altered blood pressure (n = 127)
p value*
Spearman
p value*
HOMA-IR and BMI
0.366
0.031
0.394
< 0.001
HOMA-IR and WC
0.345
0.042
0.345
< 0.001
*Spearman correlation test.
In the logistic regression analysis, blood pressure was affected
only by HOMA-IR (odds ratio − OR = 2.0; p = 0.001).
Discussion
In many parts of the world, the prevalence of adult
diseases, considered risk factors for cardiovascular diseases,
has increased in pediatric population. Few studies have
investigated the correlation/association between IR and blood
pressure, especially in this population.
In this study, there was a positive association between
mean values of HOMA-IR index and altered blood pressure
in adolescents (p < 0.001). In the Bogalusa Heart Study, also
conducted on adolescents, the HOMA-IR values were higher
than those observed in our study. In another study carried out
in Rio de Janeiro, the authors also reported higher HOMA-IR
indexes, although the study group was composed of adults
rather than adolescents.30,31 In a pilot study conducted in
Eastern Europe involving 128 children, HOMA-IR indexes
were similar to our findings.32
The prevalence of IR in our study group was 23.5%,
considering a HOMA-IR cut-off point of 3.16, proposed by
Keskin et al.27 In Cochabamba, Bolivia, a study on 61 children
and adolescents adopted33 a different HOMA-IR cut-off (3.5),
and reported a 39.4% prevalence of IR. A higher prevalence
of IR was found in children and adolescents with high systolic
pressure (p < 0.05).
In this study, HOMA-IR was not correlated with changes
in blood pressure by using the absolute cut-off points.
However, a significant direct correlation was found
between mean HOMA-IR values and changes in blood
pressure percentiles (ρ = 0.323; p < 0.001). This is in
accordance with a study carried out in India, involving
2,640 adolescents.34
Female adolescents with altered blood pressure had
higher mean HOMA-IR values (p < 0.05), which was not
observed in the normotensive group. Previous studies7,34
have reported a high prevalence of altered HOMA-IR
among female adolescents, which may be in part explained
by differences in body fat distribution or pubertal stages as
compared with boys. With respect to sexual maturation,
girls may enter puberty two years earlier than boys. In the
absence of other known variables, these findings suggest
that girls tend to be more resistance to insulin than boys
due to sex-linked genes.35
323
Arq Bras Cardiol. 2016; 106(4):319-326
It is worth mentioning that previous studies have not reported
differences in the mean values of HOMA-IR between sexes,33,36
and one study has found a higher IR among boys than girls17.
Further studies are needed to elucidate these conflicting results.
By logistic regression, our study identified, for the first time,
that adolescents with altered HOMA-IR are twice as likely to
have altered blood pressure (OR = 2.0; p = 0.001)
Other variables, such as BMI and WC did not affect the
chance of having altered blood pressure. This result differed
from that found in a study carried out in the south of Brazil
on 1,950 children and adolescents, describing a positive
relationship of systolic pressure to BMI and WC.37,38
Some studies have reported an association between
BMI and HOMA-IR, which may be explained by the
increased anabolic effect of insulin and growth hormone
related to the rapid somatic growth of children during
puberty. This change in insulin sensitivity results from
changes in body fat distribution in this period of life.17,36
In the present study, a significant, moderate correlation
was observed between BMI and HOMA-IR (ρ = 0.394;
p < 0.001, for adolescents with altered blood pressure; and
ρ = 0.366; p < 0.031, for normotensive adolescents. This is
in accordance with previous investigations that showed
that the prevalence of IR is more than twice as high among
overweight and obese children and adolescents.36,39,40
When analyzed by sex, we observed that male
adolescents of both groups had higher mean WC, similarly
to previous studies.7,36
In addition, we found a positive correlation between WC
and HOMA-IR (ρ = 0.345; p < 0.001 for altered blood
pressure group; and ρ = 0.345; p = 0.042 for normotensive
group). Singh and colleagues also found a strong correlation
between HOMA-IR and WC,36 and studies conducted in Brazil
reported a significant association between WC and HOMA-IR
in female adolescents.39,41
Our study differs from previous studies in the analysis of
correlations between variables (particularly HOMA-IR and
BMI) by group, i.e. between adolescents with altered blood
pressure and normotensive subjects.
The study has some limitations that need to be considered.
First, the lack of a comprehensive assessment of body
composition including other methods such as skinfold thickness
or electrical bioimpedance analysis, and second, the possible
inaccuracy of the method used for assessing sexual maturation.
Morais et al.
Original Article
Conclusion
There was a significant association of IR with blood
pressure, and the impact of IR on blood pressure.
The correlation and association between markers of
cardiovascular diseases was more pronounced in adolescents
with altered blood pressure, suggesting the need for primary
prevention strategies for cardiovascular risk factors in
childhood and adolescence.
Acknowledgements
We thank CNPq for the funding, and the Hypertension
League of the Federal University of Goias (Liga de Hipertensão
da Universidade Federal de Goiás), for all the support.
Morais PRS, Sousa ALL, Povoa TIR, Jardim PCBV; Statistical
analysis and Writing of the manuscript: Morais PRS, Sousa
ALL, Jardim PCBV; Obtaining financing: Sousa ALL, Jardim
TSV, Nascente FMN, Mendonça KL, Povoa TIR, Carneiro CS,
Jardim PCBV; Critical revision of the manuscript for intellectual
content: Morais PRS, Sousa ALL, Jardim TSV, Povoa TIR, Souza
WKSB, Jardim PCBV.
was reported.
Sources of Funding
This study was funded by CNpq.
Conception and design of the research and Acquisition
of data: Morais PRS, Sousa ALL, Jardim TSV, Nascente FMN,
Mendonça KL, Povoa TIR, Carneiro CS, Ferreira VR, Souza
WKSB, Jardim PCBV; Analysis and interpretation of the data:
Study Association
Polyana Resende Silva de Morais, from Universidade Federal
de Goiás.
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Arq Bras Cardiol. 2016; 106(4):319-326
Morais et al.
Original Article
Arq Bras Cardiol. 2016; 106(4):319-326
326
Back to The Cover
Original Article
Assessment of Intima-Media Thickness in Healthy Children Aged 1
to 15 Years
Liz Andréa Villela Baroncini, Lucimary de Castro Sylvestre, Roberto Pecoits Filho
Pontifícia Universidade Católica do Paraná, PR – Brazil
Abstract
Background: Carotid intima-media thickness (CIMT) has been shown to be increased in children and adolescents
with traditional cardiovascular risk factors such as obesity, hypertension, and chronic kidney disease, compared with
those of healthy children.
Objective: To assess the influence of sex, age and body mass index (BMI) on the CIMT in healthy children and adolescents
aged 1 to 15 years.
Methods: A total of 280 healthy children and adolescents (males, n = 175; mean age, 7.49 ± 3.57 years; mean BMI,
17.94 ± 4.1 kg/m²) were screened for CIMT assessment. They were divided into 3 groups according to age: GI,
1 to 5 years [n = 93 (33.2%); males, 57; mean BMI, 16 ± 3 kg/m²]; GII, 6 to 10 years [n = 127 (45.4%); males, 78;
mean BMI, 17.9 ± 3.7 kg/m²], and GIII, 11 to 15 years [n = 60 (21.4%); males, 40; mean BMI, 20.9 ± 4.5 kg/m²].
Results: There was no significant difference in CIMT values between male and female children and adolescents
(0.43 ± 0.06 mm vs. 0.42 ± 0.05 mm, respectively; p = 0.243). CIMT correlated with BMI neither in the total
population nor in the 3 age groups according to Pearson correlation coefficient. Subjects aged 11 to 15 years had
the highest CIMT values (GI vs. GII, p = 0.615; GI vs. GIII, p = 0.02; GII vs. GIII, p = 0.004).
Conclusions: CIMT is constant in healthy children younger than 10 years, regardless of sex or BMI. CIMT increases after
the age of 10 years. (Arq Bras Cardiol. 2016; 106(4):327-332)
Keywords: Child; Carotid Artery; Carotid Intima-Media Thickness; Atherosclerosis; Ultrasonography.
Introduction
In 1986 Pignoli et al.1 and in 2010 O´Leary and Bots,2
established B-mode imaging as a useful tool for detecting
and monitoring changes in intimal plus medial thickness.
This method allows for the evaluation of changes in the arterial
wall in areas without localized plaques. Therefore, carotid
intima-media thickness (CIMT) measurements have been
assessed in several observational and interventional studies.
The noninvasive nature of B-mode imaging has made it popular
for use in the pre-clinical diagnosis and follow-up of patients
with atherosclerosis.3-5
The assessment of cardiovascular risk in pediatric patients
is challenging. Cardiovascular events or death rarely occur
in children, but changes in the cardiovascular system can
be identified at an early age in pediatric populations.6 CIMT
has been shown to be increased in children with traditional
Mailing Address: Liz Andréa Villela Baroncini •
PUC-PR. Rua Buenos Aires, 764, ap. 601, Batel. Postal Code 80250-070,
Curitiba, PR – Brazil
Manuscript received June 13, 2015; revised manuscript November 29, 2015;
accepted November 30, 2015.
DOI: 10.5935/abc.20160030
327
cardiovascular risk factors, such as obesity, hypertension, and
chronic kidney disease, as compared to healthy children.7,8
However, previous studies assessing sex differences in CIMT
in healthy pediatric populations have generated conflicting
results.9-11 These conflicts are probably secondary to the
methodologies applied and the fact that the studies included
children older than 10 years and adults in the same analyses.10
Consequently, the aim of the present study was to evaluate
the influence of sex, age, and BMI on CIMT, and to establish
parameters for CIMT in healthy children and adolescents
aged 1 to 15 years.
Methods
Subjects
We selected 280 consecutive healthy Caucasian
children and adolescents (males, n = 175; mean age,
7.49 ± 3.57 years), who underwent echocardiography for
assessment of an innocent cardiac murmur referred by a
private pediatrician. The population in the present study was
part of the private health care system.
Exclusion criteria were children diagnosed with diabetes,
dyslipidemia, hypertension, any systemic disease, and those
considered overweight or obese (≥ 85th percentile) for
their age.12,13
Baroncini et al.
Intima-media thickness in healthy children
Original Article
Children were not sedated before the exams. Children who
refused to undergo the ultrasound examination and those who
did not allow a proper or complete examination, such as very
young children, were excluded from the study.
Before the exam, the ultrasonographist collected
information on demographic characteristics and cardiovascular
risk factors of each parent. Parents were asked about the
presence of hypertension, diabetes mellitus, dyslipidemia,
coronary artery disease (CAD), and current smoking habit.
Hypertension was defined as a history of treated
hypertension. Smoking history was coded as never or current
smoker. Subjects were classified as having diabetes when
treated for insulin-dependent or non-insulin-dependent
diabetes. The use of lipid-lowering drugs was assessed.
A history of myocardial infarction, angioplasty or coronary
artery bypass graft surgery was recorded, and a positive CAD
history was defined as the presence of any of these diseases.
Children from parents under treatment for any of these
diseases aforementioned were excluded from the study.
The subjects were divided into 3 groups according to age:
1 to 5 years (GI), 6 to 10 years (GII), and 11 to 15 years (GIII).
Institutional ethical committee approval was obtained for the
study. The legal representative of each child provided written
informed consent before examination. Children older than
10 years also signed a consent form.
Ultrasound measurements
All CIMT measurements were made using high-resolution
B-mode ultrasonography (Philips Medical Systems’ HD11
platform) with a broadband width linear array transducer
L 3–12 MHz. Sonography and readings were conducted
by a trained and certified sonographer. The subjects were
examined in the supine position with the neck extended
and the probe in the anterolateral position. On longitudinal
2D ultrasound images of the carotid artery, the near wall
and the far wall are displayed as 2 echogenic lines (the
adventitia and intima) that are separated by the hypoechoic
media. The distance between the leading edge of the first
bright line of the far wall (lumen-intima interface) and the
leading edge of the second bright line (media-adventitia
interface) is defined as the CIMT.
For this study, we measured the CIMT on the distal 10 mm
of the far wall of both the right and left common carotid artery.
After zooming and freezing the image, we manually measured
the CIMT using electronic calipers. Five measurements were
recorded on each side and the average of these measurements
was used for the final CIMT analyses.
Quantitative variables are described by mean, median,
minimum, and maximum values and standard deviation.
Qualitative variables are described as frequencies and
percentages. Kolmogorov-Smirnov test was used to test the
normality of the distribution. CIMT measurements of both sexes
were compared using Student t test for independent samples.
The age groups were compared using the analysis of variance
model with one parameter (ANOVA) and the least significance
difference for multiple comparisons. Pearson correlation
coefficient was used to evaluate the linear association between
CIMT and BMI. Multivariate analysis was performed by adjusting
a multiple linear regression model using CIMT as the dependent
variable and sex, age, and BMI as independent variables.
A p-value < 0.05 indicated statistical significance. The sample
size was not calculated at the present study because there are no
normative values for CIM in healthy children and adolescents.
Data were analyzed with the SPSS v. 20.0 computer program.
Results
This study included 280 healthy children and adolescents
(males, n = 175; mean age, 7.49 ± 3.57 years; mean
BMI, 17.94 ± 4.1 kg/m²; mean CIMT, 0.43 ± 0.06 mm).
Their characteristics are provided in Table 1. No significant
differences in CIMT values were observed between male and
female children and adolescents in the total population or
among the age groups (Table 2). CIMT was not correlated to
BMI in the total population or among the age groups (Table 2).
Subjects older than 10 years had the highest CIMT values
(Tables 1 and 2, Figure 1).
Table 1 – General characteristics of the study population
Groups
N (%)
Male/Female (n)
BMI (kg/m²; mean ± SD)
CIMT (mm; mean ± SD)
GI
93 (33.2%)
57/36
16 ± 3
0.42 ± 0.06
GII
127 (45.4%)
78/49
17.9 ± 3.7
0.42 ± 0.05
GIII
60 (21.4%)
40/20
20.9 ± 4.5
0.45 ± 0.05
Total
280
175/105
17.94 ± 4.1
0.43 ± 0.06
*p
0.013
Groups
†P
GI vs GII
0.615
GI vs GIII
0.02
GII vs GIII
0.004
BMI: body mass index; CIMT: carotid intima-media thickness; SD: standard deviation. GI: 1 to 5 years; GII: 6 to 10 years; GIII: 11 to 15 years. * Analysis of variance with one
parameter, p < 0.05. † Least significant difference test, p < 0.05.
Arq Bras Cardiol. 2016; 106(4):327-332
328
Baroncini et al.
Original Article
Table 2 – Correlations between carotid intima-media thickness (CIMT), sex and body mass index (BMI) among age groups and in the
entire study population
Age (years)
1a5
6 a 10
11 a 15
Total
Sex
N
CIMT
(mm; mean ± SD)
Male
57
0.43 ± 0.06
Female
36
0.42 ± 0.05
Male
78
0.42 ± 0.05
Female
49
0.41 ± 0.05
Male
40
0.45 ± 0.05
Female
20
0.45 ± 0.05
Male+Female
280
Male
175
0.43 ± 0.06
Female
105
0.42 ± 0.05
*p
†BMI
p
0.62
0.17
0.11
0.23
0.01
0.91
0.98
-0.01
0.92
0.243
0.11
0.056
0.12
0.127
0.10
0.32
SD: standard deviation. * Student t test for independent samples. † Pearson correlation coefficient.
0.47
0.46
CIMT
(mean ± SE; CI95%)
0.45
0.44
0.43
0.42
0.41
0.40
1 to 5
6 to 10
11 to 15
Age (years)
Figure 1 – Carotid intima-media thickness (CIMT) among age groups.
Discussion
Much information is available concerning CIMT in adults,
but little information exists regarding CIMT in healthy
pediatric populations, despite the need for early detection
and prevention of cardiovascular disease.9 Most studies of
CIMT in pediatric patients have compared healthy children
with children who have cardiovascular risk factors, such as
hypertension, diabetes, dyslipidemia, obesity, and metabolic
syndrome. Additionally, most studies have included subjects
aged 10 years or older.14-16
In the present study we only included subjects younger
than 15 years, and we found that in very young (< 10 years
old) healthy children, we were unable to detect any significant
329
Arq Bras Cardiol. 2016; 106(4):327-332
difference in CIMT when we considered sex and BMI as
independent variables. These findings agree with previous
studies2,6-16 that concluded that the normal carotid arterial
wall is unaffected by age or sex until approximately 18 years
of age, after which time, there is diffuse progressive intimal
thickening. However, we cannot exclude the possibility that
our results could be due to the fact that the imaging method
used here (high-resolution B mode ultrasonography) is not
able to detect such small differences in CIMT due to its low
sensitivity. In our study, we confirmed that, as in adults,17 CIMT
increases with age. These findings could be related to the
fact that, by the age of 10, most boys and girls are beginning
puberty and undergoing hormonal changes that induce a
significant increase in total body fat percentage.9,18
Baroncini et al.
Original Article
Other possible explanation is that CIMT increases
as a physiological reaction of the vessel to adapt the
age‑dependent rise in blood pressure.6 In fact, CIMT changes
could reflect non-atherosclerotic and adaptive responses to
aging and mechanical stress.6,19 In the present study, we only
included healthy children with normal BMI. CIMT appears
to coincide with the normal development of children and
increases with age, as it does in adults. Koçyiğit et al. 20
have studied 91 healthy children aged 7 to 15 years and
observed an age-related physiologic thickening of the carotid
intima‑media that was not related to sex. CIMT is considered
a reflection of multiple risk factors, but primary contributors
to intima-media thickening are age and hypertension, which
do not necessarily reflect the atherosclerotic process. 21-23
Some studies have corroborated these findings. Lande et al.14
have concluded that CIMT is increased in childhood primary
hypertension and is independent of the effects of obesity.
Therefore, in the present study, we attempted to assess
CIMT in healthy children and adolescents between 1
and 15 years, and to fill a major gap in medical pediatric
literature. Our findings could be used to evaluate other
children of the same age with comorbidities, such as obesity,
hypertension, diabetes mellitus, and dyslipidemia, and
children whose parents have cardiovascular risk factors.
Di Pino et al.24 have reported that subjects with altered
glucose tolerance had associated morphological and functional
alterations of the arterial wall; however, these alterations are
not likely to be related to hyperglycemia, but, instead, related
primarily to aging. Opposing results have also been reported.
For example, Stabouli et al.25 have studied a similarly aged
population and observed that obese children and adolescents
have greater CIMT than non-obese subjects, independent of
blood pressure. Giannini et al.26 have concluded that both
obese and thin children present early signs of atherosclerosis,
including increased oxidative stress, impaired inflammation,
and insulin sensitivity, as well as increased CIMT values.
Pediatric epidemiological studies, as well as case-control
and observational studies in children, have confirmed
that CIMT is increased in the presence of risk factors
such as hypertension, dyslipidemia, diabetes mellitus,
and obesity.15-16,27-29 Further, traditional cardiovascular risk
factors already present in childhood predict the occurrence
of preclinical carotid atherosclerosis in adulthood. 30,31
However, the availability of normative CIMT data for
children is limited and most studies have compared CIMT
values from children with those from adult populations.
Conclusion
Among healthy children younger than 15 years, there is
no significant difference in CIMT between males and females.
BMI was not correlated to CIMT in healthy children under the
age of 15 years. CIMT is constant in children younger than
10 years, regardless of sex and BMI. CIMT increases after the
age of 10 years.
Conception and design of the research: Baroncini LAV,
Sylvestre LC, Pecoits Filho R; Acquisition of data: Baroncini
LAV, Sylvestre LC; Analysis and interpretation of the data and
Critical revision of the manuscript for intellectual content:
Baroncini LAV, Pecoits Filho R; Statistical analysis and Writing
of the manuscript: Baroncini LAV.
was reported.
Sources of Funding
Study Association
This article is part of the thesis of Post Doctoral submitted
by Liz Andréa Villela Baroncini, from Pontifícia Universidade
Católica do Paraná.
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Original Article
Arq Bras Cardiol. 2016; 106(4):327-332
332
Back to The Cover
Review Article
Network Meta-analysis to Synthesize Evidence for Decision Making
in Cardiovascular Research
Leonardo Roever1 and Giuseppe Biondi-Zoccai2,3
Universidade Federal de Uberlândia – Departmento de Pesquisa Clínica¹, Uberlândia, MG - Brazil; Department of Medico-Surgical Sciences
and Biotechnologies, Sapienza University of Rome2, Latina – Italy; Department of AngioCardioNeurology, IRCCS Neuromed3, Pozzilli – Italy
Abstract
Clinical decision-making requires synthesis of evidence
from literature reviews focused on a specific theme.
Evidence synthesis is performed with qualitative assessments
and systematic reviews of randomized clinical trials, typically
covering statistical pooling with pairwise meta-analyses.
These methods include adjusted indirect comparison
meta-analysis, network meta-analysis, and mixed-treatment
comparison. These tools allow synthesis of evidence and
comparison of effectiveness in cardiovascular research.
Introduction
Clinical decision-making requires a balanced judgment
between tasks, skills, resources, and values. This is largely
beyond the reach of most researchers, and often depends
on external factors that cannot be easily modulated (such as
economic resources or religious beliefs).1-5
Systematic reviews seem to be particularly useful when
combining homogenous randomized controlled trials (RCTs)
and pairwise meta-analysis. Computational methods used for
pairwise meta-analysis have seen momentous improvements
over time, and now include patient-level approach, metaregression, and adjustment for small study effects. The simple
term network meta-analysis includes all methods of synthesis
encompassing extensive evidence, indirect comparisons, mixedtreatment comparison, and multiple treatment meta-analysis.5,6
This article aims to summarize the key features of network
meta-analysis and its potential impact on cardiovascular
decision-making.
Evidence base
Hierarchy of evidence
Evidence-based medicine emphasizes the importance of
systematic research of current evidence that follows a specific
hierarchy in clinical evidence, basic (bench, in vitro, or
Keywords
Meta-Analysis; Evidence-Based Medicine; Review;
Research; Cardiovascular Diseases; Comparative Study.
Mailing Address: Leonardo S. Roever-Borges •
Universidade Federal de Uberlândia. Av. Pará, 1720, Umuarama.
Postal code 38400-902, Uberlândia, MG – Brazil
Artigo recebido em 08/09/15; revisado em 29/09/15; aceito em 19/10/15.
DOI: 10.5935/abc.20160052
333
animal) distinctive scientific experiments, studies with healthy
volunteers, case reports and patients series, cross-sectional
studies, case-control studies, cohort studies, and RCTs.
This hierarchy is mirrored by a hierarchy in secondary
research (i.e., synthesis of evidence) which includes qualitative
assessments, systematic reviews, study-level pairwise metaanalyses, study-level meta-regression analyses, and finally,
patient-level meta-analyses (Figure 1).7,8 A tertiary level of
evidence and research consists of umbrella reviews, overviews
of reviews, and meta-epidemiological studies.
From pairwise meta-analysis to network meta-analysis
Decision making is more complex than a pairwise
meta-analysis since it moves from a two-dimensional to a
multidimensional analytical framework. Several methods
are being developed, such as adjusted indirect comparison,
multitreatment meta-analysis, multi-arm meta-analysis,
multivariable meta-analysis, network meta-analysis, and
mixed-treatment comparison.
A pairwise meta-analysis can be defined as a pooledweighted estimate of homogeneous trials comparing two
treatments head to head (e.g., A and B), with typically
proportional weights, to study accurately the size or number
of events (Figure 2). And what should we do when we have
two separate sets of trials, a first comparing A versus B, and
a second comparing A versus C? We perform an adjusted
indirect comparison under the assumption that patients,
interventions, and outcomes measured in both sets of tests
are similar. And what if we then recognize that of the studies
comparing A versus B and B versus C, only a few compared
A versus C? Should we then discard all the information
resulting from the indirect comparison, or could we explore
the information and provide effect estimates, therefore, more
precise and accurate of A versus C, based on both direct and
indirect evidence? This is precisely what a network metaanalysis does; it combines direct and indirect evidence (where
available) to provide more precise and accurate (therefore,
valid both internally and externally) effect estimates to guide
decision making in complex scenarios.
Reviewing process
Designing and registering the review
Reviews should be designed before the data are effectively
retrieved, and the evaluation protocol should be published as
soon as finalized in a dedicated repository site. Several guidelines
are available to design, conduct, and report a systematic peer
review and network meta-analysis.9,10
Roever & Biondi-Zoccai
Network meta-analysis for evidence synthesis
Review Article
In vitro studies
Editorials
Animal Studies
Case reports and series
Retrospective studies
Prospective observational studies
Ethinical and logistic issues
Secondary Research
Internal and external validity
Primary Research
Randomized clinical trials
Quantitative reviews
Systematic reviews
Pairwise meta-analyses
Network meta-analyses
Umbrella reviews
Figure 1 - Evidence hierarchy of primary research and secondary research in cardiovascular medicine.
A
A
B
C
A
B
A
B
C
D
Figure 2 - Conceptual framework moving from univariate meta-analysis (top left panel) to pairwise meta-analysis (top right panel), network meta-analysis
(bottom left panel), and multivariate meta-analysis (bottom right panel). A, B, C, and D represent competing treatments for the same condition; continuous
lines represent direct comparisons stemming from head-to-head randomized trials; dashed lines represent indirect comparisons; and different colors represent
different endpoints of interest.
Searching, selecting, abstracting, and appraising evidence
The search should be performed in various databases
(MEDLINE / PubMed, Cochrane Library, Europe PubMed
Central, SciELO, LILACS, Embase, and others) to appropriate
evidence. The selection of the studies is an important step
in any systematic review. The studies should have moderate
to high methodological quality and, at the same time that
they are different trials based on convenience samples,
they should represent similar views on a continuum of the
clinical condition and a specific management strategy or set
of strategies. Finally, all studies included in the review should
be assessed for internal validity.11-14
Choosing the framework, package, model, and statistic
Choosing the statistical framework
Most biostatistical inferences are based on a frequentist
approach with its defining resources: null hypothesis, alternative
hypothesis, hypothesis testing, p value, and confidence interval.
Therefore, they can be limited by computational problems in
case of a complex evidence network. The Bayesian framework
has been the dominant framework for network meta-analysis for
allowing more flexible modeling and adjustment for less–thansimple evidence networks.15-22 Despite the arguments above,
Arq Bras Cardiol. 2016; 106(4):333-337
334
Review Article
recent developments in theoretical work and improvements
in computational efficiency have largely bridged the gap
between frequentist and Bayesian analysis in terms of precision,
accuracy, and flexibility. Thus, similar results are obtained with
state-of-the-art methods, regardless of the use of frames or a
frequentist-Bayesian approach.
Choosing the statistical package
To date, WinBUGS has been the most widely used
package; it is relatively easy to command and is expressly
designed for flexible Bayesian modeling and analysis. R has
also been increasingly used, as it can activate WinBUGS
routines, and may offer important tools for specific
computations or sensitivity analyses. R can also be employed
for frequentist network meta-analysis. Stata (StataCorp,
College Station, TX, USA) and SAS (SAS, Cary, NC, USA)
have also been adopted.20
Choosing the statistical model and between fixed and
random effects
Relatively common events may best be analyzed with
a binomial model, whereas uncommon events or those
occurring over variable periods of time can be handled most
effectively with a Poisson model.
Choosing the appropriate statistics
Odds ratios, relative risks, risk differences, numbers needed
to treat, probabilities of being best, rankograms, and surface
under the cumulative ranking curves can all be generated from
a binomial model.19, 20 Relative risks are easier to understand
but suffer from a forced reduction when in the fraction of the
two risks, the numerator approaches one. Both odds ratios and
relative risks disregard the duration of follow-up, and hazard
ratios should be preferred and considered more reliable when
the follow‑up is not uniform.23,24
The choice of risk estimator, probability of being best,
rankograms, and surface under the cumulative ranking
curve are now considered even more important in helping
the reader identify which treatment or group of treatments
should be considered most likely better than the others.25
Incorporating moderators: network meta-regression
One of the strong features of a meta-analysis is its ability to
assess interaction effects with meta-regression, thus quantifying
the impact of moderators or covariates in estimating the effect.
Network meta-analysis is suitable for meta-regression, given
its characteristics of flexible modeling.24-26
Appraising between-study heterogeneity
Evaluation of the homogeneity of similar studies is a
key aspect of any systematic review. Standard methods to
assess the heterogeneity between studies in pairwise metaanalysis calculations include the Cochran’s Q and I-squared
statistics. If the p value stemming from the Cochran’s Q
statistic is <0.05, then play of chance alone is an unlikely
explanation for the variability in effect estimates stemming
335
Arq Bras Cardiol. 2016; 106(4):333-337
from individual studies. I-squared is interpreted as showing
absent or mild between-study inconsistency if < 25%,
moderate inconsistency if < 50%, and moderate to severe
inconsistency for values > 50%.4,5
Appraising inconsistency between direct and indirect
estimates
The most important underlying assumption of metaanalysis network is that the studies are similar enough to be
considered together. Evaluation of inconsistencies in direct
and indirect estimates is essential to support the validity of
any network meta-analysis. Several approaches are available,
but in simple terms, any meta-analysis network in which the
direct and indirect estimates differ substantially should be
viewed with caution or completely ignored.17
Appraising small study effects and publication bias
Small study effects may distort the overall assessment of
the clinical evidence, providing estimates of inaccurate or
biased effect. This is most often due to publication bias or
other factors. Therefore, the assessment of small study effects is
critical to support the validity of any network meta-analysis.27
A network meta-analysis dominated by small studies
cannot be considered valid, and its results should be
probably disregarded or, at best, used to generate
hypotheses. Several approaches have been suggested to
test for small study effects, including inspection of funnel
plots after correction for subgroup summary estimates,
regression testing, and the Copas method.17,28
Combining multiple effect estimates: multivariate
network meta-analysis
Multivariate meta-analysis is performed on separate
sets of analysis, so the reader is left with the difficult
choice of considering which end point is more meaningful.
One solution is to create a net composite end point (e.g.,
nonfatal stroke, nonfatal bleeding, myocardial infarction,
or death). This approach has limited benefits in terms of
increased precision and forces us to consider all compounded
end point components as equally important. When the results
obtained with competing risks are used, there is also a risk of
heterogeneous or spurious average effects (for example, when
bleeding and thrombotic events are combined).
Multivariate meta-analysis is a specific application of
multivariate analysis to define meta-analysis when a set of
dependent variables is analyzed simultaneously, and thus when
comparing different treatments, the only treatment that is most
likely and more consistently capable of providing a clinical
improvement may be identified. This approach is beneficial
when a specific hierarchy between the different results is
lacking, and when every single result, if considered isolated, has
no clinical relevance to guide decision making on their own.4
A relevant question is whether, when assembled, end
points that were only evaluated in secondary analyses may
be trusted like end points that were the primary outcomes of
the included studies. The risk of distortion due to reporting
bias is higher in the first case, as is the risk of type I error.
Review Article
Moving from study-level to patient-level data: individual
patient network meta-analysis
Meta-analysis has always been criticized for using mostly studylevel or aggregated data, and lacking originality and ecological risk.
Individual patient-level meta-analysis overcomes this limitation
and has many other advantages: it may improve internal validity,
test subgroup hypothesis, and evaluate covariates of interest.
Network meta-analysis may be performed at both study level
and patient level using an approach of one or two stages depending
on the framework, package, model, and statistics of preference.
While more challenging, especially in terms of logistics and
cooperativeness, patient-level network meta-analysis should be
considered the standard reference for any evidence synthesis effort.
State-of-the-art reporting of network meta-analyses
Network meta-analyses have been the focus of many
standardization efforts in order to increase their robustness
and validity while increasing its usability among decision
makers.5 State-of-the-art reports should consist of explicit
information about the methods, clarify the evidence network,
include sound analytical methods, appraise the validity of
the homogeneity and consistency assumptions, and lack
substantial small study effects. Sensitivity analyses are crucial
to ensure the reader of any network meta-analysis that the
results are similar in statistical direction and magnitude despite
different assumptions or computational methods.
Future perspectives
Moving from evidence synthesis to action
The results of a network meta-analysis should be used to
guide decision making, define how to best interpret the results
of the evaluation and apply them in clinical practice, and to fully
implement the intervention in details with the most favorable
risk-benefit balance. This is best done by absolute risk estimates,
numbers needed to treat, and rankograms, basing judgment on
credible or confidence intervals, rather than on point estimates,
while recognizing the simultaneous effect of a particular
intervention on various end points.13 With this, when two or more
interventions seem to have a similar beneficial risk-benefit profile,
the one easier or cheaper to implement should be favored.
The future of network meta-analysis: toward accessibility
and integration
The future of network meta-analysis depends on the
difficult process of navigating between the Scylla of state-
of-the-art processes of conducting a valid systematic
review and the Charybdis of effective dissemination
and successful implementation by decision makers and
stakeholders. Research and clinical practice have been
dominated over the past decades by simple and easy to
use tools providing new solutions to complex problems.
An excellent resource for clinical research methods is
survival analysis using the Kaplan-Meier method, with its
precise, accurate, and robust results in everyday research,
despite its application in a multitude of very different and
sometimes difficult contexts.
In the future, network meta-analysis and synthesis
evidence will be possible with the concomitant application
of simple, yet robust packages to perform network
meta-analysis on various platforms such as tablets and
smartphones, and the creation of intelligent trial repositories
that can upload automatically the information obtained
through individual data in a kind of cumulative network
meta-analysis. No individual meta-analysis should be seen
as the end, but rather, as a tool to provide a distilled and
purified form of the available evidence to guide more
accurately the clinical practice.
Conclusions
Decision making in cardiovascular practice is often based
on complex, yet incomplete evidence. Network meta-analysis
represents a uniquely versatile and powerful tool to improve
cardiovascular decision making.
Conception and design of the research, Acquisition
of data, Writing of the manuscript and Critical revision
of the manuscript for intellectual content: Roever L,
Biondi-Zoccai G.
was reported.
Sources of Funding
Study Association
Arq Bras Cardiol. 2016; 106(4):333-337
336
Review Article
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Arq Bras Cardiol. 2016; 106(4):333-337
Back to The Cover
Viewpoint
Protective Effect of Aortic Stenosis on the Coronary Arteries.
Hypothetic Considerations to an Old Enigma
Paulo Roberto Barbosa Evora, Livia Arcêncio, Alfredo José Rodrigues, André Schmidt
Faculdade de Medicina de Ribeirão Preto – Universidade de São Paulo, São Paulo, SP – Brazil
Abstract
A literature overview of angiographic studies has shown
that the prevalence of significant coronary disease in
patients with aortic stenosis (AS) varies from 20 to 60%.
Early necropsy studies suggested that patients with AS
had a lower than expected incidence of coronary artery
disease (CAD), originating the concept of a protective
effect of AS on the coronary arteries. The myth of AS
protection against CAD would be better explained as
endothelium‑myocardial interaction (crosstalk) protection
triggered by left ventricular overload. Therefore, the
cGMP/NO pathway induced by the AS overload pressure
would explain the low incidence of CAD, which is
compatible with the amazing natural long-term evolution
of this cardiac valve disease.
Introduction
An overview of literature angiographic studies has shown
that the prevalence of the significant coronary disease in
patients with aortic stenosis (AS) varies from 20 to 60%.
Early necropsy studies suggested that patients with AS had
a lower than expected incidence of coronary artery disease
(CAD), originating the concept of a protective effect of AS
on the coronary arteries.1,2
Some publications illustrate this concept.
Among 88 patients with AS requiring valve replacement at
Hammersmith Hospital, twenty-two (34%) had significant
CAD (diameter < 50%).3 Morrison et al.4 analyzed coronary
arteriograms of 239 patients investigated for valvular heart
disease during a five-year period. Significant CAD was
present in 85% of patients with mitral valve disease and in
only 33% of patients with aortic valve disease. There was,
however, a significant inverse association between CAD
severity and valve disease severity in patients with
aortic valve disease.4 A total of 574 patients with severe
AS (mean age of 65.9 ± 9.6 years) were assessed in a
Korean study, with significant CAD being reported in
61 patients (10.6%). There was a low incidence of significant
Keywords
Aortic Valve Stenosis; Coronary Artery Disease;
Coronary Angiography.
Mailing Address: Paulo Roberto Barbosa Evora •
Rua Rui Barbosa, 367, Ap.15, Postal Code 14015-120, Ribeirão Preto, SP – Brazil
Manuscript received October 19, 2015; manuscript revised November 17,
DOI: 10.5935/abc.20160039
338
CAD in a population of Korean patients with severe AS.
Coronary angiography before AVR was considered in
patients with multiple cardiovascular risk factors, or in
patients older than 69 years without risk factors.5
A retrospective observational Mayo Clinic study suggests
that coronary artery bypass grafting (CABG) associated with
AVR has similar operative mortality, albeit with improved
overall survival during the long-term follow-up in patients
undergoing AVR without CABG.6 However, a large Society
of Thoracic Surgeons database study demonstrated that the
addition of CABG to AVR increased surgical morbidity and
mortality, raising the critical conjecture that revascularization
might have an impact on long-term survival. Also, the most
recent American Heart Association and American College of
Cardiology guidelines7 downplay the importance of CABG at
the time of surgical AVR and the indication for revascularization
in patients with coronary artery lesions > 70% has been
downgraded from a class I to a class IIa indication, minimizing
the importance of 50% to 70% stenotic lesions.8
Based on these literature data, some key points are
clearly established:
1) Early necropsy studies suggest that patients with AS had
a lower CAD incidence.1,2
2) Significant CAD was present in 85% of patients with
mitral valve disease and angina, but in only 33% of patients
with aortic valve disease and angina.3-6
3) A Society of Thoracic Surgeons database study
demonstrated that the addition of CABG to AVR increased
surgical morbidity and mortality.7,8
4) The most recent American Heart Association and
American College of Cardiology guidelines downplay the
importance of CABG at the time of surgical AVR and the
indication for revascularization in patients with coronary artery
lesions greater than 70% has been downgraded from a class
I to a class IIa indication, deemphasizing the importance of
50% to 70% stenotic lesions.7,8
5) Transcatheter aortic valve implantation (TAVI)
changed the guidelines for AS in patients with high
comorbidity, without any consistent rule, concerning
CABG in the presence of moderate CAD. While CABG
may favorably influence the long-term outcome in patients
undergoing surgical implantation of aortic prosthesis, this
information is not yet applicable to TAVI, because it has
not been possible to establish the profile of its long‑term
outcome. 6 Many patients who have severe AS have
angina without CAD, and both can be free of angina with
valve replacement. This information is very important,
considering the advent of Transcatheter Valves.
Evora et al.
Aortic stenosis and coronary artery disease
Viewpoint
The myth (Paradigm? Mistery? Puzzle?) of AS protection
against CAD is still impossible to overlook. There is no
hypothesis, or even speculation about the small incidence of
severe CAD in association with AS. For the present text we
performed an analysis of the national data, which confirmed
the worldwide data (Figure 1).
The first relevant information was the well-demonstrated
fact that in ventricular hypertrophy secondary to chronic
systemic hypertension or aortic valve disease, coronary
diameters are increased, as documented by Kimball et al.9
In 32 patients with AS, the coronary artery luminal diameters
were compared with those of 24 control subjects without
LV hypertrophy using a derived index. Patients with AS
had significantly larger coronary arteries than the control
subjects.9,10 In patients with AS, LV hypertrophy progression
is associated with left anterior descending and left circumflex
coronary artery increased dimensions, whereas the right
coronary artery remains unchanged. It is interesting to
mention that despite the enlargement of the left coronary
artery, its cross-sectional area per 100 g of LV muscle mass
decreased. Hence, the increase in coronary artery size appears
to be inadequate when LV hypertrophy severity increases.
Another interesting observation is that left coronary artery
size decrease after valve replacement at an equal rate with
LV muscle mass regression. Also, enlargement of the coronary
arteries has been reported in patients with LV hypertrophy at
necropsy and in clinical studies of patients with aortic valve
disease who were not yet candidates for surgery. As time goes
by, the severity of aortic valve stenosis is accompanied by
significant hypertrophy, growing increase in left coronary artery
dimensions, and no changes in the right coronary artery.11
At this point we have to add other key points, in an attempt
to obtain some clues to establish some hypotheses:
Number of patients
250
3) Coronary artery size increase seems to be insufficient
when LV hypertrophy severity increases.9-11
4) An enlarged left coronary artery size in the preoperative
period, decreases after valve replacement at an equal rate with
the LV muscle mass regression.11
5) As time goes by, aortic valve stenosis severity increases in
association with significant LV mass increase, a further increase
in left coronary artery dimensions, whereas those of the right
coronary artery remains unchanged.11
These data were concisely presented by Kauffman et al.12:
1) Coronary artery size increases as LV mass increases in both
primary and secondary hypertrophy. 2) The enlargement of
left coronary cross-sectional area is independent from the
cause of LV mass increase. 3) Coronary artery dimensions are
inappropriate concerning LV hypertrophy. Thus, the stimulus
for coronary artery growth is not influenced by the underlying
disease, but seems to depend on the LV hypertrophy degree.12
“These data allow for a pivotal conclusion: The association
of coronar y enlargement is clear, emphasizing the
phenomenon that is present only in the left hypertrophic
ventricle and resulting in pressure overload, as the
coronary artery size remains decreased after the aortic
valve prosthesis implant”.
The next step was to direct our attention to the
microvasculature, endothelium function, and nitric oxide.
HC - FMRPUSP
(205 - 2015)
150
85.4%
38
50
0
2) In patients with aortic valve stenosis, LV hypertrophy
progression is associated with an increase in left coronary
dimensions, while right coronary artery dimensions
remain unchanged.9-11
223
200
100
1) Increased coronary diameters are systematically observed
in association with ventricular hypertrophy secondary to
chronic systemic hypertension or aortic valve disease.
14.6%
Valve
prosthesis
Valve prosthesis +
Myocardial revascularization
Figure 1 – Aortic valve prosthesis associated or not with myocardial revascularization at Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo SP,
Brazil (2005 – 2015) (isolated aortic valve stenosis, after excluding congenital aortic stenosis and bicuspid aortic valve).
Arq Bras Cardiol. 2016; 106(4):338-341
339
Evora et al.
Viewpoint
ACQUIRED AORTIC VALVE STENOSIS
PRESSURE OVERLOAD
MYOCARDIAL HYPERTROPHY
ASSOCIATED TO LOW INCIDENCE OF CAD.
(Pressure overload-independent increase of the
left coronary artery diameter).
CROSSTALK ENDOTHELIAL
CELL/CARDIOMYOCYTE CELL
NO
PROTECTION AGAINST VASOSPASM,
THROMBOSIS AND ATHEROSCLEROSIS
Figure 2 – Physiopathological suggestion for the small incidence of coronary artery disease and natural history (> 50 years without symptoms) in patients with acquired
aortic valve stenosis.
Changes in the microvasculature could lead to a decrease
in coronary flow reserve and thus could be associated with
the inadequate growth of the epicardial coronary arteries.
However, it has been shown in patients with aortic valve
disease that coronary flow reserve tends to normalize
after successful valve replacement, suggesting that the
microvasculature is not altered by hypertrophy and is not
associated with an increase in the microvascular bed crosssectional area.11 Therefore, using logical thinking, myocardial
hypertrophy would be involved in the pressure overload.
Endothelial regulation of vascular activity by relaxing
and contracting factors has been well established.
Experimental evidence suggests a similar modulation of
myocardial contractile performance by endocardial and
coronary vascular endothelium.13 The human heart has a
plurality of cell types, with fibroblasts and other connective
tissue cells being the most abundant. The remaining cell
mass consists of cardiomyocytes (CM), endothelial cells
(EC), smooth muscle cells, mast cells, and immune-related
cells. CM are surrounded by the dense capillary network,
which is critical for maintaining constant blood flow.14
The several studies along this line of research allow us to
consider the concept of EC-CM crosstalk. Several failed
clinical studies targeting cell-cell interactions emphasize
the need to understand the molecular interactions
between various cells in situ.
340
Arq Bras Cardiol. 2016; 106(4):338-341
In conclusion, the myth of AS protection against CAD
would be better presented as endothelium-myocardial
interaction (crosstalk) protection triggered by left ventricular
overload. Therefore, the cGMP/NO pathway induced by
the AS overload pressure would explain the low incidence
of CAD, which is compatible with the amazing natural
long-term evolution of this cardiac valve disease (Figure 2).
data and Writing of the manuscript: Evora PRB; Analysis and
interpretation of the data: Evora PRB, Arcêncio L, Rodrigues AJ,
Schmidt A; Critical revision of the manuscript for intellectual
content: Evora PRB, Arcêncio L, Rodrigues AJ, Schmidt A.
was reported.
Sources of Funding
Study Association
Evora et al.
Viewpoint
References
1. Horan MJ Jr, Barnes AR. Calcareous aortic stenosis and coronary artery
disease. Am J Med Sci. 1948; 215(4):451-5.
2.
Nakib A, Lillihei CW, Edwards JE. The degree of coronary atherosclerosis in
aortic valvular disease. Arch Pathol. 1965;80(5):517-20.
3. Exadactylos N, Sugrue DD, Oakley CM. Prevalence of coronary artery
disease in patients with isolated aortic valve stenosis. Br Heart J.
1984;51(2):121-4.
4.
Morrison GW, Thomas RD, Grimmer SF, Silverton PN, Smith DR. Incidence
of coronary artery disease in patients with valvular heart disease. Br Heart J.
1980;44(6):630-7.
5. Cho EJ, Park SJ, Chang SA, Jeong DS, Lee SC, Park SW, et al. Incidence of
coronary artery disease before valvular surgery in isolated severe aortic
stenosis. Chin Med J (Engl). 2014;127(22):3963-9.
6. Thalji NM, Suri RM, Daly RC, Greason KL, Dearani JA, Stulak JM, et al.
The prognostic impact of concomitant coronary artery bypass grafting
during aortic valve surgery: implications for revascularization in the
transcatheter era. J Thorac Cardiovasc Surg. 2015;149(2):451-60.
7. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton
RA, et al; American College of Cardiology; American College of Cardiology/
American Heart Association; American Heart Association. 2014 AHA/
ACC guideline for the management of patients with valvular heart
disease: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg.
2014;148(1):e1-e132.
8.
Salerno TA. Coronary revascularization in the setting of surgical aortic valve
replacement: do we need extra icing on the cake? J Thorac Cardiovasc Surg.
2015;149(2):460-1.
9. Kimball BP, LiPreti V, Bui S, Wigle ED. Comparison of proximal left
anterior descending and circumflex coronary artery dimensions in
aortic valve stenosis and hypertrophic cardiomyopathy. Am J Cardiol.
1990;65(11):767-71
10. Abdulali SA, Baliga BG, Clayden AD, Smith DR. Coronary artery luminal
diameter in aortic stenosis. Am J Cardiol. 1985;55(4):450-3.
11. Villari B, Hess OM, Meier C, Pucillo A, Gaglione A, Turina M, et al. Regression
of coronary artery dimensions after successful aortic valve replacement.
Circulation. 1992;85(3):972-8.
12. Kaufmann P, Vassalli G, Lupi-Wagner S, Jenni R, Hess OM. Coronary artery
dimensions in primary and secondary left ventricular hypertrophy. J Am Coll
Cardiol. 1996;28(3):745-50.
13. Paulus WJ, Vantrimpont PJ, Shah AM. Paracrine coronary endothelial control
of left ventricular function in humans. Circulation. 1995;92(8):2119-26.
14. Brutsaert DL, Fransen P, Andries LJ, De Keulenaer GW, Sys SU. Cardiac
endothelium and myocardial function. Cardiovasc Res. 1998;38(2):281-90.
Arq Bras Cardiol. 2016; 106(4):338-341
341
Back to The Cover
Case 3/2016 – 36-Year-Old Man with Anomalous Origin of the Right
Coronary Artery in the Left Sinus of Valsalva and Interarterial Course
Edmar Atik, Roberto Kalil Filho, Marcelo Jatene
Hospital Sírio Libanês de São Paulo, São Paulo, SP – Brazil
Clinical data: Three months ago, after physical effort,
the patient had four episodes of paleness, excessive
sweating and fatigue, relieved when lying down in supine
position. In addition, the patient had pain of 2-hour
duration in the left hemithorax at normal activity level a
few days ago.
Physical examination showed good general condition,
not pale, anicteric, eupneic, normal pulse, and no palpable
pulse in the suprasternal notch was detected. Body weight
was 85 kg, height 170 cm, BP 120/70 mmHg, HR 75 bpm.
No abnormalities in the precordium, normophonetic heart
sounds, and no heart murmurs. No changes in the lungs or
abdomen were detected.
Complementary tests
Electrocardiogram showed sinus rhythm, no signs of atrial
or ventricular overload and no changes in the ventricular
repolarization. AP = +50o, AQRS = +40o, AT = +60o
Chest radiography showed normal heart area and
pulmonary vascular bed (Figure 1).
Echocardiography showed no contractile or morphological
changes, normal-sized cardiac chambers and normal
ventricular function (71%).
Coronary Computed Tomography Angiography revealed
anomalous origin of the right coronary artery from the left
Valsalva sinus, with interarterial course between aorta and
pulmonary trunk, with distinct narrowing of its proximal third
and coronary ostium. The interarterial course of the right
coronary artery was estimated at 10 mm (Figure 2).
Cardiac catheterization revealed the same aspect of the
dominant right coronary artery, with anomalous origin from the
left sinus of Valsalva and proximal course with sharp angulation
and no obstructions (Figure 2). Left anterior descending
artery and circumflex artery originate from the bifurcated left
coronary artery; long diagonal and septal branches; absence
of collateral circulation or arterial obstruction.
Keywords
Cardiac Surgical Procedures; Coronary Vessel Anomalies /
surgery; Heart Defects, Congenital; Sinus of Valsalva; Cardiac
Catheterization.
Mailing Address: Edmar Atik •
Office. Rua Dona Adma Jafet, 74 conj.73, Bela Vista.
Postal Code 01308‑050, São Paulo, SP – Brazil
Manuscript received July 14, 2015; revised manuscript November 24, 2015;
accepted 24 November, 2015.
DOI: 10.5935/abc.20160051
342
TcMIBI stress myocardial scintigraphy did not show
ischemia, but indicated pain in the left sternal border, of
low intensity and minutes of duration. Images obtained after
isotonic exercise and at rest showed normal perfusion of the
left ventricular walls.
Functional images combined with ECG (GSPECT) indicate
normal motion and thickness of the left ventricular wall, and
normal ejection fraction of the left ventricle (65%).
Clinical Diagnosis: Anomalous origin of the right coronary
artery from the left Valsalva sinus, with interarterial course
between the ascending aorta and pulmonary trunk, with
signs and symptoms of arterial obstruction, but no evidence
of myocardial ischemia.
Clinical reasoning: symptoms of low cardiac output
combined with chest pain (even non-specific) suggest, a priori,
aortic valve or coronary arterial malformation. The former was
rejected due to the absence of heart murmurs. The abnormal
origin of right coronary artery in the left sinus of Valsalva and
its compression in the interarterial course were demonstrated
by tomography.
Differential diagnosis: the same clinical picture may be
seen in other coronary abnormalities, including the anomalous
origin of the left coronary artery from the pulmonary trunk,
but with large collateral circulation from the right coronary,
enabling the development until adult age, in addition to the
left coronary artery originating from the right sinus of Valsalva,
with significant interarterial compression.
Management: The indication of surgery was evident in
light of the clinical presentation of low cardiac output, chest
pain (even non-specific), and unfavorable anatomy of the
right coronary artery with interarterial compression, due
to the risk of sudden death and/or ventricular arrhythmias,
although no evidence of ischemia was detected by
myocardial scintigraphy.
During the heart surgery, dissection of the right coronary
artery originating from next to the left coronary ostium in the
left sinus of Valsalva with an interarterial course between the
aorta and pulmonary trunk was performed. The right coronary
artery exhibited non-obstructive plaques in its proximal third,
where it was cut and anastomosed to the anterior wall of the
aorta with continuous suture (7-0 Prolene).
Comments: Anomalous origin of the right or left coronary
artery from the sinus of Valsalva is a rare, congenital abnormality,
and most of patients are asymptomatic. However, despite
this apparently favorable condition, identified during routine
or symptom assessment, the indication of surgery should be
considered in order to prevent sudden death. This is a literature
consensus, and few authors adopt a different viewpoint due to a
conservative attitude. This approach may be used in the absence
of symptoms or myocardial ischemia. Right coronary artery
Atik et al.
Right coronary artery with interarterial course
Figure 1 – Chest radiograph shows normal heart area and pulmonary vascular bed. The elongated, dilated right upper arch may result from the modest increase of
ascending aorta.
Figure 2 – Similar projections of coronary arteries by computed tomography angiography (A, B) and cardiac catheterization (C, D) highlight the origin of the right coronary
artery in the left sinus of Valsalva, the interarterial course and sharp narrowing in its beginning. AO: aorta; RC: right coronary artery; LC: left coronary artery; RV: right
ventricle; LV: left ventricle; PT: pulmonary trunk.
Arq Bras Cardiol. 2016; 106(4):342-344
343
Atik et al.
Right coronary artery with interarterial course
anomalies are ten times more common than in the left coronary
artery. Physical effort is the trigger of ischemic symptoms, often
fatal and without notice, be it for the interarterial obstruction,
be it for the coronary artery arising from the aorta at an
acute angle. The necessity of surgery is based on symptoms,
regardless of the negative result for ischemia. The currently most
accepted surgical techniques recommend reimplantation of the
coronary artery in the sinus of Valsalva. Both coronary artery
bypass surgery and the internal thoracic artery bypass have not
been the approaches of choice due to the possibility of future
obstructions, similarly to the placement of stents, which would
continue to be exposed to the action of the arteries.1-3
References
1. Shimizu T, Iwaya S, Suzuki S, Sakamoto N, Sugimoto K, Nakazato K, et
al. Sudden cardiac arrest associated with an anomalous aortic origin of
the left coronary artery from the opposite sinus of Valsalva. Intern Med.
2014;53(22):2601-4.
2.
344
Bagur R, Gleeton O, Bataille Y, et al. Right coronary artery from the left sinus of
Valsalva. Multislice CT and transradial PCI. World J Cardiol. 2011;3(2):54-6.
Arq Bras Cardiol. 2016; 106(4):342-344
3.
Cho SH, Joo HC, Yoo KJ, Youn YN. Anomalous origin of right coronary artery
from left coronary sinus: surgical management and clinical result. Thorac
Cardiovasc Surg. 2015;63(5):360-6.
Back to The Cover
Case Report
Meng-Luen Lee1 and Ing-Sh Chiu2,3
Department of Pediatrics – Division of Pediatric Cardiology – Changhua Christian Children’s Hospital1, Changhua; Department of Surgery –
Division of Cardiovascular Surgery – Changhua Christian Children’s Hospital2, Changhua; Department of Surgery – Division of Cardiovascular
Surgery – College of Medicine – National Taiwan University Hospital3, Taipei – Taiwan
Introduction
The platypnea-orthodeoxia syndrome (POS) is a rare
clinical condition characterized by dyspnea occurring in
the upright position and relieved in the supine position
(platypnea) associated with oxygen desaturation noted in
the upright position (orthodeoxia). 1 A diagnosis of POS
requires two of the following criteria: 1) orthodeoxia,
2) platypnea, 3) presence of an interatrial communication,
4) right-to-left shunt, and 5) absence of pulmonary arterial
hypertension or right atrial hypertension. 1,2 POS can
originate in the heart, lungs, abdomen, or elsewhere due
to either an intracardiac (cardiac POS) or intrapulmonary
shunt, or a ventilation-perfusion mismatch.1 However, a
venovenous malformation (VVM) as a cause of cardiac POS
has never been reported in the literature.1
We report here the case of a 24-year-old female
patient who presented with cardiac POS due to a VVM.
The syndrome emerged insidiously 16 years after an
extracardiac total cavopulmonary connection (TCPC) for a
complex of congenital cardiovascular malformations and
was successfully treated with percutaneous transvenous
coil embolization.
Case Report
A 24-year-old female patient complained of frequent
yawning over the past month while standing up at work.
Her lips were occasionally cyanotic, as noticed by her mother.
The patient had undergone extracardiac TCPC at the age
of 8 years due to a complex of congenital cardiovascular
malformations, including heterotaxy/asplenia/right atrial
isomerism, bilateral superior vena cava, common atrium,
common atrioventricular valve, double-inlet and double‑outlet
left ventricle, dextro-transposition of the great arteries,
supravalvular pulmonary stenosis, left aortic arch, and total
anomalous pulmonary venous connection.
During evaluation at the outpatient clinic, the patient
presented orthodeoxia detected by pulse oximetry, with an
oxygen saturation (SpO2) of 96% in the supine position and
88% in the upright position. Platypnea was not observed at
that time. With a diagnostic suspicion of secondary pulmonary
arteriovenous malformation (PAVM) following the TCPC, the
patient was admitted for further evaluation and treatment.
On admission, she weighed 63 kg and her height was
166 cm. Her blood pressure was 120/71 mmHg, pulse rate
was 88 beats/min, and respiratory rate was 20 breaths/min.
Laboratory tests showed a hemoglobin level of 15.6 g/dL,
and normal liver function and blood coagulation tests.
No information regarding the underlying cause of the
orthodeoxia could be obtained from plain chest radiograph
and electrocardiogram evaluations.
Cardiac catheterization, performed after the patient
granted informed consent, showed an SpO2 on the ascending
aorta of 93%. Peak systolic pressure in the inferior vena
cava, TCPC conduit, left superior vena cava, and branch
pulmonary arteries were all 16 mmHg. Pulmonary capillary
wedge pressure was 13 mmHg, end-diastolic left ventricular
pressure was 9 mmHg, and transpulmonary capillary gradient
was 7 mmHg. An angiography showed three anomalous
systemic veins corresponding to a VVM draining in sequence
from the inferior vena cava, hepatic vein, pulmonary veins,
and pulmonary venous atrium (functional left atrium)
(Figures 1A and 1B). This VVM caused a right-to-left shunt,
accounting for the oxygen desaturation.
A percutaneous transvenous coil occlusion was performed
uneventfully. After the procedure, an angiography of the
inferior vena cava showed complete occlusion of the VVM
(Figures 1C and 1D). At a 12-month follow-up, the patient
reported that the yawning-orthodeoxia had disappeared, and
a postural change test showed no oxygen desaturation in the
upright and supine positions, with SpO2 measurements of
~92–96% (> 90%).
Discussion
Keywords
Dyspnea / etiology; Arteriovenous Malformations / etiology;
Arteriovenous Malformations / surgery; Pulmonary Circulation;
Septal Occluder Device.
Mailing Address: Meng-Luen Lee •
Changhua Christian Hospital. No. 135 Nanhsiao St., Changhua.
Postal Code 50050, Taiwan.
Manuscript received March 18, 2015; manuscript revised August 20, 2015;
accepted September 02, 2015
DOI: 10.5935/abc.20160059
345
Table 1 summarizes the definition, mechanisms and
etiologies, and diagnostic criteria of POS.
Six implications should be highlighted in the present case.
First, the patient’s manifestations presented insidiously
with yawning-orthodeoxia 16 years after a TCPC, thus
angiography was indicated to identify the underlying
causes of oxygen desaturation, which included obstruction/
stenosis of the TCPC or pulmonary arteries, pulmonary
arterial hypertension related to increased pulmonary arterial
resistance, thrombosis of the superior vena cava, and
development of a PAVM or VVM.
Lee & Chiu
Platypnea-orthodeoxia syndrome
Case Report
Figure 1 – A new cardiac platypnea-orthodeoxia syndrome due to a venovenous malformation (1A and 1B). Angiography showing three anomalous systemic venous
channels (venovenous malformations) draining in sequence from the inferior vena cava, hepatic vein, pulmonary veins, and pulmonary venous atrium (functional left atrium).
The numbers with arrows point to the venovenous malformations, the empty star shows the total cavopulmonary connection, and the solid star shows the pulmonary venous
atrium (1C and 1D). Angiography of the inferior vena cava after percutaneous transvenous coil embolization shows complete obliteration of the venovenous malformation.
Second, our patient did not experience platypnea
in the past or when she sought help for the problem
discussed in this case. Considering the high incidence of
PAVM and interatrial shunts after the Fontan operation 3
(43% and 57%, respectively), POS is not an uncommon
complication. In fact, POS emerged as a complication
in eight patients with PAVM/intra-atrial shunts who
underwent the Fontan operation, but none had a VVM.3
One of these patients had platypnea, and three others had
orthodeoxia,3 which shows that not all patients present
with platypnea and orthodeoxia simultaneously, and their
detection is only possible with a postural change test.3
Platypnea may be difficult to identify without a careful
evaluation of dyspnea, 3 whereas orthodeoxia could be
masked by profound cyanosis or even overlooked due to
subtle desaturation in the upright position, as seen in our
patient who had an SpO2 of 88%.
Patients with POS occasionally only complain of fatigue4
and not platypnea. In addition, assessment of our patient
with the New York Heart Association (NYHA) functional
classification was limited due to a mild oxygen desaturation
in the upright position (orthodeoxia). Thus, semiology and
oximetry were fundamental in the initial evaluation of this
patient, who had presented with upright yawning and
orthodeoxia. We initially considered that the complaint
of yawning could be simply a subtle symptom of fatigue.
Arq Bras Cardiol. 2016; 106(4):345-348
346
Lee & Chiu
Case Report
Table 1 – Platypnea-orthodeoxia syndrome
Definition1,2
Platypnea: dyspnea noted in the upright position and relieved in the supine position
Orthodeoxia: oxygen desaturation noted in the upright position
Criteria*1,2
[1] IAC, [2] RA–LA shunt, [3] No PAH/RAH, [4] Platypnea, [5] Orthodeoxia
Mechanisms1,2
[1] Intracardiac RA–LA shunt (PFO, ASD, ASA)
a. RA–LA shunt without pressure gradient
– Etiologies:
Aortic aneurysm, cardiac tamponade, pericardial effusion, constrictive pericarditis, pneumonectomy, decreased RA
compliance due to acute myocardial infarction, prominent Eustachian valve or large Chiari network, kyphosis, RA
lipomatosis, RA myxoma, etc.
b. RA–LA shunt with pressure gradient
– Etiologies:
PTE, idiopathic PAH, right hydrothorax, PAH in CLD, pneumonectomy, etc.
[2] Intrapulmonary right-to-left shunt
– Etiologies:
PAVM, HPS, Osler-Weber-Rendu syndrome, etc.
[3] Ventilation/perfusion mismatch
– Etiologies:
Emphysema, COPD, amiodarone toxicity, autonomic dysfunction, HPS, etc.
ASA:Atrial septal aneurysm; ASD: Atrial septal defect; CLD: Chronic lung disease; COPD: Chronic obstructive pulmonary disease; HPS: Hepatopulmonary syndrome;
IAC: Interatrial communication; LA: Left atrial; PAH: Pulmonary arterial hypertension; PAVM: Pulmonary arteriovenous malformation; PFO: Patent foramen ovale;
PTE: Pulmonary thromboembolism; RA: Right atrial; RAH: Right atrial hypertension.
*Two of these five criteria establish the diagnosis of platypnea-orthodeoxia syndrome1,2.
However, the yawning-orthodeoxia was a manifestation of
POS, which was later identified to be due to a VVM as the
underlying cardiovascular pathology.
Third, VVM may cause oxygen desaturation in several
cyanotic congenital heart diseases after bidirectional Glenn
shunt (BDGS), with an incidence of 31–33%.5,6 The presence
of PAVM should not preclude angiographic evaluation of the
venae cavae for the establishment of the diagnosis of the VVM.
It is difficult to detect a VVM before the Fontan operation,7
and the malformation may only become hemodynamically
important after this procedure.5-7 Venae cavae angiography
with a balloon occlusion test in the distal collector of VVM
can offer a better visualization of a VVM.7
Fourth, a rule establishes that two clinical conditions with
an anatomical and a functional component must coexist to
cause POS.1,2 However, this rule has exceptions. Kumar et al.8
reported the case of a 57-year-old woman with hereditary
hemorrhagic telangiectasia and PAVM who presented with
POS without an interatrial defect. It holds truth for the
present patient who manifested VVM as a new functional
component of cardiac POS, which has never been reported
in the English literature.1,2
Fifth, the event that orchestrated the occurrence of
orthodeoxia in our patient is fascinating from an embryologic
point of view. The VVM leading to the orthodeoxia was
caused by a persistent communication between the
proximal segment of the left umbilicovitelline vein with
the left horn of the sinus venosus. Development of a VVM
is known to occur due to reopening of systemic venous
channels when the cavae are subjected to an elevated
pressure that is transmitted backward in the pulmonary
artery after a BDGS. 5-7 In patients who underwent the
Fontan operation, a positive pressure gradient between
347
Arq Bras Cardiol. 2016; 106(4):345-348
the cavae or the pulmonary arteries and the pulmonary
veins (which normally ranges from 5–10 mmHg) facilitates
an antegrade blood flow from the pulmonary veins to the
lung.7 In our patient, the transpulmonary capillary gradient
was 7 mmHg. Ironically, this gradient was high enough to
divert the flow from the inferior cava to the anomalous left
pulmonary veins, simulating a right-to-left shunt through
the VVM. In addition to the influence of this gradient,
gravity may have potentially increased the reversed flow
from the pulmonary artery to the anomalous left pulmonary
veins.9 Under these scenarios, a combination of decreased
blood flow to the lung and increased right-to-left shunt
through the VVM in our patient may have predisposed
to oxygen desaturation, even if insidious. This means that
in the long run, a VVM may predispose some patients
with univentricular heart repaired with TCPC to present
orthodeoxia or platypnea.
Sixth, a percutaneous transvenous coil occlusion is an
adequate procedure to treat a small VVM.5,6 Guérin et al.7 have
reported two patients with large intrahepatic VVMs causing
oxygen desaturation after a modified Fontan operation.
The VVMs in both patients were successfully occluded with
the Amplatzer septal occluder.
Conclusion
Both semiology and oximetry evaluation were fundamental in
the initial assessment of our patient, who presented with upright
yawning and mild orthodeoxia. The yawning‑orthodeoxia
syndrome may be a variant of POS. VVM has never been
reported as a functional component of cardiac POS in the
literature. Small VVM may be effectively treated by transvenous
coil occlusion.
Lee & Chiu
Case Report
Sources of Funding
data, Analysis and interpretation of the data, Writing of
the manuscript and Critical revision of the manuscript for
intellectual content: Lee ML, Chiu IS
Study Association
was reported.
References
1.
Cheng TO. Platypnea-orthodeoxia syndrome: etiology, differential diagnosis,
and management. Catheter Cardiovasc Interv. 1999;47(1):64-6.
2. Rodrigues P, Palma P, Sousa-Pereira L. Platypnea-orthodeoxia syndrome in
review: defining a new disease? Cardiology. 2012;123(1):15-23.
3. Suzuki H, Ohuchi H, Hiraumi Y, Yasuda K, Echigo S. Effects of postural
change on oxygen saturation and respiration in patients after the Fontan
operation: platypnea and orthodeoxia. Int J Cardiol. 2006;106(2):211-7.
6. McElhinney DB, Reddy VM, Hanley FL, Moore P. Systemic venous
collateral channels causing desaturation after bidirectional cavopulmonary
anastomosis: evaluation and management. J Am Coll Cardiol.
1997;30(3):817-24.
7.
Guérin P, Losay J, Baron O. Transcatheter occlusion of an intrahepatic venovenous
fistula after modified Fontan circulation by implantation of an Amplatzer atrial
septal occluder. Catheter Cardiovasc Interv. 2005;64(1):117-20.
4.
Sorrentino M, Resnekov L. Patent foramen ovale associated with platypnea
and orthodeoxia. Chest. 1991;100(4):1157-8.
8. Kumar N, Kraemer RR, Murthy RK, Hartig JR. Platypnea-orthodeoxia
as a presentation of hereditary hemorrhagic telangiectasia. Circulation.
2012;126(22):2645-7.
5.
Magee AG, McCrindle BW, Mawson J, Benson LN, Williams WG, Freedom
RM. Systemic venous collateral development after the bidirectional
cavopulmonary anastomosis. Prevalence and predictors. J Am Coll Cardiol.
1998;32(2):502-8.
9. Hsia TY, Khambadkone S, Redington AN, Migliavacca F, Deanfield JE, de
Leval MR. Effects of respiration and gravity on infradiaphragmatic venous
flow in normal and Fontan patients. Circulation. 2000;102(19 Suppl
3):III148-53.
Arq Bras Cardiol. 2016; 106(4):345-348
348
Back to The Cover
Image
Congenital Muscular Interventricular Septal Malformation with
Complex Anatomical Features
Zafer ışılak, Mehmet Uzun, Ejder Kardeşoğlu, Ömer Uz, Uğur Küçük
Department of Cardiology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul – Turquia
A 21 year-old male patient was admitted with symptoms
of exertional dyspnea and palpitation. The physical
examination revealed a grade 3/6 systolic murmur, best
heard over the left 3-4th intercostal space. Transthoracic
echocardiography disclosed a separate chamber (asterisk)
in the interventricular septum. The apical portion of the
chamber consisted of muscle tissue and the basal portion
consisted of membranous and aneurysmatic tissue (Panel A).
There was a muscular “tunnel-like” structure connecting
the left ventricle and chamber at mid ventricular level.
The color and continuous wave Doppler imaging revealed a
bidirectional flow across the passage (Panel B, C).
The patient underwent three dimensional transthoracic
echocardiographic examinations, which revealed two separate
septa. Between these septa there was a third chamber
(asterisk). It was connected to both left (via the tunnel at
the muscular septum) and right ventricles (via the defect
in the membranous septal aneurysm). The membranous
Keywords
Heart Defects, Congenital; Ventricular Septum; Heart
Septal Defects, Ventricular.
Mailing Address: Ugur Kucuk •
Cardiology. GATA Haydarpasa Training Hospital. Postal Code 341000,
Istanbul – Turkey
Manuscript received October 13, 2015; manuscript revised November 24,
2015, accepted November 24, 2015.
DOI: 10.5935/abc.20160045
349
septal aneurysm was separated from the left ventricle by
a thin membrane, without any passage across it (Panel D).
MRI findings were consistent with echocardiographic images
(Panel E). Ventriculography and coronary angiography were
performed. The coronary arteries were normal; the left
ventriculography showed the muscular and membranous/
aneurysmatic portions of the malformation (Panel F).
The patient was advised to undergo a surgical procedure,
but he refused and was discharged with recommendations
about control visits.
Conception and design of the research: ışılak Z;
Acquisition of data: Uz O; Writing of the manuscript: Küçük
U; Critical revision of the manuscript for intellectual content:
Uzun M, Kardeşoğlu E.
was reported.
Sources of Funding
Study Association
Back to The Cover
Letter to the Editor
Fernando A . Atik
Instituto de Cardiologia do Distrito Federal, Brasília, DF – Brazil
Dear Editor,
The article “Use of short-term circulatory support as a
bridge in pediatric transplantation”, recently published1 in
Arquivos Brasileiros de Cardiologia has aroused great interest.
Caneo et al.1 published the largest national experience
with the use of circulatory support in children. The authors,
according to the reported experience, demonstrated that the
use of ventricular assist devices increased the possibility for
children in cardiogenic shock to undergo transplantation,
although mortality outcomes remained very high, according
to international experiences.2,3
Although it is a noteworthy experience for Brazil, it is
appropriate that some details should be observed.
About the risk stratification, for instance, Caneo et al.1
grouped patients in Interagency Registry for Mechanically
Assisted Circulatory Support (INTERMACS) 1 and 2 in the
Keywords
Advanced Cardiac Life Support; Heart Defects, Congenital;
Heart Transplantation; Outcome Assessment (Health Care).
Mailing Address: Fernando A. Atik •
Instituto de Cardiologia do Distrito Federal. SQNW 110, bloco J, AP 308,
Noroeste. Postal Code 70686-550, Brasília, DF – Brazil
Manuscript received November 15, 2015; revised manuscript January 21,
2016; accepted January 22, 2016.
same category, which certainly results in differences in shock
severity and therapeutic response.
More important than the initial assessment is the patient’s
response to treatment. It is absolutely necessary that the
child have time for correction of multiple-organ dysfunction
prior to the transplantation. Caneo et al.1 had a mean time
of 19 days to perform the transplantation in the group
undergoing mechanical circulatory assistance, but one patient
was transplanted within 6 hours! How do the authors manage
the assisted child in relation to maintenance or not in the
transplant waiting list? What are the recipient’s minimum
conditions to accept a possible donor during this circulatory
assistance phase?
Resource allocation is limited in our country, so it is
important to use them sensibly and in those with a better
chance of survival. Additionally, the number of donors is
insufficient to meet the demand of recipients. Wouldn’t the use
of a donor to a recipient in INTERMACS 1 and 2 be a waste
of a donor to another recipient with better chances? Ethical
dilemmas are certainly involved in this discussion.
I would like to congratulate Caneo et al.1 for bringing
such an important experience into the Brazilian cardiology
community. Last but not least, the lack of availability of this
technology in our country constitutes a serious problem,
which must have the support of the competent entities,
so that there is training and rationalization of use in heart
transplantation reference centers.
DOI: 10.5935/abc.20160047
References
1.
Canêo LF, Miana LA, Tanamati C, Penha JG, Shimoda MS, Azeka E, et al. Use
of short-term circulatory support as a bridge in pediatric transplantation. Arq
Bras Cardiol. 2015;104(1):78-84.
2. Reinhartz O, Maeda K, Reitz BA, Bernstein D, Luikart H, Rosenthal DN, et
al. Changes in risk profile over time in the population of a pediatric heart
transplant program. Ann Thorac Surg. 2015;100(3):989-95.
350
3.
Zafar F, Khan MS, Bryant R, Castleberry C, Lorts A, Wilmot I, et al. Pediatric
heart transplant waiting list mortality in the era of ventricular assist devices.
J Heart Lung Transplant. 2015;34(1):82-8.
Atik
Bridge to Pediatric Heart Transplantation
Letter to the Editor
Reply
Dear Editor,
The article “Use of short-term circulatory support as a
bridge in pediatric transplantation” represents our initial
experience with short-term circulatory assist devices,
more precisely the use of both extracorporeal membrane
oxygenation (ECMO) and the centrifugal pump for this
purpose. The concepts and clinical management in this phase,
explained in the manuscript, represented an important step
in the development of our team. Although our mechanical
circulatory support (MCS) program was started in 1999, only
recently, after adequate investment in equipment and training
of our staff, we achieved more favorable results with ECMO.1
Our recently published experience with pediatric
heart transplantation (HTx)2 shows that, until April 2012,
we performed 114 HTx and used ECMO in only two
patients. Over the past three years, however, there has
been an exponential increase in that number and we
performed more than 70 HTx using more than 25 MCS
devices (unpublished data). Certainly, the use of MCS has
contributed to this increase in volume, due the inclusion of
borderline recipients, Interagency Registry for Mechanically
Assisted Circulatory Support (INTERMACS) 1 and 2, not so
well compensated clinically. Moreover, we observed a 70%
increase in the number of congenital heart disease as a cause
of HTx indication in our list. Our early mortality, which was
consistent with the international literature,1 increased as
a result of the practice described above,2 which made us
review our protocols. Many of the questions raised in the
letter sent by Atik had already been disscussed in our team.
access to more appropriate devices. On the other hand, the
mortality of these patients in the waiting list, according to our
experience and before the advent of the MCS, was markedly
elevated,3 which led us to invest in the program.
Among the lessons learned, it is now known that patients
that have some dysfunction in other organs, in addition to heart,
are removed from the waiting list until the problem resolved.
The mentioned case that remained in the waiting list for a
very short time refers to an acute failure in a patient already
listed, who, after the setting up of the MCS, received an organ,
in fact, is only an anecdotal case.
Currently, our service has launched the clinical protocol
of the pneumatic paracorporeal ventricular assist device
developed in our Department of Bioengineering, which
is available in sizes 15, 30 and 65 mL for institutional
patients. We live in a time of greater maturity in clinical
management, anticoagulation and nutritional support with
the use of these devices.
Regarding the ethical aspects mentioned in the letter,
we would like to emphasize that the proper allocation of
organs to these patients is a constant concern of our team.
To consider the use of an borderline donor in unfavorable cases
may be a viable alternative. By proposing the use of MCS to
the family, we must keep in mind that we are not necessarily
heading towards HTx and that will only be considered at the
appropriate time. To recognize our limitations is part of the
evolution of a high-quality MCS and HTx program.
Sincerely,
It is known that short–term MCS devices was not designed
to be used as a bridge to the HTx, and this is well emphasized
in our manuscript, as well as the inherent characteristics of
the Brazilian public health service, in which we do not have
Luiz Fernando Caneo
Leonardo A. Miana
Marcelo B. Jatene
References
1.
Miana LA, Caneo LF, Tanamati C, Penha JG, Guimarães VA, Miura N, et al.
Post-cardiotomy ECMO in pediatric and congenital heart surgery: impact
of team training and equipment in the results. Rev Bras Cir Cardiovasc.
2015;30(4):409-16.
3.
Jatene MB, Miana LA, Pessoa AJ, Riso A, Azeka E, Tanamati C, et al. Pediatric
heart transplantation in refractory cardiogenic shock: a critical analysis of
feasibility, applicability and results. Arq Bras Cardiol. 2008;90(5):329-33.
2. Miana LA, Azeka E, Caneo LF, Turquetto AL, Tanamati C, Penha JG, et al.
Pediatric and congenital heart transplant: twenty-year experience in a
tertiary Brazilian hospital. Rev Bras Cir Cardiovasc. 2014;29(3):322-9.
Arq Bras Cardiol. 2016; 106(4):350-351
351

Original Article - Arquivos Brasileiros de Cardiologia

Transcription

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