Left Atrial Remodeling and Response to Valsartan in the Prevention

Transcription

Left Atrial Remodeling and Response to Valsartan in the Prevention
of Recurrent Atrial Fibrillation: The GISSI-AF Echocardiographic Substudy
Staszewsky et al: LA Remodeling in AF and Valsartan
Lidia Staszewsky, MD1, Maylene Wong, MD1, Serge Masson, PhD1, Elena Raimondi, MSc1,
Silvana Gramenzi, MD2, Gianni Proietti, MD3, Dario Bicego, MD4, Carlo Emanuelli, MD5,
Giancarlo Pulitanò, MD6, Filippo Taddei, MD7, Enrico B. Nicolis, MSc1, Ernesto Correale, MD8,
Gianna Fabbri, MD9, Federico Bertocchi, MD10, Maria Grazia Franzosi, Biol D1,
Downloaded from http://circimaging.ahajournals.org/ by guest on November 1, 2016
Aldo P. Maggioni, MD9, Gianni Tognoni, MD11, Marcello Disertori, MD12, Roberto Latini, MD1,
on behalf of GISSI-AF Investigators*
1
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
acollog
ogic
icchee ““Mario
Mar Negri”, Milan,
Ma
Italy; 2 Ospedale Fatebenefratelli
nefratelli e Oftalmico, Division of Cardiology, Milan, Italy; 3Azienda USL 4,
Cardiology Unit, Terni, Italy; 4Ospedale Nuovo Girolamo Fracastoro, Cardiology Unit,
U
San Bonifacio,
Italy; 5Division of Cardiology,
i
iology,
Presidio Ospedaliero di Cremona, Italy; 6POL Mado
Madonna della
Consolazione, Reggio Calabria,
C
Italy; 7Ospedale Riuniti, Cardiology Unit, Cardiovascular
Cardiovaa
Department,
Bergamo, Italy; 8Azienda
d Ospedaliera
d li Sant’Anna e San Sebastiano,
b i
Cardiology
di l
Unit,
i Caserta, Italy;
9
ANMCO Research Center, Florence, Italy; 10Novartis Italy SpA, Origgio, Italy; 11Consorzio Mario
Negri Sud, Chieti, Italy; 12Department of Cardiology, Ospedale Santa Chiara, Trento, Italy.
* A complete list of the investigators who participated in the echocardiographic substudy is presented
in the appendix.
This work was presented in part at the Scientific Sessions of the American Heart Association,
(Circulation 2009;20S-385 and Circulation, 2010; 122: A14269).
Correspondence to:
Lidia Staszewsky, Department of Cardiovascular Research, Istituto “Mario Negri”, Via Giuseppe La
Masa 19, 20156 Milan, Italy.
Phone +39 239014508, Fax: +39 233200049, email: [email protected]
Journal Subject Codes: arrhythmias, secondary prevention, remodeling, echocardiography.
Abstract
BackgroundʊLeft atrial (LA) dilatation precedes or appears early after the onset of atrial fibrillation
(AF) and factors in perpetuating the arrhythmia. Angiotensin receptor blockers were proposed for
reversing LA remodeling. We evaluated the effect of valsartan on LA remodeling in patients with a
recent episode of AF and the effect of LA size on AF recurrence (AFr).
Methods and ResultsʊLA and left ventricular (LV) echocardiographic variables were measured at
baseline, 6 and 12 months in 340 patients from GISSI-AF, a trial testing valsartan prevention of AFr.
ver 12 months.
months
thss. Changes in patients
Reversal of remodeling was considered as a decrease in LA size over
AF
Fr were
weree aanalyzed.
nnaaly
with and without recurrence and the relationship to duration of AFr
Patients were
t history of hypertension (85.3%) and cardioversion in th
th
h previous 2 weeks
68.4±8.8 years-old, with
the
t previous 6 months (40.4%). Baseline LA maximal volu
u
(87.4%), or 2 AFr in the
volume
(LAVmax) was
0 ml/m2), LV dimensions and function were relatively normal.
norm
m Over 12 months
severely increased (>40
54.4% of patients had AFr. LAVmax was unchanged by rhythm, time or randomized treatment. Higher
baseline LAVmax and lower LA emptying fraction (LAEF) were linearly related to increasing AFr
duration during follow-up.
ConclusionsʊGISSI-AF patients in sinus rhythm and history of AF showed severely increased
LAVmax with mostly normal LV volume, mass, systolic and diastolic function. Valsartan for 1 year
did not reverse LA remodeling or prevent AFr. Since half of the patients without AFr had severe LA
dilatation, mechanisms other than structural remodeling triggered recurrence.
Clinical Trial RegistrationʊURL: http:///www.clinicaltrials.gov. Unique identifier: NCT00376272.
Key Words: atrial fibrillation; remodeling; left atrium; echocardiography; clinical trial
Abbreviations
AF=atrial fibrillation
AFr=atrial fibrillation recurrence
ARB=angiotensin receptor blockers
BP=blood pressure
BSA=body surface area
Echo=echocardiographic
Infarto Miocar
arrd - Atrial
GISSI-AF = Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
Miocardico
Fibrillation
LA=left atrium
ing fraction
LAEF=left atrial emptying
LAV=left atrial volume
LAVmax=left atrial maximal volume
LAVmin=left atrial minimum volume.
The hypothesis that long-term renin-angiotensin system (RAS) inhibition could reverse the LA
remodeling process and, thereby contribute to the prevention of AFr, was formally tested in the doubleblind randomized ”Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico - Atrial
Fibrillation” (GISSI-AF) trial (1-2). The entirely neutral results of the study were somewhat surprising
(3), given the wealth of positive evidence. Data from experimental AF implicated RAS in the
remodeling associated with atrial electrical heterogeneity and abnormal conduction, and atrial
hypertrophy and interstitial fibrosis (4,5). In contrast RAS inhibitors attenuated the progression of atrial
fibrosis, shortened AF duration and improved LA function (6-8). Molecular studies of atrial samples in
sin
i II
II receptors
rece
re
cept
ce
ptor
pt
orss tthat promoted
or
patients with persistent AF showed up-regulated ACE and angiotensin
structural and electrical remodeling of the atrium (9).
n
nical
trials in patients with left ventricular dysfunction show
w that ACE
Post-hoc analyses of clinical
showed
s receptor blockers (ARBs) reduced the onset of new AF (1
sin
1
inhibitors and angiotensin
(10-11)
and in
i
ffollowing
ll i cardioversion
di
i off paroxysmall and
d persistent
i
prospective studies of patients
AF, RAS
inhibitors in addition to amiodarone prevented recurrences of AF (12).
We report the results from the GISSI-AF echo study that explored whether the expected effect of
valsartan to reverse LA remodeling would prevent AF recurrences. In addition LAV and LV anatomy
and function were assessed to estimate left ventricular resistance to LA emptying.
Methods
The GISSI-AF trial, was a double-blind randomized placebo controlled multicenter study that enrolled
1442 patients in sinus rhythm with a history of AF to test whether the ARB valsartan could reduce the
recurrence of AF (see Expanded Methods - Patients in the GISSI-AF main study - in the Online Data
Supplements). The primary end points were time to the first recurrence of AF and the proportion of
patients who had more than one episode of AF over the 1-year observation period.
In the echocardiographic substudy, 340 patients (24% of the GISSI-AF population) were enrolled at 33
sites that were qualified by the central core laboratory to record echocardiograms according to a prespecified protocol (see Echocardiography in the Online Data Supplements). The study was approved by
institutional review committees and subjects gave informed consent.
Heart rate and blood pressure (BP) were measured before performing the echo exams. The recordings
were acquired on CD or videotape and sent to the core laboratory for centralized reading with
Medimatic’s software, (Genova, Italy).
Centralized Reading
Measurements were repeated
p
peated
(3 times for sinus rhythm, 5 times for AF) and followe
followed
e the American
n
and European Societies of Echocardiography recommendations (13). Atrial and ven
ventricular
chamber
dimensions were indexed by body surface area. Since LA volumes calculated from the apical 2 and 4
chamber views (2APCH, 4APCH) resulted in similar values (14), the reported LA volumes were
measured from only 4APCH view which was also the most consistently recorded and produced the
most complete serial recordings. The within-reader reproducibility for LAVmax was analyzed from the
difference between duplicate measurements versus the mean measurement for each, and calculated as
the limits of agreement (mean difference±1.96 x SD). Reproducibility was also estimated from the
measurement error as within-subject SD, expressed as repeatability (2.77 x measurement error) (15).
Data from 50 randomly selected patients showed reproducibility for LAVmax as -0.03±1.98 mL and
repeatability, 3.95 mL.
Detection of AF recurrence
AF recurrence was detected by the transtelephonic transmission of ECG signals sent weekly, during
symptomatic episodes and during the follow up visits to the primary physician and to the Coordinating
Center. Each event was adjudicated blindly by a central reader and was verified by an ad-hoc
committee (2).
Statistical Methods
The effects of treatments were analyzed according to intention to treat. Continuous variables were
expressed as mean±SD or as medians [Q1-Q3], when required. Categorical variables were reported as
rouups iin
n ba
base
seli
se
linn characteristics
li
absolute numbers and percentages. Differences between treatment groups
baseline
f continuous variables and by chi-square test for categorica
a variables.
were assessed by t test for
categorical
t time to first recurrence of AF were identified by univariat
th
t analysis and
Variables associated with
univariate
o
ortional
s
multivariable Cox proportional
hazards models. The covariates age, gender, >2 epis
episodes
of AF in the 6
d successful
f l cardioversion
di
i in
i the
h 2 weeks
k bbefore
f
d
months before enrollment and
randomization
were
considered in the multivariable models. The prognostic value of each echocardiographic variable was
evaluated separately. Changes of echocardiografic variables from baseline to 12 months follow up were
normally distributed, therefore analysis of covariance (ANCOVA) was used to evaluate differences in
changes between valsartan and placebo groups after adjustment for their respective baseline value. For
LAVmin index and LAEF the model was further adjusted for LAVmax index entered as a continuous
variable.
LA volumes showed a non-normal distribution therefore a log transformation was applied.
Within-patient changes in LA volumes and LAEF over time for patients with and without AFr were
compared by a repeated measures-analysis of variance (“proc mixed”), where AFr was considered
according to its time of recurrence (0-6 months and >6-12 months). The total duration of AFr over 1
year was obtained by summing the number of days of each episode for each patient. A categorical
variable was entered by tertiles of days of AF duration for patients with AFr and a separate category for
patients without AFr.
The association between LA volumes at baseline and at 12 months with the total duration of AFr were
evaluated by means of analysis of variance (ANOVA), testing for trend across tertiles whenever
statistically significant associations emerged. Differences in LA volumes and LAEF as least squares
means from baseline to 12 months by categories of duration of AF, adjusted for their respective
baseline value were tested using ANCOVA.
To determine the variables independently related to LAVmax>40ml/m
l/m2, univariate
tee and
a multivariable
epis
ep
issod
odes
es of
of AF in the previous
stepwise logistic regression analyses were performed, adjusting for: 2 episodes
6 months, cardioversion
n in previous 2 weeks from randomization, duration of last qu
qualifying
u
episode of
atrial fibrillation >7 days,
y heart failure, LVEF<40%, or both, anticoagulants, amiod
ys,
amiodarone, statins and
aspirin as concomitant treatments,
t
ECG LV hypertrophy and hemoglobin.
All P values were two-tailed and a value of <0.05 was considered statistically significant. The
statistical analyses were done with SAS software (version 9.1).
Sample Size
The sample size calculation for the quantitative outcome was based on an expected absolute reduction
of LAVmax of at least 6.7±20 mL (mean±SD) between valsartan and placebo groups at 12 months. The
number of patients per group required to have a power of 80% with a two-sided alpha error equal to
0.05, assuming a drop-out rate of 30% (due to inadequate quality of echocardiograms and /or missing
examinations) was calculated to be 200 (2).
Results
Patient Data
The mean age of the 340 patients studied at baseline, was 68.4±8.8 years (±SD), 36.2% were women,
and 85.3% had been hypertensive for 6 months. The date of the first episode of AF in the patients
clinical history, was known in 262/340 (77%) of the subjects and the median time between the onset of
the arrhythmia to randomization was 12 months (range 6 days to 31 years). At least 2 episodes of AF in
the previous 6 months were experienced by 40.4% of the patients, 87.4% were cardioverted in the
Therre were
w no differences
previous 2 weeks and in 39.7% the duration of the last episode was >7 days. There
lace
la
cebo
ce
bo ((Table
Tabb 1) except for the
Ta
in baseline characteristics of the patients randomized to valsartan or to pplacebo
o stroke in the treatment group (p=0.03). Compared to the no
o
more common history of
no-Echo
cohort
l in the echocardiographic substudy had higher, prevalenc
lled
c of HF, LVEF<40
(n=1102), patients enrolled
prevalence
y disease, peripheral embolism, were more frequently curren
n smokers, had
or both, peripheral artery
current
higher heart rate, were more likely to have a QRS >120 ms and were less treated with ACE inhibitors
(See Additional Table in the Online Data Supplements).
Echo Data
At baseline, mean LAVmax was severely increased, 43.1r15.0 ml/m2 (normal LAVmax/BSA: <29
mL/ m2).ҏ LA minimal volume was moderately increased 23.4r12.3 ml/m2 and LAEF was slightly to
moderately depressed 47.6r13.2%. LV end-systolic and end-diastolic volumes and ejection fraction
were within normal ranges while meanrSD wall thickness was slightly increased 10.9r1.4mm (normal
for men: 6-10mm) and LV mass was normal, 81.2r17.7 g/m2 (normal for men: 52-102 g/m2). While the
mean values for Doppler mitral flow variables were normal, 36 % of patients showed abnormal E/A,
28% and 48% an abnormal DT and/or IVRT, respectively. In 128/340 patients with both, peak mitral E
velocities and tissue Doppler mitral annular velocities the mean septal E/e' was 12.4r8.2 (normal: 8).
Thirty seven percent of patients had mild mitral regurgitation, 15.0% moderate, 3% severe and 45% no
regurgitation.
Echo Variables: Baseline and 12 Month by Treatment Group
None of the Echo variables were affected by valsartan treatment from baseline to 12 months (Table 2).
These results were confirmed in a per-protocol analysis done in the 252 patients (88%) who took the
study drug for at least 80% days of observation. The lack of effect off valsartan on
LAVmin and on
nL
tation
onn (covariate
(co
cova
vari
va
riat
ri
aatte LAVmax,
LAEF over time was found to be independent of baseline atrial dilatation
ANCOVA: p=0.34 and 0.20 respectively).
u
umes
To determine if LA volumes
were influenced by the number of patients developing recurrences of AF
n rhythm at the end of the study (n=221) were analyzed separately
nus
see
over time, patients in sinus
and did not
show any effect of treatment on LA dimensions and function (data not shown).
AF Recurrences.
AF recurred in 54% of the patients during the one year follow up. AF recurrence was associated with a
history of 2 episodes of AF in the previous 6 months (p=0.0004). The median number of recurrences
per patient was 2 [1-4] with an overall median duration of 19.5 [4-95] days over 12 months. Half of the
AF recurrences took place within the first 2 months. Predictors of AFr were baseline LAVmin as
increases in 1 mL/m2 increments, (HR, 1.02; 95%CI, 1.01 to 1.03, p=0.003) and LAEF, as decreases in
1% units (HR, 1.02; 95%CI, 1.00 to 1.03, p=0.01).
Left Atrial Volumes: With and Without AF Recurrences.
LA volumes and LAEF according to rhythm and time are summarized in Table 3 for combined
treatment groups. Baseline, 6 and 12 month data were available in 256/340 patients (75%). At baseline,
patients without AFr and with early AFr (0-6 months) had similar LAVmax that did not change
significantly over time. Patients with late AFr (>6-12 months) had smaller LAVmax compared to the
other two groups, although differences were not statistically significant. Patients with early AFr (0-6
months) tended to have larger LAVmin and smaller LAEF than the other two groups. Independent of
AFr, LA function improved over 12 months (more evident in the first 6 months) as shown by a
decrease in LAVmin (p=0.04) and an increase in LAEF, (p=0.0001)..
Left Atrial Volumes: Duration
D
of AF Recurrence
n to the duration of AF recurrence are summarized in Table 4 and Figure 1.
LA variables in relation
Patients with AFr were grouped into tertiles of number of days in recurrent AF overr one year follow up
(T1: 1-6, T2:7-58; T359 days). Increasing days of AFr duration were linearly related to increasing
baseline LA volumes (p<0.0001) and decreasing LAEF (p<0.0001). Of note patients who remained in
sinus rhythm had larger baseline volumes and lower LAEF than patients with the shortest AFr duration
of 1-6 days. An analysis of patients with severely increased LAV (40mL/m2) but without AFr,
showed a lower rate of 2 episodes of AF in the previous 6 months and fewer smokers than pts with 1
AFr (all p<0.05). Changes from baseline to 12 months across AF duration categories were not
significant for LA volumes, but resulted statistically significant for LAEF (Figure 2).
LA Maximal Volume: Associated Independent Variables
The independent factors associated with LAVmax 40 mL/m2 were: last qualifying episode of AF >7
days vs. 7days (OR, 4.16; 95% CI 2.42-7.15; p=<0.0001), ECG LV hypertrophy present vs. absent
(OR, 4.65; 95% CI 1.86-11.62; p=0.001), older age by one year (OR, 1.03; 95% CI 1.01-1.07; p=0.01)
and decreased hemoglobin by 1g/dL (OR, 1.26; 95% CI 1.04-1.51; p=0.02).
Discussion
The findings of the GISSI-AF echo substudy were consistent with the main trial which found that 320
mg daily of valsartan for 1 year did not reduce the incidence of recurrent AF. The substudy showed in
addition that treatment had no effect on left atrial volumes and function in patients with or without AF
recurrence. Earlier experimental evidence implicating the RAS in the
he LA remodeli
remodeling
liin process (4,5) and,
n and
ndd ffun
u ct
un
c io
ionn w
the reversal of the fibrosis and improvement in electrical conduction
function
with angiotensin
receptor blocker and ACE
C inhibition (6-8), were supported by clinical studies that showed
CE
shh
a significant
reduction in recurrence of AF (10-12). Why did ARB treatment fail to reverse LA re
remodeling
e
in
g risk for AF recurrence with qualifying cardiovascular cri
gh
GISSI-AF patients at high
criteria?
The main trial revealed that of the 2 entry criteria, history of AF and at least one cardiovascular
condition, 85% had only hypertension for 6 months as the other criteria (Table 1). Thus, GISSI-AF
patients were unlike those in successful ARB trials of preventing AF recurrence who were mainly in
heart failure (11). Only 10% of our patients had a positive history of heart failure or LVEF of <40%.
The echocardiographic results further substantiated the absence of overt left ventricular disease. LV
ejection fraction was normal as was LV end-diastolic volume and mass and Doppler variables of LV
diastolic function. The only exceptions were the minimal increases in LV wall thickness and in E/e’
ratio. Therefore, this apparent normality in LV structure and function may partly explain the lack of
beneficial effects of the ARB valsartan.
LA remodeling or dilatation appears to progress over time depending on the underlying cardiovascular
disease (17-18) or on the arrhythmia itself (19). While LA volume reflects an average effect of LV
filling pressures over time (20-21), the LA volumes were severely increased in the face of only
minimal increase in LV wall thickness. On further analysis 25 to 48% of patients exceeded the normal
range of Doppler diastolic measurements and specifically 25% recorded a septal E/e' ratio 15, a value
associated with increased LV filling pressures (22). Nevertheless, with the majority of patients
demonstrating normal LV volumes, mass and standard filling velocities, AF itself appears to be the
dominant mechanism for LA remodeling (19).
ilat
il
atat
at
atio
at
io
on? L
What were the quantitative consequences of recurrent AF alone on LA ddilatation?
LA volumes were
severely dilated to a mean
an of 40 ml/m2; however, the degree of dilatation is not un
unheard
n
of and similar
LA volumes have been reported in small AF ablation studies (23). Further findings of severe LA
dilatation were that the volumes
v
were unalterable not only to ARB treatment, but al
also unchangeable
over time, independent of rhythm, intermittent sinus rhythm and time to first AFr. Finally, with
recurrent AF, the larger the LA volume, the more prolonged are the episodes of future AFr (Figure 2), a
changing perspective on "AF begets AF through LA remodeling". The question this study raises: Is
there left atrial remodeling beyond which there is no reversibility and inevitable progression of
recurrent AF to chronic AF?
Perhaps of some encouragement, although LAVmax was unchanged, LA function did respond during
the one year by significantly increasing LAEF and decreasing LAVmin (Table 3). A possible
explanation is that 87% of the patients had been cardioverted within 2 weeks before randomization.
Parallel evidence from experimental AF demonstrated that loss of atrial contractility after cardioversion
is followed by a partial or full functional recovery even though the amount of fibrosis persists (24-25).
However, improvement in LA function in our study was limited (Table 4, Figure 2) and did not occur
in patients with the longest AFr duration of 59 days. The data again imply that there is a limit to LA
dilatation beyond which the atrium is no longer responsive to a pharmacologic intervention or, less
likely, that a longer exposure is necessary to achieve a therapeutic response (3).The neutral results with
ARB treatment on atrial remodeling, independent of the severely dilated LAVmax at baseline offer
little optimism for a trial of more prolonged ARB therapy.
The relation between LA volume and AF in patients with cardiovascular disease is complex and few
data are available regarding LA dimensions measured over time in such patients (2
(26
(26-27).
6
The GISSITablle 2)) and
andd as
as hhypertension is a
AF patients were predominantly hypertensive with controlled BP (Table
significant risk factor for
o AF (28) and predictor of LA size (18) our results suggest that
or
t any BP in the
presence of recurrent AF
F is too high and should be treated, an hypothesis yet to be ttested (29).
w that an increase of 10 mmHg in BP, increased the risk off AF independently
wed
Prediction models showed
of age, sex, and ECG LV hypertrophy (30). Belluzzi et al. (31) credibly demonstrated that targeting
systolic BP between 130 and 139 mmHg with ramipril in patients with lone AF and normal LA and LV
structures, reduced the risk of AF recurrence. Initiating hypertensive treatment in patients with AF
when systolic BP exceeds 120 mm Hg has been proposed (29) in particular with anti-RAS therapies
(28-32). Besides using LA size as a target organ for the aggressive treatment of BP in managing AF,
the availability of newer drugs and procedures will also have to prove their effectiveness. Measuring
LAVs will be central to selecting patients, tailoring treatment and evaluating outcomes for this
challenging rhythm.
Conclusions
In our study population, mainly hypertensive with severely dilated left atria, valsartan treatment for 1
year had no effect on reversing LA remodeling. LAVmax did not vary over time in patients with and
without AF recurrence and pointed out that advanced atrial remodeling has a low probability of
reversal. The degree of remodeling at baseline was strongly and linearly related to the duration of
future AF recurrences and possibly affected the time to the first AF recurrence. Patients without
recurrence also had severely enlarged LAVmax (>40 mL/m2) indicating that mechanisms other than
structural remodeling underlie recurring AF. Some of our incidental findings called attention to specific
arch in unders
rsta
t
ta
factors in AF mechanisms that underscored the need for further research
understanding
AF
pathogenesis.
Acknowledgments
We thank all patients, nurses and cardiologists who participated in the echocardiographic
GISSI-AF substudy, Maria Amigoni, MD for her help in preparing the substudy proposal, Simona
Barlera, MSc, Donata Lucci, MSc and Chiara Favero, MSc for statistical advice and Mrs. Alessandra
Carnaghi for secretarial assistance.
Sources of Funding
The GISSI Studies as well as the present substudy are supported by Associazione Nazionale Medici
Cardiologi Ospedalieri (ANMCO) and by Istituto di Ricerche Farmacologiche Mario Negri. Funding
ct of tthe
he ttrial,
rial
ri
al,, th
al
tthe
h collection,
was provided by Novartis, which had no role in the design or conduct
o of the data, or the writing of the report.
on
analysis, or interpretation
Disclosures
k Maggioni,
i i Franzosi,
i Tognonii and
d Disertori
i
Drs. Latini, Masson, Wong, Staszewsky,
received
institutional research support or honoraria from Novartis Pharma. Dr. Bertocchi is an employee of
Novartis Italy SpA. No other potential conflict of interest relevant to this article was reported.
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Table 1. Baseline Clinical and ECG Characteristics
Characteristics
Valsartan
N=171
68.1±8.8
68 (39.8)
28.0±4.1
Age-yr
Females - no.(%)
Body-mass index - Kg/m2
Blood pressure - mmHg
Systolic
136.4±15.3
Diastolic
81.1±8.1
Inclusion criteria - no.(%)
2 episodes of AF in previous 6 mo
70 (41.2)
Cardioversion in previous 2 wk
151 (88.3)
Duration of last qualifying episode of AF >7
66 (38.6)
days
Heart failure, LVEF<40%, or both
18 (10.5)
History of hypertension for 6 mo or more
144 (84.2)
Diabetes mellitus
22 (12.9)
History of stroke
11 (6.4)
(6. )
Peripheral artery disease
ase
14 (8.2)
Documented coronary artery disease
23 (13.5)
Atrial fibrillation alonee
23 (13.5)
Coexisting conditions - no.(%)
Peripheral embolism
3 (1.8)
Previous transient ischemic
h
hemic
attack
11 (6.4)
Renal dysfunction
5 (2.9)
Chronic obstructive pulmonary disease
15 (8.8)
Neoplasia
5 (2.9)
Current smoker
12 (7.0)
Electrocardiographic findings at randomization
Heart rate - bpm
62.1±10.2
QRS interval>120 msec - no.(%)
18 (10.5)
Left ventricular hypertrophy - no. (%)
20 (11.7)
Pathologic Q waves - no. (%)
5 (2.9)
Concomitant cardiovascular therapies - no. (%)
Amiodarone
69 (40.4)
Sotalol
11 (6.4)
Class I antiarrhythmic agents
60 (35.1)
ACE inhibitors
87 (50.9)
Calcium-channel blockers
49 (28.7)
Beta-blockers
50 (29.2)
Digitalis
10 (5.9)
Diuretics
68 (39.8)
Aldosterone blockers
11 (6.4)
Statins
50 (29.2)
Oral anticoagulants
102 (59.7)
Aspirin
42 (24.6)
AF = atrial fibrillation; LVEF = left ventricular ejection fraction.
Placebo
N= 169
68.6±8.8
55 (32.5)
27.5±4.2
139.6±16.9
81.2±8.5
66 (39.5)
146 (86.4)
69 (40.8)
18 (10.7)
1146
46 ((86.4)
86.4
86
.4))
.4
27 ((16.0)
16.0
16
.00)
3 (1.8)
(1.8)
8)
7 (4.1)
15 (8.9)
24 (14.2)
3 (1.8)
3 (1.8)
5 (3.0)
18 (10.7)
6 (3.6)
18 (10.7)
62.1±9.5
22 (13.0)
15 (8.9)
5 (3.0)
60 (35.5)
14 (8.3)
56 (33.1)
86 (50.9)
53 (31.4)
42 (24.9)
7 (4.1)
59 (34.9)
12 (7.1)
40 (23.7)
104 (61.5)
46 (27.2)
Table 2. Echocardiographic Variables at Baseline and 12 Months (n=286 patients)
SBP (mmHg)
Valsartan
Placebo
DBP (mmHg)
Valsartan
Placebo
Heart rate (bpm)
Valsartan
Placebo
LAVmax /BSA (mL/m2)
Valsartan
Placebo
LAVmin/BSA (mL/m2)
Valsartan
Placebo
LAEF (%)
Valsartan
Placebo
LVTH (mm)
Valsartan
Placebo
LVmass/BSA (g/m2)
Valsartan
Placebo
LVEDV/BSA (mL/m2)
Valsartan
Placebo
LVESV/BSA (mL/m2)
Valsartan
Placebo
LVEF (%)
Valsartan
Placebo
E /A
Valsartan
Placebo
DT (ms)
Valsartan
Placebo
IVRT (ms)
Valsartan
Placebo
E/e’
Valsartan
Baseline
12 months
Change
137±16
140±18
137±18
139±19
-0.4±1.4
-0.5±1.4
Treatment*
0.97
0.26
81±9
82±9
80±9
82±9
-1.1±0.7
0.0±0.7
64±10
63±10
65±11
65±12
1.3±0.9
1.1±0.9
42.6±15.5
41.9±14.6
42.2±14.7
41.4±14.5
-0.7±0.8
-0.1±0.8
0.94
0.58
0.34
23.4±12.9
22.5±11.6
22.4±12.6
20.6±10.9
-1
-1.0±0.7
1.0
.0±0
±0.7
±0
.7
-2.0±0.7
-2.0±0
±0.7
±0
.7
47.7±13.5
47.9±12.6
50.5±13.0
51.7±12.4
2.3±0.9
4.1±0.9
11.0 ±1.5
10.7 ±1.4
10.9 ±1.4
10.6 ±1.6
0.0±0.1
-0.2±0.1
0.16
0.33
0.96
81.3±17.9
78.3±16.6
80.0±16.9
75.7±17.7
-1.6±1.2
-1.6±1.2
52.8±16.9
52.6±14.5
52.3±15.0
52.8±14.9
-0.6±0.8
0.8±0.8
22.4±13.3
21.4±12.1
20.6 ±12.1
21.1±11.1
-1.8±0.6
-0.6±0.5
0.20
0.14
0.19
59.6±12.7
60.5±12.3
62.2±12.0
61.5±11.3
2.4±0.7
1.2±0.7
1.3±0.8
1.3±0.8
1.2±0.8
1.1±0.6
0.0±0.1
-0.2±0.1
194±56.0
202±60.0
194±57.0
204±56.0
-3.4±4.8
5.1±4.7
0.09
0.21
0.23
87±22.0
88±22.0
87±24.0
90±24.0
-2.1±2.2
1.7±2.3
12.5±10.9
13.2±7.3
1.7±0.7
0.09
Placebo
12.2±5.3
11.8±5.2
0.0±0.7
HR=heart rate, SBP= systolic blood pressure, DBP= diastolic blood pressure;
LAVmax/BSA= left atrial maximal volume index, LAVmin/BSA= left atrial minimum
volume index, LAEF=left atrial emptying fraction, LVTH: left ventricular wall thickness,
LVEDV/BSA= left ventricular end diastolic volume index, LVESV/BSA= left ventricular
end systolic volume index, LVEF= left ventricular ejection fraction, E/A = early to late
diastolic mitral inflow, DT= deceleration time, IVRT= isovolumetric relaxation time,
E/e’= early diastolic mitral inflow velocity/early diastolic septal mitral annular relaxation
velocity (available in 90/286 patients). Data are means±SD. Changes are least squares
means±SEMҠҏ*: ”ANCOVA” used to evaluate differences in changes from baseline to 12
months follow-up between valsartan and placebo groups after adjustment for variables
value at baseline.
Table 3. Time Course of Echocardiographic Variables According to the Time of First Recurrence of Atrial Fibrillation.
Patients with no AF recurrence
(n=109)
Patients with AF recurrence 0-6
mos
(n=115)
Baseline 6 months
12
months
Patients with AF recurrence >6-12
mos
(n=32)
Baseline
6 months 12 months
P value*
Time
Baseline
6 months
12 months
LAVmax/B
SA (mL/m2)
40.7±12.3
41.8±13.0
40.5±13.6
44.7±15.
8
44.3±15.2
44.2±14.5
38.3±13.3
38.7±11.6
37.5±13.3
0.42
Time*AF
recurrenc
e
0.78
LAV
min/BSA
(mL/m2)
LAEF
(%)
21.3±10.3
20.2±9.9
19.8±10.6
25.8±13.
3
23.7±13.0
23.9±12.0
19.4±9.0
19.0±7.7
18.5±10.8
0.04
0.67
48.8±12.4
52.8±11.4
52.9±11.1
45.4±13.
45
4±13
3
49.3±13.8
49
3±13 8
48.7±13.6
48
7±13 6
49.5±12.2
49
9 5±12
5 12 2
52.3±11.4
53.0±13.3
0.0001
0.83
Data are means±SDҠҏ Abbreviations (see Table 2 legend).
n *: Repeated measures ANOVA.
nd).
Table 4. Left Atrial Volumes and Emptying Fraction Relative to Duration of AF Recurrence
LAVmax/BSA (mL/m2)
Baseline
12 months
41.7±14.5
41.1±14.5
LAVmin/BSA (mL/m2)
Baseline
12 months
22.0±11.5
20.2±11.1
LAEF (%)
Baseline
12 months
48.8±12.3
52.5±11.1
No AF (n=113)
AF recurrence
duration (days)
35.4±14.0
35.7±14.4
17.2±9.6
17.0±9.8
53.9±12.3
54.9±11.6
Tertile 1 [1-6)
(n=44)
44.0±15.8
44.1±14.8
24.3±13.2
22.2±12.2 47.2±12.8
52.9±11.1
Tertile 2 [7-58)
(n=44)
49.7±14.2
48.5±13.1
31.0±13.0
29.6±12.4 40.1±13.5
41.6±14.1
Tertile 3 (59)
(n=44)
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0
<0
.0
000
0011
<0.0001
ANOVA*
<0.0001
0.0001
01
<0.0001
<0.0001
<0.0001
<0.0001
Trend °
Data are means±SD. Abbreviations (see Tablee 2 legend).*: ANOVA p value, °: trend p valuee
Figure Legends
Figure 1. Baseline Left Atrial Volumes and Duration of AF Recurrence
Data are means±SD. Tertiles of AF recurrence duration: Tertile 1= 0-7 days, tertile 2= 7-58 days, tertile
3 59 days. LAVmax/BSA= left atrial maximal volume , LAVmin/BSA= left atrial minimum volume,
LAEF= left atrial emptying fraction. Linear trend for all variables (p<0.0001). F and P values are
calculated by ANOVA. Grey areas represent normal mean values±SD (from references 13 and 16).
Figure 2. Changes in Left Atrial Variables Relative to Rhythm and Duration of AF Recurrence
Data are least square means (LS)±SEM to assess changes in LAV and
nd LA
LAEF
EF bbetween
etwe
et
we baseline and 12
months in patients with no AF recurrence and with recurrences in days of duration. Tertile 1= 0-6 days,
t 3 59 days. Variables are adjusted for baseline values. F
tile
tertile 2= 7-58 days, tertile
For linear trend,
A
p=0.004, calculated by ANCOVA.
Left Atrial Remodeling and Response to Valsartan in the Prevention of Recurrent Atrial
Fibrillation: The GISSI-AF Echocardiographic Substudy
Lidia Staszewsky, Maylene Wong, Serge Masson, Elena Raimondi, Silvana Gramenzi, Gianni
Proietti, Dario Bicego, Carlo Emanuelli, Giancarlo Pulitanò, Filippo Taddei, Enrico B. Nicolis,
Ernesto Correale, Gianna Fabbri, Federico Bertocchi, Maria Grazia Franzosi, Aldo P. Maggioni,
Gianni Tognoni, Marcello Disertori and Roberto Latini
Circ Cardiovasc Imaging. published online September 16, 2011;
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas,
TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-9651. Online ISSN: 1942-0080
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circimaging.ahajournals.org/content/early/2011/09/16/CIRCIMAGING.111.965954
Data Supplement (unedited) at:
http://circimaging.ahajournals.org/content/suppl/2011/09/16/CIRCIMAGING.111.965954.DC1.html
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
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SUPPLEMENTAL MATERIAL
Supplemental methods:
Patients in the GISSI-AF main study: inclusion criteria were two or more episodes of
symptomatic ECG-documented AF in the previous 6 months or successful cardioversion,
electrical or pharmacological between 48 hours and 14 days before randomization).
Patients had to have one of the following conditions: heart failure or a history of
documented left ventricular dysfunction (ejection fraction <40%), history of hypertension
for 6 months or longer, type 2 diabetes, a history of stroke, peripheral vascular disease,
coronary artery disease or lone atrial fibrillation with left atrial dilatation (left atrial diameter
of >45 mm in men and >40 mm in women). All participants had been on a stable regimen
of treatment for AF and of any underlying cardiovascular disorder for at least 1 month
before enrollment and were permitted to continue previously prescribed ACE inhibitors,
beta-blockers and amiodarone. Patients were excluded if they had clinically significant
valvular disease; or were scheduled to undergo catheter ablation or implantation of a
pacemaker or defibrillator.
Echocardiography: The recordings were taken in parasternal long-axis and short-axis at
the levels of the aortic valve, chordae and mid papillary muscle, and apical two and fourchamber views. Baseline tracings were recorded at randomization and at 6 and 12
months. The measurements were left atrial (LA) diameters, maximal LA volume (before
mitral valve opening) and minimal LA volume (after atrial contraction), LA total emptying
fraction [maximal–minimal LA volumes/maximal LA volume] (LAEF), left ventricular (LV)
end-systolic and end-diastolic volumes, LV end-diastolic mean wall thickness and, LV
mass (2D method) (1). All patients had Pulsed-wave Doppler recordings of mitral inflow
velocities and pulmonary venous flow waveforms to measure, transmitral early diastolic
velocity (peak E wave) late diastolic velocity (peak A wave), E/A ratio, deceleration time of
E velocity (DT), isovolumic relaxation time (IVRT), pulmonary systolic, diastolic and
CIRCCVIM/2011/965954_R2
1
reversed atrial flow. The values out of the normal range according to age groups (41-60
and >60 years) (2) were considered for the identification of patients with abnormal mitral
inflow velocities and time intervals, Tissue Doppler recordings were provided by 19 sites
with sufficient technical and recording capabilities. Peak E wave velocities from four apical
chamber transmitral inflow and diastolic relaxation e’ velocities from mitral septal and
lateral annular tissue Doppler were combined to derive E/e’. Mitral regurgitation (MR) was
measured as regurgitant area/LA area in the apical view displaying the largest regurgitant
area and was graded: mild (5-20%), moderate (>20 -<40%), and severe (≥40%) an
eccentric jet increased the degree of MR by 1 grade (3).
References
1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH,
Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart
WJ; Chamber Quantification Writing Group; American Society of Echocardiography's
Guidelines and Standards Committee; European Association of Echocardiography.
Recommendations for chamber quantification: a report from the American Society of
Echocardiography's Guidelines and Standards Committee and the Chamber
Quantification Writing Group, developed in conjunction with the European Association
of Echocardiography, a branch of the European Society of Cardiology. J Am Soc
Echocardiogr. 2005;18: 1440-1463.
2. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner
AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation
of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009;
22:107-133.
3. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, Gatewood RP Jr.
Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation
1987; 75: 175-183.
CIRCCVIM/2011/965954_R2
2
APPENDIX
Participating Centers and Investigators
Switzerland - Lugano (E. Pasotti). Italy - Bagno a Ripoli (A. Fantini), Bari Carbonara (N.
D’Amato), Bergamo (A. Gavazzi, F. Taddei), Bovolone (G. Rigatelli, S. Boni), Catania (M.
Gulizia, G. Francese), Catanzaro (F. Perticone), Città di Castello (D. Severini), Cremona
(S. Pirelli, C. Emanuelli), Fidenza (P. Pastori), Firenze (GM. Santoro, C. Minneci), Napoli
Federico II (M. Prastaro), Palermo Cervello (L. Buffa), Pavia (R. Rordorf), Pesaro (A.
Pierantozzi), Pietra Ligure (A. Nicolino), Reggio Calabria (G. Pulitanò, A. Ruggeri), Roma
Sant’Andrea (L. De Biase, S. Cangianiello), Saluzzo (P. Allemano), San Bonifacio (R.
Rossi, D. Bicego), San Daniele del Friuli (L. Mos, O. Vriz), Sarzana (R. Petacchi, D.
Bertoli), Terni (M. Bernardinangeli, Gianni. Proietti, M. Gagliardi), Trento Villa Bianca (G.
Cioffi, E. Buczkowska), Trento Santa Chiara (M. Disertori, P. Zeni), Varese (F. Caravati).
CIRCCVIM/2011/965954_R2
3
Supplemental Table:
Baseline Clinical and ECG Characteristics in Echo-Cohort and Non Echo-Cohort patients
Characteristics
Echo-cohort
N=340
§
68.4±8.8
Non-Echo
cohort
N=1110
67.6±9.4
123 (36.2)
421 (38.2)
0.50
27.7±4.2
27.9±4.4
0.57
138.0±16.2
81.2±8.3
138.8±17.0
81.7±8.9
0.46
0.33
136 (40.4)
297 (87.4)
135 (39.7)
36 (10.6)
290 (85.3)
49 (14.4)
14 (4.1)
445 (42.2)
979 (88.8)
328 (29.8)
78 (7.1)
941 (85.4)
162 (14.7)
45 (4.1)
0.59
0.45
0.001
0.04
0.97
0.89
0.98
Peripheral artery disease
Documented coronary artery disease
Atrial fibrillation alone
Coexisting conditions - no.(%)
21 (6.2)
38 (11.2)
47 (13.8)
38 (3.5)
141 (12.8)
125 (11.3)
0.03
0.43
0.22
Peripheral embolism
Previous transient ischemic attack
6 (1.8)
15 (4.4)
4 (0.4)
39 (3.5)
0.01
0.46
10 (2.9)
33 (9.7)
11 (3.2)
30 (8.8)
30 (2.7)
73 (6.6)
34 (3.1)
91 (8.3)
0.83
0.06
0.89
0.05
62.1±9.8
40 (11.8)
35 (10.3)
64.1±10.7
87 (7.9)
96 (8.7)
0.003
0.03
0.38
Age-yr
Female sex - no.(%)
2
Body-mass index - Kg/m
Blood pressure - mmHg
Systolic
Diastolic
Inclusion criteria - no.(%)
≥2 episodes of AF in previous 6 mo
Cardioversion in previous 2 wk
Duration of last qualifying episode of AF >7 days
Heart failure, LVEF<40%, or both
History of hypertension for 6 mo or more
Diabetes mellitus
History of stroke
Renal dysfunction
Chronic obstructive pulmonary disease
Neoplasia
Current smoker
Electrocardiographic findings at randomization
Heart rate - bpm
QRS interval>120 msec - no.(%)
Left ventricular hypertrophy - no. (%)
P value
0.20
Pathologic Q waves - no. (%)
10 (2.9)
53 (4.8)
0.14
Concomitant cardiovascular therapies - no. (%)
Amiodarone
129 (37.9)
372 (33.8)
0.16
Sotalol
25 (7.4)
75 (6.81)
0.73
Class I antiarrhythmic agents
116 (34.1)
351 (31.9)
0.44
ACE inhibitors
173 (50.9)
649 (58.9)
0.009
Calcium-channel blockers
102 (30.0)
326 (29.6)
0.88
Beta-blockers
92 (27.1)
344 (31.2)
0.14
Digitalis
17 (5.0)
46 (4.2)
0.51
Diuretics
127 (37.4)
405 (36.8)
0.84
Aldosterone blockers
23 (6.8)
69 (6.3)
0.74
Statins
90 (26.5)
278 (25.2)
0.65
Oral anticoagulants
206 (60.6)
609 (55.3)
0.08
Aspirin
88 (25.9)
307 (27.9)
0.48
§
AF = atrial fibrillation; LVEF = left ventricular ejection fraction . P value compare Eco-cohort
to Non-Echo cohort
CIRCCVIM/2011/965954_R2
4

Left Atrial Remodeling and Response to Valsartan in the Prevention

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