Bourassa, Martial G.

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Journal of the American College of Cardiology Vol. 45, No. 5, 2005
© 2005 by the American College of Cardiology Foundation ISSN 0735-1097/05/$30.00
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ublished by Elsevier Inc. doi:10.1016/j.jacc.2004.12.008DITORIAL COMMENT
ngiotensin II Inhibition
nd Prevention of
trial Fibrillation and Stroke*
artial G. Bourassa, MD, FACC
ontreal, Quebec, Canada
trial fibrillation (AF), the most common cardiac arrhyth-
ia encountered in clinical practice, is a growing public
ealth problem. Atrial fibrillation currently affects more
han two million individuals in the U.S., and its age-
djusted prevalence is expected to exceed five million by the
ear 2050 (1,2). Patients with hypertension and heart failure
re at high risk of developing AF and, in both conditions,
F increases the risk of cardiovascular morbidity and mortal-
ty, particularly the risk of fatal or nonfatal stroke (3–8).
See pages 705 and 712
The development and maintenance of AF are associated
ith changes in cardiac structure, function, and electrical
roperties known as cardiac remodeling (9). Although the
echanisms leading to AF are complex and the process of
ardiac remodeling is still incompletely understood, several
ines of evidence accumulated over the past five years suggest
hat the renin-angiotensin aldosterone system (RAAS)
lays a major role in the pathogenesis of AF. Both hyper-
ension and heart failure are associated with activation of the
AAS, and in patients with heart failure, greater activation
f the RAAS with increasing severity of ventricular dys-
unction is associated with a greater risk of AF (4). Angio-
ensin II is a potent promoter of fibrosis, and atrial fibrosis,
frequent finding in patients with AF, may lead to
ntra-atrial conduction disturbances and to persistent sus-
eptibility to AF (4). Increased angiotensin-converting en-
yme (ACE) expression and changes in angiotensin receptor
xpression occur in the atria of patients with AF. In
umans, angiotensin II type 1 receptor stimulation causes
trial hypertrophy and fibrosis, whereas angiotensin II type
receptor stimulation counteracts this effect. Patients with
F have reduced type 1 and increased type 2 angiotensin II
eceptor density (10). Furthermore, there is also evidence
uggesting that both ACE and RAAS polymorphisms play
role in predisposing patients to AF (11,12). However, the
trongest arguments for a major role of RAAS in AF come
rom the accumulating evidence that RAAS inhibition
revents the emergence and recurrence of AF.
*Editorials published in the Journal of the American College of Cardiology reflect the
iews of the authors and do not necessarily represent the views of JACC or ther
merican College of Cardiology.
From the Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.Atrial fibrillation occurring during the course of experi-
ental heart failure induced by rapid atrial pacing is
ccompanied by atrial electrical and structural remodeling,
ncluding atrial dilation, contractile dysfunction, and fibrosis
9). Recent data suggest that ACE inhibitors attenuate this
trial remodeling in experimental models of AF (13). At
east two recent clinical studies have shown that, compared
o placebo, treatment with an ACE inhibitor markedly
educes the incidence of AF in patients with left ventricular
ysfunction (3,4). In the Trandolapril Cardiac Evaluation
TRACE) study, the ACE inhibitor trandolapril reduced
he incidence of AF by 47% after acute myocardial infarc-
ion in patients with left ventricular dysfunction (3). In a
etrospective analysis of patients from the Montreal Heart
nstitute included in the Studies Of Left Ventricular Dys-
unction (SOLVD), the ACE inhibitor enalapril decreased
he incidence of AF by 77% over a mean follow-up of 2.9
.0 years (4). Moreover, Ueng et al. (5) have reported that
he addition of enalapril to amiodarone significantly de-
reased the rate of immediate recurrences and facilitated
ubsequent long-term maintenance of sinus rhythm after
lective electrical cardioversion in patients with persistent AF.
More recent experimental data suggest that RAAS inhi-
ition by angiotensin II receptor antagonists (ARBs) also
revents the promotion of AF by suppressing the develop-
ent of electrical and structural cardiac remodeling (14). In
ddition, Madrid et al. (6) have shown that pre-treatment with
he ARB irbesartan could also reduce the recurrence of AF
fter electrical cardioversion in amiodarone-treated patients.
In this issue of the Journal, two subgroup analyses of the
osartan Intervention for End point reduction in hyperten-
ion (LIFE) study extend these observations and provide
urther evidence, in hypertensive patients with electrocar-
iogram (ECG)-documented left ventricular hypertrophy,
or the benefit of RAAS inhibition, compared to beta-
drenergic blockade, in the prevention of new-onset AF and
n the reduction of cardiovascular morbidity and mortality
ssociated with new-onset or persistent AF (7,8). In the
ubgroup of patients with a history of AF or ECG-
ocumented AF, as compared to atenolol-based therapy,
osartan-based therapy reduced the primary composite end
oint of the LIFE study (cardiovascular mortality, fatal or
onfatal stroke, and fatal or nonfatal myocardial infarction)
y 42% and the occurrence of stroke by 45% over 4.8  1.0
ears of follow-up (7). In patients in sinus rhythm at entry,
osartan-based therapy reduced new-onset AF by 33% and
ubsequent stroke by 51% compared to atenolol-based
herapy, despite similar blood pressure reduction. Patients
ho developed new-onset AF in the losartan group had
0% fewer primary composite end points and 51% fewer
trokes than those in the atenolol group (8).
It is interesting to note that in the LIFE study, rates of
yocardial infarction and hospitalization for angina pectoris
ere similar in patients treated with losartan and in those
eceiving atenolol, suggesting that RAAS inhibition is perhaps
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721JACC Vol. 45, No. 5, 2005 Bourassa
March 1, 2005:720–1 Editorial Comments effective as beta-blockade in the prevention of acute coronary
yndromes. Such a hypothesis requires further study. On the
ther hand, hospitalization for heart failure was less frequent,
nd there was a trend for fewer sudden cardiac deaths, with the
tenolol versus the losartan regimen, indicating that both
reatment modalities are complementary, not mutually exclu-
ive, in hypertensive patients.
This novel approach has considerable clinical relevance,
n view of the high risk associated with AF and of the
remendous burden that it places on our health care re-
ources. Reduction of blood pressure and reverse cardiac
emodeling following ACE inhibition and angiotensin re-
eptor blockade may not have been the only or the principal
echanism of action in these recent studies (3–8), since AF
revention occurred despite the presence of a normal mean
lood pressure in the TRACE study (3), and despite similar
lood pressure reduction with both treatment regimens in
he LIFE study (7,8). Thus, more experimental data are
eeded to establish the role of RAAS inhibition on cardiac
emodeling and AF prevention. Additional clinical data are
lso needed to compare the relative efficacy of ACE inhib-
tors and ARBs on the reduction of the incidence of AF in
atients with hypertension and heart failure who are at
ncreased risk of developing new-onset AF, and on the
aintenance of sinus rhythm following electrical cardiover-
ion in patients with long-standing, persistent AF. The role
f RAAS inhibition in AF caused by conditions other than
ypertension and heart failure, as well as “lone” AF, needs
urther study. Finally, the knowledge that AF can be
revented opens new and previously unsuspected avenues of
ntervention, such as increased intake of long-chain n-3
olyunsaturated fatty acids through fish consumption (15)
nd use of anti-inflammatory drugs (16).
eprint requests and correspondence: Dr. Martial G. Bourassa,
esearch Center, Montreal Heart Institute, 5000 Belanger Street,
ontreal, Quebec, Canada H1T 1C8. E-mail: martial.bourassa@
cm-mhi.org.
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4. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the
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(SOLVD) trials. Circulation 2003;107:2926–31.
5. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus
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persistent atrial fibrillation. Results of a prospective and controlled
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6. Madrid AH, Bueno MG, Rebollo JMG, et al. Use of irbesartan to
maintain sinus rhythm in patients with long-lasting persistent atrial
fibrillation. Circulation 2002;106:331–6.
7. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity
and mortality in hypertensive patients with a history of atrial fibrilla-
tion: the Losartan Intervention for End Point Reduction in Hyper-
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Angiotensin II inhibition and prevention of atrial fibrillation and stroke**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology. 

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Angiotensin II inhibition and prevention of atrial fibrillation and stroke**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.

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