Current Vascular Pharmacology, 2010, 8, 769-774 769

A Link Between Hypertension and Atrial Fibrillation: Methods of Treat-

ment and Prevention

Tonje A. Aksnes1,* and Sverre E. Kjeldsen2

1
Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway; 2Department of Cardiology, Oslo Univer-
sity Hospital, Ullevål, Oslo, Norway and Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI,
USA

Abstract: Atrial fibrillation is the most common clinically significant cardiac arrhythmia and is associated with markedly
increased risks of cardiovascular diseases. Atrial fibrillation and hypertension often coexist and are both responsible for
considerable morbidity and mortality. Aggressive treatment of hypertension, especially with a blocker of the renin-
angiotensin system, may postpone or prevent development of atrial fibrillation and reduce thromboembolic complications.
Awareness of the risk of developing atrial fibrillation in hypertensives may be of great importance and focus on preven-
tion of atrial fibrillation development with optimal antihypertensive treatment may reduce morbidity, mortality and health
care expenditures.
Keywords: Angiotensin-converting enzyme inhibitors, angiotensin II type I receptor blockers, atrial fibrillation, hypertension,
renin-angiotensin system.

ATRIAL FIBRILLATION AND HYPERTENSION
Atrial fibrillation is the most common clinically signifi-
cant sustained cardiac arrhythmia and it is associated with
markedly increased risks of cardiovascular morbidity and
mortality. It is a disease of aging and the prevalence doubles
with each decade after 50 years and approaches 10% in those
more than 80 years of age [1]. Hypertension increases the
risk of atrial fibrillation about a twofold which is modest.
However, due to the high prevalence of hypertension in the
population, hypertension accounts for more cases of atrial
fibrillation than any other risk factor. Hypertension is associ-
ated with left ventricular hypertrophy, structural changes and
enlargement of the left atria, and slowing of atrial conduction
velocity. These changes in cardiac structure and physiology
favour the development or atrial fibrillation, and increase the
risk of thromboembolic complications like stroke.
In the Framingham Heart Study [1], hypertension and
diabetes mellitus were independent risk factors for atrial fib-
rillation development when controlling for age and other
predisposing conditions. Hypertension conferred a 1.5- and a
1.4-fold risk in men and women, respectively, with a popula-
tion-attributable risk of 14% for atrial fibrillation [1, 2].
In the PIUMA-study Verdecchia et al. [3], followed more
than 2500 initially untreated hypertensive patients with sinus
rhythm for up to 16 years (mean 5.3 years) and 61 patients
developed new atrial fibrillation (28 with an isolated episode,
13 with recurrent episodes and 20 with chronic atrial fibrilla-
tion). The patients who developed atrial fibrillation were
significantly older and had significantly higher office and
24-hour systolic blood pressure, larger left ventricular
*Address correspondence to this author at the Department of Cardiology,
Oslo University Hospital, Ullevål, N-0407 Oslo, Norway; Tel: +47
22119100; Fax: +47 22119181 ; E-mail: TonjeAmb.Aksnes@ulleval.no
mass, larger left atrial diameter, lower heart rate and in-
creased body mass index (BMI) [3].
In a smaller study by Ciaroni et al. [4], 19 of 97 (19.5%)
initially untreated hypertensive patients developed atrial fib-
rillation during 25 months follow-up. Independent predictors
of new-onset atrial fibrillation were age, left ventricular
mass, daytime and night-time ambulatory systolic blood
pressure, maximal duration and dispersion of the P-waves in
electrocardiogram (ECG), left atrial dimension and peak
velocity of the A-wave on echocardiography. In the Mani-
toba Follow-Up Study, multivariate analysis showed a 1.42
times higher risk of atrial fibrillation in hypertensive subjects
compared with normotensive subjects when followed for 44
years [5], indicating that atrial fibrillation often develops in
hypertensives.
Also in the LIFE study, systolic blood pressure was one
of the baseline characteristics important for prediction of
new-onset atrial fibrillation, with a 6% increase of atrial fib-
rillation per 10 mm Hg increase in systolic blood pressure
[6]. The LIFE study patients with new-onset atrial fibrillation
had approximately twofold increased risk of cardiovascular
events, about threefold risk of fatal and non-fatal stroke, and
fivefold increased rate of hospitalization for heart failure [6].
In the ALLHAT trial, baseline atrial fibrillation or atrial
flutter also increased cardiac morbidity and mortality [7].
The hazard ratio (HR) for all-cause mortality was 2.82 (2.36-
3.37, p-value<0.001), for coronary heart disease (CHD) 1.64
(1.22-2.21, p-value<0.01), for heart failure 3.17 (2.38-4.25,
p-value<0.001), and the most dramatic outcome related to
atrial fibrillation was the much higher event rate for stroke
with a HR of 3.63 (2.72-4.86, p-value<0.001) [7]. An as in-
dicated in Fig. 1, atrial fibrillation and hypertension com-
bined are important risk factors for cardiovascular diseases
in these patients.

1570-1611/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

770 Current Vascular Pharmacology, 2010, Vol. 8, No. 6
Fig. (1). Hypertension (BT
) and atrial fibrillation (AF) are both
risk factors for cardiovascular disease (CVD).
ATRIAL FIBRILLATION AND ANTIHYPERTEN-
SIVE TREATMENT
Antihypertensive drugs reduce the risk for atrial fibrilla-
tion by lowering blood pressure. However, some antihyper-
tensive drugs may also reduce the risk for atrial fibrillation
through other mechanisms as indicated by Fig. 2. There have
been few prospective studies on development of atrial fibril-
lation in hypertensives, but there are several secondary
analyses of large randomised trials and some meta-analyses.
Blockers or the renin-angiotensin system (RAS) like angio-
tensin-converting enzyme inhibitors (ACEIs) and angio-
tensin II-receptor blockers (ARBs) are important parts of the
treatment regimens for hypertension and in recent years there
have been studies reporting beneficial effects of blockade of
RAS in reducing new-onset atrial fibrillation.
Fig. (2). Antihypertensive treatment may reduce the risk of devel-
oping atrial fibrillation in hypertensives.
RAS-Blockers (ACEIs and ARBs)
In an early meta-analysis of 11 randomised, controlled
human trials by Healey et al. [8], the authors found that
RAS-blockers significantly reduced the relative risk of new
atrial fibrillation with 28% (15-40%), but this benefit was
limited to patients with systolic left ventricular dysfunction
or left ventricular hypertrophy. In another meta-analysis by
Kalus et al. [9], the use of an ACEI or an ARB was associ-
ated with a 49% (35-72%) relative reduction in new-onset
atrial fibrillation, a 53% (24-92%) lower failure rate of elec-
trical cardio-version of atrial fibrillation, and a 61% (20-
75%) lower rate of recurrence of atrial fibrillation after elec-
trical cardio-version.
In a recent meta-analysis by Schneider et al. [10], the
effects of RAS-blockade for the prevention of atrial fibrilla-
tion were investigated, aiming to define when the inhibition
Aksnes and Kjeldsen
is most effective. 23 randomised studies with a total of
87048 patients were included (6 hypertension trials, 2 post-
myocardial infarction trials, 3 heart failure trials (primary
prevention), 8 studies after cardio-version and 4 on medical
prevention of paroxysmal atrial fibrillation (secondary pre-
vention)) [10]. RAS-blockade reduced the odds ratio for
atrial fibrillation by 32% (0.22-0.43, p-value < 0.00001),
with similar effects of ACEIs and ARBs [10]. In primary
prevention RAS-blockade was most effective in patients with
left ventricular hypertrophy and/or heart failure [10]. In sec-
ondary prevention, RAS-blockade reduced the odds for atrial
fibrillation recurrence after cardio-version by 45% (0.34-
0.89, p-value = 0.01) and on medical therapy by 63% (0.27-
0.49, p-value < 0.00001) [10]. However, no effect was found
in those with the most refractory atrial fibrillation [10]. The
authors concluded that RAS-blockade should be considered
as an additional treatment option for the prevention of atrial
fibrillation [10]. However, we must remember that most of
the trials included in these meta-analyses were not designed
to investigate atrial fibrillation.
Initially RAS is activated as a compensatory mechanism
in the body e.g. in heart failure and hypertension, but with
the progression of the disease it may have a more detrimental
role. RAS may promote atrial and ventricular arrhythmias
explained by increased cardiac hypertrophy, fibrosis, and
heterogeneity of the cardiac tissue [11]. Other electrophysi-
ological effects of RAS activation have also been suggested
e.g. experimental results have shown that RAS may have
direct pro-arrhythmic effects on membrane and ion channels
and increased oxidative stress may contribute to an increased
arrhythmic incidence [12, 13]. Blockade of the RAS may
prevent left atrial dilatation, atrial fibrosis, dysfunction and
conduction velocity slowing, and some studies also indicat-
ing direct anti-arrhythmic properties. Favourable effects of
RAS-blockers on cardiac alterations like atrial enlargement
and left ventricular hypertrophy (LVH) may explain the re-
duction in new-onset atrial fibrillation [14, 15].
In the meta-analysis by Schneider et al. [10], no signifi-
cant reduction in the odds ratio (OR) for atrial fibrillation
was detected in the hypertension trials (OR=0.89 (0.75-
1.05), p-value = 0.17). However, there was significant het-
erogeneity between the trials included and the LIFE [6] and
the VALUE [16] trials, both large hypertension trial testing
the effect of ARBs, detected significant reductions in the
rates of new-onset atrial fibrillation.
In the LIFE study, treatment with an ARB (losartan) sig-
nificantly reduced the incidence of new-onset atrial fibrilla-
tion with a relative risk of 0.67 (0.55-0.83, p-value< 0.001)
compared with treatment with a beta-blocker (atenolol), de-
spite similar blood pressure reduction, indicating that the
antihypertensive effect is not the whole explanation [6]. The
ARB was also more effective than the beta-blocker treatment
in reducing the risk of a combined endpoint of cardiovascu-
lar morbidity and mortality, as well as stroke and cardiovas-
cular death in hypertensive patients with electrocardio-
graphic left ventricular hypertrophy and atrial fibrillation
[17].
In the VALUE trial a significant reduction of new-onset
atrial fibrillation from 4.34% after treatment with a calcium
channel blocker (amlodipine) to 3.67% after treatment with
A Link Between Hypertension and Atrial Fibrillation
the ARB (valsartan) was found, giving a significant unad-
justed hazard ratio of 0.843 (0.713-0.997, p-value = 0.0444)
in favour of RAS-blockade [16]. Blood pressure lowering in
the VALUE trial was slightly greater with calcium channel
blocker than with the ARB, which again suggests that
mechanisms beyond blood pressure control may have con-
tributed to the beneficial effect of the ARB [16, 18].
In contrast to these observations, two older hypertension
studies, the CAPPP [19] and the STOP-2 [20] studies, found
no reduction in atrial fibrillation with treatment with ACEIs
compared to beta-blockers, calcium channel blockers, and
diuretics. However, in these oldest studies, detection accu-
racy for new-onset atrial fibrillation is poor, being mainly
registered by adverse event reports. To compare, if the effect
on atrial fibrillation in the VALUE trial was based merely on
adverse event rates, no effect of ARB would have been de-
tected [18, 21] and therefore a definite conclusions about the
preventive effect of ACEIs can not be drawn based on these
studies. However, recently has also results from the large
ALLHAT trial been published, showing no consistent sig-
nificant effect of RAS-blockade [7]. In the ALLHAT trial
42418 participants were randomised to 4 antihypertensive
treatment arms comparing the ability of an ACEI (lisinopril),
a dihydropyridine calcium channel blocker (amlodipine), an
alpha-adrenoreceptor blocker (doxazosin) relative to a thiaz-
ide-like diuretic (chlorthalidone) to prevent incident atrial
fibrillation [7]. New-onset atrial fibrillation or atrial flutter
occurred in 641 participants (2.0%) and, excluding doxa-
zosin (due to the early termination of doxazosin-arm in the
year 2000 and shorter follow-up time in these patients; mean
3.2 years vs. mean 4.9 years), did not differ by antihyperten-
sive treatment group [7].
Fogari et al. have published many studies on atrial fibril-
lation development in patients with hypertension [22-24]. In
one study the recurrence of atrial fibrillation was lower after
treatment with ARB (losartan) and amiodarone than with
calcium channel blocker (amlodipine) and amiodarone [22].
In another study the effects of ARB (valsartan), ACEI (rami-
pril) and calcium channel blocker (amlodipine) were com-
pared and a lower atrial fibrillation recurrence was found
with RAS-blockade compared to amlodipine despite similar
blood pressure lowering, suggesting beneficial effects of
RAS-blockade beyond blood pressure lowering [23]. In a
third study of hypertensive diabetic patients, combination
treatment with ARB/calcium channel blocker (valsartan/
amlodipine) was superior to beta-blocker/calcium channel
blocker (atenolol/amlodipine) on atrial fibrillation preven-
tion, despite similar effects on peripheral blood pressure
[24]. The beneficial effects of ARB/calcium channel blocker
(valsartan/amlodipine) were more pronounced in those pa-
tients concurrently treated with amiodarone or propafenone
than in patients treated with other anti-arrhythmic drugs or
without anti-arrhythmic treatment [24].
The 2007 ESH/ESC hypertension guidelines summarized
evidence from post hoc analyses of heart failure and hyper-
tension trials and suggested ARBs or ACEIs as preferred
drugs in hypertensive patients at risk of developing atrial
fibrillation [25]. Due to new data presented e.g. ONTAR-
GET [26], TRANSCEND [27], PROFESS [28] and I-
PRESERVE [29] the ESH reappraisal of guidelines on hy-
Current Vascular Pharmacology, 2010, Vol. 8, No. 6 771
pertension management recently published in Journal of Hy-
pertension, modifies these recommendations [30]. In ON-
TARGET [26] new atrial fibrillation was just slightly less
frequent with ARB (telmisartan) than with ACEI (ramipril)
treatment, indicating no difference between these two types
of RAS-blockade. The placebo-comparisons in the TRAN-
SCEND [27] and the PROFESS [28] trials, could not con-
firm a protective effect of ARBs against onset of atrial fibril-
lation. The 2007 ESH/ESC guidelines also referred to the
results of small studies suggesting that the RAS-blockade
may exert favourable effects on recurrent atrial fibrillation
and facilitate sinus rhythm after cardio-version [22, 31, 32].
However, recently the CAPRAF [33] and GISSI-AF [34]
trials are not supportive of this protective effects of ARBs
against recurrence of atrial fibrillation. In GISSI-AF 1442
patients (85% with a history of hypertension) with at least
two episodes of atrial fibrillation in the previous 6 months
scheduled for cardio-version and frequently treated with
ACEI and class I and III anti-arrhythmic drugs were random-
ised to either ARB (valsartan) or placebo with a mean fol-
low-up of 223 days [34]. Incidence of atrial fibrillation was
51.4% on valsartan and 52.1% on placebo (HR=0.99, p-
value=0.84), indicating no effect [34].
The HOPE study included patients with high cardiovas-
cular risk without heart failure and left ventricular systolic
dysfunction and randomised the patients to treatment with
ACEI (ramipril) or placebo [35]. No statistical significant
difference in the proportion of patients who developed atrial
fibrillation was found between the ACEI and placebo, and
treatment with ACEI had no protective effect on develop-
ment of atrial fibrillation with an OR of 0.92 (0.68-1.24, p-
value = 0.57) [35]. In the TRANSCEND trial, patients intol-
erant to ACEIs with cardiovascular disease or diabetes with
end-organ damage, were randomised to treatment with ARB
(telmisartan) or placebo, and no significant effect on new-
onset atrial fibrillation was found [27]. 182 (6.4%) patients
treated with ARB compared with 180 (6.3%) patients treated
with placebo developed new atrial fibrillation with a hazard
ratio of 1.02 (0.83-1.28, p-value = 0.829) [27]. However,
HOPE [35] and TRANSCEND [27] are not “pure” hyperten-
sion trials, although included a large numbers of hyperten-
sives (
50% in HOPE [35],
76% in TRANSCEND [27]),
and this may explain why these trials failed to detect a bene-
ficial effect of RAS-blockade.
In the recently presented ACTIVE I trial, treatment with
an ARB (irbesartan) in high-normotensive patients with
atrial fibrillation reduced the secondary endpoint of heart
failure hospitalization compared to placebo during 4.5 years
of follow-up with a hazard ratio of 0.86 (0.76-0.98, p-value =
0.018), despite only a -3 /-2 mmHg reduction in blood pres-
sure [36]. Although, irbesartan failed to reduce the primary
composite end point of stroke, myocardial infarction, and
vascular death in atrial fibrillation patients randomised to
treatment, it did reduce the secondary end point of heart fail-
ure hospitalizations with 14% and this may be of importance
in this large high-risk population [36]. We have recently also
shown that hypertensive patients included in the VALUE
trial with new-onset diabetes mellitus had a significantly
higher event rate of new-onset atrial fibrillation with a haz-
ard ratio of 1.49 (1.14-1.94, p = 0.0031) compared with pa-
tients without diabetes mellitus, and this may explain some
772 Current Vascular Pharmacology, 2010, Vol. 8, No. 6
of these patients concomitant high risk of hospitalization for
heart failure [37]. Preventing the progression from high
blood pressure to atrial fibrillation to heart failure may be of
great importance not only for the patients, but also for the
health care system.
Beta-Blockers
The use of beta-blockers as first-line therapy for hyper-
tension has lately been questioned [25, 38], but beta-blockers
have undoubtedly effects in atrial fibrillation rate-control and
a possible effect in maintaining sinus rhythm, especially in
heart failure and in cardiac postoperative settings [39-41]. In
a systematic review including almost 12000 patients with
systolic heart failure (about 90% received RAS-blockade)
and therefore a high risk of atrial fibrillation, the incidence of
new-onset atrial fibrillation was significantly lower in the
patients treated with beta-blockers compared with those as-
signed to placebo with a relative risk reduction of 27% (14-
38%, p-value <0.001) [41]. A history of atrial fibrillation and
systolic heart failure may be a specific indication for using
beta-blockers. Treatment with sotalol, a non-selective beta-
blocker with class III anti-arrhythmic activity, is effective in
maintaining sinus rhythm after cardio-version, but has pro-
arrhythmic effects and is not recommended as antihyperten-
sive treatment. In hypertension trials like the LIFE study, the
ARB-based therapy (losartan) was superior to beta-blocker
(atenolol) in reducing the risk of new and recurrent atrial
fibrillation [6]. However, it is also difficult to draw conclu-
sions from the results of trials comparing two or more active
antihypertensive treatment regimens, due to uncertainty
whether the observed effects may represent a detrimental
effect of one regiment or a beneficial effect of the other or
vice versa.
Possible mechanisms of action of the plain beta-blockers
to reduce risk of atrial fibrillation may be prevention of ad-
verse remodelling and ischemia, reduced sympathetic drive
or counteract of the beta-adrenergic shortening of action po-
tential which otherwise could contribute to perpetuation of
atrial fibrillation [39, 41]. However, recurrence rate of atrial
fibrillation is known to be high, even after beta-blocker pro-
phylaxis [42].
Calcium Channel Blockers
Calcium channel blockers (CCBs) are a heterogeneous
group of drugs with antihypertensive properties. Non-
dihydropyridines like diltiazem and verapamil are used to
slow the ventricular response in atrial fibrillation, and vera-
pamil has also been investigated for its effectiveness in
maintaining sinus rhythm after cardio-version. Calcium low-
ering drugs could hypothetically attenuate the calcium-
overload in tachycardia-induced electrical remodelling of the
atria [43]. In a study by De Simone et al. additional treat-
ment with verapamil significantly reduced the recurrence of
atrial fibrillation within 3 months compared with propafe-
none alone [44]. However, other studies have shown more
disappointing results [43, 45]. In the VALUE trial the ARB
valsartan was more effective than the CCB amlodipine in
preventing new-onset atrial fibrillation [16].
In a retrospective study using a national integrated medi-
cal and pharmacy claims database in the US almost 5500
Aksnes and Kjeldsen
patients treated for hypertension with an ACEI were com-
pared to an equal number of matched patients treated with a
CCB and at about four years of follow-up the incidence of
new atrial fibrillation was significantly lower in the ACEI-
treated patients with a HR of 0.85 (0.74-0.97)) [46]. In a
nested case-control analysis from the United Kingdom-based
General Practice Research Database, similar results was
found [47]. 4661 patients with atrial fibrillation and 18641
matched controls from a hypertension population was com-
pared and the authors found that treatment with ACEIs (OR
75 (0.65-0.87)), ARBs (OR 0.71 (0.57-0.89)) or beta-
blockers (OR 0.78 (0.67-0.92)) were associated with a lower
risk for atrial fibrillation than treatment with CCBs [47].
However, in observational studies like these, bias in treat-
ment can not be excluded and blood pressure control and
changes cannot be evaluated [47].
Diuretics
Diuretics are often included in antihypertensive treatment
regimens, but the effect on new-onset atrial fibrillation has to
our knowledge seldom been investigated. However, as writ-
ten about previously in this paper, new-onset atrial fibrilla-
tion or atrial flutter occurrence did not differ between anti-
hypertensive treatment regimens in the ALLHAT trial (in-
cluding thiazide-like diuretic chlorthalidone) [7]. In the Vet-
eran Affairs Cooperative Study on Single-Drug Therapy in
Mild-Moderate Hypertension comparing different antihyper-
tensive agents, hydrochlorothiazide was associated with a
significant reduction in left ventricular mass and a greater
overall reduction in left atrial size than the other agents [48,
49]. Left ventricular mass and left atrial size are both known
atrial fibrillation risk factors, but it has been suggested that
the reduction of left ventricular mass with diuretics is mainly
due to reduction of ventricular diameter and volume and not
wall thickness or hypertrophy and a possible effect on atrial
fibrillation development is not known [49].
Alpha-Adrenoreceptor Blocker
Alpha-blockers have a specific indication in the presence
of benign prostatic hypertrophy, however evidence concern-
ing the benefits of alpha-blocker is much more limited than
other antihypertensive agents as the only large hypertension
trial testing an alpha-blocker (the doxazosin-arm of the
ALLHAT trial) [50] was interrupted before crucial evidence
could be obtained, and the overall benefits or harm of alpha-
blockers for antihypertensive therapy remain unproved and
alpha-blockers are therefore not recommended as first choice
antihypertensives in current guidelines. In the recent paper
from the ALLHAT trial, new-onset atrial fibrillation was
higher in those assigned to the alpha-blocker (doxazosin)
compared to the patients treated with thiazide-like (chlortha-
lidone) with an OR of 1.346 (p-value 0.02) during 3.2 years
of follow-up [7].
CONCLUSION
Awareness of the increased risk of atrial fibrillation in
hypertensive patients may warrant closer follow-up as atrial
fibrillation has a marked effect on cardiovascular outcome
and management of atrial fibrillation (e.g. anticoagulation)
should be integrated into the follow-up of hypertensive pa-
A Link Between Hypertension and Atrial Fibrillation
tients. Antihypertensive treatment is effective in reducing the
risk for atrial fibrillation by its blood pressure reduction per
se, but blockers of the RAS, like ACEI and ARB, also seem
to reduce the incidence of atrial fibrillation by attenuating
changes in cardiac structure and function. Prevention is a
new strategy in treatment of atrial fibrillation, as it has been
more common to focus on prevention of adverse outcome
and rate- and rhythm-control of the final condition. Anti-
arrhythmic treatment has side effects and many patients have
contraindications to anticoagulation, so prevention of atrial
fibrillation development would be a preferable alternative.
Prevention and new treatment regimens of atrial fibrillation
are needed, considering the increasing elderly population and
limited efficacy, costs and side effects of current anti-
arrhythmic drugs. Delaying or postponing the progression of
atrial fibrillation has the potential to reduce morbidity, mor-
tality and health care expenditures. The evidence to support
using ACEIs and ARBs as anti-arrhythmic therapy in pa-
tients with atrial fibrillation is still not solid. However, in
view of a possible beneficial effect and a low incidence of
side effects, treatment with RAS-blockade may be tried in
patients with high risk of developing atrial fibrillation or in
patients having recurrent atrial fibrillation, especially in pa-
tients with other indication for their use (e.g. hypertension,
heart failure, and diabetes mellitus).
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