Journal of Human Hypertension (2008) 22, 380388

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REVIEW

Hypertension and cardiac arrhythmias:

a review of the epidemiology,
pathophysiology and clinical implications
K-H Yiu and H-F Tse
Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong,
Hong Kong, China

Hypertension is commonly associated with cardiac

arrhythmias in patients with and without concomitant
cardiovascular disease. Experimental and epidemiological studies have demonstrated potential links
between hypertension and atrial and ventricular arrhythmias, although the underlying pathophysiological mechanism remains unclear. Nonetheless, the importance
of hypertension as a cause of atrial and ventricular
arrhythmias is not well recognized. In particular,
the occurrence of left ventricular hypertrophy is a
strong predictor for the development of AF, ventri-

cular ectopy and sudden cardiac death. Recent

prospective clinical trials reveal that antihypertensive therapy may delay or prevent the occurrence
of cardiac arrhythmias and sudden cardiac death in
patients with hypertension. Although antihypertensive
agents that block the reninangiotensinaldosterone
system appear to protect against cardiac arrhythmias,
this needs to be confirmed by current ongoing clinical
trials.
Journal of Human Hypertension (2008) 22, 380388;
doi:10.1038/jhh.2008.10; published online 13 March 2008

Keywords: atrial fibrillation; arrhythmia; sudden cardiac death

Introduction

Epidemiology

Concomitant cardiac arrhythmias are commonly

seen in patients with hypertension, although the
mechanism of this association is unclear. The
contribution of hypertension to the development of
atrial and ventricular arrhythmias is unrecognized
and thus undertreated. Recent clinical trials have
demonstrated the possible preventive role of antihypertensive agents, in particular those that induce
blockade of the reninangiotensinaldosterone system (RAAS). The aim of this paper is to review the
epidemiology, underlying mechanisms and clinical
implications of atrial and ventricular arrhythmias
in hypertensive patients. We searched MEDLINE
using the following terms individually and/or in
combination: atrial fibrillation (AF), left ventricular hypertrophy (LVH), hypertension, ventricular
arrhythmias and sudden cardiac death (SCD). In
addition, abstracts from international cardiovascular
meetings were studied to identify unpublished
studies.

Atrial fibrillation

Correspondence: Professor H-F Tse, Division of Cardiology,

Department of Medicine, Queen Mary Hospital, The University
of Hong Kong, Room 1928, Block K, Hong Kong, China.
E-mail: hftse@hkucc.hku.hk
Received 28 November 2007; revised 19 January 2008; accepted
26 January 2008; published online 13 March 2008

Atrial fibrillation is the most common sustained

arrhythmia in adults and is associated with an
increased risk for cardiovascular morbidity, mortality
and stroke.1,2 The incidence of AF increases with age;
a prevalence of 0.1% in adults younger than 55 years
increases to 9% in adults older than 80 years.3,4 In
the Framingham Heart Study, the lifetime risk for
developing AF was one in four in men and women
aged 40 years or above.5 Among different risk
factors, hypertension is one of the important
independent risk factors for the development of
AF.6 In the Cardiovascular Health Study of subjects
older than 65 years of age, the risk for developing
new-onset AF was higher in hypertensive patients:
the relative risk was 1.11 after adjustment for age
and other covariates.7
The Framingham Study cohort8 also demonstrated
that hypertension and diabetes were the only
cardiovascular risk factors that were responsible
for the development of new-onset AF. Hypertension
was responsible for more AF in the population
(14%) than any other risk factor due to its high
prevalence. After adjusting for age, hypertension
increased the risk of AF by 80% in female patients
and 70% in male patients. In addition, evidence of
LVH on ECG was associated with at least a threefold
increased risk for AF. In the Progetto Ipertensione

Hypertension and cardiac arrhythmias

K-H Yiu and H-F Tse
381

Umbria Monitoraggio Ambulatoriale (PIUMA) Study,

age and left ventricular (LV) mass as measured by
echocardiogram were independent predictors for
new-onset AF after a mean follow-up period of 5.3
years.9 The high prevalence of coexistent hypertension
and AF is also reflected by the high proportion of
hypertensive patients who require antihypertensive
treatment (470%) and who are participating in
major clinical trials on AF, such as the Atrial
Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) Study10 and the Stroke
Prevention Using an Oral Thrombin Inhibitor in
Atrial Fibrillation (SPORTIF III) Study.11
Ventricular arrhythmia

In patients with hypertension, the most important

determinant for the occurrence of ventricular arrhythmia is the presence of LVH. Several studies
have shown that hypertensive patients with LVH
have an increased frequency of premature ventricular ectopic beats and ventricular arrhythmias.1215 In
the Framingham Heart Study, echocardiographic
evidence of LVH was associated with ventricular
arrhythmia independent of conventional cardiovascular risk factors.12 In untreated hypertensive
patients, non-sustained ventricular arrhythmia
was observed in up to 5% of patients during 24-h
Holter monitoring.14
Sudden cardiac death

The presence of LVH is strongly correlated with

SCD, although a direct causal relationship has not
been identified.16,17 In the Framingham Heart
Study,17 an incremental increase in LV mass by
50 g m
2 conferred a 45% higher risk of SCD in
hypertensive subjects aged 440 years. Increased LV
mass and LVH were also associated with a long-term
risk of sudden death. The presence of asymptomatic
complex or frequent ventricular arrhythmia in the
absence of coronary artery disease was also associated with a 62% increase in mortality.18 Electrophysiological studies in hypertensive patients with
LVH have nonetheless yielded conflicting
results.19,20 In symptomatic hypertensive patients,
the presence of LVH increased susceptibility to the
development of malignant ventricular arrhythmia
during programmed ventricular stimulation.20

Pathophysiology
The development of atrial and ventricular arrhythmias in hypertensive patients and patients with LVH
appears to be complex. It is, nonetheless, clearly
evident that hypertension and LVH exert a robust
proarrhythmic effect on the heart.
Atrial fibrillation

In patients with hypertension, several mechanisms

may contribute to the development of AF (Figure 1).

Figure 1 Potential mechanisms of atrial fibrillation related to

hypertension.

Reninangiotensinaldosterone system. It has been

well demonstrated that activation of the RAAS
occurs in patients with hypertension21 and is
strongly implicated in the development of AF.22
Evidence is accumulating that explains the link
between RAAS and AF: there are two receptor
subtypes that act as binding sites for angiotensin
II, namely AT1 and AT2. Most of the known effects
of angiotensin II in adult tissue are attributable to
the actions AT1 receptor and acts antagonistically by
the action of AT2.23 In addition to its known
physiological effects (vasoconstriction, aldosterone
and vasopressin release, sodium and water retention
and sympathetic facilitation), AT1 also induces
atrial myocyte hypertrophy and fibrosis that predispose an individual to development of AF.24 Upregulation of the AT1 receptor in the left atrium in
patients with AF, but not the AT2 receptor, has been
demonstrated.25 In contrast, there is downregulation
of AT1 and upregulation of AT2 in the right
atrium.26 Angiotensin II is known to induce proliferation of fibroblasts and extracellular matrix
protein accumulation via activation of the mitogenactivated protein kinases.27 Experimental studies
show that inhibition of this angiotensin II pathway
attenuates the formation of fibrosis and diminishes
the incidence of AF.28 In a hypertensive rat heart
model, the degree of atrial fibrosis correlated with
the susceptibility for development of atrial tachycardia.29 Structural remodelling of the atria related
to the activation of RAAS can thus contribute to the
development of AF in hypertension.
In an animal model, rapid atrial pacing resulted in
atrial electrical remodelling, characterized by shortening of the atrial effective refractory period and
loss of the normal rate adaptation of refractoriness.30
Blockade of RAAS can prevent the development of
electrical remodelling for short (3 h),31 but not long
periods of time (15 weeks).32 It has been postulated
that an increased angiotensin II level is proarrhythmic due to increased intracellular calcium. The
latter is due to increased intake of extracellular
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K-H Yiu and H-F Tse
382

calcium and increased release from the sarcoplasmic reticulum through the activation of membrane
L-type calcium channels or phosphatidylinositol
phospholipase C pathways.33,34 In addition, activation of RAAS may lead to inflammation: this has
also been implicated in the pathogenesis of AF.35
Experimental studies have shown that angiotensin II
possesses proinflammatory properties, inducing the
production of reactive oxygen species, inflammatory
cytokines and adhesion molecules.36 In accordance
with this observation, angiotensin II receptor blockade has been shown to significantly reduce multiple
markers of inflammation (C-reactive protein, TNF-a,
IL-6 and monocyte chemotactic protein-1) in hypertensive patients.37
Haemodynamic changes in atria. The excessive
increase in afterload imposed by hypertension will
lead to cardiac compensation with progressive
thickening of the LV wall and consequent LVH.
Histologically, LVH is characterized by hypertrophy
of existing cardiomyocytes surrounded by connective tissue with cardiac fibrosis.38,39 In addition to
the established relationship between LVH and
adverse cardiovascular events,40 previous studies
have shown that the presence of LVH may
also predispose to the development of cardiac
arrhythmia.8,12 Increased stiffness of the LV after
LVH will inevitably lead to diastolic dysfunction
that subsequently contributes to the occurrence of
AF.41,42 Long-standing increased LA (left atrial)
pressure due to impaired LV relaxation in the
hypertensive heart will also eventually lead to LA
enlargement. In the Framingham Heart Study,43 both
the duration of elevated blood pressure and the level
of systolic blood pressure were associated with the
development of LA dilatation. The consequent
distention and stretching of the atria related to
hypertension can alter atrial electrophysiological
properties, including shortening of the effective
refractory period and increased dispersion of
refractoriness with subsequent increased vulnerability to AF.44,45

Ventricular arrhythmia

The presence of LVH is the most important determinant for the occurrence of ventricular arrhythmia
and/or SCD in hypertensive patients. The pattern of
LVH may also have important implications for the
prognosis and type of cardiovascular complications
in hypertensive patients. Previous studies have
shown that hypertensive patients with chronic
LVH may be more prone to severe ventricular
arrhythmias, whereas concentric hypertrophy is
more related to ischaemic events that result from
abnormal coronary autoregulation.46 As shown in
Figure 2, several mechanisms have been proposed to
explain the relationship between the presence of
LVH and ventricular arrhythmias in hypertension.
Journal of Human Hypertension

Figure 2 Potential mechanisms of ventricular arrhythmias

related to hypertension.

Electrophysiology disturbance. It has been well

established that prolongation and dispersion of LV
repolarization are associated with an increased risk
of ventricular tachyarrhythmias including torsade
de pointe and ventricular tachycardia. One of the
salient features in myocardial hypertrophy is the
presence of early after-depolarization and triggered
activity that may increase the dispersion of repolarization to cause sustained arrhythmia.47 Indeed,
prolongation of the QT interval, similar to a
pharmacologically induced proarrhythmic effect,
has also been observed in LVH.48 In addition, QT
dispersion that represents the degree of repolarization inhomogeneity in the heart is associated with
LVH49 and hypertension.50 At a cellular level,
structural remodelling induced by hypertension is
associated with impaired cellcell communication
at the gap junction and increased susceptibility to
ventricular arrhythmia induced by hypokalaemia
in an animal model.51 Nonetheless, vulnerability
to ventricular fibrillation is not related to abnormal
calcium channel handling.52 Although there
remains much speculation about the underlying
mechanism, it is established that electrical instability induced by hypertension and LVH is
an important mechanism in inducing ventricular
arrhythmia.
Myocardial ischaemia. Hypertension and LVH
may also cause myocardial ischaemia through other
mechanisms. Hypertrophy of the LV will lead to a
mismatch between myocardial blood supply and
oxygen consumption. In hypertensive patients with
or without LVH, decreased diastolic coronary blood
flow may cause subendocardial ischaemia.53 Microvascular dysfunction with myocardial ischaemia
has been reported in both prehypertensive and
hypertensive patients even in the absence of
LVH,54,55 suggesting that impaired myocardial perfusion may develop in the early stage of hypertension.

Hypertension and cardiac arrhythmias

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383

The presence of myocardial ischaemia may trigger

the onset of ventricular arrhythmia and SCD in
patients with hypertension.
Myocardial fibrosis. Experimental studies have
shown that pressure overloading of the LV is
associated with increased collagen synthesis and
degradation.56 Excessive accumulation of fibrillar
collagen is a characteristic feature of hypertensive
heart disease. The increased myocardial fibrosis
may lead to distortion of the tissue structure and
increased stiffness of the myocardium to cause LV
diastolic dysfunction.57 These structural changes in
the myocardium related to increased myocardium
fibrosis can lead to nonhomogeneous propagation of
electrical impulses and give rise to ventricular
arrhythmias due to re-entry.
Neuroendocrine effects. Excessive activation of the
sympathetic nervous system and the RAAS has been
demonstrated in the pathogenesis of essential
hypertension as well as in the development of
LVH.22,58 Sympathetic activation has been shown
to exert a direct proarrhythmic effect that may lead
to ventricular arrhythmia and SCD.59,60 No direct
link has been demonstrated between angiotensin II
and ventricular arrhythmias. Nevertheless, angiotensin II can lead to LVH by increasing blood
pressure or possibly via direct trophic actions on
the heart61 that subsequently increase vulnerability
to ventricular arrhythmias and SCD.

Clinical implication
While the pathophysiology of cardiac arrhythmias
in hypertension is unknown, the identification of a
close link between blood pressure control and the
presence of LVH with the development of cardiac
arrhythmias offers possibilities for therapeutic intervention and prevention of AF, ventricular arrhythmias and SCD in hypertensive patients by means of
blood pressure control and LVH regression. Existing
evidence demonstrates that optimal blood pressure
control and regression of LVH with antihypertensive
therapy are associated with improved LV diastolic
function, reduced LA size and changes in plasma
catecholamines that may contribute to the prevention of cardiac arrhythmias.6264 Among different
classes of antihypertensive agents, angiotensin
receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) appear to have
better efficacy in terms of reduction of cardiac
arrhythmias.65 Blockade of RAAS has been proven
to regress LVH and likely explains, in part, its
protective effect in arrhythmias. The regression of
LVH by ARB in patients with hypertension is
independent of its blood pressure-lowering effect.66
Furthermore, regression of hypertensive LVH is seen
independently of lowering blood pressure.67 Experimental studies have shown that blockade of ARB or

ACEI attenuates atrial structural remodelling with

fibrosis and atrial electrical remodelling, both
factors that predispose to AF.68,69
Atrial fibrillation

The effect of specific class of antihypertensive

agents on the prevention of AF remains unclear.
Retrospective studies70 suggest that blockade of
RAAS with ACEI in patients with hypertension
reduces the relative risk of developing AF by 15%
compared with CCB (calcium channel blocker).
Patients with a prior history of AF appear to derive
greater benefit from ACEI-based therapy in the
prevention of AF.66,71,72 Emerging data from the
analysis of large prospective clinical studies also
demonstrate the beneficial effects of blockade of
RAAS in preventing AF in patients with hypertension. In the Losartan Intervention For Endpoint
Reduction in Hypertension (LIFE) Study, ARB-based
therapy (losartan) was associated with a 33%
reduction in the incidence of AF and with a
significant reduction in the incidence of subsequent
stroke compared with b-blocker-based therapy
(atenolol).73 Similarly, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) Trial,
ARB-based therapy (valsartan) had a 16% risk
reduction in the incidence of AF compared with
CCB-based therapy (amlodipine) after adjustment
for confounding covariates.71 In patients with concomitant hypertension and AF, ARB-based therapy
(losartan) in combination with amiodarone was also
more effective than CCB-based therapy (amlodipine)
in preventing the recurrence of AF.74 Nevertheless,
meta-analysis of three major clinical trials (Captopril
Prevention Project (CAPP), Swedish Trial in Old
Patients with Hypertension-2 (STOP-H-2) and LIFE)
including 12 114 patients with hypertension have
failed to show a consistent reduction in AF with
ACEI and ARB.75 In addition to the blockade of
RAAS with specific agents, both the blood pressurelowering effect and LVH regression of different
antihypertensive agents make an important contribution to the prevention of AF. Recent analysis of
data from the LIFE Study reveals that regression of
electrocardiographic LVH during antihypertensive
therapy was a major determinant for the prevention
of AF, independent of the blood pressure lowering
and the effect of ARB-based therapy.72
Several prospective clinical studies (Table 1) are
currently underway to address whether blockade of
RAAS with ARB can prevent AF in patients with
hypertension. The GISSI-AF Trial intends to examine the incidence of recurrent AF in a broad
spectrum of cardiovascular risk patients including
hypertension (n 1402) with valsartan versus placebo.76 The Irbesartan for the Prevention of Atrial
Arrhythmias and Cardiac Electrical Remodeling
(I-PACE) Trial investigates the effect of irbesartan
versus placebo in hypertensive patients with atrial
tachyarrhythmias and implanted pacemakers.77 The
Journal of Human Hypertension

Hypertension and cardiac arrhythmias

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384

Table 1 Ongoing studies of AF involving blockade of reninangiotensinaldosterone system in hypertension patients

Name of study

Study design

Study population

Duration

AF end points

GISSI-Atrial Fibrillation
Trial76

A prospective, multicentre,
randomized, double-blind,
controlled trial of valsartan
vs placebo

1 year

Primary end points:

(1) the first recurrence of AF
(2) the number of patients
with more than one AF
episode over the whole
follow-up period

Irbesartan for the Prevention

of Atrial Arrhythmias
and Cardiac Electrical
Remodeling in Patients with
Hypertension and Permanent
Pacemakers
(I-PACE)77
Atrial Fibrillation
Clopidogrel Trial with
Irbesartan for prevention of
Vascular Events-I
(ACTIVE-I) Trial78

A prospective, multicentre,
randomized, double-blind,
controlled trial of irbesartan
vs placebo

(1) Symptomatic AF in recent

6 months or successful
cardioversion between
14 days and 48 h
(2) History of heart failure
with left ventricular ejection
fraction o40%/hypertension/
diabetes/stroke/cardiovascular
disease
(1) Permanent, atrial or dualchamber pacemaker implanted
42 months before enrolment
(2) History of prior diagnosis
of hypertension and/or treated
for hypertension or two
documented BP4130/85
(1) Permanent AF or at least
two episodes of intermittent
AF in the past 6 months
(2) Systolic BP of at least
110 mm Hg

6 months

Primary end point:

time to recurrent atrial high
rate episodes (220 min
1 for
42 min)

Varies, to
achieve the
target numbers
of primary
outcome events

Secondary end point:

recurrence of AF

1 year

Primary end point:

the difference in the
number of days with
symptomatic and
asymptomatic AFs
recorded on
transtelephonic monitoring
Secondary end point:
newly diagnosed AF

Japanese Rhythm
Management Trial II for
Atrial Fibrillation
(J-RHYTHM II study)79

ONgoing Telmisartan Alone

and in Combination with
Ramipril Global Endpoint
Trial (ONTARGET)80

ACTIVE-I is a partial
factorial, double-blind,
controlled trial of irbesartan
vs placebo in patients
participating in ACTIVE-A
or ACTIVE-W
A randomized prospective
multicentre controlled
trial of candesartan vs
amlodipine

A randomized prospective
multicentre trial to evaluate
(1) telmisartan+ramipril vs
ramipril
(2) telmisartan vs ramipril

(1) History of paroxysmal

AF within preceding 6
months; and
(2) Hypertension, defined
as a systolic
BPX140 mm Hg and/or a
diastolic BPX90 mm Hg
Age455 years and with
history of coronary artery
disease/stroke/diabetes/
peripheral artery disease

3.55.5 years

Abbreviations: AF, atrial fibrillation; BP, blood pressure.

Atrial fibrillation Clopidogrel Trial with Irbesartan

for prevention of Vascular Events-I (ACTIVE-I) Trial
assesses the effect of irbesartan versus placebo on
the prevention of AF recurrence in patients with
multiple cardiovascular risk factors and paroxysmal
AF.78 The Japanese Rhythm Management Trial II for
Atrial Fibrillation (J-RHYTHM II Study) compares
the effect of candesartan versus amlodipine for
treatment of paroxysmal AF in patients with
hypertension.79 The Ongoing Telmisartan Alone
and in Combination with Ramipril Global Endpoint
Trial (ONTARGET) Study investigates the efficacy of
telmisartan, ramipril and combination therapy with
telmisartan plus ramipril for reducing cardiovascular events, including AF in high-risk patients with
controlled blood pressure. This study will provide
important data on the potential incremental benefit
of ACEI, ARB or both in preventing AF, independent
of blood pressure lowering.80 Finally, data concerning the potential effect of blockade of RAAS with
aldosterone antagonists, such as spironolactone and
eplerenone, for AF prevention in patients with
hypertension are lacking. Further studies are needed
to discern their association.
In regard to the treatment of AF in patients with
hypertension, recent randomized trials have demonstrated similar clinical outcomes with rate-control
Journal of Human Hypertension

and rhythm-control strategy, in terms of quality of

life, stroke and mortality.8184 These studies highlighted the low clinical efficacy of current antiarrhythmic agents to maintain sinus rhythm. This
probably contributes to the stroke risk associated
with rhythm control, especially in a high-risk
hypertensive population. Therefore, in patients with
hypertension and AF, the use of oral anticoagulant
with warfarin should be considered for stroke
prevention, irrespective of whether rate or rhythmcontrol strategy is used.85 However, one of the major
drawbacks of warfarin is the potential of increasing
risk of haemorrhagic events. Therefore, the risk and
benefit of warfarin therapy must be assessed
individually for every patient. Compared with
warfarin, aspirin is less effective in preventing
stroke, and can only be recommended for patients
who refuse or cannot safely take warfarin.
In those patients who need ventricular rate
control, either b-blocker and/or a rate-limiting CCBs
(diltiazem or verapmail) is a suitable initial choice
of therapy in patients with hypertension. In patients
with impaired LV function or LVH, the use of Class I
and III antiarrhythmic agents is associated with an
increase risk of proarrhythmia. Therefore, only
amiodarone is recommended for rhythm control in
patients with hypertension and LVH.85

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Ventricular arrhythmia

Data on the prevention of ventricular arrhythmias

and SCD in patients with hypertension are limited.
Previous studies suggested that regression of LVH
with captopril reduced the number of ventricular
ectopy.86 Until recently, the only data available on
the impact of LVH regression and SCD came from
LIFE.87 In this study, the presence of regression of
electrocardiographic LVH during antihypertensive
therapy was associated with a 30% lower risk of
SCD independent of blood pressure lowering and
other known predictors for SCD. Furthermore, ARBbased therapy seemed to provide similar cardioprotection against SCD compared with b-blocker-based
therapy. Although b-blocker has been shown to
prevent SCD in patients with heart failure and
myocardial infarction,88,89 casecontrol studies in
patients with hypertension suggested that b-blocker
was associated with an increased risk of SCD.90
Similarly, the use of thiazide diuretic has been
linked to an increased risk of cardiac arrhythmia.
Siscovick et al.91 had shown a dose-dependent
increase in SCD in patients treated with thiazide
diuretic. Although the exact mechanism remains
unknown, it is possible that undetected hypokalaemia related to the use of high-dose diuretic can lead
to ventricular arrhythmia including torsade de
pointes. Indeed, the use of non-potassium-sparing
diuretic was associated with a twofold increased
risk of SCD compared with the use of potassiumsparing diuretic.90 In contrast, recent studies
demonstrated that candesartan-based and amlodipine-based regimens produced no statistical
differences in the risk of SCD in high-risk hypertensive patients.92 Nevertheless, future studies are
needed to confirm whether alleviation of LV
structural remodelling related to hypertension by
LVH regression with different classes of antihypertensive agents can prevent ventricular arrhythmias
and SCD.
In hypertensive patients with asymptomatic and
non-sustained ventricular arrhythmias, there is no
role for prophylactic use of antiarrhythmic agents.
In these hypertensive patients, especially those with
LVH or LV dysfunction and those who suffered from
sustained and symptomatic ventricular tachycardia
not related to a reversible causes, implantable
cardioverter defibrillator should be considered for
prevention of SCD.

Conclusions
Experimental and epidemiological studies have
established a close link between hypertension,
LVH and cardiac arrhythmias. In patients with
hypertension, alteration of cardiac haemodynamic,
structural and electrophysiological properties imposed by hypertension and LVH can contribute to
the development of AF, ventricular arrhythmias
and SCD. Effective antihypertensive therapy with

different agents to lower blood pressure and, more

importantly, to regress LVH can prevent AF and
SCD. Whether the use of ACEI or ARB to block the
RAAS is more effective in preventing cardiac
arrhythmias in patients with hypertension remains
to be determined by current ongoing clinical trials.

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