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Credits:
Prabhat kumar ,MBBS and Anil K. Gehi, MD.
Department of Medicine, University of North Carolina at Chapel Hill.
Corresponding Author: Anil K. Gehi, MD, Assistant Professor of Medicine, University of North Carolina at Chapel Hill. 160 Dental Circle, CB 7075, Chapel Hill, NC 27599.
Metabolic syndrome, a constellation of conditions including obesity, dyslipidemia, hypertension and insulin resistance, has increased to epidemic proportions. Metabolic syndrome has been recognized as a risk factor for cardiovascular morbidity and is likely related to the epidemic of cardiovascular diseases. Perhaps not coincidentally, its growth in incidence has paralleled that of atrial fibrillation. Various components of metabolic syndrome have been known to have a role in the pathogenesis of atrial fibrillation. With the conglomeration of components seen in the metabolic syndrome, the risk for atrial fibrillation increases greatly. Several studies have elucidated the role of metabolic syndrome in the development of atrial fibrillation. Its role on the atrial substrate makes it an important determinant of progression of disease and failure of therapeutic strategies such as catheter ablation. Control of the various components of metabolic syndrome may ultimately lead to better outcomes in atrial fibrillation patients.
Atrial fibrillation (AF), already the most common arrhythmia worldwide, continues its growth to epidemic proportions. 1, 2 Perhaps not coincidentally, the conglomeration of insulin resistance, hypertension, dyslipidemia, and obesity known as the metabolic syndrome (MS) also has grown in preva- lence to epidemic proportions, particularly in the adult U.S. population. 3 The association of AF with an increased risk for stroke4 and mortality is well known. 5, 6 However, the association of MS with cardiovascular disease is now becoming more evident. 7, 8 The MS has been associated with increased prevalence of coronary heart disease and cerebrovascular disease.7, 9 It has also been associated with worsened coronary heart disease outcomes and cardiovascular mortality.7 More recently, a body of evidence has linked the MS with both the incidence of AF and outcomes of management of AF. In this review, we present the evidence and potential underpinnings of this convergence of epidemics.
The American Heart Association / National Heart, Lung, and Blood Institute (AHA/NHLBI) 2005 scientific statement 10 defined the metabolic syndrome as the presence of at least three of the fol lowing criteria:.
• Waist circumference greater than or equal to 40 inches (102 cm) in men or 35 inches (88cm) in women
• Triglycerides greater than or equal to 150 mg/ dl (1.7 mmol/L) or on drug treatment for elevated triglycerides
• High density lipoprotein (HDL) cholesterol less than 40 mg/dL (1.03 mmol/L) in men or 50 mg/dL (1.3 mmol/L) in women or on drug treatment for reduced HDL
• Systolic blood pressure greater than or equal to 130 mmHg or diastolic blood pressure greater than or equal to 85 mmHg or on antihypertensive drug treatment in a patient with a history of hy- pertension
• Fasting glucose greater than or equal to 100 mg/ dL or on drug treatment for elevated glucose
Based on the more conservative ATP III definition (fasting glucose >= 110 mg/dL), the age-adjusted U.S. prevalence of MS was 24% with Mexican Americans having the highest prevalence overall (32%).11 Prevalence increases with age such that
those over 60 have an astounding 44% prevalence of MS.11 Based on 2000 census data, nearly 50 mil- lion U.S. residents have the metabolic syndrome and its prevalence is only increasing with time.
The simultaneous epidemic of AF in the U.S. and worldwide populations prompts one to consider whether the two may be linked. There are several hypothetical reasons why this may be the case.
Various components of the MS are known risk factors for AF. These factors have been hypothesized to be involved in the pathogenesis of AF by various mechanisms (Figure 1).
However, recent studies have shown that all these components of the MS together may have an additive effect on the risk for AF.12
According to our current understanding, the pathogenesis of AF involves a complex interplay of AF triggers and abnormal atrial substrate re- quired to sustain the arrhythmia. Various com- ponents of the MS may act as risk factors for AF by their effect on AF triggers or the atrial sub- strate. Below we review the potential mechanisms for the MS components in the causation of AF.
Figure 1: Factors involved in the pathogenesis of Atrial fibrillation.This figure summarizes the pathogenetic mechanisms for atrial fibrillation of the various components of the metabolic syndrome. Note the multiple effects of each component of metabolic syndrome
|
Hypertension is the commonest modifiable risk factor for AF. 13 It is seen in almost 60% of patients
Figure 1
with AF.14-16
Hypertension leads to left ventricular
hypertrophy and diastolic dysfunction resulting
in pathological remodeling of the left atrium predisposing
to AF. Diastolic dysfunction results in
left atrial stretching of enlargement,17
important
to the pathogenesis AF.18
In animal models, hypertension
has also been shown to induce structural
changes including interstitial fibrosis. 19-21
In
addition to mechanical remodeling and left atrial
enlargement, electrical remodeling of the left atrium
is known to occur with longstanding hypertension.22
Global and regional conduction delays
are seen in patients with longstanding systemic
hypertension.22
Moreover, changes in angiotensin
II level leads to electrophysiological changes in the
left atrial myocardium causing left atrial conduc-
tion delay.23
Insulin resistance and diabetes are another risk
factor associated with the development of AF.
The Framingham Heart Study clearly established
diabetes mellitus and glucose intolerance as a potential
risk
factor
for
AF.13
Mechanistically diabetes
mellitus
predisposes
to
AF
in
a
way
similar
to
hypertension.
Diabetes mellitus leads to left ventricular
hypertrophy and diastolic dysfunction,24
leading to mechanical and electrical remodeling
of the atrium. 25
Apart from left ventricular
hypertrophy and diastolic function, many other
mechanisms of atrial remodeling in diabetes mellitus
have
been
suggested
based
on
animal
experiments.
Advanced
glycation end-products (AGEs)
and receptors for AGEs (RAGE) have been known
to cause interstitial scarring in the left atrium.
Angiotensin II blockers are known to prevent anatomic
and
electrical
remodeling
likely
by
blocking
AGE-RAGE.28
In addition to structural remodeling,
the
atria
of
diabetic
animals
also
demonstrate
increased
intra-atrial conduction time providing
the electrical substrate for AF. Diabetes mellitus
and the MS affect the cardiac autonomic system,
which may contribute to arrhythmogenicity.29, 30
Finally, diabetes mellitus may lead to ischemic or
non-ischemic cardiomyopathy also predisposing
to AF through the resultant left atrial enlargement.26, 27
Hypertriglyceridemia and low HDL-cholesterolemia
are the lipid disorders seen with metabolic syndrome. Low HDL-cholesterol, has been found
to increase the risk of AF by 20-40%. 15, 31, 32
However,
data for hypertriglyceridemia are inconsistent.
Proposed mechanisms of predisposition to AF due
to the dyslipidemia are arrhythmogenicity due to
altered membrane composition leading to altered
excitability 33
as well as pro-inflammatory effects. 34
Obesity is an important component of the MS and
is known to be associated with an increased risk
for AF. Data from the Framingham heart study
showed an increased risk of new-onset AF for
obesity (BMI>=30) with an adjusted hazard ratio
of 1.52 and 1.46 for men and women respectively
compared to subjects with normal BMI. 35
A metaanalysis
of 16 studies found a 49% increased risk
of obese patients developing AF as compared to
non-obese patients.36
The role of obesity has been
explained by multiple mechanisms. Obesity is a
risk factor for insulin resistance and diabetes mellitus
and hence is a potential pathway for predisposition
to AF. A direct correlation has been
seen between increasing BMI and left atrial size. 37
Left atrial enlargement may be the most important
mechanism through which obesity increases
the risk of AF, since after adjusting for left atrial
enlargement obesity is no longer a risk factor for
atrial fibrillation in the Framingham Heart Study
cohort.35
However, other mechanisms which have
been suggested include the systemic inflammatory
state
seen
with
obesity.
Inflammation
is
known
to
be a risk factor for AF 38
and obese patients are
known to have elevated hsCRP levels, a marker
of systemic inflammation.39
Another factor which
may predispose to AF in patients with obesity is
obstructive sleep apnea, a well described risk factor for AF.40-42
It is apparent that various components of MS predispose
to AF in isolation. However, the combination
of these components seen in the metabolic
syndrome may act in a synergistic manner (Figure
1). The final common pathway in the pathogenesis
of AF can be grouped as atrial structural and electrical
remodeling, inflammatory processes, and
cardiac autonomic changes.
Atrial structural and electrical remodeling is of
paramount importance in providing the substrate
for initiation and maintenance of AF. As described
above, various components of MS cause atrial remodeling.
Structural remodeling with interstitial
fibrosis leads to heterogeneous electrical substrate
with differences in conduction velocities promoting
AF.43
Fibroblasts in these areas of interstitial
fibrosis may couple with cardiomyocytes electrically
and promote reentry and ectopic activity.44
Electrical remodeling alters ion channel function
and calcium handling of the cells and promotes
initiation and maintenance of atrial fibrillation.45
The cardiac autonomic nervous system is important
in the pathogenesis of AF.
beta-adrenoceptor activation46
Vagal discharge,47beta-adrenoceptor activation 48
and atrial sympathetic
hyperinnervation49
have been implicated in
the arrhythmogenesis of AF. Autonomic dysfunction is known to be associated with metabolic syndrome and has been shown to get worse with increasing
number of MS factors present.50
Inflammation is considered one of the basic pathophysiological
substrates in the causation and progression
of
AF.
Atrial
inflammation
has
been
seen
in
the
histological
specimens
of
lone
AF
patients
as
opposed
to patients with sinus rhythm.51
Inflammation
provides an anatomic and electrical substrate
for AF. A vast body of evidence supporting
the inflammation hypothesis of atrial fibrillation
comes from studies of inflammatory biomarkers.38
Moreover, inflammation has a role in early recurrence of atrial fibrillation after catheter ablation.52
As previously discussed, several components of
the MS (obesity, insulin resistance, dyslipidemia)
have been shown to be proinflammatory.
Thus, various components of MS are known to affect
these
pathogenetic
factors
of
AF.
As
these
factors
are affected by multiple components of MS,
their role in the pathogenesis of AF becomes additive
and
complex.
Recent
studies
have
looked
at
the
MS as a whole and the risk of AF.
53-56
It has
been shown that as the number of components of
AF increases, the risk of development of AF goes
up.
53, 57
The fact that AF is one of the important
cardiovascular effects of metabolic syndrome has
more recently been brought to notice by the stud-
ies detailed below.
52
Several population-based studies have demonstrated
the increased risk of incident AF among
patients with the metabolic syndrome (Table 1).
Umetani et al analyzed 592 hospitalized patients
without structural heart disease. Among 21% of
patients with metabolic syndrome, AF occurred in
9% compared with 4% of those without metabolic
syndrome. In multivariable analyses, the OR for
AF with metabolic syndrome was 2.8. 54
Watanabe
et al studied 28,449 participants without baseline
AF in the Niigata preventive medicine community-based
study. The metabolic syndrome was
present in 13% of participants. During a mean
follow-up of 4.5 years, AF developed in 265 participants.
The
HR
for
AF
among
participants
with
MS,
compared to those without MS, was 1.78.55
Chamberlain et al analyzed the risk of AF in the
Atherosclerosis Risk in Communities (ARIC)
Study. Among 15,094 participants over a mean
follow-up of 15.4 years, there were 1238 cases of
incident AF. At baseline, 46% of black and 40% of
white participants had the metabolic syndrome.
The HR for AF among participants with, compared
to those without, the metabolic syndrome
was 1.67 and did not differ by race. In addition,
the risk for incident AF increased with increasing
number of MS components such that those with
all 5 components had a HR of 4.4 compared to
those with no components. 12
Echahidi et al analyzed the risk of post-operative AF after coronary
artery bypass surgery among 5085 patients. Metabolic
syndrome
was
present
in
46%
of
patients
and
post-operative
AF occurred in 27%. Among patients
<=50
years
old,
MS
was
associated
with
a
RR
of
2.4 with development of post-operative AF.58
Vyssoulis et al studied a population of over 15,000
patients with hypertension.57 The prevalence of
MS ranged from 32% to 48%, depending on the
definition used. The odds of having AF in those
with MS ranged from 1.61 to 1.99. Importantly, the
prevalence of AF increased with each additional
component of the MS. Altieri et al demonstrated
a high incidence of AF (16%) in a population of
Hispanic patients with metabolic syndrome.59
The
authors suggested mechanisms of this association
may include sinus node remodeling, atrial fibrosis,
and older age which are all seen in a population
with MS.
Table 1: Studies showing association of atrial fibrillation with metabolic syndrome
|
Atrial fibrillation is a progressive disease and various
etiological
factors
provide
substrate
for
its
initiation
as well as maintenance and progression.
Hence patients with MS continue to develop substrate
for AF even after treatment and are likely
to have worsened outcomes (Table 2). Multiple
studies have suggested that MS may influence
the outcome of catheter ablation therapy. In a large
prospective study of catheter ablation of AF,
1496 patients were followed up for a mean of 21
months. Patients with MS had a 39% recurrence
rate compared to 32% for patients without MS (p
= 0.005).60
A study by Chang et al.61
from Taiwan
enrolled 282 patients undergoing catheter
ablation for AF. The authors found a higher incidence
of
recurrent
AF
in
patients
with MS (55%
vs.
24%,
p
<
0.001).
Notably,
it
was
more
common
to
see
recurrent
atrial
fibrillation
originating
from
non-pulmonary
veinous
sites
in
patients
with
MS
(45%
vs.
20%,
p=0.037),
suggesting
an
effect
of
MS
on
left
atrial
substrate.
In
an
analysis
of
predictors
of
late
recurrence
of
AF
after
catheter
ablation
by
Cai
et al., MS was an independent predictor of
late recurrence (OR = 4.41, 95% CI 1.56-12.46, p
= 0.005).62
Berkowitsch et al reported the results
of pulmonary vein isolation in patients with AF
with either cryo-balloon or by circumferential
pulmonary vein isolation with radiofrequency
catheter ablation in 702 consecutive patients with
AF. The presence of MS was independently associated
with
a
higher
risk
of
recurrent
AF
(46.4%
in
patients
with
MS
vs.
56.8%
among
patients
without
MS,
p
=
0.006) over 15.6 (inter-quartile range
12.7-42.3) months.63
Table 2: Studies showing increased risk of recurrent atrial fibrillation after catheter ablation in patients with metabolic syndrome.
|
Altered anatomic and electrical substrate is a major
factor
in
the
progression
of
AF
and
has
an
adverse
effect
on
outcomes
of
medical
and
catheter
ablation
therapy. Atrial fibrillation is known to
promote the structural and electrical remodelingof the atria and control of AF by medical therapy
or catheter ablation should have a favorable effect
on the substrate. However, evidence suggests that
risk factors for AF such as MS have a direct effect
on the creation and promotion of the arrhythmogenic
substrate.
Hence,
control
of
these
risk
factors
by
optimum intervention may potentially slow
the progression of the remodeling process. Data
suggests that optimal control of blood pressure,
maintenance of ideal body weight, control of lipid
disorders and intervention for insulin resistance
would help to control the arrhythmogenic substrate.
Reduction in the risk of atrial fibrillation with treatment
of hypertension has been well documented
in various studies of antihypertensive therapy
for hypertension. A meta-analysis of treatment of
hypertension using renin- angiotensin system inhibitors
showed
a
reduction
in
the relative risk of
atrial fibrillation by 15-40%, however this benefit
was limited to patients with left ventricular systolic
dysfunction or left ventricular hypertrophy.64
Other meta-analyses of studies using ARBs and
ACEIs showed similar reduction in new onset atrial
fibrillation
as
well
better
outcome
with
electrical
cardioversion
and lower
recurrence later.65, 66
Control of diabetes mellitus with treatment reduced
the
risk
of
atrial
fibrillation
in
a
large
study.67
Another study showed the reduction of risk of
atrial fibrillation recurrence after catheter ablation
in
patients
with
diabetes
mellitus
and
insulin
resistance
with the use of pioglitazone.68
Use of
lipid lowering drugs like statins has been shown
to reduce the risk of atrial fibrillation.69, 70
However,
use
of
pioglitazone
or
statin
may
reduce
the
risk
of
atrial
fibrillation
through
their
direct
effect
on
inflammatory process rather than their effect
on insulin resistance or dyslipidemia. Similarly,
control of obesity may affect atrial fibrillation indirectly
by
its
effect on insulin resistance and obstructive
sleep apnea.
The above account suggests that those factors involved
in the pathogenesis of AF work in an interactive
manner.
Therapeutic
interventions
have
pleiotropic
effect and their action on reduction
of AF risk is frequently through multiple effects.
Further evidence supporting the benefit of treatment
for
MS
as
a
whole
in
reducing
AF
outcomes
will
improve
our understanding in this area.
Metabolic syndrome, a constellation of associated
conditions, has increased to epidemic proportions.
It has been recognized as a risk factor for cardiovascular
morbidity
and
is
likely
related
to
the
epidemic
of cardiovascular diseases. Recently it has
been recognized that atrial fibrillation may be associated
with the ongoing epidemic of metabolic
syndrome. Various components of metabolic syndrome
have
been known to have a role in pathogenesis
of atrial fibrillation. Recent studies have
elucidated the role of metabolic syndrome in the
causation of atrial fibrillation. Its role on the atrial
substrate makes it an important determinant of
progression of disease and failure of therapeutic
strategies such as catheter ablation. Control of the
various components of metabolic syndrome may
ultimately lead to better outcomes in AF patients.
No disclosures relevant to this article were made by the authors.
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