Download Arrhythmia Risk and Arterial Stiffness

Cardiac Arrhythmia
Cardiac Arrhythmia
Chapter 3
Abstract
Arrhythmia Risk and Arterial Stiffness
Ioana Mozos*
Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, Romania
Corresponding Author: Ioana Mozos, Department of
Functional Sciences, Discipline of Pathophysiology, T.
Vladimirescu Street 14, 300173, Timisoara, Romania,
Email: [email protected]
*
First Published December 10, 2016
Conflict of Interests: The author declares that there is
no conflict of interest regarding the publication of this
chapter.
Copyright: © 2016 Ioana Mozos.
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
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Considering the high prevalence of cardiac arrhythmia, often related to cardiovascular mortality, it was the
aim of the present paper to review the type of arrhythmia
associated with arterial stiffness, the main mechanisms
linking arrhythmia risk and arterial stiffness, focusing on
the latest studies in the area, their implications for cardiovascular prevention, clinical practice and therapy.
The relationship between increased heart rate and
pulse wave velocity (PWV) is explained by the autonomic
tone, functional changes of the elastic fibers in the vascular wall, increased metabolic rate leading to an increased
oxidative stress and low grade inflammation. The most
important links between PR interval prolongation and increased arterial stiffness are neurohormonal pathways and
aging. More links were found between atrial fibrillation
and arterial stiffness including: left atrium remodeling,
mitral regurgitation, vascular inflammation and smooth
muscle cell contraction, gradual ischemic myocardial
damage, impaired endothelial function due to increased
serum uric acid and homocysteine, neurohormonal factors (aldosterone and natriuretic peptides), hypertension
and aging. The association between arterial stiffness and
impaired ventricular repolarization may be explained by
electrophysiological myocardial remodeling and coronary
atherosclerosis.
Risk assessment for the occurrence of rhythm and
conduction disorders should include arterial stiffness.
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Introduction
Cardiovascular diseases continue to be the leading
mortality causes worldwide. The underlying substrate is,
in most cases, atherosclerosis, with a latent evolution and
a possible fatal clinical debut. Sudden cardiac death, related to fatal ventricular arrhythmias, is a common mortality
cause. Markers of cardiovascular arrhythmia and sudden
cardiac death risk deserve special attention.
Arterial stiffness is a noninvasive marker of subclinical atherosclerosis and arteriosclerosis, based on changes
of vascular structure(rupture of elastin fibers, accumulation of collagen, fibrosis and necrosis of muscle fibers,
inflammation and calcium deposits in the media of the
vascular wall) and function [1], reducing distensibility of
the arterial wall and impairing the buffering capacity of
the arteries to pulsatile cardiac ejection [2].
sure or ankle-brachial index. Intima-media-thickness
(IMT) is a measure of arterial thickening and predictor
of myocardial infarction and stroke risk [8] and resting
ankle-brachial index (ABI) is the most commonly used
test to diagnose lower-extremity atherosclerosis [9]. Pulse
pressure, the difference between systolic and diastolic
blood pressure, is a surrogate marker of proximal aortic
stiffness and vascular aging, linked to cardiovascular morbidity and mortality [10,11].
The association between endothelial dysfunction and
arterial stiffness has been demonstrated by several studies,
related especially to reduction of nitric oxide and up-regulation of endogenous endothelin-1 production, explaining why condition exhibiting endothelial dysfunction are
also associated with increased arterial stiffness [12,13].
Objectives
Arterial stiffness can be assessed by pulse wave velocity (PWV) measurement, the gold standard measure
of aortic stiffness [3]. Arterial stiffness and endothelial
dysfunction predict, beyond standard cardiovascular risk
factors, future cardiovascular events [2, 4-6], especially
coronary heart disease and stroke.When arteries stiffen,
PWV increases, and excessive aortic stiffness contributes
to damage and inflammation in the arterial wall, increasing the likelihood of plaque rupture [7].
Considering the high prevalence of cardiac arrhythmia, often related to cardiovascular mortality, it was the
aim of the present paper to review the type of arrhythmia
associated with arterial stiffness, the main mechanisms
linking arrhythmia risk and arterial stiffness, focusing on
the latest studies in the area, their implications for cardiovascular prevention, clinical practice and therapy.
Several other markers of atherosclerosis may be used
besides PWV, such as intima-media thickness, pulse pres-
Heart rate, a hemodynamic parameter and marker of
sympathetic activity and basal metabolic rate, plays differential roles in the development of arterial stiffness and
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Heart Rate and Arterial Stiffness
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subclinical atherosclerosis during young adults, as reported by Chen et al. in the Bogalusa Heart Study, including
255 Black and 659 White subjects and demonstrating a
significant positive association between resting heart rate
and PWV, independently of blood pressure and age [14]. A
higher heart rate may increase arterial stiffness by accelerating the fatigue of elastic fibers due to increased number
of repetitive streching cycles, impairing relaxation of large
arteries due to shorter diastole, enabling vascular smooth
muscle cell growth and synthesis of the components of the
extracellular matrix [14]. The increase of PWV with heart
rate is more important in Blacks than in Whites [14]. Park
et al. also reported a gradually increase of brachial-ankle
pulse wave velocity with heart rate, independent of classic
cardiovascular risk factors, in a study including 641 Korean adults, in a health examination program, concluding that early detection of increased resting heart rate is
important for preservation of arterial function and assessment of cardiovascular risk [15]. Several other studies have shown that arterial distensibility varies inversely
with heart rate, related to the vagal tone [16,17]. Silva et al.
found and tested a formula, related to changes in arterial
distensibility and heart rate, demonstrating that reduction
of arterial distensibility with heart rate was more important in arteries that supply end capillaries with high permeability and low reflection coefficients [18].
Considering the influence of the sympathetic tone
on both heart rate and vascular stiffness, it has been sug6
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gested that the change in sympathetic tone determines
the heart-rate-dependent PWV variations [14]. An increased sympathetic tone is responsible for an increased
vascular tone and resistance and is associated with an increased oxygen consumption and increased production
of proinflammatory cytokines able to impair nitric oxide
release and cause endothelial dysfunction [15]. A higher
heart rate may reflect an increased metabolic rate, leading to increased oxidative stress and low-grade inflammation [15]. Heart rate variability, a measure of autonomic
control, was associated with indices of early carotid damage in 100 peri- and postmenopausal women, suggesting
that autonomic regulation is involved in vascular damage,
together with estrogen level and metabolic changes [19].
Augmentation index, a marker of endothelial dysfunction
and arterial stiffness is corrected for heart rate according
to several methodologies. Conflicting results have been
obtained regarding the association between heart rate and
intima-media-thickness [14].
The PR Interval and Arterial Stiffness
PR interval prolongation exceeding 200 ms characterizes the first-degree atrioventricular block and is very
common in clinical practice, its prevalence increasing
with age and several clinical conditions [20,21]. It is related to increased vagal tone in young and degenerative
changes in old subjects, with a prolongation of the interval between the P wave onset and His bundle potenwww.avidscience.com
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tial, reflecting a delay within the atrioventricular junction
[20,22]. It was considered “benign” by several authors, but
lately it has been associated with a high risk for incident
atrial fibrillation and heart failure hospitalization, pacemaker implantation, adverse cardiovascular outcomes
and all-cause mortality [23-25].
PR interval lenght was independently associated with
endothelial dysfunction and increased arterial stiffness,
in a study including 88 healthy subjects, with no history
of cardiovascular diseases, suggesting the presence of a
systemic, intermediate, pathological state of the vasculature related to PR prolongation, before clinically manifest
cardiovascular events [20]. An association between PR interval duration and arterial stiffness was present even in
subjects with a normal PR interval duration (< 200 ms),
suggesting the need to redefine the normal range of PR interval [20]. PR prolongation increases intra-atrial pressure
and activates neurohormonal pathways, impairing thereby the vascular function [24]. A higher risk of adverse
cardiovascular outcomes was also noticed in subjects with
a PR interval exceeding 149 ms [24]. Gosse et al. demonstrated a link between baseline increased pulse pressure
or arterial stiffness with the prolongation of the PR interval with aging, suggesting that increased arterial stiffness favors the increase in the PR interval with age [21].
PR interval prolongation was associated with endothelial
dysfunction assessed by brachial flow-mediated dilatation
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and endothelial repair activation assessed by measuring
circulating endothelial progenitor cells by flow cytometry,
in 348 high-risk patients with prior coronary artery disease [25]. PR interval prolongation may be considered as a
marker for vascular damage and repair but it could also be
an accompanying phenomenon during the atherosclerotic
process [25]. PR interval prolongation may be a marker of
subclinical cardiovascular disease, mediated through endothelial dysfunction [25].
Atrial
Stiffness
Fibrillation
and
Arterial
Atrial fibrillation, the most common arrhythmia, is
associated with an increased risk of stroke. Conflicting
results have been obtained regarding the interaction between atrial fibrillation and arterial stiffness.
Several studies revealed an interplay between systemic atherosclerosis, assessed by different methods, and the
occurrence of atrial fibrillation (Table 1). Arterial stiffness
was found as an important determinant of left atrium remodeling, considering the association with the left atrial
diameter according to a study including 33 patients with
atrial fibrillation after external cardioversion [31]. Possible links between arterial stiffness and left atrial diameter might be mitral regurgitation, associated with higher
cardio-ankle vascular index values (CAVI), inflammation, vascular smooth muscle cell contraction and stretchwww.avidscience.com
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induced release of metalloproteinase-12 in atrial tissues
[31,36]. An elevated aortic stiffness is able to increase the
diameter of the left atrium and increase the risk of atrial
fibrillation and stroke, suggesting that atrial fibrillation is
the pathophysiological link between arterial stiffness and
stroke, according to a study including 310 hypertensive
patients and reporting significant correlations between
left atrial diameter as a determinant of atrial fibrillation
risk and PWV, independent of other confounding factors [35]. The aorta may be considered, according to its
embryological origin, as a third chamber of the left heart,
enabling a continuous flow of the stroke volume [37]. Left
atrial diameter was significantly increased and independently associated with arterial stiffness in patients with
obstructive sleep apnea, atrial remodeling contributing
to the increased risk of atrial fibrillation [33]. Subclinical atherosclerosis may cause gradual ischemic myocardial damage, enabling premature apoptosis of myocytes,
arterial fibrosis, structural and electrical remodeling of
the atria, due to fibrosis and hypertrophy, and occurrence
of areas with impaired or blocked conduction, facilitating reentry arrhythmias [7,11].Arterial stiffness was also
associated with abnormal microvascular structure and
function, with an increased susceptibility to intermittent
microvascular ischemia due to abnormal microvascular
reactivity and inward eutrophic or hypertrophic vascular
remodeling [7].
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Table 1: Studies linking arterial stiffness and arrhythmia risk.
Arrhythmia or
marker of arrhythmia risk
Atrial fibrillation (AF)
incidence
Marker of arterial stiffness
Atrial fibrillation
Brachial-ankle pulse wave
velocity
Carotid intima-media thickness Atherosclerosis and arterial stiffness play a
(cIMT)
role in AF etiopathogenesis
Atrial fibrillation
relapse
CAVI (cardio-ankle vascular
index)
Atrial fibrillation
Pulse pressure
Atrial fibrillation (AF)
Measurement of timing of
Korotkoff sounds
Non valvular atrial
fibrillation (NVAF)
Atrial fibrillation
Atrial fibrillation
Atrial fibrillation
hospitalization
PR interval
Left atrial diameter
(determinant of atrial
fibrillation risk)
QT interval prolongation
Left atrial size
(determinant of atrial
fibrillation risk)
In patients with hypertension, the presence
of AF was associated with arterial stiffness,
related to serum uric acid and homocysteine levels
Arterial stiffness at baseline predicts
atrial fibrillation relapse after electrical
cardioversion
The prevalence of AF increased with
widening PP
Study population
Reference
ARIC Study (13,907 patients)
Chen et al,
2016 [11]
MESA Study (6,640 patients)
Rotterdam Study (5,220 patients)
132 patients with both hypertension and atrial fibrillation and 136
hypertensive patients
Shi et al, 2016
[26]
31 patients with atrial fibrillation
treated with electrical cardioversion
25,109 participants from the Reasons for Geographic and Racial
Differences in Stroke study recruited between 2003 and 2007
853 hypertensive patients before
administration of antihypertensive
treatment
Fumagalli et
al, 2016 [27]
2,027 patients enrolled in the
Atrial fibrillation Registry for
Ankle-brachial Index Prevalence
Assessment-Collaborative Italian
Study (ARAPACIS)
Proietti et al,
2015 [29]
6,630 participants from the Multi-Ethnic Study of Atherosclerosis
In patients with atrial fibrillation, arterial
33 patients with atrial fibrillation
stiffness is associated with age and AF length after external cardioversion
and after electrical cardioversion, and could
represent an important factor for left atrium
remodeling and AF maintenance
Carotid intima-media thickness Arterial thickening can predict future AF
4,846 middle-aged subjects from
(cIMT)
the general population
Roetker et al,
2014 [30]
Fumagalli et
al, 2014 [31]
Arterial stiffness is a strong predictor of
future atrial fibrillation in hypertensive
patients, independently of age, 24-h pulse
pressure and left atrial diameter
Carotid intima-media thickness Non valvular atrial fibrillation and systemic
(cIMT)
atherosclerosis are closely associated; persistent/permanent NVAF was an independent
predictor of abnormal cIMT, suggesting a
higher atherosclerotic burden in patients with
long-standing NVAF
Pulse pressure (PP)
PP is a significant risk factor for AF
CAVI (cardio-ankle vascular
index)
Prolonged QT and
Pulse wave velocity (PWV),
Tpeak-Tend intervals
augmentation indices
(predictors of ventricular arrhythmia risk)
Atrial fibrillation
Ankle-brachial index (ABI)
PR interval
Mechanisms explaining the link, findings
Pulse pressure, QKD interval
(the interval between the QRS
complex on the ECG and the
detection of the last Korotkoff
sound)
Flow-mediated dilation (FMD)
and brachial-ankle pulse wave
velocity (PWV)
PWV
PWV
PWV, pulse pressure (PP)
Myocardial and electrophysiological remodeling due to increased ventricular load, or
subendocardial ischemia due to microvascular atherosclerosis in the coronary artery
ABI is a simple and cheap method to better
define the prevalence of vascular disease in
patients with non valvular atrial fibrillation
Increased arterial stiffness favors the increase
of the PR interval with age
54 healthy participants
PR prolongation increases intra-atrial pressure and activates neurohormonal pathways,
impairing thereby the vascular function
Left atrial diameter is significantly increased
and independently associated with arterial stiffness in patients with obstructive
sleep apnea
PWV is independently associated with QT
interval prolongation
An elevated aortic stiffness is able to increase
the diameter of the left atrium and the risk of
atrial fibrillation and stroke
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Ghazi et al,
2016 [10]
Cremer et al,
2015 [28]
Adamsson
Eryd et al,
2014 [8]
Mozos,
2014 [6]
2,027 non valvular atrial fibrillation patients
Violi et al,
2013 [32]
1,034 untreated hypertensive
patients
Gosse et al,
2011 [21]
88 healthy subjects
Chan et al,
2011 [20]
73 middle-aged subjects with or
without obstructive sleep apnea
Drager et al,
2010 [33]
2,666 community-dwelling
individuals
310 hypertensive patients
Maebuchi et
al, 2008 [34]
Lantelme et al,
2008 [35]
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Compared with paroxysmal AF patients, persistent
AF patients had higher PWV values, serum homocysteine
and uric acid concentrations, and left atrial diameters according to a study including patients with hypertension
and atrial fibrillation [26]. PWV was higher in hypertensive patients with atrial fibrillation compared to those
without [26]. Increased serum uric acid and homocysteine
impair vascular structure and function due to decrease
in nitric oxide, increased production of reactive oxygen
species, vascular inflammation and proliferation of vascular smooth-muscle cells with inhibition of endothelial
cell growth [26,38,39]. However, therapy of hypertension
should also consider lowering of arterial stiffness in order
to prevent the occurrence of atrial fibrillation [26].
Aldosterone and natriuretic peptides, markers of
neurohormonal activation, are increased in atrial fibrillation and influence atrial remodeling [20]. The mentioned
markers are reversed on cardioversion [40]. Hypertension
and aging, two important risk factors of incident atrial fibrillation, are both associated with an increased arterial
stiffness, but arterial stiffness was revealed as a strong predictor of future atrial fibrillation in hypertensive patients,
independently of age, 24-h pulse pressure and left atrial
diameter in a study including 853 hypertensive patients,
before administration of antihypertensive therapy [28].
Low-grade inflammation could be the link between aortic
stiffness and left atrium dilation [27].
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Higher pulse pressure (PP) was associated with left
atrial enlargement [41] and an increased prevalence of
atrial fibrillation, especially in adults < 75 years [10]. The
link between AF and PP is, probably, arterial stiffness,
which increases with age, promoting left ventricular hypertrophy, impairing left ventricular relaxation and enabling left atrium enlargement due to the increase in the
intra-atrial pressure, atrial dysfunction and enlargement
[10,42]. Yoon et al. went further and assessed echo-doppler derived variables of ventricular stiffness and ventriculo-arterial interaction as predictors of new-onset atrial
fibrillation in patients with heart failure [43]. Persistent/
permanent non valvular atrial fibrillation (NVAF) was an
independent predictor of abnormal intima-media thickness, suggesting a higher atherosclerotic burden in patients
with long-standing NVAF and that atherosclerosis might
favor the progression of paroxysmal to long-standing
atrial fibrillation, as reported by Proietti et al. in a study
enrolling 2,027 patients [29]. Intima-media thickness values were predictors of hospitalization for NVAF during a
follow up of 15.3 years of 4,846middle-aged subjects from
the general population, suggesting that arterial thickening
can predict future atrial fibrillation [8]. A high prevalence
of pathological ankle-brachial index was reported among
patients with nonvalvular atrial fibrillation, progressively
increasing from paroxysmal to permanent AF [32].
After midlife, wave reflection is reduced in the larger
muscular arteries, enabling more pulsatile energy to penwww.avidscience.com
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etrate the small arteries, resulting in damages due to the
barotrauma and an increased cardiovascular risk [7]. In
elderly atrial fibrillation patients who underwent electrical cardioversion, baseline arterial stiffness predicted atrial fibrillation relapse at follow up in a study including 31
patients with atrial fibrillation [27]. Modulation of vascular properties could represent a possible target to reduce
atrial fibrillation in elderly patients [27].
Aldosterone, known for its effect in regulating electrolyte balance, has been shown to impair endothelial
function, related to high blood pressure and atherosclerosis [44]. The vascular effects of aldosterone depend on
oxidative stress: at low oxidative stress, aldosterone promotes nitric oxide production, enabling vasodilation, but
with increased oxidative stress, endothelial dysfunction
and vasoconstriction will prevail [45].
On the other hand, Reiffel revealed that the arterial
stiffness index and left ventricular hypertrophy cannot be
used to predict the risk of atrial fibrillation in hypertensive patients, considering 53 hypertensive patients with or
without atrial fibrillation and 17 nonhypertensive controls
with AF [46]. Carotid ultrasound or measurement of arterial stiffness were not recommended in prediction of atrial
fibrillation by the findings of several large studies (ARIC,
MESA and Rotterdam Study), despite the role of atherosclerosis and arterial stiffness in AF etiopathogenesis [11].
The conflicting results of the several studies assessing
the relationship between arterial stiffness and atrial fibril14
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lation may be explained by the cross-sectional study designs, inter- and intra-observer method’s variability, different characteristics, size and inclusion criteria of study
populations, self-reporting of some data (history of AF),
selection biases due to missing data or antihypertensive
therapy, use of different and multiple statistical methods
[10,26,29].
Ventricular Arrhythmia Risk and Arterial Stiffness
The QT interval, the electrocardiographic expression
of ventricular depolarization and repolarization, is a predictor, if prolonged, of ventricular arrhythmia [47,48].The
Tpeak-Tend interval, measured as the difference between
QT and QTpeak interval, has been accepted as a measure
of transmural dispersion of repolarization, related to arrhythmogenesis [49,50].
Prolonged QT and Tpeak-Tend intervals were associated with endothelial dysfunction, arterial stiffness, impaired coronary perfusion and accelerated arterial aging
in a study including 54 healthy participants [6]. Several
mechanisms may explain the association between subclinical arterial disease and impaired repolarization, such
as myocardial and electrophysiological remodeling due
to increased ventricular load, or subendocardial ischemia
due to microvascular atherosclerosis in the coronary artery, or parallel evolution of subclinical arterial disease
and coronary atherosclerosis [6,34].
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Conclusions
Arterial stiffness and atherosclerosis play an important role in arrhythmia occurrence and recurrence and it
may allow early detection of subjects most susceptible to
develop future arrhythmias. The relationship between increased resting heart rate and PWV is explained by the
autonomic tone, functional changes of the elastic fibers
in the vascular wall, increased metabolic rate leading to
an increased oxidative stress and low grade inflammation.
The most important links between PR interval prolongation and increased arterial stiffness are neurohormonal
pathways and aging. More links were found between atrial fibrillation and arterial stiffness including: left atrium
remodeling, mitral regurgitation, vascular inflammation
and smooth muscle cell contraction, gradual ischemic
myocardial damage, impaired endothelial function due
to increased serum uric acid and homocysteine, neurohormonal factors (aldosterone and natriuretic peptides),
hypertension and aging. The association between arterial
stiffness and impaired ventricular repolarization may be
explained by electrophysiological myocardial remodeling
and coronary atherosclerosis.
Delaying atherosclerosis progression and controlling
atherosclerosis risk factors would result in a lower incidence of persistent atrial fibrillation and ventricular arrhythmia. Risk assessment for the occurrence of rhythm
and conduction disorders should include arterial stiffness
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and other markers of subclinical atherosclerosis. Further
follow up studies are needed to find and evaluate new
mechanisms linking arterial stiffness and rhythm and
conduction disorders.
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