Influence of Inflammation and Atherosclerosis in Atrial Fibrillation

Abstract

Background
Inflammation markers have been associated with cardiovascular diseases including atrial fibrillation. This arrhythmia is the most frequent, with an incidence of 38/1000 person-years. Purpose of ReviewThe aims of this study are to discuss the association between inflammation, atherosclerosis and atrial fibrillation and its clinical implications. Recent Findings and SummaryAtherosclerosis is a chronic inflammatory disease and inflammation is a triggering factor of atherosclerotic plaque rupture. In addition to coronary artery disease, clinical conditions identified as risk factors for atrial fibrillation (AF) are also associated with the inflammatory state such as obesity, diabetes mellitus, hypertension, heart failure, metabolic syndrome and sedentary lifestyle. Biomarkers of inflammation, oxidative stress, coagulation, and myocardial necrosis have been identified in patients with atrial fibrillation and these traditional risk factors. Some markers of inflammation were identified as predictors of recurrence of this arrhythmia, subsequent myocardial infarction, stroke by embolism, and death. Thus, approaches to manipulate the inflammatory pathways may be therapeutic interventions, benefiting patients with AF and increased inflammatory markers.

Full text

EVIDENCE BASED MEDICINE (L. ROEVER, SECTION EDITOR)
Influence of Inflammation and Atherosclerosis
in Atrial Fibrillation
Rose Mary Ferreira Lisboa da Silva
1
#Springer Science+Business Media New York 2017
Abstract
Background Inflammation markers have been associated
with cardiovascular diseases including atrial fibrillation.
This arrhythmia is the most frequent, with an incidence
of 38/1000 person-years.
Purpose of Review The aims of this study are to discuss the
association between inflammation, atherosclerosis and atrial
fibrillation and its clinical implications.
Recent Findings and Summary Atherosclerosis is a chronic
inflammatory disease and inflammation is a triggering
factor of atherosclerotic plaque rupture. In addition to
coronary artery disease, clinical conditions identified as
risk factors for atrial fibrillation (AF) are also associated
with the inflammatory state such as obesity, diabetes
mellitus, hypertension, heart failure, metabolic syndrome
and sedentary lifestyle. Biomarkers of inflammation, ox-
idative stress, coagulation, and myocardial necrosis have
been identified in patients with atrial fibrillation and
these traditional risk factors. Some markers of inflam-
mation were identified as predictors of recurrence of
this arrhythmia, subsequent myocardial infarction, stroke
by embolism, and death. Thus, approaches to manipu-
late the inflammatory pathways may be therapeutic in-
terventions, benefiting patients with AF and increased
inflammatory markers.
Keywords Atherosclerosis .Atrial fibrillation .
Inflammation .Cardiovascular disease .Thrombogenesis .
Lipid profile
Introduction
There is a link between inflammation, atherosclerosis, and atrial
fibrillation (AF). Therefore, inflammation markers have been
associated with cardiovascular diseases such as coronary artery
disease, peripheral arterial disease, and stroke [1••,2–4].
Inflammation markers have also been used to predict car-
diovascular events in patients with AF. The association be-
tween C-reactive protein (CRP) and AF has been postulated
in conditions such as after coronary bypass surgery, cardio-
version, and catheter ablation [5,6,7•]. Other biomarkers of
inflammation (interleukin-6—IL-6), coagulation (D-dimer
and von Willebrand factor), oxidative stress (growth differen-
tiation factor 15—GDF-15), myocardial necrosis (cardiac tro-
ponin I), renal function (creatinine clearance, proteinuria), and
the natriuretic peptides (N-terminal pro-B-type natriuretic
peptide—NT-proBNP, BNP) play a key role to cardiovascular
events in patients with AF besides the ones known clinical risk
factors [8•,9]. IL-6 has been related to mortality, including
embolic events, major bleeding, and myocardial ischemia. Its
addition to CHA
2
DS
2
-VASc risk score improves reclassifica-
tion by 28% [10•]. However, there is evidence that IL-6 does
not improve the risk prediction if it is associated with other
biomarkers as NT-proBNP, troponin, GDF-15, cystatin C
[11•]. GDF-15 is a marker of inflammation and oxidative
stress. Its association with bleeding and mortality is explained
by its effect on the cellular stress and the inhibition of platelet
aggregation [12].
These emerging factors related to inflammation play an
important role in the pathophysiology of AF and its approach,
This article is part of the Topical Collection on Evidence Based Medicine
*Rose Mary Ferreira Lisboa da Silva
roselisboa@uol.com.br
1
Department of Internal Medicine, Faculty of Medicine, Federal
University of Minas Gerais, Avenue Alfredo Balena, 190, room 246,
Centro, 30130-100 Belo Horizonte, MG, Brazil
Curr Atheroscler Rep (2017) 19:2
DOI 10.1007/s11883-017-0639-0

with prognostic implications. This has more impact, taking
into account the epidemiology of AF. The incidence of AF
is 38/1000 person-years, with approximately 55% female.
There is an increase in its prevalence with age, with 35% of
patients with AF are at least 80 years old. This arrhythmia
increases by two times the risk of heart failure, five times the
risk of stroke and two times the mortality, which is 25% per
year, adjusted for age and sex. Beyond these morbidity and
mortality, the annual cost is $ 26 billion for the management of
patients with AF [13•,14•].
Inflammatory and Atherosclerosis
Atherosclerosis is a chronic inflammatory disease that in-
volves several cells and the immune system in its pathogenesis
in addition to dyslipidemia. The aggression against vascular
endothelium is the first step in the process of atherosclerosis.
This aggression is by irritating stimuli, such as dyslipidemia,
metabolic syndrome, central obesity, sedentary lifestyle, dia-
betes, hypertension, or pro-inflammatory mediators. Thus, ar-
terial endothelial cells begin to express adhesion molecules for
capturing leukocytes on their surfaces. As a result, the perme-
ability of the artery intima layer increases, favoring the en-
trance and retention of lipoproteins (cholesterol-containing
low-density lipoprotein (LDL)) in the subendothelial matrix.
There is leukocyte migration into the intima, monocyte matu-
ration into macrophages, and absorption of lipids, producing
foam cells. Monocytes are induced by chemotactic proteins
for the subendothelial matrix where they differentiate into
macrophages, which in turn capture the oxidized LDL. The
recruitment of smooth muscle cells (SMCs) from the tunica
media of the artery wall into to tunica intima is also part of the
atherosclerotic process. SMCs produce extracellular matrix
molecules, including interstitial collagen and elastin, in the
intima, and form a fibrous cap of the atherosclerotic plaque.
This fully developed plaque consists of cellular elements and
extracellular matrix components, in addition to part of lipids
and necrotic core, which is mainly formed by debris of dead
cells. Unstable plaques (that ruptured) show intense inflam-
matory activity, especially in their side edges, extensive pro-
teolytic activity, little collagen, and thin fibrous cap. There are
few SMCs and abundant macrophages. The lipid or necrotic
core, in the central region of the plaque, presents extracellular
lipid and dead cells. The atherosclerotic plaque rupture allows
blood coagulation components to come into contact with the
tissue factors within the plaque resulting in thrombosis, the
final complication of atherosclerosis [15••].
Inflammation is a triggering factor of atherosclerotic plaque
rupture. The inflammatory cells which accumulate on the plaque
are mainly macrophages derived from monocytes, besides acti-
vated T lymphocytes cells, dendritic cells, and activated degran-
ulation mast cells [16]. Thus, the inflammatory mediators in
atherogenesis are cellular effectors, regulatory cytokines,
chemokines, growth factors, and humoral factors [17].
There is involvement of immune cells in inflammatory ath-
erosclerosis arm. Overexpression of T helper 1-derived cyto-
kines including tumor necrosis factor and interferon-g has
been associated with plaque destabilization. Moreover, regu-
latory T cells and B cells are involved in pro- and anti-
atherogenic actions. B-2 cells (subtype of cells B—classical
B cells) appear to be pro-atherogenic effects and B-1 cells
appear to attenuate the atherosclerotic process through the
secretion of IL-10 [18].
However, despite the experimental studies having shown par-
ticipation of inflammation and immunity in atherogenesis, their
role in human atherosclerosis is not well established [19].
Moreover, approximately 75% of the coronary heart disease
single-nucleotide polymorphisms occur in or near genes without
obvious linkages with atherothrombosis. And new perspectives
on the molecular pathways include the role of micro-RNAs as
fine tuners of atherosclerosis progression [20].
Inflammation, Atherosclerosis, Risk Factors, and Atrial
Fibrillation
Despite the knowledge that structural and electrical changes in
the atria may trigger and perpetuate AF [13•], the relationship
between inflammation and AF is evidenced by conditions
such as pericarditis, postoperative cardiac surgery, and myo-
carditis [21••]. Furthermore, clinical conditions identified as
risk factors for AF are also associated with the inflammatory
state such as obesity, diabetes mellitus, hypertension, metabol-
ic syndrome, sedentary lifestyle, heart failure, and coronary
artery disease [14•].
In obese patients, there is the secretion of pro-inflammatory
cytokines and infiltrating immune cells such as macrophages.
These cytokines reach the atrium and the blood circulation by
means of paracrine factors [22••]. In order to promote inflam-
mation and insulin resistance in obese individuals, other my-
eloid immune cells are involved, including neutrophils, eosin-
ophils, and mast cells. There is also evidence of increased
levels of IL-17 and IL-22 in obesity, which may explain the
predisposition of those subjects to diseases mediated by in-
flammation [23]. Another mechanism that explains the rela-
tionship between obesity and AF is the increase of the left
atrium [13•].
Diabetes mellitus increase the risk of developing AF in
40% and it is estimated that 2.5% of patients with AF have
diabetes [14•]. In diabetic patients, there is an increase of
inflammatory and pro-coagulant biomarkers. The pro-
inflammatory cytokines such as IL-6 and tumor necrosis
factor-alpha (TNF-α) are increased and related to atheroscle-
rosis. There is an increase in plasminogen activator inhibitor-1
levels which is a potent inhibitor of fibrinolysis. Another bio-
marker of hypercoagulability, D-dimer, also has its increased
2 Page 2 of 7 Curr Atheroscler Rep (2017) 19:2

plasma levels in diabetics as well as Von Willebrand factor, a
biomarker of endothelial dysfunction [24•]. All these bio-
markers are involved in the development and progression of
atherosclerosis leading to cardiovascular events.
Among patients with AF, 49 to 90% have high blood pres-
sure [25•]. Experimental studies demonstrate the role of an-
giotensin II in immune cell activation and stimulus for secre-
tion of IL-6, IL-8, and TNF-α[22••]. There is also activation
of effector T lymphocytes with production of pro-
inflammatory mediators such as IL-17 [26]. Activation of
the renin-angiotensin-aldosterone system also occurs by in-
creasing the pressure of the left ventricular diastolic in hyper-
tensive patients. Another structural remodeling mechanism to
deflagrate AF is atrial fibrosis [22••,26].
The metabolic syndrome is a cluster of risk factors for
cardiovascular disease including diabetes, hypertension, obe-
sity, and dyslipidemia. These risk factors are also associated
with sedentary lifestyle and unhealthy diet. Thus, there is a
link between metabolic syndrome and AF [27].
Many risk factors are similar to heart failure and AF.
Therefore, there is an increase of the prevalence of AF [14•].
Heart failure can precede or follow AF. A third of patients
with AF have heart failure and more than half of patients with
heart failure have AF [28•]. In addition to the structural mech-
anisms, neurohormonal activation is also responsible for this
vicious cycle.
The relationship between inflammation and atherosclerosis
has been previously discussed in this text. Coronary artery
disease (CAD) is a systemic condition with immune inflam-
matory components. AF risk factors also are similar to CAD.
The prevalence of CAD in patients with AF is 36 to 82% and
occurs in subclinical coronary atherosclerosis in 74% of pa-
tients with AF [29]. Beyond the relationship between ische-
mia, atrial infarction, inflammation, and AF, there is the role of
platelet-bound stromal cell-derived factor-1[30]. In patients
with AF and ischemic heart disease, there is an increase of
plasma stromal cell derived factor-1 compared to patients with
sinus rhythm. This factor may be involved in atrial remodeling
because of its association with the recruitment of inflammato-
ry cells.
In the literature, there are evidences of interaction between
systemic atherosclerosis and occurrence of non-valvular AF
[31•,32–34,35•]. In the Atherosclerosis Risk in Communities
(ARIC) study with 14,462 participants initially without CAD,
after a median clinical follow-up of 21.6 years, the association
between AF and myocardial infarction was observed, espe-
cially in women [31•]. Persistent/permanent AF was one of
the independent predictors of abnormal carotid intima-media
thickness, suggesting a greater atherosclerotic burden in these
patients with AF [32]. It was also observed an association
between coronary artery calcium and increased risk of AF
mainly in patients under 61 years of age [33]. In the Multi-
Ethnic Study of Atherosclerosis (MESA) study, with 6568
participants, the ankle-brachial index <1.4, indicating periph-
eral arterial disease, was associated with the development of
AF during follow-up of 8.5 years. There was also an associa-
tion between peripheral artery disease and stroke, but not me-
diated by AF [34]. In addition to the association between
cardiovascular risk factors and the incidence of AF, these risk
factors were elevated more than 15 years before the diagnosis
of AF, with the increasing prevalence of stroke, myocardial
infarction, and heart failure close to diagnostic AF [35•].
There are other risk factors for AF whose pathogenesis is
by atrial structural or electrical abnormalities or autonomic
stimulation [36••]. Ageing causes structural changes in the
heart and atrial fibrosis. Among patients with AF, 30% have
some type of heart valve disease. The increased pressure and/
or volume of the left atrium in patients with mitral valve dis-
ease or prosthetic heart valves are responsible for the atrial
remodeling and possible pathophysiology of AF. In patients
with inherited cardiomyopathies, including channelopathies,
the arrhythmogenic mechanisms are implicated in the gener-
ation AF. Vagal activation, hypoxia, and hypercapnia, beyond
inflammation, are triggering AF in patients with sleep apnea
and chronic obstructive pulmonary disease. Athletes may
have AF by increased vagal tone and atrial volume. Other risk
factors are chronic renal failure, hyperthyroidism, alcoholism,
smoking, and genetic predisposition [13•,36••]. There is also
an association between AF and uric acid, which may be a
marker of arrhythmia or a target of treatment [37].
Clinical Evidence and Implications
The process of inflammation and AF is quite complex. Local
or systemic inflammation results in AF and AF promotes in-
flammation. High levels of neutrophils and lymphocytes and
inflammatory markers have been reported in patients with AF
compared with those in sinus rhythm. Inflammation induces
structural and electrical remodeling, which triggers the AF. In
turn, AF induces an inflammatory response by mechanisms
not yet fully understood, perpetuating arrhythmia [22••].
There is also a relationship between inflammation and
thromboembolism. Inflammatory biomarkers (CRP, IL-6) in-
duce endothelial dysfunction and increase the expression of
von Willebrand factor, triggering clotting [22••,38]. The pro-
inflammatory cytokines partially activate the leukocytes,
which can activate platelets and interact with them, contribut-
ing to the pro-thrombotic state.
Thus, due to the association between inflammation and AF,
various mediators of inflammation have been studied. These
inflammatory mediators can be used to identify patients at risk
for AF and also risk of subsequent myocardial infarction,
stroke by embolism, and mortality (Table 1)[8•,10•,11•,
21••,22••,38,40].
CRP is an acute phase reactant synthesized by hepatocytes
and is a prototype of inflammation marker. Its synthesis is
Curr Atheroscler Rep (2017) 19:2 Page 3 of 7 2

stimulated by the interleukins, such as IL-6. It induces chemo-
taxis mediated by monocyte chemoattractant protein-1 and in-
duces pro-coagulant activity [8•,21••]. CRP has been associated
to recurrence of AF and myocardial infarction [6,7•,10•,21••].
IL-6 is produced by immune cells and accessory immune cells
(such as monocytes and macrophages) and vascular smooth
muscle cells, endothelial cells, and ischemic cardiomyocyte
[21••]. This marker has been associated with stroke, systemic
embolism, major bleeding, and death. Also, it has been associat-
ed with recurrence of AF after cardioversion and ablation [7•,8•,
10•,21••,22••]. In patients with AF and use of oral anticoagu-
lants, this biomarker was significantly associated with increased
risk of mortality after adjusting for clinical factors. However,
there is evidence that IL-6 does not improve the risk prediction
if it is associated with other biomarkers [11•].
IL-2 is produced mainly by activated T lymphocytes [21••].
This interleukin is associated with shortening of the duration
of the action potential by abnormal calcium processing.
Therefore, it can cause atrial electrical remodeling. Its role in
AF prediction is not well determined, but it is a predictor of
AF after cardioversion [22••].
The evidence of the influence of IL-1 in the pathogenesis of
AF is not well determined. There are differences in IL-8 and
IL-10 levels in patients with AF occurring after surgery.
Regarding IL-18, there is increasing level in patients with
AF recurrence after cardioversion [22••].
Other pro-inflammatory molecule is TNF-α, which is syn-
thesized by macrophages and monocytes. It has pleiotropic
properties. It interferes with calcium homeostasis, shortening
of the duration of the action potential. It actives fibroblasts
with atrial fibrosis. TNF-αalso increases cardiomyocyte apo-
ptosis and myolysis. All these actions contribute to the struc-
tural and electrical atrial remodeling and greater vulnerability
towards atrial fibrillation [22••]. In patients with rheumatic
valvular AF, there is a correlation of this marker with increas-
ing diameter of the left atrium. TNF levels are also increased
higher in patients with persistent AF than in those with par-
oxysmal AF. This marker was also a predictor of ischemic
stroke in patients with non-valvular AF [21••,22••].
Galectin-3 is carbohydrate-binding protein that has
action on macrophage chemotaxis, phagocytosis, neutro-
phil extravasation, proliferation, oxidative stress, apopto-
sis, and angiogenesis. Therefore, it has been implicated
in the pathogenesis of atherosclerosis [39]. In patients
without structural heart disease undergoing ablation of
persistent AF, its high plasma levels were predictors of
arrhythmia recurrence [40].
Thus, approaches to manipulate the inflammatory path-
ways may be therapeutic interventions, benefiting patients
with AF and increased inflammatory markers. There is
evidence that the colchicine prevents the occurrence of
AF after cardiac surgery and after ablation. Its action is
attributed to the decrease in CPR and IL-6 [22••].
Nevertheless, more studies are necessary, given that a
meta-analysis showed that colchicine did not reduce the
occurrence of AF significantly, postoperatively [41••].
Corticosteroids can reduce the incidence of AF in the
postoperative period of cardiac surgery. The single mod-
erate prophylactic dose of dexamethasone or hydrocorti-
sone demonstrated this benefit [42]. However, its adverse
effects must be considered, such as hyperglycemia, infec-
tion, gastrointestinal bleeding [22••].
Other therapies have been directed towards the use of an-
tioxidants such as N-acetylcysteine, vitamin C and E in com-
bination with N-3-polyunsaturated fatty acids, which can de-
crease the incidence of AF after cardiac surgery that reaches
60% with a peak in the second and third days [43].
Statins have anti-inflammatory and anti-oxidative proper-
ties. Meta-analysis of randomized controlled trials showed
that pretreatment with statins decreased by approximately
two thirds the risk of postoperative AF in patients undergoing
cardiac surgery [44••]. The postulated mechanisms are reduc-
tion of lipids, plaque stabilization, reduction of levels of CPR,
and antioxidant and antiarrhythmic effects. A population-
based case-control study demonstrated that long-term statin
use before diagnosis of AF reduces the risk of patients devel-
oping AF compared to the group of individuals who have
never used a statin [45].
Tabl e 1 Inflammatory mediators
related to AF Inflammatory
mediators
Secretion Influences in AF
CRP hepatocytes recurrence of AF and myocardial infarction
IL-6 monocytes, macrophages,
cardiovascular components
risk of recurrence of AF and death
IL-2 activated T lymphocytes predictor of AF after cardioversion and surgery
IL-18 monocytes and macrophages recurrence AF after cardioversion
TNF-αmonocytes and macrophages predictor of ischemic stroke
Galectin-3 activated macrophages fibrotic and inflammatory processes with AF
recurrence after catheter ablation
CRP: C-reactive protein; IL: interleukin; TNF-α: tumor necrosis factor-alpha.
2 Page 4 of 7 Curr Atheroscler Rep (2017) 19:2

Other drugs for the prevention of AF are angiotensin-
converting enzyme inhibitors and angiotensin receptor
blockers. The role of angiotensin II in the pathogenesis
of AF was detailed above when treating hypertension as
one of the AF risk factors. In hypertensive patients, there
was less risk of new-onset AF with the use of angiotensin-
converting enzyme inhibitors or angiotensin receptor
blockers. Among patients with previous stroke or tran-
sient ischemic attack, angiotensin receptor blockers were
better than angiotensin-converting enzyme inhibitors to
reduce the risk of AF [46]. In patients with
nonparoxysmal AF and low left ventricular ejection frac-
tion undergoing ablation, the use of angiotensin-
converting enzyme inhibitor was associated with im-
proved outcome [47].
To better score risk stratification, more accessible bio-
markers have been used to compose a score that also includes
the age and history of stroke or transient ischemic attack. It is
the ABC-stroke score. The biomarkers are troponin and NT-
proBNP [48,49]. This score is a predictor of stroke and sys-
temic embolism with higher accuracy than both the
CHA
2
DS
2
-VASc and ATRIA scores for patients with AF in
use of oral anticoagulants.
Future Directions for Randomized Clinical Trials Based
on the Current State of the Art
As the pathophysiology of AF is multifactorial, the ap-
proach must be personalized. Similar to the decision on
rhythm or frequency control, based on conditions such as
age, symptoms, left atrial size, ventricular systolic dys-
function, i.e., clinical and imaging parameters, biomarkers
maybeusedtopredicttheriskofAF[50].
To identify patients at risk for AF, randomized trials are
required for refined screening with the use of biomarkers.
This successful approach may have a favorable impact on
morbidity and mortality by preventing the persistence of ar-
rhythmia. However, despite the prevention of AF, the use of
targeted therapies for inflammation may not be associated
with reduction of inflammation markers. A randomized con-
trolled trial of 212 consecutive patients without prior AF un-
dergoing first-time on-pump coronary artery bypass grafting
and treated with 80 mg of atorvastatin for 7 days prior to
surgery demonstrated a reduction in the incidence of arrhyth-
mia. Nevertheless, there was no reduction in the levels of
high-sensitive CRP or IL-6 [51].
Randomized clinical trials should consider comorbidities,
gender differences, and different nonpharmacological and phar-
macological treatments for AF patients. Basic and clinical re-
search methods for risk stratification of patients with AF should
include the complex interaction between risk factors, structural,
ionic, electrical, autonomic, and genetic changes [52].
Conclusions
Therefore, the identification of inflammatory markers related
to AF improves not just the knowledge of the pathophysiolo-
gy of this common arrhythmia, as well as its risk prediction.
On the other hand, atherosclerosis is one of the risk factors for
AF. Thus, research on targeted therapies for inflammation and
atherosclerosis is essential for individual approach to patients
with AF. However, the approach directed to inflammation
may not result in a decrease in inflammatory markers despite
reduced recurrence of the arrhythmia.
Compliance with Ethical Standards
Conflict of interest Rose Mary Ferreira Lisboa da Silva declares to
have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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