Inflamm. Res. (2015) 64:383–393 DOI 10.1007/s00011-015-0827-8
Inflammation Research
REVIEW
Inflammation, a link between obesity and atrial fibrillation Alina Scridon1 • Dan Dobreanu1,2 • Philippe Chevalier3 • Ra˘zvan Constantin S¸ erban1,2
Received: 2 April 2015 / Revised: 21 April 2015 / Accepted: 23 April 2015 / Published online: 1 May 2015 Springer Basel 2015
Abstract Despite the long belief that the role of the adipose tissue was restricted to that of a passive store of triglycerides and a rich source of fatty acids, accumulating data demonstrates that the adipose tissue acts as an endocrine organ, capable of producing a large number of cytokines incriminated in generating a systemic inflammatory status. At its turn, this adiposity-related proinflammatory status appears to promote a large range of cardiovascular disorders, including atrial fibrillation (AF). Recent studies suggest that, in addition to systemic adiposity, the volume of the pericardial fat of the entire heart, and particularly of that overlying the atria, may represent an even more important risk factor for AF. This review focuses on the most relevant clinical and experimental data that bridge adiposity-induced inflammation and AF, and provides, through a multidisciplinary approach, a discussion that integrates both the current knowledge regarding the prolific activity of systemic and pericardial adipose tissue as sources of inflammatory mediators and the main effects of adiposity-induced inflammation on the most relevant electrophysiological, structural, and autonomic mechanisms responsible for AF.
Responsible Editor: John Di Battista. & Alina Scridon [email protected] 1
Physiology Department, University of Medicine and Pharmacy of Tıˆrgu Mures¸ , 38, Gheorghe Marinescu Street, 540139 Tıˆrgu Mures¸ , Romania
2
Emergency Institute for Cardiovascular Diseases and Transplantation Tıˆrgu Mures¸ , 540136 Tıˆrgu Mures¸ , Romania
3
Service de Rythmologie, Hospices Civils de Lyon, Hoˆpital Louis Pradel, 69500 Bron Cedex, France
Keywords Inflammation Adipokines Atrial fibrillation Obesity Pericardial fat
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. The presence of the arrhythmia leads not only to important decrease in the quality of life, but also to substantial morbidity and mortality from stroke, heart failure, cognitive decline, and dementia [1]. Together with heart failure and type II diabetes mellitus, AF is considered to be one of the three growing cardiovascular epidemics of the 21st century [2]. Large epidemiological studies have identified advancing age, diabetes mellitus, hypertension, heart failure, and coronary artery disease as the most important risk factors for non-valvular AF [3]. In a prospective study including over 3500 patients, Gami et al. reported a 14 % increase in the prevalence of AF over 4.7 years of follow-up, identifying male gender, advancing age, hypertension, coronary artery disease, heart failure, and smoking as the most relevant risk factors for AF [4]. Particularly, the increasing proportion of the elderly population, which seems to be more ‘ill’ than it was a few decades ago and to present more often hypertension, diabetes mellitus, heart failure, coronary artery, and valvular heart disease, was considered to underlie this AF epidemic [5]. Indeed, the Rochester study, developed over a period of 30 years, demonstrated an increase in the prevalence of coronary artery disease, valvular heart disease, a history of prior myocardial infarction, and to a lesser extent of heart failure and diabetes mellitus with advancing age [6]. However, the relatively modest increase in the prevalence of these widely accepted risk factors for AF can only
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partially explain the twofold to threefold increase in the prevalence of AF over the last 30 years. One other factor that may explain this finding is obesity, whose prevalence is increasing worldwide, paralleling the escalation in the AF prevalence. The association between body mass index (BMI), the most widely used marker of obesity, and both AF occurrence and persistence has been demonstrated in a large number of studies [7]. BMI was identified as a strong predictor of incident AF, with every 1 kg/m2 increase in BMI causing a 3–8 % higher risk for new-onset AF [4, 8]. In the same vein, the meta-analysis of Wanahita et al., including 16 population-based and postcardiac surgery cohort studies, demonstrated a 49 % increase in the risk of incident AF with obesity, and this risk increased in parallel with increased BMI [7]. Similar associations between BMI and AF were also found in the Manitoba follow-up study [9], the Renfrew/Paisley Study [10], and the Multifactor Primary Prevention Study [11]. Conceptually, this association is unsurprising, given that obesity is frequently associated with traditional risk factors for AF, promoting and aggravating comorbidities such as hypertension, ischemic heart disease, diabetes mellitus, or heart failure, all of which have been incriminated in AF occurrence (Fig. 1). Nevertheless, large studies including age- and sex-matched normal-weight referents demonstrated that even after correction for potential confounders such as hypertension, diabetes mellitus, heart failure or smoking, obesity remains an independent risk factor for AF genesis and progression [8], associating a 2.4-fold increase in the risk of AF [12].
On the contrary, in a traditional African population in whom waist circumference and BMI were very low, Koopman et al. reported extremely low rates of AF (0.3 %), further supporting a causal relationship between obesity and AF [13]. Interestingly, recent data suggest that, despite the independent association between obesity and AF, this relationship may actually be less evident in patients older than 65 years [14]. While at younger age every 5 kg/m2 increase in BMI was associated with a 15 % increase in the risk of new-onset AF, this was far less significant in elderly individuals [4]. These findings suggest that, with advancing age, the pathophysiological impact of other aging-related factors such as hypertension, ischemic heart disease, or heart failure may actually overwhelm the deleterious effects of obesity.
Fig. 1 Venn diagram demonstrating the overlap between obesity, atrial fibrillation, and selected clinical correlates. One or several of these clinical correlates often provide the link between obesity and atrial fibrillation. However, an area of overlap unmediated by any of the classical clinical correlates can also be noticed, indicating a direct link between obesity and atrial fibrillation
Fig. 2 Mechanisms linking obesity to atrial fibrillation. Obesityrelated cardiac and non-cardiac conditions (outer circle) promote pathophysiological mechanisms (middle circle) that eventually favor the genesis and the persistence of the arrhythmia by causing atrial remodeling, autonomic imbalance, and increasing atrial ectopic activity (inner circles). AF atrial fibrillation
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Mechanisms linking obesity to atrial fibrillation Although numerous studies have demonstrated a direct association between obesity and AF, the mechanisms linking these two conditions are far from clear. So far, a number of different pathophysiological mechanisms (Fig. 2), including atrial dilation, neurohormonal activation, and increased left ventricular diastolic filling pressure, have been proposed to explain this association. Particularly, cardiac remodeling in response to obesity appears as a key element in obesity-related AF. Metabolic, hemodynamic, and ischemic abnormalities seen in obese
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patients seem to account for significant alterations in atrial electrophysiology and structure. Left atrial (LA) dilation, an important AF precursor, is a common finding among obese patients [15]. Obesity-related alterations such as increased plasma volume, left ventricular diastolic dysfunction, and enhanced neurohormonal activity may underlie this finding [16]. Indeed, a 10-year echocardiographic follow-up study in obese patients demonstrated a 2.4-fold increase in LA volume [17]. In the Framingham Heart Study, although BMI was significantly associated with the risk of new-onset AF in univariate analysis, the correlation was lost when corrected for LA diameter, suggesting that LA dilation may be one of the most important mechanisms linking obesity to AF [8]. The strong, causal relationship between obesity and obstructive sleep apnea could also explain, at least partially, the increased AF propensity seen in obese patients [18]. Multiple pathophysiological mechanisms related to obstructive sleep apnea, including autonomic imbalance with sympathetic overactivity, prolonged and repetitive hypoxemia episodes, abnormal heart rate variability, hypoxic pulmonary vasoconstriction, left ventricular diastolic dysfunction, and increased cardiac wall stress due to exaggerated intrathoracic pressure variations, could be involved in AF pathogenesis. However, in the study of Gami et al., despite a strong association between obstructive sleep apnea and incident AF, BMI predicted new-onset AF independent of the presence of obstructive sleep apnea, suggesting that although obstructive sleep apnea may participate to AF occurrence in obese patients, this cannot be the only link between obesity and AF [4]. Inflammation, a link between obesity and atrial fibrillation Obesity has been associated with low-grade systemic inflammation, while inflammation is known to promote both AF onset and persistence. Taken together, these two observations suggest that obesity-induced systemic inflammation may provide a direct link between obesity and AF. Atrial fibrillation—an inflammatory disorder Evidence for an inflammatory contribution to AF was initially suggested by the high incidence of AF in inflammatory conditions such as pericarditis and myocarditis [19], as well as after cardiac surgery [20]. Moreover, in the post-cardiac surgery setting, the temporal course of AF occurrence correlates well with the dynamics of the inflammatory status. Bruins et al. found that interleukin (IL)-6 rises initially and peaks 6 h after surgery, while C-reactive protein (CRP) levels peak on post-
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operative day 2, with complement-CRP complexes peaking on post-operative day 2 or 3 [20]. The incidence of postoperative AF follows a similar pattern, peaking on postoperative day 2 or 3. Additionally, in patients with metastatic melanoma or renal cell carcinoma, intravenous administration of high-dose recombinant IL-2 was associated with high incidence of AF, further supporting a direct, causal relationship between inflammation and AF [21]. Numerous other studies have also demonstrated a strong correlation between inflammatory markers’ levels and the presence or the future development of AF. CRP, a sensitive marker of inflammation, has probably been best studied in relationship with AF. Chung et al. were among the first to demonstrate a strong association between elevated plasma CRP levels and AF [22]. Moreover, patients with persistent AF presented significantly higher levels of CRP than those with paroxysmal AF, suggesting that inflammation might participate not only to AF induction, but also to the maintenance of the arrhythmia. Later on, an increasing number of studies provided similar results, demonstrating that CRP levels are higher in AF patients compared to controls with no history of AF, and higher in persistent AF patients compared to paroxysmal AF patients [23]. Similarly, higher levels of high-sensitivity CRP (hs-CRP), IL-6, and tumor necrosis factor alpha (TNF-a) were also reported in the plasma of AF patients compared with sinus rhythm controls [24]. Elevation of fibrinogen and complement activation may also contribute to AF occurrence and perpetuation, as evidenced by the high plasma fibrinogen levels and activated C3 and C4 complement isoforms in the presence of AF [20]. The higher incidence of AF during winter reported in one epidemiological study adds further support for a causal relationship between inflammation and AF, the authors suggesting that an inflammatory response to infectious diseases in winter may be responsible for AF frequency escalation in this season [25]. Finally, the presence of inflammatory infiltrates, myocyte necrosis, and fibrosis in atrial biopsy specimens from patients with lone AF refractory to antiarrhythmic therapy, together with the complete absence of such abnormalities in atrial biopsies from sinus rhythm controls, further supports the role of inflammation in AF pathogenesis [26]. Furthermore, the role of inflammation does not seem to be confined to promoting AF genesis and persistence. A significant number of studies have also related inflammation to a decreased likelihood of effective pharmacological or electrical cardioversion, as well as to a higher risk of AF recurrence after successful cardioversion. In several studies, high baseline CRP, TNF-a, IL-6, IL-2, IL-10, and serum amyloid A levels were strong predictors of AF recurrence after successful cardioversion, whereas lower levels of plasma CRP correlated to an increased likelihood of successful cardioversion [23, 27].
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Using a prospective study over 9.4 years, Hermida et al. provided the first proof that inflammation may also be a strong predictor of mortality among AF patients [28]. The authors demonstrated that higher hs-CRP levels were associated with increased mortality in AF patients, independent of other cardiovascular risk factors, with mortality rates approximately twice higher in AF patients with the highest hs-CRP levels compared to those in the lowest tertile. On the other hand, aggressive CRP lowering strategies using drugs that possess known antiinflammatory effects, such as glucocorticoids, N-3 fatty acids, statins, angiotensin converting enzyme inhibitors (ACEIs), or angiotensin II receptor blockers (ARBs), seem to efficiently alleviate the AF burden [29, 30]. The corresponding reduction in AF prevalence with these agents appears to be proportional with the degree of CRP lowering [23, 30]. Moreover, experimental studies have also suggested that part of the potent antiarrhythmic effect of amiodarone may actually rely on an antiinflammatory effect, via suppression of synthesis of several cytokines, including IL-6 and TNF-a [31]. In the same vein, Merritt et al. reported that carvedilol, which was efficient in reducing post-operative AF, may also have antiinflammatory and antioxidant properties [32]. Taken together, these results validate the pivotal role that inflammation plays in AF genesis and persistence. The decrease in inflammatory marker levels observed after cardioversion may suggest that at least part of the inflammatory syndrome observed in these patients may be due to AF itself. On the other hand, data such as the increased incidence of AF in the setting of inflammatory states such as cardiac surgery or pericarditis, and the observation that baseline CRP levels predict future occurrence of AF, incriminate an initial inflammatory status in AF genesis. It is also likely that inflammation and AF favor and aggravate each other, generating a vicious circle. The adipose tissue—a prolific source of inflammatory cytokines For a long time, the role of the adipose tissue was considered to be restricted to that of a passive store of triglycerides and a rich source of fatty acids. However, an increasing number of evidence demonstrated that the adipose tissue acts as an endocrine organ, capable of producing a large number of cytokines incriminated in generating a systemic inflammatory status. At its turn, this obesity-related pro-inflammatory status appears to be involved in a large range of cardiovascular disorders. Given that high CRP levels, a classic marker of systemic inflammation, have been related to an increased risk of future AF, while obese patients appear to present substantially higher plasma levels of CRP compared to
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Fig. 3 Schematic representation of adipocytes as a source of both pro-inflammatory and antiinflammatory factors that modulate the inflammatory response. Molecules depicted in red act as proinflammatory factors, promoting systemic inflammation. The proinflammatory effects of factors such as leptin, resistin, and Angptl2 are modulated via macrophage activation. Molecules depicted in blue act as antiinflammatory factors. Angptl2 angiopoietin-like protein 2, IL-1b interleukin-1b, IL-1RA IL-1 receptor antagonist, IL-6 interleukin-6, IL-8 interleukin-8, IL-10 interleukin-10, MCP-1 monocyte chemoattractant protein-1, TGF-b transforming growth factor beta, TNF-a tumor necrosis factor alpha
normal-weight subjects [33], it has been hypothesized that at least part of the increased risk of AF seen in obese patients may be due to this obesity-induced low-grade systemic inflammation. The adipose tissue may promote systemic inflammation through three main pathways: lipotoxicity-induced inflammation, secretion of various factors that stimulate the synthesis of inflammatory mediators in other tissues, and secretion of inflammatory factors by the adipose tissue itself [34]. However, it appears that in obese patients, most of the inflammatory cytokines originate within the adipocytes themselves [35] (Fig. 3). These pro-inflammatory cytokines, together with a number of protective factors also expressed and synthesized by the adipose tissue, are termed collectively adipocytokines. The adipose tissue is recognized as a prolific source of both primary inflammatory cytokines and specific inflammatory mediators. Primary inflammatory cytokines include IL-6, IL-8, IL1b, interferon-c, TNF-a, and TGF-b [36]. Among these cytokines, TNF-a and IL-6 appear to play a central role in obesity-induced inflammation. Furthermore, it appears that serum concentrations of both IL-6 and TNF-a correlate significantly with the amount of adiposity, as quantified by the BMI [37, 38]. One of the most relevant clinical proofs for the role of the adipose tissue in generating a low-grade systemic inflammation was provided by Marfella et al. The authors demonstrated increased serum levels of CRP, TNF-a, IL-6,
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and IL-18 in a population of 67 obese females compared to 40 non-obese controls [39]. In multivariate analysis, BMI and the waist-to-hip ratio were the only independent predictors of increased serum levels of IL-6, TNF-a, and CRP. Furthermore, a significant 10 % reduction in body weight was associated with relevant reductions in IL-6, IL-18, TNF-a, and CRP concentrations. More recently, Fontana et al. provided more evidence for the adipose tissue as origin of obesity-related systemic inflammation [40]. By determining adipokine concentrations in portal vein and radial artery plasma samples from 25 extremely obese patients during gastric bypass surgery, the authors showed that portal vein plasma IL-6 levels correlated and were significantly higher than peripheral artery levels, indicating visceral fat as the main source of IL-6 in these patients. Since IL-6 is one of the most potent stimulators of CRP synthesis by the liver, the observation of a direct secretion of IL-6 into the portal vein provided evidence for the existence of a direct link between visceral fat and systemic inflammation. Besides these pro-inflammatory cytokines, the adipose tissue also produces a number of antiinflammatory factors such as IL-1 receptor antagonist, which blocks selectively the activity of IL-1, and IL-10, a factor with intrinsic antiinflammatory properties [41]. The adipose tissue has been found to secrete more than 50 cytokines and other inflammation-promoting molecules. While some of these molecules can also be synthesized by other cells, particularly the macrophages, others are specific or mainly synthesized by the adipose tissue. Once synthesized, these specific inflammatory mediators act on a variety of tissues, through endocrine, paracrine, autocrine, or juxtacrine mechanisms, influencing different physiological and pathophysiological processes. These specific inflammatory mediators include molecules such as leptin, adiponectin, resistin, and angiopoietin-like protein 2 (Angptl2). Circulating levels of leptin, a molecule synthesized primarily by the adipose tissue, have been correlated with the mass of body adiposity. Once synthesized, leptin promotes systemic inflammation by acting at various levels, increasing phagocytic activity [42] and enhancing synthesis of leukotrienes, nitric oxide, and various proinflammatory cytokines by macrophages and monocyte cells [43]. Furthermore, leptin has been shown not only to promote chemotaxis and release of reactive oxygen species by the neutrophils [44], creating a systemic pro-oxidant environment, but also to induce proliferation, differentiation, activation, and cytotoxicity of natural killer cells [45]. At whole-body level, one of the main targets of leptin is represented by the macrophages, and leptin mRNA expression and circulating leptin levels are strongly modulated by various inflammatory mediators such as IL-1
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and IL-6 [46]. Experimental studies demonstrated that mice with genetic leptin deficiency are less prone to develop inflammatory diseases [47], while leptin administration promoted both inflammation and platelet activation and increased T-cells-mediated inflammation of the liver [48]. Taken together, these observations indicate that leptin, a pleiotropic hormone involved in body weight regulation, plays a significant role in generating systemic inflammation in obese patients. Furthermore, recent data suggest that leptin may be responsible for modulating the development of atrial fibrosis in response to overactivation of the reninangiotensin system [49]. Adiponectin is an adipocyte-derived plasma protein widely recognized for its protective effects against obesity and obesity-related inflammatory-based disorders such as atherosclerosis, type II diabetes mellitus, or rheumatoid arthritis. Adiponectin intervenes at various levels of inflammatory responses, promoting apoptotic cells phagocytosis and preventing accumulation of cell detritus [50], preventing monocyte adhesion to endothelial cells, and reducing the release of inflammatory proteins such as TNF-a [51]. Furthermore, treatment with recombinant adiponectin proved efficient in diminishing hepatic inflammation in a mouse model of steatohepatitis [52]. Carnevale et al. recently demonstrated significantly lower plasma levels of adiponectin in AF patients compared to sinus rhythm controls [53], while Shimano et al. showed a significant correlation between adiponectin levels and plasma levels of serum carboxy-terminal telopeptide of collagen type I, a degradation marker of type I collagen, among persistent AF patients, linking adiponectin to LA structural remodeling [54]. Resistin and adiponectin exhibit opposite inflammatory effects. However, while adiponectin is an adipocytederived plasma protein, resistin secretion is not confined to adipose cells. Actually, the relevant secretion of resistin by monocytes and macrophages is one of the strongest arguments supporting the involvement of resistin in inflammatory processes [34]. Furthermore, in several studies, plasma resistin levels significantly correlated with cell adhesion molecules and other markers of inflammation [55], while in mononuclear cells resistin has been shown to promote IL-6 and TNF-a synthesis [56]. Experimental studies demonstrated that high levels of other factors secreted by the adipose tissue, such as Angptl2, are also associated with systemic inflammation [57]. Angptl2-induced inflammation appears to involve monocyte and macrophage activation via integrin signaling. In mice, Angptl2 activation induced chronic inflammation characterized by leucocyte adhesion to vessel walls and increased vascular permeability. Additionally, deletion of the Angptl2 gene was associated with reduced inflammation, while Angptl2 gene overexpression promoted inflammation [57].
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All these experimental and clinical data reinforce the belief that the adipose tissue, besides being a passive store for triglycerides and a major source of fatty acids, is also capable of generating a low-grade inflammatory syndrome, which, in turn, may contribute to the high AF propensity observed in obese patients. At present, adipocytes are acknowledged as a prolific source of inflammatory mediators that may directly contribute to AF pathogenesis. Meanwhile, factors such as adiponectin, IL-1 receptor antagonist, and IL-10 seem to confer protection against obesity-related inflammatory-based disorders, including AF. Further studies are expected to provide more insights into the obesity–inflammation–AF relationship, to identify new adipocyte-derived mediators and new therapeutic targets for AF prophylaxis.
Pericardial fat—a new paradigm in the obesity– atrial fibrillation relationship Recent cardiac computed tomography and magnetic resonance imaging studies suggested that, in addition to systemic adiposity, the volume of the pericardial fat of the entire heart, and particularly of that overlying the atria, may represent another important risk factor for AF. More importantly, the effect of pericardial fat on AF burden appears to be independent of other traditional risk factors for AF, including BMI, every 10 ml increase in pericardial fat volume being associated with a 13 % escalation in the odds of AF [58]. The direct involvement of the adipose tissue surrounding the heart in AF pathogenesis is further supported by the study of Thanassoulis et al., who demonstrated that, after adjusting for established AF risk factors, including BMI, pericardial fat, but not intrathoracic or visceral abdominal fat, was significantly associated with prevalent AF [59]. These results, together with the observation of a stronger association between pericardial fat and AF occurrence compared to that between BMI and AF, suggest that adipose tissue location may actually be more important than its abundance. Furthermore, even for the adiposity surrounding the heart, significant interregional differences seem to exist. While the volume of the adipose tissue of the entire heart has been most widely studied in association with AF, the volume of periatrial adiposity may be an even better predictor of future AF [60]. Among 49 patients with paroxysmal or persistent AF, Girerd et al. reported a significant correlation between several inflammatory markers’ levels and the thickness of periatrial fat located between the LA and the esophagus or between the LA and the descending aorta, while no correlation was found between the thickness of total, ventricular, or interventricular groove adiposity and any of the tested inflammatory markers,
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suggesting that pericardial fat surrounding the LA, rather than the pericardial fat itself, is a key determinant of inflammation in AF patients [61]. Similar results were reported by Batal et al., who found that the periatrial fat that correlated the best with AF burden was that located posteriorly, between the esophagus and the LA [60]. Inflammation, a link between pericardial fat and atrial fibrillation Although the precise mechanisms underlying the relationship between pericardial fat and increased AF propensity are not fully elucidated, recent experimental and clinical studies have provided valuable insights. By producing inflammatory cytokines and causing interactions with atrial myocytes, pericardial fat may have direct arrhythmogenic potential. Furthermore, the direct apposition of this fat tissue to the myocardium may facilitate these proarrhythmic properties. Several recent studies provided proof of a direct correlation between pericardial fat and increased levels of inflammatory markers such as monocyte chemoattractant protein-1 (MCP-1), IL-1, IL-6, soluble IL-6 receptor/IL-6 complex, and TNF-a, independently of various clinical variables, including obesity, diabetes mellitus, or chronic therapy with statins or ACEIs [62]. These results indicate the adipose tissue deposited around the heart as a major source of pro-inflammatory molecules. Indeed, in vitro studies demonstrated that pericardial fat is a relevant source of proinflammatory cytokines such as MCP-1, IL-1, IL-6, TNF-a, and resistin [18, 62]. However, similar to central fat, pericardial fat also secretes adiponectin, a molecule with important antiinflammatory effects. While the pro-inflammatory mediators released by the pericardial fat have been associated with increased propensity to AF, Kourliouros et al. showed that increased adiponectin release by the pericardial fat was associated with freedom from AF after cardiac surgery [63]. To date, it remains unclear whether the adipocytokines secreted by the pericardial fat are released directly into the cardiac tissue, promoting atrial arrhythmogenesis via a paracrine mechanism. The complete lack of any fascia between the adipocytes and the myocardium and the common coronary blood supply for both the pericardial fat and the myocardium allows us to hypothesize that inflammatory mediators secreted by the adipocytes may easily diffuse into the adjacent cardiomyocytes. It is generally accepted that AF pathogenesis involves the coexistence of three arrhythmogenic mechanisms— rapidly discharging triggers or foci; substrate abnormalities that promote wavelet reentry; and autonomic imbalance, which may promote trigger activity and modify the
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substrate to facilitate the arrhythmia. An increasing body of evidence supports the hypothesis that pericardial fat, serving as an abundant source of inflammatory mediators, may promote AF by causing alterations in any of these three mechanisms: increasing ectopic activity through a direct local effect on atrial electrical properties; promoting atrial fibrosis and fatty infiltration of the atria, responsible for creating the anatomical substrate needed for AF persistence; and modulating the intrinsic autonomic nervous system of the heart (Fig. 4). In AF patients, high dominant frequency sites and complex fractionated atrial electrograms, incriminated in the onset and the persistence of reentry circuits, have been identified in the near vicinity of areas with significant pericardial fat, suggesting that pericardial fat may modulate atrial electrophysiological properties [64]. Furthermore, Chang et al. demonstrated that AF patients with metabolic syndrome had shorter duration of complex fractionated atrial electrograms and higher incidence of ectopic activity outside the pulmonary veins, suggesting that fatty infiltration of the atria may promote degeneration
of myocardial cells and increase atrial automaticity, promoting AF onset, and, in the same time, may interfere with atrial conduction of electrical impulses, promoting AF persistence [65]. Pericardial fat is also postulated to exert local effects by its proximity to the pulmonary vein ostia. In AF patients, areas located near the pulmonary vein ostia have been incriminated as the main sources of atrial abnormal automaticity. Using cardiac computed tomography imaging, Batal et al. reported that peri-esophageal fat was the only pericardial fat associated with AF burden [60]. Since the esophagus descends along the posterior wall of the atria, often in close contact with the pulmonary vein ostia, local inflammatory mediators produced by the periatrial fat may promote increased activity of ectopic foci in this area. This hypothesis is further supported by the fact that removal of the peri-esophageal fat pad during posterior pericardiectomy was associated with decreased post-operative AF rates [66]. Thus, the increased atrial automaticity observed in AF patients may be due, at least partially, to a direct effect of inflammatory cytokines on sarcolemmal ion channels and to increased local oxidative
Fig. 4 Predominant inflammatory mechanisms bridging adiposity and atrial fibrillation. Total body and local pericardial adiposity, serving as an abundant source of adipocytokines, may promote atrial fibrillation by increasing atrial automaticity, causing atrial structural and electrical remodeling, and modulating the activity of the intrinsic
autonomic nervous system of the heart. By favoring both atrial ectopic activity and reentry, adipocytokines may play substantial roles in both atrial fibrillation induction and persistence. AP action potential, PVs pulmonary veins
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stress in the presence of abnormally increased amounts of pericardial fat. Furthermore, inhomogeneous fat infiltration of atrial walls was incriminated in promoting dispersion of atrial action potentials’ duration, and thus to favor the maintenance of reentry circuits. Additionally, pericardial fat may also increase atrial resting membrane potential, reducing the depolarizing threshold and facilitating the development of ectopic foci [67]. Another mechanism that may explain the relationship between pericardial fat-induced inflammation and AF could result from the interaction with ganglionated plexuses. Indeed, pericardial fat contains abundant ganglionated plexuses, and factors released by the adipose tissue could significantly influence their activity. Given that variations in autonomic tone are known to play a crucial role in AF initiation and perpetuation, this mechanism may be extremely relevant in explaining the pericardial fat-AF relationship. Stimulation of pericardiac ganglionated plexuses has been shown to induce parasympathetic-mediated shortening of atrial effective refractory periods, atrial conduction slowing, and decreased heart rate, and thus to promote reentry, but also to increase calcium transient in pulmonary veins’ and atrial myocardial cells through a sympathetic effect, and thus to increase delayed after depolarizations-related atrial automaticity [68]. In the same time, ganglionated plexuses ablation alone significantly reduced pulmonary vein firing and AF inducibility [68]. Given that most ganglionated plexuses are located in the pericardial fat pads next to the posterior wall of the LA, this mechanism could also explain the finding that the posterior LA fat thickness is a stronger predictor of AF than other regional pericardial fat indexes. Direct sympathetic recordings in obese patients have demonstrated a chronic sympathetic overactivity [69]. In the study of Lin et al., similar sympathetic overstimulation as that seen in obese patients induced significantly more triggered beats in adipocyte-incubated LA myocytes compared to control LA myocytes [67], supporting a high arrhythmogenic potential of adipocytes mediated by the autonomic nervous system. Furthermore, a number of cytokines released by the adipose tissue appear to have potent effects in regulating nerve growth. For example, IL-6 appears to promote cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway [70]. Other recent studies demonstrated a relevant correlation between pericardial adiposity-induced inflammation and LA volume, suggesting that pericardial fat may also promote atrial structural remodeling. While atrial electrical abnormalities are vital for AF onset, atrial fibrosis is a mandatory substrate for AF persistence. A number of adipokines found in the pericardial fat, such as IL-6, MCP-1, angiotensin II, TNF-a, TGF-b1, platelet-derived growth factor, or connective tissue growth factor, are well recognized for their profibrotic properties [71]. Recent studies on the secretome from
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pericardial fat support the involvement of additional proinflammatory adipokines, such as activin A, a member of the TGF-b superfamily, matrix metalloproteinases, and angiogenic factors such as the vascular endothelial growth factor or thrombospondin-2 in promoting atrial structural remodeling and fibrosis and favoring AF [71]. Additionally, in the study of Kourliouros et al., increased levels of adiponectin in pericardial fat specimens were associated with maintenance of sinus rhythm following cardiac surgery, whereas pericardial adiponectin release was lower in patients who developed AF [63]. Furthermore, Ybarra et al. found a significant negative correlative between adiponectin levels and LA size, suggesting an antifibrotic effect of adiponectin [72]. The exact mechanisms linking pericardial fat-induced inflammation to atrial fibrosis remain unclear. Several cytokines synthesized by the adipose tissue have been shown to activate fibroblasts, causing extracellular matrix deposition and fibrosis. High TNF-a levels, as those seen in the pericardial fat of AF patients, have been associated with increased collagen deposition and abnormal calcium handling [73]. Similarly, IL-2 also appears to increase intracellular diastolic calcium concentrations through inadequate reuptake by the sarcoplasmic reticulum. Then, myocyte calcium overload may promote apoptosis of atrial myocytes, triggering CRP-binding to apoptotic cells and consequent activation of the complement pathway, causing tissue damage and local fibrosis of the atrial tissue.
Clinical implications and future research Further research is expected to provide valuable insights into our understanding regarding the role of obesity and pericardial fat in AF genesis and persistence. Such understanding may help improving currently available methods for preventing AF and its redoubtable complications. An increasing number of evidence has demonstrated the indisputable role of obesity in AF pathogenesis. While the influence of obesity in promoting AF in an individual patient may be modest, its burden in the entire population may be substantial, given the high prevalence of obesity in the general population. Therefore, even a small decrease in the prevalence of obesity may be expected to reduce significantly AF burden in the general population. Indeed, the Women’s Health Study demonstrated that in women younger than 60 years rapid increase in BMI was associated with a significant 41 % increase in the risk of new-onset AF compared to women that maintained a BMI below 30 kg/m2 throughout the study [74]. Additional studies support the hypothesis that the decreased propensity to AF associated with weight loss may rely on the reduction of inflammatory mediators released by the adipose tissue [38]. Taken together, these results support the
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hypothesis that long-term control of BMI may be a safe method for reducing inflammatory status and consequently AF burden. Interventional studies have also tried to directly modulate the pro-inflammatory activity of pericardial fat through weight loss, physical activity, and various drugs including statins or ACEIs/ARBs [62, 75]. However, to date, none of these strategies have managed to convincingly attenuate inflammatory signals in pericardial adipose stores, suggesting that more aggressive interventions may be needed to modulate this process. Nevertheless, prior to this important step, better understanding of AF pathogenesis and of the nature of the role that pericardial fat plays in AF pathogenesis may be needed. To date, no study has provided any information regarding the effect of weight loss on pericardial adiposity and AF risk. Studying the effect of additional weight loss strategies such as bariatric surgery on pericardial fat and AF risk may also be of interest.
Conclusions Our understanding of the role that the adipose tissue and particularly the epicardial fat plays in AF pathogenesis is still evolving. An increasing number of studies have brought indisputable evidence for the role that inflammation, both local and systemic, plays in the adipose tissueAF relationship. Novel strategies aiming to modulate obesity-related inflammation may provide valuable tools for AF prevention and/or treatment. Acknowledgments This work was supported by the University of Medicine and Pharmacy of Tıˆrgu Mures¸ Research Grant number 16/11.12.2013. Conflict of interest of interest.
The authors declare that they have no conflict
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Inflammation Research
REVIEW
Inflammation, a link between obesity and atrial fibrillation Alina Scridon1 • Dan Dobreanu1,2 • Philippe Chevalier3 • Ra˘zvan Constantin S¸ erban1,2
Received: 2 April 2015 / Revised: 21 April 2015 / Accepted: 23 April 2015 / Published online: 1 May 2015 Springer Basel 2015
Abstract Despite the long belief that the role of the adipose tissue was restricted to that of a passive store of triglycerides and a rich source of fatty acids, accumulating data demonstrates that the adipose tissue acts as an endocrine organ, capable of producing a large number of cytokines incriminated in generating a systemic inflammatory status. At its turn, this adiposity-related proinflammatory status appears to promote a large range of cardiovascular disorders, including atrial fibrillation (AF). Recent studies suggest that, in addition to systemic adiposity, the volume of the pericardial fat of the entire heart, and particularly of that overlying the atria, may represent an even more important risk factor for AF. This review focuses on the most relevant clinical and experimental data that bridge adiposity-induced inflammation and AF, and provides, through a multidisciplinary approach, a discussion that integrates both the current knowledge regarding the prolific activity of systemic and pericardial adipose tissue as sources of inflammatory mediators and the main effects of adiposity-induced inflammation on the most relevant electrophysiological, structural, and autonomic mechanisms responsible for AF.
Responsible Editor: John Di Battista. & Alina Scridon [email protected] 1
Physiology Department, University of Medicine and Pharmacy of Tıˆrgu Mures¸ , 38, Gheorghe Marinescu Street, 540139 Tıˆrgu Mures¸ , Romania
2
Emergency Institute for Cardiovascular Diseases and Transplantation Tıˆrgu Mures¸ , 540136 Tıˆrgu Mures¸ , Romania
3
Service de Rythmologie, Hospices Civils de Lyon, Hoˆpital Louis Pradel, 69500 Bron Cedex, France
Keywords Inflammation Adipokines Atrial fibrillation Obesity Pericardial fat
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. The presence of the arrhythmia leads not only to important decrease in the quality of life, but also to substantial morbidity and mortality from stroke, heart failure, cognitive decline, and dementia [1]. Together with heart failure and type II diabetes mellitus, AF is considered to be one of the three growing cardiovascular epidemics of the 21st century [2]. Large epidemiological studies have identified advancing age, diabetes mellitus, hypertension, heart failure, and coronary artery disease as the most important risk factors for non-valvular AF [3]. In a prospective study including over 3500 patients, Gami et al. reported a 14 % increase in the prevalence of AF over 4.7 years of follow-up, identifying male gender, advancing age, hypertension, coronary artery disease, heart failure, and smoking as the most relevant risk factors for AF [4]. Particularly, the increasing proportion of the elderly population, which seems to be more ‘ill’ than it was a few decades ago and to present more often hypertension, diabetes mellitus, heart failure, coronary artery, and valvular heart disease, was considered to underlie this AF epidemic [5]. Indeed, the Rochester study, developed over a period of 30 years, demonstrated an increase in the prevalence of coronary artery disease, valvular heart disease, a history of prior myocardial infarction, and to a lesser extent of heart failure and diabetes mellitus with advancing age [6]. However, the relatively modest increase in the prevalence of these widely accepted risk factors for AF can only
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partially explain the twofold to threefold increase in the prevalence of AF over the last 30 years. One other factor that may explain this finding is obesity, whose prevalence is increasing worldwide, paralleling the escalation in the AF prevalence. The association between body mass index (BMI), the most widely used marker of obesity, and both AF occurrence and persistence has been demonstrated in a large number of studies [7]. BMI was identified as a strong predictor of incident AF, with every 1 kg/m2 increase in BMI causing a 3–8 % higher risk for new-onset AF [4, 8]. In the same vein, the meta-analysis of Wanahita et al., including 16 population-based and postcardiac surgery cohort studies, demonstrated a 49 % increase in the risk of incident AF with obesity, and this risk increased in parallel with increased BMI [7]. Similar associations between BMI and AF were also found in the Manitoba follow-up study [9], the Renfrew/Paisley Study [10], and the Multifactor Primary Prevention Study [11]. Conceptually, this association is unsurprising, given that obesity is frequently associated with traditional risk factors for AF, promoting and aggravating comorbidities such as hypertension, ischemic heart disease, diabetes mellitus, or heart failure, all of which have been incriminated in AF occurrence (Fig. 1). Nevertheless, large studies including age- and sex-matched normal-weight referents demonstrated that even after correction for potential confounders such as hypertension, diabetes mellitus, heart failure or smoking, obesity remains an independent risk factor for AF genesis and progression [8], associating a 2.4-fold increase in the risk of AF [12].
On the contrary, in a traditional African population in whom waist circumference and BMI were very low, Koopman et al. reported extremely low rates of AF (0.3 %), further supporting a causal relationship between obesity and AF [13]. Interestingly, recent data suggest that, despite the independent association between obesity and AF, this relationship may actually be less evident in patients older than 65 years [14]. While at younger age every 5 kg/m2 increase in BMI was associated with a 15 % increase in the risk of new-onset AF, this was far less significant in elderly individuals [4]. These findings suggest that, with advancing age, the pathophysiological impact of other aging-related factors such as hypertension, ischemic heart disease, or heart failure may actually overwhelm the deleterious effects of obesity.
Fig. 1 Venn diagram demonstrating the overlap between obesity, atrial fibrillation, and selected clinical correlates. One or several of these clinical correlates often provide the link between obesity and atrial fibrillation. However, an area of overlap unmediated by any of the classical clinical correlates can also be noticed, indicating a direct link between obesity and atrial fibrillation
Fig. 2 Mechanisms linking obesity to atrial fibrillation. Obesityrelated cardiac and non-cardiac conditions (outer circle) promote pathophysiological mechanisms (middle circle) that eventually favor the genesis and the persistence of the arrhythmia by causing atrial remodeling, autonomic imbalance, and increasing atrial ectopic activity (inner circles). AF atrial fibrillation
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Mechanisms linking obesity to atrial fibrillation Although numerous studies have demonstrated a direct association between obesity and AF, the mechanisms linking these two conditions are far from clear. So far, a number of different pathophysiological mechanisms (Fig. 2), including atrial dilation, neurohormonal activation, and increased left ventricular diastolic filling pressure, have been proposed to explain this association. Particularly, cardiac remodeling in response to obesity appears as a key element in obesity-related AF. Metabolic, hemodynamic, and ischemic abnormalities seen in obese
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patients seem to account for significant alterations in atrial electrophysiology and structure. Left atrial (LA) dilation, an important AF precursor, is a common finding among obese patients [15]. Obesity-related alterations such as increased plasma volume, left ventricular diastolic dysfunction, and enhanced neurohormonal activity may underlie this finding [16]. Indeed, a 10-year echocardiographic follow-up study in obese patients demonstrated a 2.4-fold increase in LA volume [17]. In the Framingham Heart Study, although BMI was significantly associated with the risk of new-onset AF in univariate analysis, the correlation was lost when corrected for LA diameter, suggesting that LA dilation may be one of the most important mechanisms linking obesity to AF [8]. The strong, causal relationship between obesity and obstructive sleep apnea could also explain, at least partially, the increased AF propensity seen in obese patients [18]. Multiple pathophysiological mechanisms related to obstructive sleep apnea, including autonomic imbalance with sympathetic overactivity, prolonged and repetitive hypoxemia episodes, abnormal heart rate variability, hypoxic pulmonary vasoconstriction, left ventricular diastolic dysfunction, and increased cardiac wall stress due to exaggerated intrathoracic pressure variations, could be involved in AF pathogenesis. However, in the study of Gami et al., despite a strong association between obstructive sleep apnea and incident AF, BMI predicted new-onset AF independent of the presence of obstructive sleep apnea, suggesting that although obstructive sleep apnea may participate to AF occurrence in obese patients, this cannot be the only link between obesity and AF [4]. Inflammation, a link between obesity and atrial fibrillation Obesity has been associated with low-grade systemic inflammation, while inflammation is known to promote both AF onset and persistence. Taken together, these two observations suggest that obesity-induced systemic inflammation may provide a direct link between obesity and AF. Atrial fibrillation—an inflammatory disorder Evidence for an inflammatory contribution to AF was initially suggested by the high incidence of AF in inflammatory conditions such as pericarditis and myocarditis [19], as well as after cardiac surgery [20]. Moreover, in the post-cardiac surgery setting, the temporal course of AF occurrence correlates well with the dynamics of the inflammatory status. Bruins et al. found that interleukin (IL)-6 rises initially and peaks 6 h after surgery, while C-reactive protein (CRP) levels peak on post-
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operative day 2, with complement-CRP complexes peaking on post-operative day 2 or 3 [20]. The incidence of postoperative AF follows a similar pattern, peaking on postoperative day 2 or 3. Additionally, in patients with metastatic melanoma or renal cell carcinoma, intravenous administration of high-dose recombinant IL-2 was associated with high incidence of AF, further supporting a direct, causal relationship between inflammation and AF [21]. Numerous other studies have also demonstrated a strong correlation between inflammatory markers’ levels and the presence or the future development of AF. CRP, a sensitive marker of inflammation, has probably been best studied in relationship with AF. Chung et al. were among the first to demonstrate a strong association between elevated plasma CRP levels and AF [22]. Moreover, patients with persistent AF presented significantly higher levels of CRP than those with paroxysmal AF, suggesting that inflammation might participate not only to AF induction, but also to the maintenance of the arrhythmia. Later on, an increasing number of studies provided similar results, demonstrating that CRP levels are higher in AF patients compared to controls with no history of AF, and higher in persistent AF patients compared to paroxysmal AF patients [23]. Similarly, higher levels of high-sensitivity CRP (hs-CRP), IL-6, and tumor necrosis factor alpha (TNF-a) were also reported in the plasma of AF patients compared with sinus rhythm controls [24]. Elevation of fibrinogen and complement activation may also contribute to AF occurrence and perpetuation, as evidenced by the high plasma fibrinogen levels and activated C3 and C4 complement isoforms in the presence of AF [20]. The higher incidence of AF during winter reported in one epidemiological study adds further support for a causal relationship between inflammation and AF, the authors suggesting that an inflammatory response to infectious diseases in winter may be responsible for AF frequency escalation in this season [25]. Finally, the presence of inflammatory infiltrates, myocyte necrosis, and fibrosis in atrial biopsy specimens from patients with lone AF refractory to antiarrhythmic therapy, together with the complete absence of such abnormalities in atrial biopsies from sinus rhythm controls, further supports the role of inflammation in AF pathogenesis [26]. Furthermore, the role of inflammation does not seem to be confined to promoting AF genesis and persistence. A significant number of studies have also related inflammation to a decreased likelihood of effective pharmacological or electrical cardioversion, as well as to a higher risk of AF recurrence after successful cardioversion. In several studies, high baseline CRP, TNF-a, IL-6, IL-2, IL-10, and serum amyloid A levels were strong predictors of AF recurrence after successful cardioversion, whereas lower levels of plasma CRP correlated to an increased likelihood of successful cardioversion [23, 27].
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Using a prospective study over 9.4 years, Hermida et al. provided the first proof that inflammation may also be a strong predictor of mortality among AF patients [28]. The authors demonstrated that higher hs-CRP levels were associated with increased mortality in AF patients, independent of other cardiovascular risk factors, with mortality rates approximately twice higher in AF patients with the highest hs-CRP levels compared to those in the lowest tertile. On the other hand, aggressive CRP lowering strategies using drugs that possess known antiinflammatory effects, such as glucocorticoids, N-3 fatty acids, statins, angiotensin converting enzyme inhibitors (ACEIs), or angiotensin II receptor blockers (ARBs), seem to efficiently alleviate the AF burden [29, 30]. The corresponding reduction in AF prevalence with these agents appears to be proportional with the degree of CRP lowering [23, 30]. Moreover, experimental studies have also suggested that part of the potent antiarrhythmic effect of amiodarone may actually rely on an antiinflammatory effect, via suppression of synthesis of several cytokines, including IL-6 and TNF-a [31]. In the same vein, Merritt et al. reported that carvedilol, which was efficient in reducing post-operative AF, may also have antiinflammatory and antioxidant properties [32]. Taken together, these results validate the pivotal role that inflammation plays in AF genesis and persistence. The decrease in inflammatory marker levels observed after cardioversion may suggest that at least part of the inflammatory syndrome observed in these patients may be due to AF itself. On the other hand, data such as the increased incidence of AF in the setting of inflammatory states such as cardiac surgery or pericarditis, and the observation that baseline CRP levels predict future occurrence of AF, incriminate an initial inflammatory status in AF genesis. It is also likely that inflammation and AF favor and aggravate each other, generating a vicious circle. The adipose tissue—a prolific source of inflammatory cytokines For a long time, the role of the adipose tissue was considered to be restricted to that of a passive store of triglycerides and a rich source of fatty acids. However, an increasing number of evidence demonstrated that the adipose tissue acts as an endocrine organ, capable of producing a large number of cytokines incriminated in generating a systemic inflammatory status. At its turn, this obesity-related pro-inflammatory status appears to be involved in a large range of cardiovascular disorders. Given that high CRP levels, a classic marker of systemic inflammation, have been related to an increased risk of future AF, while obese patients appear to present substantially higher plasma levels of CRP compared to
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Fig. 3 Schematic representation of adipocytes as a source of both pro-inflammatory and antiinflammatory factors that modulate the inflammatory response. Molecules depicted in red act as proinflammatory factors, promoting systemic inflammation. The proinflammatory effects of factors such as leptin, resistin, and Angptl2 are modulated via macrophage activation. Molecules depicted in blue act as antiinflammatory factors. Angptl2 angiopoietin-like protein 2, IL-1b interleukin-1b, IL-1RA IL-1 receptor antagonist, IL-6 interleukin-6, IL-8 interleukin-8, IL-10 interleukin-10, MCP-1 monocyte chemoattractant protein-1, TGF-b transforming growth factor beta, TNF-a tumor necrosis factor alpha
normal-weight subjects [33], it has been hypothesized that at least part of the increased risk of AF seen in obese patients may be due to this obesity-induced low-grade systemic inflammation. The adipose tissue may promote systemic inflammation through three main pathways: lipotoxicity-induced inflammation, secretion of various factors that stimulate the synthesis of inflammatory mediators in other tissues, and secretion of inflammatory factors by the adipose tissue itself [34]. However, it appears that in obese patients, most of the inflammatory cytokines originate within the adipocytes themselves [35] (Fig. 3). These pro-inflammatory cytokines, together with a number of protective factors also expressed and synthesized by the adipose tissue, are termed collectively adipocytokines. The adipose tissue is recognized as a prolific source of both primary inflammatory cytokines and specific inflammatory mediators. Primary inflammatory cytokines include IL-6, IL-8, IL1b, interferon-c, TNF-a, and TGF-b [36]. Among these cytokines, TNF-a and IL-6 appear to play a central role in obesity-induced inflammation. Furthermore, it appears that serum concentrations of both IL-6 and TNF-a correlate significantly with the amount of adiposity, as quantified by the BMI [37, 38]. One of the most relevant clinical proofs for the role of the adipose tissue in generating a low-grade systemic inflammation was provided by Marfella et al. The authors demonstrated increased serum levels of CRP, TNF-a, IL-6,
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and IL-18 in a population of 67 obese females compared to 40 non-obese controls [39]. In multivariate analysis, BMI and the waist-to-hip ratio were the only independent predictors of increased serum levels of IL-6, TNF-a, and CRP. Furthermore, a significant 10 % reduction in body weight was associated with relevant reductions in IL-6, IL-18, TNF-a, and CRP concentrations. More recently, Fontana et al. provided more evidence for the adipose tissue as origin of obesity-related systemic inflammation [40]. By determining adipokine concentrations in portal vein and radial artery plasma samples from 25 extremely obese patients during gastric bypass surgery, the authors showed that portal vein plasma IL-6 levels correlated and were significantly higher than peripheral artery levels, indicating visceral fat as the main source of IL-6 in these patients. Since IL-6 is one of the most potent stimulators of CRP synthesis by the liver, the observation of a direct secretion of IL-6 into the portal vein provided evidence for the existence of a direct link between visceral fat and systemic inflammation. Besides these pro-inflammatory cytokines, the adipose tissue also produces a number of antiinflammatory factors such as IL-1 receptor antagonist, which blocks selectively the activity of IL-1, and IL-10, a factor with intrinsic antiinflammatory properties [41]. The adipose tissue has been found to secrete more than 50 cytokines and other inflammation-promoting molecules. While some of these molecules can also be synthesized by other cells, particularly the macrophages, others are specific or mainly synthesized by the adipose tissue. Once synthesized, these specific inflammatory mediators act on a variety of tissues, through endocrine, paracrine, autocrine, or juxtacrine mechanisms, influencing different physiological and pathophysiological processes. These specific inflammatory mediators include molecules such as leptin, adiponectin, resistin, and angiopoietin-like protein 2 (Angptl2). Circulating levels of leptin, a molecule synthesized primarily by the adipose tissue, have been correlated with the mass of body adiposity. Once synthesized, leptin promotes systemic inflammation by acting at various levels, increasing phagocytic activity [42] and enhancing synthesis of leukotrienes, nitric oxide, and various proinflammatory cytokines by macrophages and monocyte cells [43]. Furthermore, leptin has been shown not only to promote chemotaxis and release of reactive oxygen species by the neutrophils [44], creating a systemic pro-oxidant environment, but also to induce proliferation, differentiation, activation, and cytotoxicity of natural killer cells [45]. At whole-body level, one of the main targets of leptin is represented by the macrophages, and leptin mRNA expression and circulating leptin levels are strongly modulated by various inflammatory mediators such as IL-1
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and IL-6 [46]. Experimental studies demonstrated that mice with genetic leptin deficiency are less prone to develop inflammatory diseases [47], while leptin administration promoted both inflammation and platelet activation and increased T-cells-mediated inflammation of the liver [48]. Taken together, these observations indicate that leptin, a pleiotropic hormone involved in body weight regulation, plays a significant role in generating systemic inflammation in obese patients. Furthermore, recent data suggest that leptin may be responsible for modulating the development of atrial fibrosis in response to overactivation of the reninangiotensin system [49]. Adiponectin is an adipocyte-derived plasma protein widely recognized for its protective effects against obesity and obesity-related inflammatory-based disorders such as atherosclerosis, type II diabetes mellitus, or rheumatoid arthritis. Adiponectin intervenes at various levels of inflammatory responses, promoting apoptotic cells phagocytosis and preventing accumulation of cell detritus [50], preventing monocyte adhesion to endothelial cells, and reducing the release of inflammatory proteins such as TNF-a [51]. Furthermore, treatment with recombinant adiponectin proved efficient in diminishing hepatic inflammation in a mouse model of steatohepatitis [52]. Carnevale et al. recently demonstrated significantly lower plasma levels of adiponectin in AF patients compared to sinus rhythm controls [53], while Shimano et al. showed a significant correlation between adiponectin levels and plasma levels of serum carboxy-terminal telopeptide of collagen type I, a degradation marker of type I collagen, among persistent AF patients, linking adiponectin to LA structural remodeling [54]. Resistin and adiponectin exhibit opposite inflammatory effects. However, while adiponectin is an adipocytederived plasma protein, resistin secretion is not confined to adipose cells. Actually, the relevant secretion of resistin by monocytes and macrophages is one of the strongest arguments supporting the involvement of resistin in inflammatory processes [34]. Furthermore, in several studies, plasma resistin levels significantly correlated with cell adhesion molecules and other markers of inflammation [55], while in mononuclear cells resistin has been shown to promote IL-6 and TNF-a synthesis [56]. Experimental studies demonstrated that high levels of other factors secreted by the adipose tissue, such as Angptl2, are also associated with systemic inflammation [57]. Angptl2-induced inflammation appears to involve monocyte and macrophage activation via integrin signaling. In mice, Angptl2 activation induced chronic inflammation characterized by leucocyte adhesion to vessel walls and increased vascular permeability. Additionally, deletion of the Angptl2 gene was associated with reduced inflammation, while Angptl2 gene overexpression promoted inflammation [57].
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All these experimental and clinical data reinforce the belief that the adipose tissue, besides being a passive store for triglycerides and a major source of fatty acids, is also capable of generating a low-grade inflammatory syndrome, which, in turn, may contribute to the high AF propensity observed in obese patients. At present, adipocytes are acknowledged as a prolific source of inflammatory mediators that may directly contribute to AF pathogenesis. Meanwhile, factors such as adiponectin, IL-1 receptor antagonist, and IL-10 seem to confer protection against obesity-related inflammatory-based disorders, including AF. Further studies are expected to provide more insights into the obesity–inflammation–AF relationship, to identify new adipocyte-derived mediators and new therapeutic targets for AF prophylaxis.
Pericardial fat—a new paradigm in the obesity– atrial fibrillation relationship Recent cardiac computed tomography and magnetic resonance imaging studies suggested that, in addition to systemic adiposity, the volume of the pericardial fat of the entire heart, and particularly of that overlying the atria, may represent another important risk factor for AF. More importantly, the effect of pericardial fat on AF burden appears to be independent of other traditional risk factors for AF, including BMI, every 10 ml increase in pericardial fat volume being associated with a 13 % escalation in the odds of AF [58]. The direct involvement of the adipose tissue surrounding the heart in AF pathogenesis is further supported by the study of Thanassoulis et al., who demonstrated that, after adjusting for established AF risk factors, including BMI, pericardial fat, but not intrathoracic or visceral abdominal fat, was significantly associated with prevalent AF [59]. These results, together with the observation of a stronger association between pericardial fat and AF occurrence compared to that between BMI and AF, suggest that adipose tissue location may actually be more important than its abundance. Furthermore, even for the adiposity surrounding the heart, significant interregional differences seem to exist. While the volume of the adipose tissue of the entire heart has been most widely studied in association with AF, the volume of periatrial adiposity may be an even better predictor of future AF [60]. Among 49 patients with paroxysmal or persistent AF, Girerd et al. reported a significant correlation between several inflammatory markers’ levels and the thickness of periatrial fat located between the LA and the esophagus or between the LA and the descending aorta, while no correlation was found between the thickness of total, ventricular, or interventricular groove adiposity and any of the tested inflammatory markers,
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suggesting that pericardial fat surrounding the LA, rather than the pericardial fat itself, is a key determinant of inflammation in AF patients [61]. Similar results were reported by Batal et al., who found that the periatrial fat that correlated the best with AF burden was that located posteriorly, between the esophagus and the LA [60]. Inflammation, a link between pericardial fat and atrial fibrillation Although the precise mechanisms underlying the relationship between pericardial fat and increased AF propensity are not fully elucidated, recent experimental and clinical studies have provided valuable insights. By producing inflammatory cytokines and causing interactions with atrial myocytes, pericardial fat may have direct arrhythmogenic potential. Furthermore, the direct apposition of this fat tissue to the myocardium may facilitate these proarrhythmic properties. Several recent studies provided proof of a direct correlation between pericardial fat and increased levels of inflammatory markers such as monocyte chemoattractant protein-1 (MCP-1), IL-1, IL-6, soluble IL-6 receptor/IL-6 complex, and TNF-a, independently of various clinical variables, including obesity, diabetes mellitus, or chronic therapy with statins or ACEIs [62]. These results indicate the adipose tissue deposited around the heart as a major source of pro-inflammatory molecules. Indeed, in vitro studies demonstrated that pericardial fat is a relevant source of proinflammatory cytokines such as MCP-1, IL-1, IL-6, TNF-a, and resistin [18, 62]. However, similar to central fat, pericardial fat also secretes adiponectin, a molecule with important antiinflammatory effects. While the pro-inflammatory mediators released by the pericardial fat have been associated with increased propensity to AF, Kourliouros et al. showed that increased adiponectin release by the pericardial fat was associated with freedom from AF after cardiac surgery [63]. To date, it remains unclear whether the adipocytokines secreted by the pericardial fat are released directly into the cardiac tissue, promoting atrial arrhythmogenesis via a paracrine mechanism. The complete lack of any fascia between the adipocytes and the myocardium and the common coronary blood supply for both the pericardial fat and the myocardium allows us to hypothesize that inflammatory mediators secreted by the adipocytes may easily diffuse into the adjacent cardiomyocytes. It is generally accepted that AF pathogenesis involves the coexistence of three arrhythmogenic mechanisms— rapidly discharging triggers or foci; substrate abnormalities that promote wavelet reentry; and autonomic imbalance, which may promote trigger activity and modify the
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substrate to facilitate the arrhythmia. An increasing body of evidence supports the hypothesis that pericardial fat, serving as an abundant source of inflammatory mediators, may promote AF by causing alterations in any of these three mechanisms: increasing ectopic activity through a direct local effect on atrial electrical properties; promoting atrial fibrosis and fatty infiltration of the atria, responsible for creating the anatomical substrate needed for AF persistence; and modulating the intrinsic autonomic nervous system of the heart (Fig. 4). In AF patients, high dominant frequency sites and complex fractionated atrial electrograms, incriminated in the onset and the persistence of reentry circuits, have been identified in the near vicinity of areas with significant pericardial fat, suggesting that pericardial fat may modulate atrial electrophysiological properties [64]. Furthermore, Chang et al. demonstrated that AF patients with metabolic syndrome had shorter duration of complex fractionated atrial electrograms and higher incidence of ectopic activity outside the pulmonary veins, suggesting that fatty infiltration of the atria may promote degeneration
of myocardial cells and increase atrial automaticity, promoting AF onset, and, in the same time, may interfere with atrial conduction of electrical impulses, promoting AF persistence [65]. Pericardial fat is also postulated to exert local effects by its proximity to the pulmonary vein ostia. In AF patients, areas located near the pulmonary vein ostia have been incriminated as the main sources of atrial abnormal automaticity. Using cardiac computed tomography imaging, Batal et al. reported that peri-esophageal fat was the only pericardial fat associated with AF burden [60]. Since the esophagus descends along the posterior wall of the atria, often in close contact with the pulmonary vein ostia, local inflammatory mediators produced by the periatrial fat may promote increased activity of ectopic foci in this area. This hypothesis is further supported by the fact that removal of the peri-esophageal fat pad during posterior pericardiectomy was associated with decreased post-operative AF rates [66]. Thus, the increased atrial automaticity observed in AF patients may be due, at least partially, to a direct effect of inflammatory cytokines on sarcolemmal ion channels and to increased local oxidative
Fig. 4 Predominant inflammatory mechanisms bridging adiposity and atrial fibrillation. Total body and local pericardial adiposity, serving as an abundant source of adipocytokines, may promote atrial fibrillation by increasing atrial automaticity, causing atrial structural and electrical remodeling, and modulating the activity of the intrinsic
autonomic nervous system of the heart. By favoring both atrial ectopic activity and reentry, adipocytokines may play substantial roles in both atrial fibrillation induction and persistence. AP action potential, PVs pulmonary veins
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stress in the presence of abnormally increased amounts of pericardial fat. Furthermore, inhomogeneous fat infiltration of atrial walls was incriminated in promoting dispersion of atrial action potentials’ duration, and thus to favor the maintenance of reentry circuits. Additionally, pericardial fat may also increase atrial resting membrane potential, reducing the depolarizing threshold and facilitating the development of ectopic foci [67]. Another mechanism that may explain the relationship between pericardial fat-induced inflammation and AF could result from the interaction with ganglionated plexuses. Indeed, pericardial fat contains abundant ganglionated plexuses, and factors released by the adipose tissue could significantly influence their activity. Given that variations in autonomic tone are known to play a crucial role in AF initiation and perpetuation, this mechanism may be extremely relevant in explaining the pericardial fat-AF relationship. Stimulation of pericardiac ganglionated plexuses has been shown to induce parasympathetic-mediated shortening of atrial effective refractory periods, atrial conduction slowing, and decreased heart rate, and thus to promote reentry, but also to increase calcium transient in pulmonary veins’ and atrial myocardial cells through a sympathetic effect, and thus to increase delayed after depolarizations-related atrial automaticity [68]. In the same time, ganglionated plexuses ablation alone significantly reduced pulmonary vein firing and AF inducibility [68]. Given that most ganglionated plexuses are located in the pericardial fat pads next to the posterior wall of the LA, this mechanism could also explain the finding that the posterior LA fat thickness is a stronger predictor of AF than other regional pericardial fat indexes. Direct sympathetic recordings in obese patients have demonstrated a chronic sympathetic overactivity [69]. In the study of Lin et al., similar sympathetic overstimulation as that seen in obese patients induced significantly more triggered beats in adipocyte-incubated LA myocytes compared to control LA myocytes [67], supporting a high arrhythmogenic potential of adipocytes mediated by the autonomic nervous system. Furthermore, a number of cytokines released by the adipose tissue appear to have potent effects in regulating nerve growth. For example, IL-6 appears to promote cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway [70]. Other recent studies demonstrated a relevant correlation between pericardial adiposity-induced inflammation and LA volume, suggesting that pericardial fat may also promote atrial structural remodeling. While atrial electrical abnormalities are vital for AF onset, atrial fibrosis is a mandatory substrate for AF persistence. A number of adipokines found in the pericardial fat, such as IL-6, MCP-1, angiotensin II, TNF-a, TGF-b1, platelet-derived growth factor, or connective tissue growth factor, are well recognized for their profibrotic properties [71]. Recent studies on the secretome from
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pericardial fat support the involvement of additional proinflammatory adipokines, such as activin A, a member of the TGF-b superfamily, matrix metalloproteinases, and angiogenic factors such as the vascular endothelial growth factor or thrombospondin-2 in promoting atrial structural remodeling and fibrosis and favoring AF [71]. Additionally, in the study of Kourliouros et al., increased levels of adiponectin in pericardial fat specimens were associated with maintenance of sinus rhythm following cardiac surgery, whereas pericardial adiponectin release was lower in patients who developed AF [63]. Furthermore, Ybarra et al. found a significant negative correlative between adiponectin levels and LA size, suggesting an antifibrotic effect of adiponectin [72]. The exact mechanisms linking pericardial fat-induced inflammation to atrial fibrosis remain unclear. Several cytokines synthesized by the adipose tissue have been shown to activate fibroblasts, causing extracellular matrix deposition and fibrosis. High TNF-a levels, as those seen in the pericardial fat of AF patients, have been associated with increased collagen deposition and abnormal calcium handling [73]. Similarly, IL-2 also appears to increase intracellular diastolic calcium concentrations through inadequate reuptake by the sarcoplasmic reticulum. Then, myocyte calcium overload may promote apoptosis of atrial myocytes, triggering CRP-binding to apoptotic cells and consequent activation of the complement pathway, causing tissue damage and local fibrosis of the atrial tissue.
Clinical implications and future research Further research is expected to provide valuable insights into our understanding regarding the role of obesity and pericardial fat in AF genesis and persistence. Such understanding may help improving currently available methods for preventing AF and its redoubtable complications. An increasing number of evidence has demonstrated the indisputable role of obesity in AF pathogenesis. While the influence of obesity in promoting AF in an individual patient may be modest, its burden in the entire population may be substantial, given the high prevalence of obesity in the general population. Therefore, even a small decrease in the prevalence of obesity may be expected to reduce significantly AF burden in the general population. Indeed, the Women’s Health Study demonstrated that in women younger than 60 years rapid increase in BMI was associated with a significant 41 % increase in the risk of new-onset AF compared to women that maintained a BMI below 30 kg/m2 throughout the study [74]. Additional studies support the hypothesis that the decreased propensity to AF associated with weight loss may rely on the reduction of inflammatory mediators released by the adipose tissue [38]. Taken together, these results support the
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hypothesis that long-term control of BMI may be a safe method for reducing inflammatory status and consequently AF burden. Interventional studies have also tried to directly modulate the pro-inflammatory activity of pericardial fat through weight loss, physical activity, and various drugs including statins or ACEIs/ARBs [62, 75]. However, to date, none of these strategies have managed to convincingly attenuate inflammatory signals in pericardial adipose stores, suggesting that more aggressive interventions may be needed to modulate this process. Nevertheless, prior to this important step, better understanding of AF pathogenesis and of the nature of the role that pericardial fat plays in AF pathogenesis may be needed. To date, no study has provided any information regarding the effect of weight loss on pericardial adiposity and AF risk. Studying the effect of additional weight loss strategies such as bariatric surgery on pericardial fat and AF risk may also be of interest.
Conclusions Our understanding of the role that the adipose tissue and particularly the epicardial fat plays in AF pathogenesis is still evolving. An increasing number of studies have brought indisputable evidence for the role that inflammation, both local and systemic, plays in the adipose tissueAF relationship. Novel strategies aiming to modulate obesity-related inflammation may provide valuable tools for AF prevention and/or treatment. Acknowledgments This work was supported by the University of Medicine and Pharmacy of Tıˆrgu Mures¸ Research Grant number 16/11.12.2013. Conflict of interest of interest.
The authors declare that they have no conflict
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