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Heart failure epicardial fat increases atrial arrhythmogenesis
International Journal of Cardiology 167 (2013) 1979–1983
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Heart failure epicardial fat increases atrial arrhythmogenesis Yung-Kuo Lin a, Yao-Chang Chen b, Shih-Lin Chang c, Yenn-Jiang Lin c, Jenn-Han Chen d, Yung-Hsin Yeh e, Shih-Ann Chen c, Yi-Jen Chen a,⁎ a Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan b Department of Biomedical Engineering and Institute of Physiology, National Defense Medical Center, Taipei, Taiwan c National Yang-Ming University, School of Medicine; Division of Cardiology and Cardiovascular Research Center, Veterans General Hospital-Taipei, Taipei, Taiwan d Research Laboratory, Cancer Center, Wan Fang Hospital, Taipei Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan e The First Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan
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Article history: Received 20 January 2012 Received in revised form 27 March 2012 Accepted 4 May 2012 Available online 26 May 2012 Keywords: Adipokines Atrial fibrillation Epicardial fat Heart failure Obesity
a b s t r a c t Background: Obesity is an important risk factor for atrial fibrillation (AF) and heart failure (HF). The effects of epicardial fat on atrial electrophysiology were not clear. This study was to evaluate whether HF may modulate the effects of epicardial fat on atrial electrophysiology. Methods: Conventional microelectrodes recording was used to record the action potential in left (LA) and right (RA) atria of healthy (control) rabbits before and after application of epicardial fat from control or HF (ventricular pacing of 360–400 bpm for 4 weeks) rabbits. Adipokine profiles were checked in epicardial fat of control and HF rabbits. Results: The LA 90% of AP duration was prolonged by control epicardial fat (from 77 ± 6 to 87 ± 7 ms, p b 0.05, n = 7), and by HF epicardial fat (from 78 ± 3 to 98 ± 4 ms, p b 0.001, n = 9). However, control or HF epicardial fat did not change the AP morphology in RA. HF epicardial fat increased the contractility in LA (61 ± 11 vs. 35 ± 6 mg, p = 0.001), but not in RA. Control fat did not change the LA or RA contractility. Moreover, control and HF epicardial fat induced early and delayed afterdepolarizations in LA and RA, but only HF epicardial fat provoked spontaneous activity and burst firing in LA (n = 3/9, 33.3% vs. n = 0/7, 0%, n = 0/9, 0%, p b 0.05). Compared to control fat, HF epicardial fat, had lower resistin, C-reactive protein and serum amyloid A, but similar interluekin-6, leptin, monocyte chemotactic protein-1, adiponectin and adipsin. Conclusions: HF epicardial fat increases atrial arrhythmogenesis, which may contribute to the higher atrial arrhythmia in obesity. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Atrial fibrillation (AF), the most prevalent cardiac arrhythmia in clinical practice, can induce cardiac dysfunction and stroke [1]. Heart failure (HF) may contribute to and coexist with AF, and both may predispose to the occurrence of the other [2,3]. Obesity increases the prevalence of HF, hypertension, ischemic heart disease, ventricular dysfunction, and AF [4,5]. Studies showed that each increment in the body-mass index (BMI) was associated with a 3%–8% higher risk for new-onset AF [6,7]. The Framingham Heart Study also revealed a graded increase with a 5%–7% higher risk of HF for every 1 unit increase in the BMI [4]. Chamber dilatation or hypertrophy secondary to obesity could partially account for AF [8,9]. Moreover, the expanded epicardial adipose tissues in obese individuals, as an important ⁎ Corresponding author at: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111, Hsin-Lung Road, Sec. 3, Taipei 116, Taiwan. Tel.: + 886 2 28757156; fax: + 886 2 29339378. E-mail address: [email protected] (Y.-J. Chen). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.009
source of inflammatory mediators, also potentially underlie the pathophysiology of AF [10]. Total epicardial fat and the thickness of the periatrial fat were significantly larger in AF subjects compared to matched controls [11]. However, in contrast to AF, patients with HF had a smaller epicardial fat mass than controls according to cardiovascular magnetic resonance imaging using a volumetric approach [12]. Obesity is an independent risk factor for the genesis of AF as well as HF [4,5]. Therefore, the epicardial fat and the neighboring atria may interact differently in HF compared to normal individuals. Inflammation plays a critical role in the genesis of AF and HF [13,14]. Adipocytes can enhance local inflammation through increases in adipocytokines and proinflammatory cytokines [10], which may produce myocardial remodeling. Since epicardial fat directly contacts the atria, local effects of HF epicardial fat may also change the atrial electrophysiology. However, it is unclear whether epicardial fat in HF may have different cardiac effects and adipokine profiles. Previous studies showed that the left atrium (LA) has distinctive electrophysiological characteristics and plays an important role in the occurrence of AF [15,16]. It is possible that epicardial fat may have different effects on LA and right atrium
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(RA). The purposes of this study were to investigate the adipokine profiles and effects of epicardial fat on electrophysiological characteristics of the LA and RA and to evaluate whether HF may modulate their effects.
size in approximately five microscopic fields of view was measured by calculating its Feret's diameter under a light microscope (BX51, Olympus, Tokyo, Japan).
2.5. Statistical analysis 2. Materials and methods 2.1. Rabbit PV and atria tissue preparations This investigation was approved by the Institutional Animal Care and Use Committee of Taipei Medical University (IACC no. LAC-99-0098). Male white rabbits (weighing 2–3 kg) were used. HF was induced in the experimental group of rabbits by rapid ventricular pacing through programmable right ventricular pacemakers (Sigma SS303, Medtronic, Minneapolis, MN, USA), implanted as previously described [17]. Briefly, the rabbits were intubated and artificially ventilated with room air supplemented with oxygen. After opening the right third intercostal space, part of the pericardium was cut to expose the anterior surface of the heart. A unipolar pacing lead (Medtronic, Minneapolis, MN, USA: 6491) fixed to the right ventricular free wall was connected to the pacemaker, which was implanted subcutaneously in the right subaxillary area. After the animal recovered from surgery, the pacemaker was programmed to pace at 360 to 400 beats/min (bpm) for 4 weeks. Electrocardiograms (ECGs) were monitored once a week to adjust the pacing to the maximum rate, thus allowing for 1:1 capture. At the end of 4 weeks of pacing, HF was confirmed by the presentation of all signs of ascites, edema, drowsiness, and dyspnea, which are compatible with experimental and clinical HF. Control and HF epicardial fat posterior to atria were isolated from healthy (control) and HF rabbits after anaesthetized with an intraperitoneal injection of sodium pentobarbital. The epicardial fat was trimmed to remove visible blood clot, blood vessels, and other connective tissues. LA and RA tissues were prepared from healthy-rabbit LA free wall (~ 10 × 5 × 0.5 mm) and RA free wall (~ 10 × 5 × 0.5 mm) in Tyrode's solution with a composition (in mM) of 137 NaCl, 4 KCl, 15 NaHCO3, 0.5 NaH2PO4, 0.5 MgCl2, 2.7 CaCl2, and 11 dextrose as described previously [15]. The endocardial side of the preparations faced upwards and epicardial side were covered with healthy or HF LA epicardial fat. One end of a preparation was pinned with needles on top of the epicardial fat. The other end was connected to a Grass FT03C force transducer with a silk thread. The tissue strips were superfused at a constant rate (3 ml/min) with Tyrode's solution which was bubbled with 97% oxygen (O2) and 3% carbon dioxide (CO2) gas at 37 °C, and the preparations were allowed to equilibrate for 10 min before the electrophysiological study.
All continuous variables are expressed as the mean ± standard error of the mean (SEM). A repeated or non-repeated analysis of variance (ANOVA) with post-hoc Bonferroni's test was used to compare the differences before and after control or HF epicardial fat or the differences of between control and HF epicardial fat or between RA and LA. Differences in adipocyte sizes and adipokine profiles between control and HF fat tissues were compared by a Mann–Whitney rank-sum test or unpaired t-test depending on the outcome of the normality test. Pearson's Chi-square test was used to compare the incidence of triggered activity, spontaneous activity and burst firing. A p value of less than 0.05 was considered statistically significant.
3. Results 3.1. Effects of epicardial fat on the electrical activity of LA and RA myocytes As shown in Fig. 1, HF and control epicardial fat prolonged 90% of AP duration in LA. HF, but not control epicardial fat increased the contractility in LA. However, HF or control epicardial fat did not change the RMP, and APA in LA. In contrast, HF or control epicardial fat had no significant effects on RMP, APA, and APD90 (Fig. 2), but had a trend to decrease contractility in RA (p = 0.06). Fig. 3 shows the difference in the APD90 and contractility before and after control epicardial fat and HF epicardial fat were applied to RA and LA, whereas HF fat increased LA contractility in parallel with the prolongation of APD90.
2.2. Electrophysiological studies The transmembrane action potentials (APs) of the RA, and LA were recorded by using machine-pulled glass capillary microelectrodes filled with 3 M KCL. Preparations were connected to a WPI model FD223 electrometer under a tension of 150 mg. The electrical and mechanical events were simultaneously displayed on a Gould 4072 oscilloscope and Gould TA11 recorder. Signals were digitally recorded with a 16-bit accuracy at a rate of 125 kHz. An electrical stimulus with a 1-ms duration and supra-threshold strength was provided by a Grass S88 stimulator through a Grass SIU5B stimulus isolation unit. AP parameters in the LA or RA were measured with 2-Hz electrical stimuli for 30 min from contacting with control or HF epicardial fat. The resting membrane potential (RMP) was measured during the period between the last repolarization and onset of the subsequent AP. The AP amplitude (APA) was obtained from the RMP to the peak of the AP depolarization. AP durations at 90% repolarization of the APA were measured as the APD90. Early afterdepolarizations (EADs) were defined as interruption of the smooth contour of phase 2 or 3 of the APs. Delayed afterdepolarizations (DADs) were defined as the presence of a spontaneous hump-shaped depolarization of the impulse after full repolarization had occurred. Burst firing was defined as the occurrence of an accelerated spontaneous potential (faster than the basal rate) with sudden onset and termination. 2.3. Measurement of inflammatory cytokines and adipokines Epicardial fat tissues obtained from HF rabbits and control rabbits were used for the adipokines assay. In brief, the epicardial fat was frozen at − 80 °C and ground down in liquid nitrogen. The powdered epicardial fat was then dissolved in lysis buffer on the ice for 30 min, followed by centrifugation at 104 rpm for 15 min at − 4 °C. The limpid layer was extracted for analysis. An adipokine array (RayBiotech, Norcross city, GA, USA) was used to detect cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, leptin, monocyte chemotactic protein (MCP)-1, resistin, C-reactive protein (CRP), serum amyloid A (SAA), adiponectin, and adipsin by fluorescence with a laser scanner and Cy3 equivalent dye. Data were extracted with the microarray analysis software. For quantitative data analysis, GenePix Pro vers. 6.0 software was used to transform the cytokine concentrations (pg/ml) with standard curves. 2.4. Histology of epicardial fat and measurement of adipocyte size Epicardial tissues from five control and four HF rabbits were fixed in 10% formaldehyde dehydrated, and embedded in paraffin. Paraffin sections at 5 μm were stained with hematoxylin and eosin (H&E). Adipocytes were recognizable and the adipocyte
Fig. 1. Effects of epicardial fat on action potentials (APs) and contractility of the left atrium (LA) (A) Superimposed tracings and (B) average data of APs and contractility in the LA before and after treatment with HF (n = 9) and control (n = 7) epicardial fat. APA, AP amplitude; APD90, AP duration at 90% repolarization of the APA; RMP, resting membrane potential.
Y-K. Lin et al. / International Journal of Cardiology 167 (2013) 1979–1983
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Fig. 4. Examples of epicardial fat-induced delayed and early afterdepolarizations (A) Control epicardial fat induced delay afterdepolarizations (↓ in upper panel), triggered beat (* in middle panel) and early afterdepolarizations (Δ in lower panel) in LA. (B) HF epicardial fat induced delay afterdepolarizations (↓ in upper panel), triggered beat (* in middle panel) and early afterdepolarizations (Δ in lower panel) in LA. Fig. 2. Effects of epicardial fat on action potentials (APs) and contractility of the right atrium (RA) (A) Superimposed tracings and (B) average data of APs and contractility in the RA before and after treatment with HF (n = 9) and control (n = 7) epicardial fat. APA, AP amplitude; APD90, AP duration at 90% repolarization of the APA; RMP, resting membrane potential.
3.2. Adipokines profile and adipocyte morphology from control and HF epicardial fat As shown in Table 1, HF epicardial fat had significantly lower resistin, CRP, and SAA levels than control epicardial fat. However, IL-6, leptin,
As the examples shown in Fig. 4, both control (n = 7) and HF (n = 9) epicardial fat tissues could induce the occurrences of EADs and DADs in the LA (42.8% vs. 44.4%, p = NS) and RA (14.3% vs. 22.2%, p = NS). However, HF epicardial fat provoked spontaneous activity (33%) and induced burst firing (33%) in the LA (Fig. 5). In contrast, control epicardial fat did not induce spontaneous activity or burst firing in the LA. Moreover, neither control nor HF epicardial fat tissues did induce spontaneous activity or burst firings in RA.
Fig. 3. Comparisons between the effects of epicardial fat on action potentials (APs) and contractility in RA and LA. The changes of the AP duration at 90% repolarization of the AP amplitude (ΔAPD90) and contractility (Δcontractility) after control (n = 7) and heart failure (HF, n = 9) epicardial fat were significantly different in RA and LA.
Fig. 5. Examples of epicardial fat-induced left atrial (LA) spontaneous activity and burst firings. (A) Occurrences of LA spontaneous activity with a rate of 1.6 Hz. The 4 stars (*) indicated the pacing spikes (2 Hz) with driven action potentials in LA. (B) Occurrence of burst firings (3 Hz) after epicardial fat-induced LA spontaneous activity.
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Table 1 Adipokine assay of control and HF epicardial fat. Epicardial fat
Control (n = 6)
HF (n = 4)
p value
Interleukin-6 (pg/ml) Leptin (pg/ml) MCP-1 (pg/ml) Resistin (pg/ml) CRP (pg/ml) SAA (pg/ml) Adiponectin (pg/ml) Adipsin (pg/ml)
38 ± 5 171 ± 18 34 ± 4 10707 ± 1234 390 ± 44 670 ± 76 10312 ± 986 7130 ± 1149
33 ± 0 163 ± 4 31 ± 1 6093 ± 1107 227 ± 25 443 ± 28 7685 ± 984 4132 ± 1689
NS NS NS b 0.05 b 0.05 b 0.05 NS NS
Values are mean ± SEM. MCP-1 = monocyte chemotactic protein-1; CRP = C-reactive protein; SAA = serum amyloid A.
MCP-1, adiponectin, and adipsin did not significantly differ between the two groups. Moreover, TNF-α, IL-8 and IL-1β were undetectable in both control and HF epicardial fat. Thus, their concentrations were lower than the measurable range (pg/ml) from adipokines assay. Moreover, HE staining showed that the adipocytes from HF and control epicardial fat tissues had different cell morphologies (Fig. 6). Adipocytes from HF epicardial fat had a more-slender shaped morphology with a smaller size as compared to those from control epicardial fat. 4. Discussion Adipose tissue is a large endocrine organ, which could secret numerous adipokines [10]. Epicardial fat directly contacts the atria, which may have direct atrial arrhythmogenic effects [10,18]. In this study, for the first time, we demonstrated the original and novel findings that HF and control epicardial fat tissues modulated atrial electrophysiological and contractive properties. In addition, we found that HF epicardial fat had greater arrhythmogenic effects on the LA. These findings suggest that HF may induce atrial arrhythmia through interactions of epicardial fat with the LA.
Fig. 6. Cell morphology of HF and control epicardial fat. (A) Examples of histology from control and HF epicardial fat. (B) Average data of cell Feret's diameters from control adipocytes (n = 489, from 5 rabbits) and HF adipocytes (n = 502, from 4 rabbits).
Previous studies showed that HF may induce triggered activity and AF through spontaneous Ca 2+ leakage as a consequence of atrial Ca 2+ overload [3,17]. In this study, we found that HF epicardial fat prolonged the LA AP duration, but not that in the RA. Since the epicardial fat is not evenly distributed over the atrial wall, it is possible that the AP prolongation effects of epicardial fat may contribute to larger atrial dispersions and facilitate the maintenance of reentrant circuits [19]. Moreover, we found that HF epicardial fat increased the contractility of the LA, which may have been caused by a prolonged LA AP duration with more Ca 2+ influx. Therefore, HF epicardial fat may induce LA Ca 2+ overload and further induce triggered activity and burst firings as noted in the current study. Although the mechanisms for the electrophysiological effects of epicardial fat tissues were not clear, free fatty-acids had been shown to shorten the AP duration in cardiomyocytes [20]. The prolonged AP duration by epicardial fat found in this study may not be caused by the free fatty acids. HF has been shown to be more insulin resistant with elevated free fatty acid [21]. However, we did not measure free fatty acid or homeostasis assessment model (HOMA) of insulin resistance in the HF rabbits. This study also revealed that the RA and LA responded differently to the epicardial fat. A previous study showed that the RA appeared more resistant to hypoxia/reoxygenation than the LA, which may be caused by the higher expression of heat shock proteins in the RA [15]. Similarly, this study also found that the LA electrophysiological properties were more responsive to epicardial fat. Although, the mechanism was not clear, we speculated that higher expressions of heat shock protein in the RA may play a role in this difference [15,22]. An elevated body-mass index may have a distinctive role as a risk factor for HF from survival [4]. Furthermore, a controversial phenomenon (obesity paradox), indicates that obese patients with HF have a better prognosis than leaner patients [23]. In this study, we found that HF adiopocytes had smaller cell size than control adipocytes. Similarly, HF patients also had smaller epicardial fat mass and smaller adipocytes [24]. The reduced adipocyte size in HF epicardial fat might be caused by systemic and local catabolic derangements and impaired tissue oxygenation in HF. Consequently, the smaller cells size of HF adipocytes would produce lower concentrations of inflammatory cytokines and adipokines [25,26], as noted in the current study. In this study, we found that significantly lower resistin, CRP and SAA in HF epicardial fat, which was different from the known effects of HF on circulating resistin, CRP, and SAA [27,28]. Moreover, we found that adiponectin abounds in control and HF epicardial fat. Since adiponectin can increase cardiac contractility and also may increase AP duration by inhibiting delayed rectifier potassium currents [29,30], which may contribute to the effects of epicardial fat on AP and contractility. In contrast, resistin, and CRP were shown to decrease cardiac contractility [31,32], which may counteract the effects of adiponectin. Taken together, compared to control fat, the high concentrations of adiponectin with lower levels of resistin, and CRP in HF epicardial fat tissues might increase contractility and APD90 in LA. Studies have demonstrated that HF patients have raised plasma/ serum levels of inflammatory cytokines [33]. However, we found that TNF-α, IL-1β, and IL-8 were undetectable in control and HF epicardial fats. Moreover, the similar IL-6 amount in control and HF epicardial fat suggests that circulating IL-6 does not mainly arise from epicardial fat [34]. In this study, we can not exclude the possibility that epicardial fat may contain neural elements. The atrial epicardial surface is invested with a neural network, which is the source of multiple neurotransmitters including acetylcholine, adrenergic agonists and vasoactive intestinal peptide (VIP). Acetylcholine shortens atrial AP duration, which is different from the effects of epicardial fat on atrial AP [35]. VIP immunoreactive nerve fibers and VIP receptors are found throughout the heart as well as the atria [36]. VIP can lengthen rabbit atrial AP duration, increase atrial contractility and plays a role the
Y-K. Lin et al. / International Journal of Cardiology 167 (2013) 1979–1983
accumulation of myocardial cell calcium, which may potentially lead to triggered firings found in this study [37,38]. 5. Conclusions Epicardial fat may modulate the electrophysiological properties of the atria which differs between HF and control and between the RA and LA, which in turn may enhance atrial arrhythmogenesis. Acknowledgements The current study was supported by grants from the National Science Council of Taiwan (NSC99-2314-B-016-034-MY3, NSC99-2628B-038-011-MY3, NSC100-2628-B-038-001-MY4, and NSC100-2314B-038-027-MY3), from Taipei Medical University-Wan Fang Hospital (100-wf-eva-01, 100-wf-eva-12, 100-swf-01, and 100-swf-06), and from Taipei Veterans General Hospital (V99C1-120). The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Tsang TS, Gersh BJ. Atrial fibrillation: an old disease, a new epidemic. Am J Med 2002;113:432–5. [2] Li D, Melnyk P, Feng J, et al. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation 2000;101:2631–8. [3] Yeh YH, Wakili R, Qi XY, et al. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ Arrhythm Electrophysiol 2008;1:93–102. [4] Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002;347:305–13. [5] Morricone L, Malavazos AE, Coman C, Donati C, Hassan T, Caviezel F. Echocardiographic abnormalities in normotensive obese patients: relationship with visceral fat. Obes Res 2002;10:489–97. [6] Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004;292:2471–7. [7] Dublin S, French B, Glazer NL, et al. Risk of new-onset atrial fibrillation in relation to body mass index. Arch Intern Med 2006;166:2322–8. [8] Fraser HR, Turner RW. Auricular fibrillation; with special reference to rheumatic heart disease. BMJ 1955;i:1414–8. [9] Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455–61. [10] Lin YK, Chen YJ, Chen SA. Potential atrial arrhythmogenicity of adipocytes: implications for the genesis of atrial fibrillation. Med Hypotheses 2010;74:1026–9. [11] Shin SY, Yong HS, Lim HE, et al. Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2011;22(6):647–55. [12] Doesch C, Haghi D, Flüchter S, et al. Epicardial adipose tissue in patients with heart failure. J Cardiovasc Magn Reson 2010;12(1):40. [13] Yndestad A, Damas JK, Øie E, Ueland T, Gullestad L, Aukrust P. Systemic inflammation in heart failure – the whys and wherefores. Heart Fail Rev 2006;11:83–92. [14] Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104(24):2886–91.
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Heart failure epicardial fat increases atrial arrhythmogenesis Yung-Kuo Lin a, Yao-Chang Chen b, Shih-Lin Chang c, Yenn-Jiang Lin c, Jenn-Han Chen d, Yung-Hsin Yeh e, Shih-Ann Chen c, Yi-Jen Chen a,⁎ a Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan b Department of Biomedical Engineering and Institute of Physiology, National Defense Medical Center, Taipei, Taiwan c National Yang-Ming University, School of Medicine; Division of Cardiology and Cardiovascular Research Center, Veterans General Hospital-Taipei, Taipei, Taiwan d Research Laboratory, Cancer Center, Wan Fang Hospital, Taipei Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan e The First Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan
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Article history: Received 20 January 2012 Received in revised form 27 March 2012 Accepted 4 May 2012 Available online 26 May 2012 Keywords: Adipokines Atrial fibrillation Epicardial fat Heart failure Obesity
a b s t r a c t Background: Obesity is an important risk factor for atrial fibrillation (AF) and heart failure (HF). The effects of epicardial fat on atrial electrophysiology were not clear. This study was to evaluate whether HF may modulate the effects of epicardial fat on atrial electrophysiology. Methods: Conventional microelectrodes recording was used to record the action potential in left (LA) and right (RA) atria of healthy (control) rabbits before and after application of epicardial fat from control or HF (ventricular pacing of 360–400 bpm for 4 weeks) rabbits. Adipokine profiles were checked in epicardial fat of control and HF rabbits. Results: The LA 90% of AP duration was prolonged by control epicardial fat (from 77 ± 6 to 87 ± 7 ms, p b 0.05, n = 7), and by HF epicardial fat (from 78 ± 3 to 98 ± 4 ms, p b 0.001, n = 9). However, control or HF epicardial fat did not change the AP morphology in RA. HF epicardial fat increased the contractility in LA (61 ± 11 vs. 35 ± 6 mg, p = 0.001), but not in RA. Control fat did not change the LA or RA contractility. Moreover, control and HF epicardial fat induced early and delayed afterdepolarizations in LA and RA, but only HF epicardial fat provoked spontaneous activity and burst firing in LA (n = 3/9, 33.3% vs. n = 0/7, 0%, n = 0/9, 0%, p b 0.05). Compared to control fat, HF epicardial fat, had lower resistin, C-reactive protein and serum amyloid A, but similar interluekin-6, leptin, monocyte chemotactic protein-1, adiponectin and adipsin. Conclusions: HF epicardial fat increases atrial arrhythmogenesis, which may contribute to the higher atrial arrhythmia in obesity. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Atrial fibrillation (AF), the most prevalent cardiac arrhythmia in clinical practice, can induce cardiac dysfunction and stroke [1]. Heart failure (HF) may contribute to and coexist with AF, and both may predispose to the occurrence of the other [2,3]. Obesity increases the prevalence of HF, hypertension, ischemic heart disease, ventricular dysfunction, and AF [4,5]. Studies showed that each increment in the body-mass index (BMI) was associated with a 3%–8% higher risk for new-onset AF [6,7]. The Framingham Heart Study also revealed a graded increase with a 5%–7% higher risk of HF for every 1 unit increase in the BMI [4]. Chamber dilatation or hypertrophy secondary to obesity could partially account for AF [8,9]. Moreover, the expanded epicardial adipose tissues in obese individuals, as an important ⁎ Corresponding author at: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111, Hsin-Lung Road, Sec. 3, Taipei 116, Taiwan. Tel.: + 886 2 28757156; fax: + 886 2 29339378. E-mail address: [email protected] (Y.-J. Chen). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.009
source of inflammatory mediators, also potentially underlie the pathophysiology of AF [10]. Total epicardial fat and the thickness of the periatrial fat were significantly larger in AF subjects compared to matched controls [11]. However, in contrast to AF, patients with HF had a smaller epicardial fat mass than controls according to cardiovascular magnetic resonance imaging using a volumetric approach [12]. Obesity is an independent risk factor for the genesis of AF as well as HF [4,5]. Therefore, the epicardial fat and the neighboring atria may interact differently in HF compared to normal individuals. Inflammation plays a critical role in the genesis of AF and HF [13,14]. Adipocytes can enhance local inflammation through increases in adipocytokines and proinflammatory cytokines [10], which may produce myocardial remodeling. Since epicardial fat directly contacts the atria, local effects of HF epicardial fat may also change the atrial electrophysiology. However, it is unclear whether epicardial fat in HF may have different cardiac effects and adipokine profiles. Previous studies showed that the left atrium (LA) has distinctive electrophysiological characteristics and plays an important role in the occurrence of AF [15,16]. It is possible that epicardial fat may have different effects on LA and right atrium
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(RA). The purposes of this study were to investigate the adipokine profiles and effects of epicardial fat on electrophysiological characteristics of the LA and RA and to evaluate whether HF may modulate their effects.
size in approximately five microscopic fields of view was measured by calculating its Feret's diameter under a light microscope (BX51, Olympus, Tokyo, Japan).
2.5. Statistical analysis 2. Materials and methods 2.1. Rabbit PV and atria tissue preparations This investigation was approved by the Institutional Animal Care and Use Committee of Taipei Medical University (IACC no. LAC-99-0098). Male white rabbits (weighing 2–3 kg) were used. HF was induced in the experimental group of rabbits by rapid ventricular pacing through programmable right ventricular pacemakers (Sigma SS303, Medtronic, Minneapolis, MN, USA), implanted as previously described [17]. Briefly, the rabbits were intubated and artificially ventilated with room air supplemented with oxygen. After opening the right third intercostal space, part of the pericardium was cut to expose the anterior surface of the heart. A unipolar pacing lead (Medtronic, Minneapolis, MN, USA: 6491) fixed to the right ventricular free wall was connected to the pacemaker, which was implanted subcutaneously in the right subaxillary area. After the animal recovered from surgery, the pacemaker was programmed to pace at 360 to 400 beats/min (bpm) for 4 weeks. Electrocardiograms (ECGs) were monitored once a week to adjust the pacing to the maximum rate, thus allowing for 1:1 capture. At the end of 4 weeks of pacing, HF was confirmed by the presentation of all signs of ascites, edema, drowsiness, and dyspnea, which are compatible with experimental and clinical HF. Control and HF epicardial fat posterior to atria were isolated from healthy (control) and HF rabbits after anaesthetized with an intraperitoneal injection of sodium pentobarbital. The epicardial fat was trimmed to remove visible blood clot, blood vessels, and other connective tissues. LA and RA tissues were prepared from healthy-rabbit LA free wall (~ 10 × 5 × 0.5 mm) and RA free wall (~ 10 × 5 × 0.5 mm) in Tyrode's solution with a composition (in mM) of 137 NaCl, 4 KCl, 15 NaHCO3, 0.5 NaH2PO4, 0.5 MgCl2, 2.7 CaCl2, and 11 dextrose as described previously [15]. The endocardial side of the preparations faced upwards and epicardial side were covered with healthy or HF LA epicardial fat. One end of a preparation was pinned with needles on top of the epicardial fat. The other end was connected to a Grass FT03C force transducer with a silk thread. The tissue strips were superfused at a constant rate (3 ml/min) with Tyrode's solution which was bubbled with 97% oxygen (O2) and 3% carbon dioxide (CO2) gas at 37 °C, and the preparations were allowed to equilibrate for 10 min before the electrophysiological study.
All continuous variables are expressed as the mean ± standard error of the mean (SEM). A repeated or non-repeated analysis of variance (ANOVA) with post-hoc Bonferroni's test was used to compare the differences before and after control or HF epicardial fat or the differences of between control and HF epicardial fat or between RA and LA. Differences in adipocyte sizes and adipokine profiles between control and HF fat tissues were compared by a Mann–Whitney rank-sum test or unpaired t-test depending on the outcome of the normality test. Pearson's Chi-square test was used to compare the incidence of triggered activity, spontaneous activity and burst firing. A p value of less than 0.05 was considered statistically significant.
3. Results 3.1. Effects of epicardial fat on the electrical activity of LA and RA myocytes As shown in Fig. 1, HF and control epicardial fat prolonged 90% of AP duration in LA. HF, but not control epicardial fat increased the contractility in LA. However, HF or control epicardial fat did not change the RMP, and APA in LA. In contrast, HF or control epicardial fat had no significant effects on RMP, APA, and APD90 (Fig. 2), but had a trend to decrease contractility in RA (p = 0.06). Fig. 3 shows the difference in the APD90 and contractility before and after control epicardial fat and HF epicardial fat were applied to RA and LA, whereas HF fat increased LA contractility in parallel with the prolongation of APD90.
2.2. Electrophysiological studies The transmembrane action potentials (APs) of the RA, and LA were recorded by using machine-pulled glass capillary microelectrodes filled with 3 M KCL. Preparations were connected to a WPI model FD223 electrometer under a tension of 150 mg. The electrical and mechanical events were simultaneously displayed on a Gould 4072 oscilloscope and Gould TA11 recorder. Signals were digitally recorded with a 16-bit accuracy at a rate of 125 kHz. An electrical stimulus with a 1-ms duration and supra-threshold strength was provided by a Grass S88 stimulator through a Grass SIU5B stimulus isolation unit. AP parameters in the LA or RA were measured with 2-Hz electrical stimuli for 30 min from contacting with control or HF epicardial fat. The resting membrane potential (RMP) was measured during the period between the last repolarization and onset of the subsequent AP. The AP amplitude (APA) was obtained from the RMP to the peak of the AP depolarization. AP durations at 90% repolarization of the APA were measured as the APD90. Early afterdepolarizations (EADs) were defined as interruption of the smooth contour of phase 2 or 3 of the APs. Delayed afterdepolarizations (DADs) were defined as the presence of a spontaneous hump-shaped depolarization of the impulse after full repolarization had occurred. Burst firing was defined as the occurrence of an accelerated spontaneous potential (faster than the basal rate) with sudden onset and termination. 2.3. Measurement of inflammatory cytokines and adipokines Epicardial fat tissues obtained from HF rabbits and control rabbits were used for the adipokines assay. In brief, the epicardial fat was frozen at − 80 °C and ground down in liquid nitrogen. The powdered epicardial fat was then dissolved in lysis buffer on the ice for 30 min, followed by centrifugation at 104 rpm for 15 min at − 4 °C. The limpid layer was extracted for analysis. An adipokine array (RayBiotech, Norcross city, GA, USA) was used to detect cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, leptin, monocyte chemotactic protein (MCP)-1, resistin, C-reactive protein (CRP), serum amyloid A (SAA), adiponectin, and adipsin by fluorescence with a laser scanner and Cy3 equivalent dye. Data were extracted with the microarray analysis software. For quantitative data analysis, GenePix Pro vers. 6.0 software was used to transform the cytokine concentrations (pg/ml) with standard curves. 2.4. Histology of epicardial fat and measurement of adipocyte size Epicardial tissues from five control and four HF rabbits were fixed in 10% formaldehyde dehydrated, and embedded in paraffin. Paraffin sections at 5 μm were stained with hematoxylin and eosin (H&E). Adipocytes were recognizable and the adipocyte
Fig. 1. Effects of epicardial fat on action potentials (APs) and contractility of the left atrium (LA) (A) Superimposed tracings and (B) average data of APs and contractility in the LA before and after treatment with HF (n = 9) and control (n = 7) epicardial fat. APA, AP amplitude; APD90, AP duration at 90% repolarization of the APA; RMP, resting membrane potential.
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Fig. 4. Examples of epicardial fat-induced delayed and early afterdepolarizations (A) Control epicardial fat induced delay afterdepolarizations (↓ in upper panel), triggered beat (* in middle panel) and early afterdepolarizations (Δ in lower panel) in LA. (B) HF epicardial fat induced delay afterdepolarizations (↓ in upper panel), triggered beat (* in middle panel) and early afterdepolarizations (Δ in lower panel) in LA. Fig. 2. Effects of epicardial fat on action potentials (APs) and contractility of the right atrium (RA) (A) Superimposed tracings and (B) average data of APs and contractility in the RA before and after treatment with HF (n = 9) and control (n = 7) epicardial fat. APA, AP amplitude; APD90, AP duration at 90% repolarization of the APA; RMP, resting membrane potential.
3.2. Adipokines profile and adipocyte morphology from control and HF epicardial fat As shown in Table 1, HF epicardial fat had significantly lower resistin, CRP, and SAA levels than control epicardial fat. However, IL-6, leptin,
As the examples shown in Fig. 4, both control (n = 7) and HF (n = 9) epicardial fat tissues could induce the occurrences of EADs and DADs in the LA (42.8% vs. 44.4%, p = NS) and RA (14.3% vs. 22.2%, p = NS). However, HF epicardial fat provoked spontaneous activity (33%) and induced burst firing (33%) in the LA (Fig. 5). In contrast, control epicardial fat did not induce spontaneous activity or burst firing in the LA. Moreover, neither control nor HF epicardial fat tissues did induce spontaneous activity or burst firings in RA.
Fig. 3. Comparisons between the effects of epicardial fat on action potentials (APs) and contractility in RA and LA. The changes of the AP duration at 90% repolarization of the AP amplitude (ΔAPD90) and contractility (Δcontractility) after control (n = 7) and heart failure (HF, n = 9) epicardial fat were significantly different in RA and LA.
Fig. 5. Examples of epicardial fat-induced left atrial (LA) spontaneous activity and burst firings. (A) Occurrences of LA spontaneous activity with a rate of 1.6 Hz. The 4 stars (*) indicated the pacing spikes (2 Hz) with driven action potentials in LA. (B) Occurrence of burst firings (3 Hz) after epicardial fat-induced LA spontaneous activity.
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Table 1 Adipokine assay of control and HF epicardial fat. Epicardial fat
Control (n = 6)
HF (n = 4)
p value
Interleukin-6 (pg/ml) Leptin (pg/ml) MCP-1 (pg/ml) Resistin (pg/ml) CRP (pg/ml) SAA (pg/ml) Adiponectin (pg/ml) Adipsin (pg/ml)
38 ± 5 171 ± 18 34 ± 4 10707 ± 1234 390 ± 44 670 ± 76 10312 ± 986 7130 ± 1149
33 ± 0 163 ± 4 31 ± 1 6093 ± 1107 227 ± 25 443 ± 28 7685 ± 984 4132 ± 1689
NS NS NS b 0.05 b 0.05 b 0.05 NS NS
Values are mean ± SEM. MCP-1 = monocyte chemotactic protein-1; CRP = C-reactive protein; SAA = serum amyloid A.
MCP-1, adiponectin, and adipsin did not significantly differ between the two groups. Moreover, TNF-α, IL-8 and IL-1β were undetectable in both control and HF epicardial fat. Thus, their concentrations were lower than the measurable range (pg/ml) from adipokines assay. Moreover, HE staining showed that the adipocytes from HF and control epicardial fat tissues had different cell morphologies (Fig. 6). Adipocytes from HF epicardial fat had a more-slender shaped morphology with a smaller size as compared to those from control epicardial fat. 4. Discussion Adipose tissue is a large endocrine organ, which could secret numerous adipokines [10]. Epicardial fat directly contacts the atria, which may have direct atrial arrhythmogenic effects [10,18]. In this study, for the first time, we demonstrated the original and novel findings that HF and control epicardial fat tissues modulated atrial electrophysiological and contractive properties. In addition, we found that HF epicardial fat had greater arrhythmogenic effects on the LA. These findings suggest that HF may induce atrial arrhythmia through interactions of epicardial fat with the LA.
Fig. 6. Cell morphology of HF and control epicardial fat. (A) Examples of histology from control and HF epicardial fat. (B) Average data of cell Feret's diameters from control adipocytes (n = 489, from 5 rabbits) and HF adipocytes (n = 502, from 4 rabbits).
Previous studies showed that HF may induce triggered activity and AF through spontaneous Ca 2+ leakage as a consequence of atrial Ca 2+ overload [3,17]. In this study, we found that HF epicardial fat prolonged the LA AP duration, but not that in the RA. Since the epicardial fat is not evenly distributed over the atrial wall, it is possible that the AP prolongation effects of epicardial fat may contribute to larger atrial dispersions and facilitate the maintenance of reentrant circuits [19]. Moreover, we found that HF epicardial fat increased the contractility of the LA, which may have been caused by a prolonged LA AP duration with more Ca 2+ influx. Therefore, HF epicardial fat may induce LA Ca 2+ overload and further induce triggered activity and burst firings as noted in the current study. Although the mechanisms for the electrophysiological effects of epicardial fat tissues were not clear, free fatty-acids had been shown to shorten the AP duration in cardiomyocytes [20]. The prolonged AP duration by epicardial fat found in this study may not be caused by the free fatty acids. HF has been shown to be more insulin resistant with elevated free fatty acid [21]. However, we did not measure free fatty acid or homeostasis assessment model (HOMA) of insulin resistance in the HF rabbits. This study also revealed that the RA and LA responded differently to the epicardial fat. A previous study showed that the RA appeared more resistant to hypoxia/reoxygenation than the LA, which may be caused by the higher expression of heat shock proteins in the RA [15]. Similarly, this study also found that the LA electrophysiological properties were more responsive to epicardial fat. Although, the mechanism was not clear, we speculated that higher expressions of heat shock protein in the RA may play a role in this difference [15,22]. An elevated body-mass index may have a distinctive role as a risk factor for HF from survival [4]. Furthermore, a controversial phenomenon (obesity paradox), indicates that obese patients with HF have a better prognosis than leaner patients [23]. In this study, we found that HF adiopocytes had smaller cell size than control adipocytes. Similarly, HF patients also had smaller epicardial fat mass and smaller adipocytes [24]. The reduced adipocyte size in HF epicardial fat might be caused by systemic and local catabolic derangements and impaired tissue oxygenation in HF. Consequently, the smaller cells size of HF adipocytes would produce lower concentrations of inflammatory cytokines and adipokines [25,26], as noted in the current study. In this study, we found that significantly lower resistin, CRP and SAA in HF epicardial fat, which was different from the known effects of HF on circulating resistin, CRP, and SAA [27,28]. Moreover, we found that adiponectin abounds in control and HF epicardial fat. Since adiponectin can increase cardiac contractility and also may increase AP duration by inhibiting delayed rectifier potassium currents [29,30], which may contribute to the effects of epicardial fat on AP and contractility. In contrast, resistin, and CRP were shown to decrease cardiac contractility [31,32], which may counteract the effects of adiponectin. Taken together, compared to control fat, the high concentrations of adiponectin with lower levels of resistin, and CRP in HF epicardial fat tissues might increase contractility and APD90 in LA. Studies have demonstrated that HF patients have raised plasma/ serum levels of inflammatory cytokines [33]. However, we found that TNF-α, IL-1β, and IL-8 were undetectable in control and HF epicardial fats. Moreover, the similar IL-6 amount in control and HF epicardial fat suggests that circulating IL-6 does not mainly arise from epicardial fat [34]. In this study, we can not exclude the possibility that epicardial fat may contain neural elements. The atrial epicardial surface is invested with a neural network, which is the source of multiple neurotransmitters including acetylcholine, adrenergic agonists and vasoactive intestinal peptide (VIP). Acetylcholine shortens atrial AP duration, which is different from the effects of epicardial fat on atrial AP [35]. VIP immunoreactive nerve fibers and VIP receptors are found throughout the heart as well as the atria [36]. VIP can lengthen rabbit atrial AP duration, increase atrial contractility and plays a role the
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accumulation of myocardial cell calcium, which may potentially lead to triggered firings found in this study [37,38]. 5. Conclusions Epicardial fat may modulate the electrophysiological properties of the atria which differs between HF and control and between the RA and LA, which in turn may enhance atrial arrhythmogenesis. Acknowledgements The current study was supported by grants from the National Science Council of Taiwan (NSC99-2314-B-016-034-MY3, NSC99-2628B-038-011-MY3, NSC100-2628-B-038-001-MY4, and NSC100-2314B-038-027-MY3), from Taipei Medical University-Wan Fang Hospital (100-wf-eva-01, 100-wf-eva-12, 100-swf-01, and 100-swf-06), and from Taipei Veterans General Hospital (V99C1-120). The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Tsang TS, Gersh BJ. Atrial fibrillation: an old disease, a new epidemic. Am J Med 2002;113:432–5. [2] Li D, Melnyk P, Feng J, et al. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation 2000;101:2631–8. [3] Yeh YH, Wakili R, Qi XY, et al. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ Arrhythm Electrophysiol 2008;1:93–102. [4] Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002;347:305–13. [5] Morricone L, Malavazos AE, Coman C, Donati C, Hassan T, Caviezel F. Echocardiographic abnormalities in normotensive obese patients: relationship with visceral fat. Obes Res 2002;10:489–97. [6] Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004;292:2471–7. [7] Dublin S, French B, Glazer NL, et al. Risk of new-onset atrial fibrillation in relation to body mass index. Arch Intern Med 2006;166:2322–8. [8] Fraser HR, Turner RW. Auricular fibrillation; with special reference to rheumatic heart disease. BMJ 1955;i:1414–8. [9] Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455–61. [10] Lin YK, Chen YJ, Chen SA. Potential atrial arrhythmogenicity of adipocytes: implications for the genesis of atrial fibrillation. Med Hypotheses 2010;74:1026–9. [11] Shin SY, Yong HS, Lim HE, et al. Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2011;22(6):647–55. [12] Doesch C, Haghi D, Flüchter S, et al. Epicardial adipose tissue in patients with heart failure. J Cardiovasc Magn Reson 2010;12(1):40. [13] Yndestad A, Damas JK, Øie E, Ueland T, Gullestad L, Aukrust P. Systemic inflammation in heart failure – the whys and wherefores. Heart Fail Rev 2006;11:83–92. [14] Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104(24):2886–91.
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