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Atrial Fibrillation and Metabolic Syndrome: Understanding the Connection


Atrial Fibrillation and Metabolic Syndrome: Understanding the Connection

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Credits:

Prabhat kumar ,MBBS and Anil K. Gehi, MD.
Department of Medicine, University of North Carolina at Chapel Hill.


Corresponding Author:  Anil K. Gehi, MD, Assistant Professor of Medicine, University of North Carolina at Chapel Hill. 160 Dental Circle, CB 7075, Chapel Hill, NC 27599.

Abstract

Metabolic syndrome, a constellation of conditions including obesity, dyslipidemia, hypertension and insulin resistance, has increased to epidemic proportions. Metabolic syndrome has been recognized as a risk factor for cardiovascular morbidity and is likely related to the epidemic of cardiovascular diseases. Perhaps not coincidentally, its growth in incidence has paralleled that of atrial fibrillation. Various components of metabolic syndrome have been known to have a role in the pathogenesis of atrial fibrillation. With the conglomeration of components seen in the metabolic syndrome, the risk for atrial fibrillation increases greatly. Several studies have elucidated the role of metabolic syndrome in the development of atrial fibrillation. Its role on the atrial substrate makes it an important determinant of progression of disease and failure of therapeutic strategies such as catheter ablation. Control of the various components of metabolic syndrome may ultimately lead to better outcomes in atrial fibrillation patients.

Introduction

Atrial fibrillation (AF), already the most common arrhythmia worldwide, continues its growth to epidemic proportions. 1, 2 Perhaps not coincidentally, the conglomeration of insulin resistance, hypertension, dyslipidemia, and obesity known as the metabolic syndrome (MS) also has grown in preva- lence to epidemic proportions, particularly in the adult U.S. population. 3 The association of AF with an increased risk for stroke4 and mortality is well known. 5, 6 However, the association of MS with cardiovascular disease is now becoming more evident. 7, 8 The MS has been associated with increased prevalence of coronary heart disease and cerebrovascular disease.7, 9 It has also been associated with worsened coronary heart disease outcomes and cardiovascular mortality.7 More recently, a body of evidence has linked the MS with both the incidence of AF and outcomes of management of AF. In this review, we present the evidence and potential underpinnings of this convergence of epidemics.


Definition of the MS

The American Heart Association / National Heart, Lung, and Blood Institute (AHA/NHLBI) 2005 scientific statement 10 defined the metabolic syndrome as the presence of at least three of the fol lowing criteria:.
• Waist circumference greater than or equal to 40 inches (102 cm) in men or 35 inches (88cm) in women
• Triglycerides greater than or equal to 150 mg/ dl (1.7 mmol/L) or on drug treatment for elevated triglycerides
• High density lipoprotein (HDL) cholesterol less than 40 mg/dL (1.03 mmol/L) in men or 50 mg/dL (1.3 mmol/L) in women or on drug treatment for reduced HDL
• Systolic blood pressure greater than or equal to 130 mmHg or diastolic blood pressure greater than or equal to 85 mmHg or on antihypertensive drug treatment in a patient with a history of hy- pertension
• Fasting glucose greater than or equal to 100 mg/ dL or on drug treatment for elevated glucose
Based on the more conservative ATP III definition (fasting glucose >= 110 mg/dL), the age-adjusted U.S. prevalence of MS was 24% with Mexican Americans having the highest prevalence overall (32%).11 Prevalence increases with age such that those over 60 have an astounding 44% prevalence of MS.11 Based on 2000 census data, nearly 50 mil- lion U.S. residents have the metabolic syndrome and its prevalence is only increasing with time.

The simultaneous epidemic of AF in the U.S. and worldwide populations prompts one to consider whether the two may be linked. There are several hypothetical reasons why this may be the case.


Why Could MS Lead to AF?

Various components of the MS are known risk factors for AF. These factors have been hypothesized to be involved in the pathogenesis of AF by various mechanisms (Figure 1).

However, recent studies have shown that all these components of the MS together may have an additive effect on the risk for AF.12

According to our current understanding, the pathogenesis of AF involves a complex interplay of AF triggers and abnormal atrial substrate re- quired to sustain the arrhythmia. Various com- ponents of the MS may act as risk factors for AF by their effect on AF triggers or the atrial sub- strate. Below we review the potential mechanisms for the MS components in the causation of AF.

Figure 1: Factors involved in the pathogenesis of Atrial fibrillation.This figure summarizes the pathogenetic mechanisms for atrial fibrillation of the various components of the metabolic syndrome. Note the multiple effects of each component of metabolic syndrome


Hypertension

Hypertension is the commonest modifiable risk factor for AF. 13 It is seen in almost 60% of patients Figure 1 with AF.14-16 Hypertension leads to left ventricular hypertrophy and diastolic dysfunction resulting in pathological remodeling of the left atrium predisposing to AF. Diastolic dysfunction results in left atrial stretching of enlargement,17 important to the pathogenesis AF.18 In animal models, hypertension has also been shown to induce structural changes including interstitial fibrosis. 19-21 In addition to mechanical remodeling and left atrial enlargement, electrical remodeling of the left atrium is known to occur with longstanding hypertension.22 Global and regional conduction delays are seen in patients with longstanding systemic hypertension.22 Moreover, changes in angiotensin II level leads to electrophysiological changes in the left atrial myocardium causing left atrial conduc- tion delay.23


Insulin Resistance / Diabetes

Insulin resistance and diabetes are another risk factor associated with the development of AF. The Framingham Heart Study clearly established diabetes mellitus and glucose intolerance as a potential risk factor for AF.13 Mechanistically diabetes mellitus predisposes to AF in a way similar to hypertension. Diabetes mellitus leads to left ventricular hypertrophy and diastolic dysfunction,24 leading to mechanical and electrical remodeling of the atrium. 25 Apart from left ventricular hypertrophy and diastolic function, many other mechanisms of atrial remodeling in diabetes mellitus have been suggested based on animal experiments. Advanced glycation end-products (AGEs) and receptors for AGEs (RAGE) have been known to cause interstitial scarring in the left atrium. Angiotensin II blockers are known to prevent anatomic and electrical remodeling likely by blocking AGE-RAGE.28 In addition to structural remodeling, the atria of diabetic animals also demonstrate increased intra-atrial conduction time providing the electrical substrate for AF. Diabetes mellitus and the MS affect the cardiac autonomic system, which may contribute to arrhythmogenicity.29, 30 Finally, diabetes mellitus may lead to ischemic or non-ischemic cardiomyopathy also predisposing to AF through the resultant left atrial enlargement.26, 27


Dyslipidemia

Hypertriglyceridemia and low HDL-cholesterolemia are the lipid disorders seen with metabolic syndrome. Low HDL-cholesterol, has been found to increase the risk of AF by 20-40%. 15, 31, 32 However, data for hypertriglyceridemia are inconsistent. Proposed mechanisms of predisposition to AF due to the dyslipidemia are arrhythmogenicity due to altered membrane composition leading to altered excitability 33 as well as pro-inflammatory effects. 34


Obesity

Obesity is an important component of the MS and is known to be associated with an increased risk for AF. Data from the Framingham heart study showed an increased risk of new-onset AF for obesity (BMI>=30) with an adjusted hazard ratio of 1.52 and 1.46 for men and women respectively compared to subjects with normal BMI. 35 A metaanalysis of 16 studies found a 49% increased risk of obese patients developing AF as compared to non-obese patients.36 The role of obesity has been explained by multiple mechanisms. Obesity is a risk factor for insulin resistance and diabetes mellitus and hence is a potential pathway for predisposition to AF. A direct correlation has been seen between increasing BMI and left atrial size. 37 Left atrial enlargement may be the most important mechanism through which obesity increases the risk of AF, since after adjusting for left atrial enlargement obesity is no longer a risk factor for atrial fibrillation in the Framingham Heart Study cohort.35 However, other mechanisms which have been suggested include the systemic inflammatory state seen with obesity. Inflammation is known to be a risk factor for AF 38 and obese patients are known to have elevated hsCRP levels, a marker of systemic inflammation.39 Another factor which may predispose to AF in patients with obesity is obstructive sleep apnea, a well described risk factor for AF.40-42


All Together is Worse?

It is apparent that various components of MS predispose to AF in isolation. However, the combination of these components seen in the metabolic syndrome may act in a synergistic manner (Figure 1). The final common pathway in the pathogenesis of AF can be grouped as atrial structural and electrical remodeling, inflammatory processes, and cardiac autonomic changes.


Atrial structural and electrical remodeling is of paramount importance in providing the substrate for initiation and maintenance of AF. As described above, various components of MS cause atrial remodeling. Structural remodeling with interstitial fibrosis leads to heterogeneous electrical substrate with differences in conduction velocities promoting AF.43 Fibroblasts in these areas of interstitial fibrosis may couple with cardiomyocytes electrically and promote reentry and ectopic activity.44 Electrical remodeling alters ion channel function and calcium handling of the cells and promotes initiation and maintenance of atrial fibrillation.45


The cardiac autonomic nervous system is important in the pathogenesis of AF. beta-adrenoceptor activation46 Vagal discharge,47beta-adrenoceptor activation 48 and atrial sympathetic hyperinnervation49 have been implicated in the arrhythmogenesis of AF. Autonomic dysfunction is known to be associated with metabolic syndrome and has been shown to get worse with increasing number of MS factors present.50


Inflammation is considered one of the basic pathophysiological substrates in the causation and progression of AF. Atrial inflammation has been seen in the histological specimens of lone AF patients as opposed to patients with sinus rhythm.51 Inflammation provides an anatomic and electrical substrate for AF. A vast body of evidence supporting the inflammation hypothesis of atrial fibrillation comes from studies of inflammatory biomarkers.38 Moreover, inflammation has a role in early recurrence of atrial fibrillation after catheter ablation.52 As previously discussed, several components of the MS (obesity, insulin resistance, dyslipidemia) have been shown to be proinflammatory.

Thus, various components of MS are known to affect these pathogenetic factors of AF. As these factors are affected by multiple components of MS, their role in the pathogenesis of AF becomes additive and complex. Recent studies have looked at the MS as a whole and the risk of AF. 53-56 It has been shown that as the number of components of AF increases, the risk of development of AF goes up. 53, 57 The fact that AF is one of the important cardiovascular effects of metabolic syndrome has more recently been brought to notice by the stud- ies detailed below. 52


Increased Incidence of AF with MS

Several population-based studies have demonstrated the increased risk of incident AF among patients with the metabolic syndrome (Table 1). Umetani et al analyzed 592 hospitalized patients without structural heart disease. Among 21% of patients with metabolic syndrome, AF occurred in 9% compared with 4% of those without metabolic syndrome. In multivariable analyses, the OR for AF with metabolic syndrome was 2.8. 54 Watanabe et al studied 28,449 participants without baseline AF in the Niigata preventive medicine community-based study. The metabolic syndrome was present in 13% of participants. During a mean follow-up of 4.5 years, AF developed in 265 participants. The HR for AF among participants with MS, compared to those without MS, was 1.78.55 Chamberlain et al analyzed the risk of AF in the Atherosclerosis Risk in Communities (ARIC) Study. Among 15,094 participants over a mean follow-up of 15.4 years, there were 1238 cases of incident AF. At baseline, 46% of black and 40% of white participants had the metabolic syndrome. The HR for AF among participants with, compared to those without, the metabolic syndrome was 1.67 and did not differ by race. In addition, the risk for incident AF increased with increasing number of MS components such that those with all 5 components had a HR of 4.4 compared to those with no components. 12 Echahidi et al analyzed the risk of post-operative AF after coronary artery bypass surgery among 5085 patients. Metabolic syndrome was present in 46% of patients and post-operative AF occurred in 27%. Among patients <=50 years old, MS was associated with a RR of 2.4 with development of post-operative AF.58 Vyssoulis et al studied a population of over 15,000 patients with hypertension.57 The prevalence of MS ranged from 32% to 48%, depending on the definition used. The odds of having AF in those with MS ranged from 1.61 to 1.99. Importantly, the prevalence of AF increased with each additional component of the MS. Altieri et al demonstrated a high incidence of AF (16%) in a population of Hispanic patients with metabolic syndrome.59 The authors suggested mechanisms of this association may include sinus node remodeling, atrial fibrosis, and older age which are all seen in a population with MS.

Table 1: Studies showing association of atrial fibrillation with metabolic syndrome


Worsened Outcomes of AF Treatment with MS

Atrial fibrillation is a progressive disease and various etiological factors provide substrate for its initiation as well as maintenance and progression. Hence patients with MS continue to develop substrate for AF even after treatment and are likely to have worsened outcomes (Table 2). Multiple studies have suggested that MS may influence the outcome of catheter ablation therapy. In a large prospective study of catheter ablation of AF, 1496 patients were followed up for a mean of 21 months. Patients with MS had a 39% recurrence rate compared to 32% for patients without MS (p = 0.005).60 A study by Chang et al.61 from Taiwan enrolled 282 patients undergoing catheter ablation for AF. The authors found a higher incidence of recurrent AF in patients with MS (55% vs. 24%, p < 0.001). Notably, it was more common to see recurrent atrial fibrillation originating from non-pulmonary veinous sites in patients with MS (45% vs. 20%, p=0.037), suggesting an effect of MS on left atrial substrate. In an analysis of predictors of late recurrence of AF after catheter ablation by Cai et al., MS was an independent predictor of late recurrence (OR = 4.41, 95% CI 1.56-12.46, p = 0.005).62 Berkowitsch et al reported the results of pulmonary vein isolation in patients with AF with either cryo-balloon or by circumferential pulmonary vein isolation with radiofrequency catheter ablation in 702 consecutive patients with AF. The presence of MS was independently associated with a higher risk of recurrent AF (46.4% in patients with MS vs. 56.8% among patients without MS, p = 0.006) over 15.6 (inter-quartile range 12.7-42.3) months.63

Table 2: Studies showing increased risk of recurrent atrial fibrillation after catheter ablation in patients with metabolic syndrome.


What Can be Done?

Altered anatomic and electrical substrate is a major factor in the progression of AF and has an adverse effect on outcomes of medical and catheter ablation therapy. Atrial fibrillation is known to promote the structural and electrical remodelingof the atria and control of AF by medical therapy or catheter ablation should have a favorable effect on the substrate. However, evidence suggests that risk factors for AF such as MS have a direct effect on the creation and promotion of the arrhythmogenic substrate. Hence, control of these risk factors by optimum intervention may potentially slow the progression of the remodeling process. Data suggests that optimal control of blood pressure, maintenance of ideal body weight, control of lipid disorders and intervention for insulin resistance would help to control the arrhythmogenic substrate.


Reduction in the risk of atrial fibrillation with treatment of hypertension has been well documented in various studies of antihypertensive therapy for hypertension. A meta-analysis of treatment of hypertension using renin- angiotensin system inhibitors showed a reduction in the relative risk of atrial fibrillation by 15-40%, however this benefit was limited to patients with left ventricular systolic dysfunction or left ventricular hypertrophy.64 Other meta-analyses of studies using ARBs and ACEIs showed similar reduction in new onset atrial fibrillation as well better outcome with electrical cardioversion and lower recurrence later.65, 66


Control of diabetes mellitus with treatment reduced the risk of atrial fibrillation in a large study.67 Another study showed the reduction of risk of atrial fibrillation recurrence after catheter ablation in patients with diabetes mellitus and insulin resistance with the use of pioglitazone.68 Use of lipid lowering drugs like statins has been shown to reduce the risk of atrial fibrillation.69, 70 However, use of pioglitazone or statin may reduce the risk of atrial fibrillation through their direct effect on inflammatory process rather than their effect on insulin resistance or dyslipidemia. Similarly, control of obesity may affect atrial fibrillation indirectly by its effect on insulin resistance and obstructive sleep apnea.


The above account suggests that those factors involved in the pathogenesis of AF work in an interactive manner. Therapeutic interventions have pleiotropic effect and their action on reduction of AF risk is frequently through multiple effects. Further evidence supporting the benefit of treatment for MS as a whole in reducing AF outcomes will improve our understanding in this area.

Conclusions

Metabolic syndrome, a constellation of associated conditions, has increased to epidemic proportions. It has been recognized as a risk factor for cardiovascular morbidity and is likely related to the epidemic of cardiovascular diseases. Recently it has been recognized that atrial fibrillation may be associated with the ongoing epidemic of metabolic syndrome. Various components of metabolic syndrome have been known to have a role in pathogenesis of atrial fibrillation. Recent studies have elucidated the role of metabolic syndrome in the causation of atrial fibrillation. Its role on the atrial substrate makes it an important determinant of progression of disease and failure of therapeutic strategies such as catheter ablation. Control of the various components of metabolic syndrome may ultimately lead to better outcomes in AF patients.

Disclosures

No disclosures relevant to this article were made by the authors.

References

1. Hart RG, Benavente O, McBride R, P1. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS: Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114:119-125
2. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE: Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370-2375
3. Ford ES, Giles WH, Mokdad AH: Increasing prevalence of the metabolic syndrome among u.s. Adults. Diabetes Care 2004; 27:2444-2449
4. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22:983-988
5. Kannel WB, Abbott RD, Savage DD, McNamara PM: Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med 1982; 306:1018-1022
6. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D: Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946-952
7. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, Rinfret S, Schiffrin EL, Eisenberg MJ: The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56:1113-1132
8. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM: Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49:403-414
9. Li W, Ma D, Liu M, Liu H, Feng S, Hao Z, Wu B, Zhang S: Association between metabolic syndrome and risk of stroke: a metaanalysis of cohort studies. Cerebrovasc Dis 2008; 25:539-547
10. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC,Jr, Spertus JA, Costa F, American Heart Association, National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112:2735-2752
11. Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356.359
12. Chamberlain AM, Agarwal SK, Ambrose M, Folsom AR, Soliman EZ, Alonso A: Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 2010; 159:850-856
13. Kannel WB, Abbott RD, Savage DD, McNamara PM: Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med 1982; 306:1018-1022
14. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW, Cobbe S, Breithardt G, Le Heuzey JY, Prins MH, Levy S, Crijns HJ, European Heart Survey Investigators: Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005; 26:2422-2434
15. Haywood LJ, Ford CE, Crow RS, Davis BR, Massie BM, Einhorn PT, Williard A, ALLHAT Collaborative Research Group: Atrial fibrillation at baseline and during follow-up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). J Am Coll Cardiol 2009; 54:2023-2031
16. AFFIRM Investigators. Atrial Fibrillation Follow-up Investigation of Rhythm Management: Baseline characteristics of patients with atrial fibrillation: the AFFIRM Study. Am Heart J 2002; 143:991-1001
17. Vaziri SM, Larson MG, Lauer MS, Benjamin EJ, Levy D: Influence of blood pressure on left atrial size. The Framingham Heart Study. Hypertension 1995; 25:1155-1160
18. Tsang TS, Barnes ME, Bailey KR, Leibson CL, Montgomery SC, Takemoto Y, Diamond PM, Marra MA, Gersh BJ, Wiebers DO, Petty GW, Seward JB: Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001; 76:467-475
19. Kistler PM, Sanders P, Dodic M, Spence SJ, Samuel CS, Zhao C, Charles JA, Edwards GA, Kalman JM: Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation. Eur Heart J 2006; 27:3045-3056
20. Lau DH, Mackenzie L, Kelly DJ, Psaltis PJ, Worthington M, Rajendram A, Kelly DR, Nelson AJ, Zhang Y, Kuklik P, Brooks AG, Worthley SG, Faull RJ, Rao M, Edwards J, Saint DA, Sanders P: Short-term hypertension is associated with the development of atrial fibrillation substrate: a study in an ovine hypertensive model. Heart Rhythm 2010; 7:396-404
21. Lau DH, Mackenzie L, Rajendram A, Psaltis PJ, Kelly DR, Spyropoulos P, Zhang Y, Olakkengil SA, Russell CH, Brooks AG, Faull RJ, Saint DA, Kelly DJ, Rao MM, Worthley SG, Sanders P: Characterization of cardiac remodeling in a large animal "onekidney, one-clip" hypertensive model. Blood Press 2010; 19:119125
22. Medi C, Kalman JM, Spence SJ, Teh AW, Lee G, Bader I, Kaye DM, Kistler PM: Atrial electrical and structural changes associated with longstanding hypertension in humans: implications for the substrate for atrial fibrillation. J Cardiovasc Electrophysiol 2011; 22:1317-1324
23. Matsuyama N, Tsutsumi T, Kubota N, Nakajima T, Suzuki H, Takeyama Y: Direct action of an angiotensin II receptor blocker on angiotensin II-induced left atrial conduction delay in spontaneously hypertensive rats. Hypertens Res 2009; 32:721-726
24. Velagaleti RS, Gona P, Chuang ML, Salton CJ, Fox CS, Blease SJ, Yeon SB, Manning WJ, O'Donnell CJ: Relations of insulin resistance and glycemic abnormalities to cardiovascular magnetic resonance measures of cardiac structure and function: the Framingham Heart Study. Circ Cardiovasc Imaging 2010; 3:257-263
25. Watanabe M, Yokoshiki H, Mitsuyama H, Mizukami K, Ono T, Tsutsui H: Conduction and Refractory Disorders in the Diabetic Atrium. Am J Physiol Heart Circ Physiol 2012
26. Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K, Takamura M, Kaneko S, Aizawa T, Fu LT: AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat. J Cardiovasc Electrophysiol 2008; 19:415-420
27. Kato T, Yamashita T, Sekiguchi A, Sagara K, Takamura M, Takata S, Kaneko S, Aizawa T, Fu LT: What are arrhythmogenic substrates in diabetic rat atria?. J Cardiovasc Electrophysiol 2006; 17:890-894
28. Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K, Takamura M, Kaneko S, Aizawa T, Fu LT: Angiotensin II type 1 receptor blocker attenuates diabetes-induced atrial structural remodeling. J Cardiol 2011; 58:131-136
29. Li L, Huang C, Ai J, Yan B, Gu H, Ma Z, Li AY, Xinyan S, Harden SW, Hatcher JT, Wurster RD, Cheng ZJ: Structural remodeling of vagal afferent innervation of aortic arch and nucleus ambiguus (NA) projections to cardiac ganglia in a transgenic mouse model of type 1 diabetes (OVE26). J Comp Neurol 2010; 518:2771-2793
30. Mabe AM, Hoover DB: Remodeling of cardiac cholinergic innervation and control of heart rate in mice with streptozotocininduced diabetes. Auton Neurosci 2011; 162:24-31
31. Chamberlain AM, Agarwal SK, Ambrose M, Folsom AR, Soliman EZ, Alonso A: Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 2010; 159:850-856
32. Watanabe H, Tanabe N, Yagihara N, Watanabe T, Aizawa Y, Kodama M: Association between lipid profile and risk of atrial fibrillation. Circ J 2011; 75:2767-2774 33. Wu CC, Su MJ, Chi JF, Wu MH, Lee YT: Comparison of aging and hypercholesterolemic effects on the sodium inward currents in cardiac myocytes. Life Sci 1997; 61:1539-1551
34. Siasos G, Tousoulis D, Oikonomou E, Zaromitidou M, Stefanadis C, Papavassiliou AG: Inflammatory markers in hyperlipidemia: from experimental models to clinical practice. Curr Pharm Des 2011; 17:4132-4146
35. Wang TJ, Parise H, Levy D, D'Agostino RB S, Wolf PA, Vasan RS, Benjamin EJ: Obesity and the risk of new-onset atrial fibrillation. JAMA 2004; 292:2471-2477
36. Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS: Atrial fibrillation and obesity--results of a metaanalysis. Am Heart J 2008; 155:310-315
37. Ayer JG, Almafragy HS, Patel AA, Hellyer RL, Celermajer DS: Body mass index is an independent determinant of left atrial size. Heart Lung Circ 2008; 17:19-24
38. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, Tracy RP, Van Wagoner DR, Psaty BM, Lauer MS, Chung MK: Inflammation as a risk factor for atrial fibrillation. Circulation 2003; 108:3006-3010
39. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB: Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282:2131-2135
40. Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE, Malouf JF, Ammash NM, Friedman PA, Somers VK: Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004; 110:364-367 41. Ng CY, Liu T, Shehata M, Stevens S, Chugh SS, Wang X: Metaanalysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. Am J Cardiol 2011; 108:4751
42. Gami AS, Hodge DO, Herges RM, Olson EJ, Nykodym J, Kara T, Somers VK: Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007; 49:565-571
43. Burstein B, Nattel S: Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008; 51:802-809
44. Yue L, Xie J, Nattel S: Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res 2011; 89:744-753
45. Wakili R, Voigt N, Kaab S, Dobrev D, Nattel S: Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest 2011; 121:2955-2968 46. Chou CC, Chen PS: New concepts in atrial fibrillation: neural mechanisms and calcium dynamics. Cardiol Clin 2009; 27:35–43,
viii 47. Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S: Cholinergic atrial fibrillation in a computer model of a two–dimen–sional sheet of canine atrial cells with realistic ionic properties. Circ Res 2002; 90:E73–87
48. Dobrev D, Voigt N, Wehrens XH: The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res 2011; 89:734-743
49. Gould PA, Yii M, McLean C, Finch S, Marshall T, Lambert GW, Kaye DM: Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation. Pacing Clin Electrophysiol 2006; 29:821-829
50. Gehi AK, Lampert R, Veledar E, Lee F, Goldberg J, Jones L, Murrah N, Ashraf A, Vaccarino V: A twin study of metabolic syndrome and autonomic tone. J Cardiovasc Electrophysiol 2009; 20:422-428
51. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A: Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96:1180-1184
52. Smit MD, Maass AH, De Jong AM, Muller Kobold AC, Van Veldhuisen DJ, Van Gelder IC: Role of inflammation in early atrial fibrillation recurrence. Europace 2012; 14:810-817
53. Chamberlain AM, Agarwal SK, Ambrose M, Folsom AR, Soliman EZ, Alonso A: Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 2010; 159:850-856
54. Umetani K, Kodama Y, Nakamura T, Mende A, Kitta Y, Kawabata K, Obata JE, Takano H, Kugiyama K: High prevalence of paroxysmal atrial fibrillation and/or atrial flutter in metabolic syndrome. Circ J 2007; 71:252-255
55. Watanabe H, Tanabe N, Watanabe T, Darbar D, Roden DM, Sasaki S, Aizawa Y: Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study. Circulation 2008; 117:1255-1260
56. Echahidi N, Mohty D, Pibarot P, Despres JP, O'Hara G, Champagne J, Philippon F, Daleau P, Voisine P, Mathieu P: Obesity and metabolic syndrome are independent risk factors for atrial fibrillation after coronary artery bypass graft surgery. Circulation 2007; 116:I213-9
57. Vyssoulis G, Karpanou E, Adamopoulos D, Kyvelou SM, Tzamou V, Michaelidis A, Stefanadis C: Metabolic syndrome and atrial fibrillation in patients with essential hypertension. Nutr Metab Cardiovasc Dis 2011
58. Echahidi N, Mohty D, Pibarot P, Despres JP, O'Hara G, Cham- pagne J, Philippon F, Daleau P, Voisine P, Mathieu P: Obesity and metabolic syndrome are independent risk factors for atrial fibrillation after coronary artery bypass graft surgery. Circulation 2007; 116:I213-9
59. Altieri PI, Figueroa Y, Banchs HL, de Lamadrid JH, Escobales N, Crespo M: Higher incidence of atrial fibrillation in the metabolic syndrome: a Hispanic population study. Bol Asoc Med P R 2011; 103:24-27
60. Mohanty S, Mohanty P, Di Biase L, Bai R, Pump A, Santangeli P, Burkhardt D, Gallinghouse JG, Horton R, Sanchez JE, Bailey S, Zagrodzky J, Natale A: Impact of metabolic syndrome on procedural outcomes in patients with atrial fibrillation undergoing catheter ablation. J Am Coll Cardiol 2012; 59:1295-1301
61. Chang SL, Tuan TC, Tai CT, Lin YJ, Lo LW, Hu YF, Tsao HM, Chang CJ, Tsai WC, Chen SA: Comparison of outcome in catheter ablation of atrial fibrillation in patients with versus without the metabolic syndrome. Am J Cardiol 2009; 103:67-72
62. Cai L, Yin Y, Ling Z, Su L, Liu Z, Wu J, Du H, Lan X, Fan J, Chen W, Xu Y, Zhou P, Zhu J, Zrenner B: Predictors of late recurrence of atrial fibrillation after catheter ablation. Int J Cardiol 2011
63. Berkowitsch A, Kuniss M, Greiss H, Wojcik M, Zaltsberg S, Lehinant S, Erkapic D, Pajitnev D, Pitschner HF, Hamm CW, Neumann T: Impact of impaired renal function and metabolic syndrome on the recurrence of atrial fibrillation after catheter ablation: a long term follow-up. Pacing Clin Electrophysiol 2012; 35:532-543
64. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ: Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005; 45:1832-1839
65. Kalus JS, Coleman CI, White CM: The impact of suppressing the renin-angiotensin system on atrial fibrillation. J Clin Pharmacol 2006; 46:21-28 66. Schneider MP, Hua TA, Bohm M, Wachtell K, Kjeldsen SE, Schmieder RE: Prevention of atrial fibrillation by Renin–Angiotensin system inhibition a meta–analysis. J Am Coll Cardiol 2010; 55:2299-2307
67. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, Heckbert SR: Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J Gen Intern Med 2010; 25:853-858
68. Gu J, Liu X, Wang X, Shi H, Tan H, Zhou L, Gu J, Jiang W, Wang Y: Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus. Europace 2011; 13:1256-1261
69. Fauchier L, Pierre B, de Labriolle A, Grimard C, Zannad N, Babuty D: Antiarrhythmic effect of statin therapy and atrial fibrillation a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2008; 51:828-835
70. Liu T, Li L, Korantzopoulos P, Liu E, Li G: Statin use and development of atrial fibrillation: a systematic review and metaanalysis of randomized clinical trials and observational studies. Int J Cardiol 2008; 126:160-170
71. Umetani K, Kodama Y, Nakamura T, Mende A, Kitta Y, Kawabata K, Obata JE, Takano H, Kugiyama K: High prevalence of paroxysmal atrial fibrillation and/or atrial flutter in metabolic syndrome. Circ J 2007; 71:252-255
72. Watanabe H, Tanabe N, Watanabe T, Darbar D, Roden DM, Sasaki S, Aizawa Y: Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study. Circulation 2008; 117:1255-1260
73. Liu HL, Lu XL, Guo ZP, Lin JX: Association between metabolic syndrome and incidence of atrial fibrillation in essential hypertensive patients without left ventricular hypertrophy. Zhonghua Xin Xue Guan Bing Za Zhi 2010; 38:15-19
74. Tang RB, Gao LY, Dong JZ, Liu XH, Liu XP, Wu JH, Long DY, Yu RH, Du X, Ma CS: Metabolic syndrome in patients with atrial fibrillation in the absence of structural heart disease from a tertiary hospital in China. Chin Med J (Engl) 2009; 122:2744-2747
75. Tang RB, Dong JZ, Liu XP, Long DY, Yu RH, Kalifa J, Ma CS: Metabolic syndrome and risk of recurrence of atrial fibrillation after catheter ablation. Circ J 2009; 73:438-443



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