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Diabetes mellitus and atrial fibrillation: Pathophysiological mechanisms and potential upstream therapies
International Journal of Cardiology 184 (2015) 617–622
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Diabetes mellitus and atrial fibrillation: Pathophysiological mechanisms and potential upstream therapies Christos A. Goudis a, Panagiotis Korantzopoulos b,⁎, Ioannis V. Ntalas b, Eleftherios M. Kallergis c, Tong Liu d, Dimitrios G. Ketikoglou e a
Department of Cardiology, General Hospital of Grevena, Greece Department of Cardiology, University of Ioannina Medical School, Greece Cardiology Department, Heraklion University Hospital, Crete, Greece d Tianjin Institute of Cardiology, Second Hospital of Tanjin Medical University, Tianjin, People's Republic of China e Department of Cardiology, Interbalkan Medical Center, Thessaloniki, Greece b c
a r t i c l e
i n f o
Article history: Received 3 November 2014 Received in revised form 21 January 2015 Accepted 3 March 2015 Available online 5 March 2015 Keywords: Diabetes mellitus Atrial fibrillation Atrial remodeling Upstream therapies
a b s t r a c t Diabetes mellitus (DM) represents one of the most important risk factors for atrial fibrillation (AF) while AF is a strong and independent marker of overall mortality and cardiovascular morbidity in diabetic patients. Autonomic, electrical, electromechanical, and structural remodeling, including oxidative stress, connexin remodeling and glycemic fluctuations seem to be implicated in AF pathophysiology in the setting of DM. The present review highlights the association between DM and AF, provides a comprehensive overview of the responsible pathophysiological mechanisms and briefly discusses potential upstream therapies for DM-related atrial remodeling. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Diabetes mellitus as a risk factor for atrial fibrillation
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice associated with increased cardiovascular morbidity and mortality [1,2]. Apart from intrinsic cardiac causes such as valve disease and congestive heart failure, classic cardiovascular risk factors such as hypertension and diabetes mellitus (DM) promote AF [3]. In fact, individuals with DM have approximately 40% greater risk of incident AF compared with unaffected individuals [4]. On the other hand, AF in diabetic patients is associated with a 61% greater risk of all-cause mortality and comparable higher risks of cardiovascular death, stroke, and heart failure [5]. Even though the precise pathophysiological mechanisms implicating DM in AF development have not been completely elucidated, autonomic, electrical, electromechanical and structural remodeling, as well as oxidative stress, connexin remodeling, and glycemic fluctuations seem to play important roles. This article highlights the association between DM and AF providing a concise overview of the underlying pathophysiological mechanisms and discusses potential upstream therapies for AF prevention in this setting.
Numerous studies have shown that DM, and poor glycemic control reflected by glycated hemoglobin A1c (HbA1c) levels are independently associated with new onset AF. In the pivotal Framingham Heart Study, DM was significantly associated with risk for AF in both sexes [3]. In the same line, the VHAH study reported that DM is a strong and independent risk factor for AF occurrence [6] while the PROACTIVE trial reported that the cumulative incidence of AF in patients with type 2 DM and macrovascular disease was 2.5% during a mean follow-up of 34.5 months [7]. Interestingly, The VALUE trial showed that hypertensive patients who developed new onset DM had a significantly higher rate of new onset AF and a higher risk of developing persistent AF [8]. Of note, Ostgren et al. demonstrated that the presence of DM in the setting of hypertension further increases the odds ratio of AF but this increase was not significant after adjusting for insulin resistance suggesting that insulin resistance may be an underlying mechanism of AF [9]. In a recent study, it was concluded that DM, HbA1c levels/poor glycemic control are independently associated with increased risk of AF [10]. Moreover, a linear trend between incident AF and HbA1c level (for every 1% point increase in HbA1c) in individuals without DM was also evident [10]. In keeping with this findings, Igushi et al. reported that the level of HbA1c, especially in patients with HbA1c N 6.5%, was associated with AF occurrence [11]. Another study showed that the prevalence of AF was significantly greater among patients with DM than in
⁎ Corresponding author at: Department of Cardiology, University of Ioannina Medical School, 45110 Ioannina, Greece. E-mail addresses: [email protected], [email protected] (P. Korantzopoulos).
http://dx.doi.org/10.1016/j.ijcard.2015.03.052 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
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non-diabetic patients but after full adjustment for other risk factors, DM was associated with a 26% increased risk of AF only among women [12]. Women with AF are more likely to suffer from DM [13,14]. In a large prospective cohort of initially healthy middle-aged women, baseline DM was a modest but statistically significant risk factor of incident AF after multivariable adjustment [15]. In specific, the risk of incident AF among women with DM was increased approximately 2-fold after adjustment for age, and this risk was attenuated to about 1.4 after more extensive multivariable adjustment for baseline risk factors, suggesting that the increased risk associated with diabetes is mainly mediated by changes of other AF risk factors such as hypertension and obesity [15]. It was also recently demonstrated that ultrasound-diagnosed nonalcoholic fatty liver disease is strongly associated with increased prevalence of persistent or permanent AF in patients with type 2 DM, independently of several clinical risk factors for AF [16]. Even though the relationship between non-alcoholic fatty liver disease and AF in type 2 DM is currently unknown, the putative role of non-alcoholic fatty liver disease in AF development may have significant implications in terms of screening the increasing population of patients with liver abnormality [16]. Apart from the aforementioned risk factors, several additional parameters (aging [17], ethnicity [18–22], hyperuricemia [23], pulse pressure [24], heart rate recovery [25], and heart failure [26]) seem to be associated with increased AF risk in the setting of DM. The clinical and demographic parameters that influence the relationship between DM and AF are presented in Table 1. In a population-based case–control study, patients receiving pharmacologic treatment for DM had 40% higher risk of developing AF than people without DM, and risk was higher with longer duration of treated DM and worse glycemic control [27]. Furthermore, it was recently indicated that in women without AF or cardiovascular disease at baseline, increasing age, adiposity, and higher HbA1c levels were preferentially associated with the early development of nonparoxysmal AF [28]. Finally, a recent meta-analysis indicated that DM is associated with about 40% increased risk of AF compared with non-DM patients and after adjusting for multiple risk factors the relative risk of AF in patients with DM is 1.24 [4]. 3. Pathophysiological mechanisms implicating diabetes mellitus in atrial fibrillation Diabetic cardiomyopathy implies diabetes-associated changes in the structure and function of the myocardium that are not directly attributable to other confounding factors, such as coronary artery disease or hypertension [26]. Diabetic cardiomyopathy can lead to left ventricular hypertrophy, increased susceptibility to ischemic injury, and congestive heart failure. The potential pathophysiological mechanisms of diabetic cardiomyopathy include myocardial hypertrophy, myocardial lipotoxicity, oxidative stress, cellular apoptosis, interstitial fibrosis, contraction–relaxation dysfunction, impaired myocardial contractile reserve, mitochondrial dysfunction, and other associated myocardial metabolic disorders [26]. On the other hand, pathophysiological mechanisms implicating DM in AF occurrence include autonomic, electrical, electromechanical and structural remodeling, oxidative stress, Table 1 Clinical and demographic risk factors associated with atrial fibrillation in the setting of diabetes mellitus. Aging Sex (female) Race (white) Obesity Hypertension Hyperuricemia Non-alcoholic fatty liver Pulse pressure Heart rate recovery Ηeart failure
connexin remodeling, and glycemic fluctuations (Fig. 1). Undoubtedly, there seems to be some overlap between the mechanisms of diabetic cardiomyopathy and those of diabetic-induced atrial remodeling. Regardless of the presence or not of diabetic cardiomyopathy specific alterations seem to be involved in atrial remodeling and will be discussed in detail.
4. Autonomic remodeling Hyperglycemia plays an important role in the pathogenesis of cardiac autonomic neuropathy by impairing nerve blood perfusion and activating cellular metabolism and redox-associated biologic pathways [29]. Autonomic dysfunction in DM patients can be caused by hyperglycemiarelated pathophysiologic pathways such as formation of advanced glycation end products (AGEs), elevated oxidative/nitrosative stress with increased production of free radicals and activation of the polyol and protein kinase C pathway, as well as poly-ADP ribosylation and neuronal damage-associated genes [29]. Diabetic patients have increased sympathetic and decreased parasympathetic cardiac activity regardless of the presence of autonomic neuropathy. Remarkably, glycemic control and treatment with ACE inhibitors may favorably influence heart rate variability in diabetic patients without autonomic neuropathy [30]. In a rat model of streptozotocin-induced DM it was indicated that sympathetic stimulation increases the incidence of AF in diabetic rats but not in controls [31]. Specifically, sympathetic stimulation significantly shortened the effective refractory period (ERP) of atrial cells in both groups, but the heterogeneity of atrial ERP was increased only in diabetic rats. Immunohistochemical staining of the right atrium aimed at determining the distribution of sympathetic nerves revealed that tyrosine hydroxylase positive nerves were significantly more heterogeneous in DM rats than in control rats whereas the heterogeneity of acetylcholine esterase positive nerves did not differ between the two groups [31]. Given that heterogenous increase in sympathetic innervation contributes to the development of AF, the creation of homogenous sympathetic milieu may confer antiarrhythmic protection. In this context, Yano et al. reported that bilateral stellectomy is effective in AF prevention in a dog rapid atrial pacing model suggesting that βadrenoreceptor blockade might prevent AF in the diabetic heart [32]. In the clinical setting, it has been demonstrated that in patients with type 2 DM with preserved left ventricular ejection fraction reduced heart rate recovery (a marker of impaired vagal activation after sympathetic withdrawal when exercise is stopped) is associated with AF [25]. Therefore, autonomic neuropathy seems to be involved in the pathophysiologic pathways linking DM and AF.
5. Electrical remodeling The main features of atrial electrical remodeling include shortening of the atrial effective refractory period (AERP), increased AERP dispersion, and loss of its frequency adaptation [33]. In the experimental setting it has been shown that diabetic atrium is characterized by increased conduction slowing, heterogeneity of conduction slowing, prolongation of action potential duration (APD), increase in spatial dispersion, absence of frequency-dependent shortening of APD, and increased incidence of APD alternans [34]. Interestingly, in a diabetic rabbit model Liu et al. indicated decreased INa currents, increased ICaL currents, increased AERP dispersion and interatrial conduction time, and increased inducibility of AF [35]. In addition, increased intra-atrial activation time in diabetic rats has also been reported [36]. In the clinical setting, Chao et al. reported that during catheter ablation of paroxysmal AF the activation time of both atria was significantly longer, while bipolar voltage was significantly decreased in the abnormal glucose metabolism group [37]. Moreover, AF recurrence rate after ablation was greater in patients with abnormal glucose metabolism [37].
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Fig. 1. Graphic representation of the main pathophysiological mechanisms linking diabetes and atrial fibrillation.
6. Electromechanical remodeling Changes in atrial excitation–contraction coupling that occur in DM were recently investigated in an alloxan-induced diabetic rabbit model [38]. It was demonstrated that atrial electromechanical function (excitation–contraction coupling) is impaired owing to increased atrial fibrosis and interatrial electrical conduction delay [38]. Recently, Ayhan et al. examined atrial conduction time and cardiac mechanical function in patients with impaired fasting glucose using tissue Doppler imaging [39]. It was evident that left atrial passive emptying volume and LA passive emptying fraction are significantly decreased in patients with impaired fasting glucose [39]. Furthermore, lateral and septal mitral annulus atrial conduction times and inter- and intra-atrial electromechanical delays (delays between electrical activation and mechanical contraction) were significantly higher in patients with impaired fasting glucose compared to controls [39]. Additionally, positive correlations were evident between both inter- and intra-atrial electromechanical delay and glucose levels, while multiple linear regression analysis revealed that glucose levels were independently associated with interatrial electromechanical delay. Collectively, these findings suggest that impaired fasting glycose may be an etiological factor for the development of AF [39]. It has also been shown that intra- and interatrial electromechanical delays are prolonged while diastolic function in both ventricles and LA mechanical function are impaired in patients with type 1 DM [40]. In the same line, Akyel et al. reported significant intra-atrial and interatrial electromechanical delays in type 2 diabetic patients compared to controls [41].
responses indicating that atrial structural remodeling characterized by diffuse interstitial fibrosis may be the major substrate for diabetesrelated AF [36]. In a very recent study using an alloxan-induced diabetic rabbit model it was demonstrated that hyperglycemia or DM contributes to atrial dilation and interstitial fibrosis, ionic remodeling, and increased vulnerability to AF, promoting initiation and perpetuation of AF [35]. Advanced glycation end products (AGEs) and AGE receptors (RAGEs) (the AGERAGE system) mediate the diffuse interstitial fibrosis of the atrial myocardium in DM rats through upregulation of expression of the connective tissue growth factor promoting structural remodeling [43]. Notably, AGE inhibitors can downregulate the expression of growth factors and significantly inhibit the progression of DM-induced atrial fibrosis [43]. Chen et al. investigated the role of Ras homolog gene family, member A (RhoA)/Rho associated coiled-coil forming protein kinase (ROCK) in atrial fibrosis in diabetic rat hearts, and the effects of fasudil hydrochloride hydrate on atrial fibrosis [44]. It was indicated that RhoA/ROCK was involved in atrial fibrosis while fasudil hydrochloride hydrate ameliorates atrial fibrosis by modulating the RhoA/ROCK pathway [44]. In the clinical setting, Kadappu et al. evaluated left atrial (LA) volume, and LA function (by strain and strain rate) as well as their association with diastolic dysfunction in patients with DM [45]. They provided evidence that LA enlargement and related LA dysfunction in DM are independent of the associated hypertension. Collectively, it could be speculated that the combination of diastolic dysfunction and diabetic atrial myopathy contribute to LA enlargement in patients with DM [45]. 8. Oxidative stress
7. Structural remodeling It is well known that fibrosis is a hallmark of atrial structural remodeling [42]. In a generic rat model of type 2 DM no difference in ERP was found but intra-atrial activation time of the DM group was much longer compared to controls [36]. Interestingly, atrial electrical stimuli in the DM rats induced significantly greater number of repetitive atrial
Oxidative stress has been implicated in the development and perpetuation of AF [46]. Indeed, diabetic hyperglycemia can lead to systemic oxidative stress in tissues and organs through different mechanisms [47]. Oxidative stress may have a particular role in diabetic atrial structural remodeling. An elegant study addressed the effect of type 2 diabetes on mitochondrial metabolism of lipid- and carbohydrate-based
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substrates and reactive oxygen species (ROS) emission in human atrial myocardium [48]. It was demonstrated that maximal capacity for mitochondrial oxidation of palmitoyl-carnitine is decreased, but mitochondrial H2O2 emission during oxidation of carbohydrate- and lipid-based substrates is increased, corresponding to increased oxidative stress in this tissue. It could therefore be speculated that mitochondrial oxidative stress may be the main source of ROS in diabetic atrial tissue [48]. 9. Connexin remodeling Gap junction remodeling seems to play a significant role in hyperglycemia-associated AF substrates. An experimental study examined the extent of expression and phosphorylation of Cx43 in diabetic rat atria indicating that DM upregulates Cx43 atrial expression and significantly decreases Cx43 phosphorylation [49]. In support of these findings, Watanabe et al. used a streptozotocin-induced diabetic rat model and found that the expression of CX43 in the diabetic group was significantly higher than CX40, suggesting that CX43 rather than CX40 represents the main type of gap junction protein in atrium [34]. These aforementioned abnormalities imply that diabetes can alter the expression and distribution of connexins resulting in atrial structural remodeling and conduction abnormalities in AF. In support of this notion experimental evidence suggests that connexin gene therapy preserves atrial conduction and prevents AF [50]. 10. Glycemic fluctuations It has been proposed that AF initiation in diabetes is due to the fluctuations of glucose levels rather than the hyperglycemic state itself [51]. In experimental models, hypoglycemia has been shown to increase vulnerability to AF. Vardas et al. reported that in canine atria AF occurred significantly more often under hypoglycemia rather than hyperglycemia [52]. The atrial refractory period was the shortest under hypoglycemia in the left atrium and the longest under normoglycemia or hyperglycemia in the right atrium [52]. In a streptozotocin-induced diabetic rat model, Saito et al. demonstrated that glucose fluctuations increase the incidence of AF by promoting cardiac fibrosis [53]. Increased ROS levels caused by upregulation of thioredoxin-interacting protein (Txnip) and NADPH oxidase expression could be the underlying mechanism of glucose fluctuations-induced fibrosis [53]. AF as a complication of hypoglycemia has been reported in several cases of diabetic patients [54,55]. Interestingly, in a community-based cohort with ≤ 10 years of follow-up, no significant association was observed between insulin resistance and incident AF [56]. In addition, Huxley et al. did not find any correlation between markers of glucose homeostasis (fasting glucose and insulin levels, HbA1c) and AF onset in subjects without diabetes or prediabetes suggesting that the severity of diabetes and long-term cumulative exposure to hyperglycemia can induce AF but not the prediabetic increased fasting glucose [10]. 11. Upstream therapies for diabetes mellitus related atrial remodeling It is well known that antiarrhythmic drugs have major limitations, including incomplete efficacy and risks of life-threatening proarrhythmic events [57,58]. Ablation procedures are efficient and relatively safe, but the large burden of AF in the population allows application of ablation treatment in only a small number of patients [59]. Atrial remodeling seems to be a major determinant of AF ablation success. McGann et al. hypothesized that late gadolinium enhancement MRI can identify LA wall structural remodeling and stratify patients who are likely or not to benefit from ablation therapy [60]. After multivariate analysis, ablation outcome was best predicted by advanced structural remodeling stage and the presence of DM whereas increased LA volume and persistent AF were not significant predictors [60]. In a very recent study, metformin use was associated with a decreased risk of AF in patients with type 2 DM who were not using other anti-diabetic medications, probably via attenuation
of atrial cell tachycardia-induced myolysis and oxidative stress [61]. However, in another very recent report intensive glycemic control did not affect the rate of new-onset AF [62]. Upstream therapies have recently attracted much attention given their appealing rationale to modulate atrial substrate without having the untoward effects of ion-channel blockers [63–65]. Several agents such as blockers of the renin-angiotensin-aldosterone (RAA) system, statins, antioxidants, n-3 fatty acids, and others may exert beneficial effects in AF although inconsistent results have been published in the literature. A proposed key mechanism of the antiarrhythmic action of RAA inhibitors relates to opposing the arrhythmogenic effects of angiotensin II, which include stimulation of atrial fibrosis and hypertrophy secondary to activation of mitogen-activated protein kinases, uncoupling gap junctions, impaired calcium handling, alteration of ion channel dynamics, activation of mediators of oxidative stress, and promotion of inflammation [66,67]. Several studies indicate that RAA inhibition suppresses the expression of RAGE and connective tissue growth factor (CTGF) as well as AGE formation [68–72]. In streptozotocin-induced diabetic rats Kato et al. demonstrated that treatment with candesartan reduces CTGF expression and effectively suppresses the development of atrial fibrotic deposition [73]. The attenuation of CTGF expression by candesartan may be derived via decreased AGE interaction with RAGE and/or from a direct effect of the drug [73]. Thiazolidinediones (TZDs) belong to a class of insulin sensitizing agents with peroxisome proliferator-activated receptor-c (PPAR-c) activation effects ameliorating insulin resistance in patients with type 2 diabetes [74]. Experimental studies have demonstrated that TZDs prevent atrial electrical and structural remodeling through their antiinflammatory and antioxidant properties [75–79]. The possible targets of PPAR-c agonists include transforming growth factor-b (TGF-b), tumor necrosis factor-a (TNF-a), atrial natriuretic peptide (ANP), superoxide dismutase (SOD), malondialdehyde (MDA), NADPH oxidase subunits, and voltage-dependent Ca2+ currents [80]. In the clinical setting, anecdotal evidence indicated a remarkable improvement of paroxysmal atrial fibrillation (AF) in 2 diabetic patients after treatment with rosiglitazone [81]. In a large population study of 12,605 patients with type 2 diabetes Chao et al. investigated the possible association between TZD use and development of new-onset AF [82]. During a mean followup of 5 years, TZD use was associated with a 31% decreased risk of newonset AF after adjustment for age, underlying diseases, and baseline medications [82]. Moreover, Gu et al. reported that pioglitazone improved the maintenance of sinus rhythm and reduced the reablation rate in patients with paroxysmal AF and type 2 DM after catheter ablation [83]. Further largescale randomized trials with long-term follow-up are needed in order to evaluate the potential role of TZDs for AF prevention in patients with diabetes [84]. Probucol, a lipid-lowering drug that has potent antioxidant effects may favorably affect atrial remodeling [85]. In an experimental model probucol decreased the C-reactive protein rise and attenuated atrial oxidative stress caused by atrial tachypacing [86]. In addition, probucol effectively inhibited atrial nerve growth factor-beta upregulation, attenuated atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and reduced the inducibility and duration of AF [86]. In another experimental study, probucol effectively attenuated atrial structural remodeling and apoptosis [87]. Moreover, Fu et al. investigated the effects of probucol on atrial structural and electrical remodeling in alloxan-induced diabetic rabbits demonstrating that probucol significantly reduces left atrial interstitial fibrosis and AF inducibility [88]. Remarkably, it was indicated that its inhibitory effects on oxidative stress, nuclear factor-κΒ (NF-κB), TGF-β, and TNF-α over-expression contribute to its anti-remodeling effects [88]. Other potential upstream therapies targeting atrial structural remodeling, inflammation and oxidative stress, such as statins [89], n-3 polyunsaturated fatty acids [90], antioxidant agents including vitamin C and E, N-acetylcysteine, and xanthine oxidase inhibitors [91,92], have been proposed as novel therapeutic interventions in the management of
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AF but their specific role in the setting of diabetes is uncertain. Further studies are needed in order to evaluate the potential role of these agents in the primary and secondary prevention of AF in diabetic patients. 12. Conclusion DM is one of the most important risk factors for the initiation and perpetuation of AF. Pathophysiological mechanisms implicated in AF occurrence in diabetic patients include autonomic remodeling, electrical, electromechanical and structural remodeling, oxidative stress, connexin remodeling, and glycemic fluctuations. DM related atrial fibrosis results in prolongation of atrial activation time and cycle length, and local reduction of atrial electrogram voltages, thus contributing to the development of the arrhythmia. Upstream therapies with antioxidant and antiinflammatory effects such as ACEI/ARBs, TZDs, and probucol may play an important role in the prevention and treatment of AF in this setting. 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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Diabetes mellitus and atrial fibrillation: Pathophysiological mechanisms and potential upstream therapies Christos A. Goudis a, Panagiotis Korantzopoulos b,⁎, Ioannis V. Ntalas b, Eleftherios M. Kallergis c, Tong Liu d, Dimitrios G. Ketikoglou e a
Department of Cardiology, General Hospital of Grevena, Greece Department of Cardiology, University of Ioannina Medical School, Greece Cardiology Department, Heraklion University Hospital, Crete, Greece d Tianjin Institute of Cardiology, Second Hospital of Tanjin Medical University, Tianjin, People's Republic of China e Department of Cardiology, Interbalkan Medical Center, Thessaloniki, Greece b c
a r t i c l e
i n f o
Article history: Received 3 November 2014 Received in revised form 21 January 2015 Accepted 3 March 2015 Available online 5 March 2015 Keywords: Diabetes mellitus Atrial fibrillation Atrial remodeling Upstream therapies
a b s t r a c t Diabetes mellitus (DM) represents one of the most important risk factors for atrial fibrillation (AF) while AF is a strong and independent marker of overall mortality and cardiovascular morbidity in diabetic patients. Autonomic, electrical, electromechanical, and structural remodeling, including oxidative stress, connexin remodeling and glycemic fluctuations seem to be implicated in AF pathophysiology in the setting of DM. The present review highlights the association between DM and AF, provides a comprehensive overview of the responsible pathophysiological mechanisms and briefly discusses potential upstream therapies for DM-related atrial remodeling. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Diabetes mellitus as a risk factor for atrial fibrillation
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice associated with increased cardiovascular morbidity and mortality [1,2]. Apart from intrinsic cardiac causes such as valve disease and congestive heart failure, classic cardiovascular risk factors such as hypertension and diabetes mellitus (DM) promote AF [3]. In fact, individuals with DM have approximately 40% greater risk of incident AF compared with unaffected individuals [4]. On the other hand, AF in diabetic patients is associated with a 61% greater risk of all-cause mortality and comparable higher risks of cardiovascular death, stroke, and heart failure [5]. Even though the precise pathophysiological mechanisms implicating DM in AF development have not been completely elucidated, autonomic, electrical, electromechanical and structural remodeling, as well as oxidative stress, connexin remodeling, and glycemic fluctuations seem to play important roles. This article highlights the association between DM and AF providing a concise overview of the underlying pathophysiological mechanisms and discusses potential upstream therapies for AF prevention in this setting.
Numerous studies have shown that DM, and poor glycemic control reflected by glycated hemoglobin A1c (HbA1c) levels are independently associated with new onset AF. In the pivotal Framingham Heart Study, DM was significantly associated with risk for AF in both sexes [3]. In the same line, the VHAH study reported that DM is a strong and independent risk factor for AF occurrence [6] while the PROACTIVE trial reported that the cumulative incidence of AF in patients with type 2 DM and macrovascular disease was 2.5% during a mean follow-up of 34.5 months [7]. Interestingly, The VALUE trial showed that hypertensive patients who developed new onset DM had a significantly higher rate of new onset AF and a higher risk of developing persistent AF [8]. Of note, Ostgren et al. demonstrated that the presence of DM in the setting of hypertension further increases the odds ratio of AF but this increase was not significant after adjusting for insulin resistance suggesting that insulin resistance may be an underlying mechanism of AF [9]. In a recent study, it was concluded that DM, HbA1c levels/poor glycemic control are independently associated with increased risk of AF [10]. Moreover, a linear trend between incident AF and HbA1c level (for every 1% point increase in HbA1c) in individuals without DM was also evident [10]. In keeping with this findings, Igushi et al. reported that the level of HbA1c, especially in patients with HbA1c N 6.5%, was associated with AF occurrence [11]. Another study showed that the prevalence of AF was significantly greater among patients with DM than in
⁎ Corresponding author at: Department of Cardiology, University of Ioannina Medical School, 45110 Ioannina, Greece. E-mail addresses: [email protected], [email protected] (P. Korantzopoulos).
http://dx.doi.org/10.1016/j.ijcard.2015.03.052 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
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non-diabetic patients but after full adjustment for other risk factors, DM was associated with a 26% increased risk of AF only among women [12]. Women with AF are more likely to suffer from DM [13,14]. In a large prospective cohort of initially healthy middle-aged women, baseline DM was a modest but statistically significant risk factor of incident AF after multivariable adjustment [15]. In specific, the risk of incident AF among women with DM was increased approximately 2-fold after adjustment for age, and this risk was attenuated to about 1.4 after more extensive multivariable adjustment for baseline risk factors, suggesting that the increased risk associated with diabetes is mainly mediated by changes of other AF risk factors such as hypertension and obesity [15]. It was also recently demonstrated that ultrasound-diagnosed nonalcoholic fatty liver disease is strongly associated with increased prevalence of persistent or permanent AF in patients with type 2 DM, independently of several clinical risk factors for AF [16]. Even though the relationship between non-alcoholic fatty liver disease and AF in type 2 DM is currently unknown, the putative role of non-alcoholic fatty liver disease in AF development may have significant implications in terms of screening the increasing population of patients with liver abnormality [16]. Apart from the aforementioned risk factors, several additional parameters (aging [17], ethnicity [18–22], hyperuricemia [23], pulse pressure [24], heart rate recovery [25], and heart failure [26]) seem to be associated with increased AF risk in the setting of DM. The clinical and demographic parameters that influence the relationship between DM and AF are presented in Table 1. In a population-based case–control study, patients receiving pharmacologic treatment for DM had 40% higher risk of developing AF than people without DM, and risk was higher with longer duration of treated DM and worse glycemic control [27]. Furthermore, it was recently indicated that in women without AF or cardiovascular disease at baseline, increasing age, adiposity, and higher HbA1c levels were preferentially associated with the early development of nonparoxysmal AF [28]. Finally, a recent meta-analysis indicated that DM is associated with about 40% increased risk of AF compared with non-DM patients and after adjusting for multiple risk factors the relative risk of AF in patients with DM is 1.24 [4]. 3. Pathophysiological mechanisms implicating diabetes mellitus in atrial fibrillation Diabetic cardiomyopathy implies diabetes-associated changes in the structure and function of the myocardium that are not directly attributable to other confounding factors, such as coronary artery disease or hypertension [26]. Diabetic cardiomyopathy can lead to left ventricular hypertrophy, increased susceptibility to ischemic injury, and congestive heart failure. The potential pathophysiological mechanisms of diabetic cardiomyopathy include myocardial hypertrophy, myocardial lipotoxicity, oxidative stress, cellular apoptosis, interstitial fibrosis, contraction–relaxation dysfunction, impaired myocardial contractile reserve, mitochondrial dysfunction, and other associated myocardial metabolic disorders [26]. On the other hand, pathophysiological mechanisms implicating DM in AF occurrence include autonomic, electrical, electromechanical and structural remodeling, oxidative stress, Table 1 Clinical and demographic risk factors associated with atrial fibrillation in the setting of diabetes mellitus. Aging Sex (female) Race (white) Obesity Hypertension Hyperuricemia Non-alcoholic fatty liver Pulse pressure Heart rate recovery Ηeart failure
connexin remodeling, and glycemic fluctuations (Fig. 1). Undoubtedly, there seems to be some overlap between the mechanisms of diabetic cardiomyopathy and those of diabetic-induced atrial remodeling. Regardless of the presence or not of diabetic cardiomyopathy specific alterations seem to be involved in atrial remodeling and will be discussed in detail.
4. Autonomic remodeling Hyperglycemia plays an important role in the pathogenesis of cardiac autonomic neuropathy by impairing nerve blood perfusion and activating cellular metabolism and redox-associated biologic pathways [29]. Autonomic dysfunction in DM patients can be caused by hyperglycemiarelated pathophysiologic pathways such as formation of advanced glycation end products (AGEs), elevated oxidative/nitrosative stress with increased production of free radicals and activation of the polyol and protein kinase C pathway, as well as poly-ADP ribosylation and neuronal damage-associated genes [29]. Diabetic patients have increased sympathetic and decreased parasympathetic cardiac activity regardless of the presence of autonomic neuropathy. Remarkably, glycemic control and treatment with ACE inhibitors may favorably influence heart rate variability in diabetic patients without autonomic neuropathy [30]. In a rat model of streptozotocin-induced DM it was indicated that sympathetic stimulation increases the incidence of AF in diabetic rats but not in controls [31]. Specifically, sympathetic stimulation significantly shortened the effective refractory period (ERP) of atrial cells in both groups, but the heterogeneity of atrial ERP was increased only in diabetic rats. Immunohistochemical staining of the right atrium aimed at determining the distribution of sympathetic nerves revealed that tyrosine hydroxylase positive nerves were significantly more heterogeneous in DM rats than in control rats whereas the heterogeneity of acetylcholine esterase positive nerves did not differ between the two groups [31]. Given that heterogenous increase in sympathetic innervation contributes to the development of AF, the creation of homogenous sympathetic milieu may confer antiarrhythmic protection. In this context, Yano et al. reported that bilateral stellectomy is effective in AF prevention in a dog rapid atrial pacing model suggesting that βadrenoreceptor blockade might prevent AF in the diabetic heart [32]. In the clinical setting, it has been demonstrated that in patients with type 2 DM with preserved left ventricular ejection fraction reduced heart rate recovery (a marker of impaired vagal activation after sympathetic withdrawal when exercise is stopped) is associated with AF [25]. Therefore, autonomic neuropathy seems to be involved in the pathophysiologic pathways linking DM and AF.
5. Electrical remodeling The main features of atrial electrical remodeling include shortening of the atrial effective refractory period (AERP), increased AERP dispersion, and loss of its frequency adaptation [33]. In the experimental setting it has been shown that diabetic atrium is characterized by increased conduction slowing, heterogeneity of conduction slowing, prolongation of action potential duration (APD), increase in spatial dispersion, absence of frequency-dependent shortening of APD, and increased incidence of APD alternans [34]. Interestingly, in a diabetic rabbit model Liu et al. indicated decreased INa currents, increased ICaL currents, increased AERP dispersion and interatrial conduction time, and increased inducibility of AF [35]. In addition, increased intra-atrial activation time in diabetic rats has also been reported [36]. In the clinical setting, Chao et al. reported that during catheter ablation of paroxysmal AF the activation time of both atria was significantly longer, while bipolar voltage was significantly decreased in the abnormal glucose metabolism group [37]. Moreover, AF recurrence rate after ablation was greater in patients with abnormal glucose metabolism [37].
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Fig. 1. Graphic representation of the main pathophysiological mechanisms linking diabetes and atrial fibrillation.
6. Electromechanical remodeling Changes in atrial excitation–contraction coupling that occur in DM were recently investigated in an alloxan-induced diabetic rabbit model [38]. It was demonstrated that atrial electromechanical function (excitation–contraction coupling) is impaired owing to increased atrial fibrosis and interatrial electrical conduction delay [38]. Recently, Ayhan et al. examined atrial conduction time and cardiac mechanical function in patients with impaired fasting glucose using tissue Doppler imaging [39]. It was evident that left atrial passive emptying volume and LA passive emptying fraction are significantly decreased in patients with impaired fasting glucose [39]. Furthermore, lateral and septal mitral annulus atrial conduction times and inter- and intra-atrial electromechanical delays (delays between electrical activation and mechanical contraction) were significantly higher in patients with impaired fasting glucose compared to controls [39]. Additionally, positive correlations were evident between both inter- and intra-atrial electromechanical delay and glucose levels, while multiple linear regression analysis revealed that glucose levels were independently associated with interatrial electromechanical delay. Collectively, these findings suggest that impaired fasting glycose may be an etiological factor for the development of AF [39]. It has also been shown that intra- and interatrial electromechanical delays are prolonged while diastolic function in both ventricles and LA mechanical function are impaired in patients with type 1 DM [40]. In the same line, Akyel et al. reported significant intra-atrial and interatrial electromechanical delays in type 2 diabetic patients compared to controls [41].
responses indicating that atrial structural remodeling characterized by diffuse interstitial fibrosis may be the major substrate for diabetesrelated AF [36]. In a very recent study using an alloxan-induced diabetic rabbit model it was demonstrated that hyperglycemia or DM contributes to atrial dilation and interstitial fibrosis, ionic remodeling, and increased vulnerability to AF, promoting initiation and perpetuation of AF [35]. Advanced glycation end products (AGEs) and AGE receptors (RAGEs) (the AGERAGE system) mediate the diffuse interstitial fibrosis of the atrial myocardium in DM rats through upregulation of expression of the connective tissue growth factor promoting structural remodeling [43]. Notably, AGE inhibitors can downregulate the expression of growth factors and significantly inhibit the progression of DM-induced atrial fibrosis [43]. Chen et al. investigated the role of Ras homolog gene family, member A (RhoA)/Rho associated coiled-coil forming protein kinase (ROCK) in atrial fibrosis in diabetic rat hearts, and the effects of fasudil hydrochloride hydrate on atrial fibrosis [44]. It was indicated that RhoA/ROCK was involved in atrial fibrosis while fasudil hydrochloride hydrate ameliorates atrial fibrosis by modulating the RhoA/ROCK pathway [44]. In the clinical setting, Kadappu et al. evaluated left atrial (LA) volume, and LA function (by strain and strain rate) as well as their association with diastolic dysfunction in patients with DM [45]. They provided evidence that LA enlargement and related LA dysfunction in DM are independent of the associated hypertension. Collectively, it could be speculated that the combination of diastolic dysfunction and diabetic atrial myopathy contribute to LA enlargement in patients with DM [45]. 8. Oxidative stress
7. Structural remodeling It is well known that fibrosis is a hallmark of atrial structural remodeling [42]. In a generic rat model of type 2 DM no difference in ERP was found but intra-atrial activation time of the DM group was much longer compared to controls [36]. Interestingly, atrial electrical stimuli in the DM rats induced significantly greater number of repetitive atrial
Oxidative stress has been implicated in the development and perpetuation of AF [46]. Indeed, diabetic hyperglycemia can lead to systemic oxidative stress in tissues and organs through different mechanisms [47]. Oxidative stress may have a particular role in diabetic atrial structural remodeling. An elegant study addressed the effect of type 2 diabetes on mitochondrial metabolism of lipid- and carbohydrate-based
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substrates and reactive oxygen species (ROS) emission in human atrial myocardium [48]. It was demonstrated that maximal capacity for mitochondrial oxidation of palmitoyl-carnitine is decreased, but mitochondrial H2O2 emission during oxidation of carbohydrate- and lipid-based substrates is increased, corresponding to increased oxidative stress in this tissue. It could therefore be speculated that mitochondrial oxidative stress may be the main source of ROS in diabetic atrial tissue [48]. 9. Connexin remodeling Gap junction remodeling seems to play a significant role in hyperglycemia-associated AF substrates. An experimental study examined the extent of expression and phosphorylation of Cx43 in diabetic rat atria indicating that DM upregulates Cx43 atrial expression and significantly decreases Cx43 phosphorylation [49]. In support of these findings, Watanabe et al. used a streptozotocin-induced diabetic rat model and found that the expression of CX43 in the diabetic group was significantly higher than CX40, suggesting that CX43 rather than CX40 represents the main type of gap junction protein in atrium [34]. These aforementioned abnormalities imply that diabetes can alter the expression and distribution of connexins resulting in atrial structural remodeling and conduction abnormalities in AF. In support of this notion experimental evidence suggests that connexin gene therapy preserves atrial conduction and prevents AF [50]. 10. Glycemic fluctuations It has been proposed that AF initiation in diabetes is due to the fluctuations of glucose levels rather than the hyperglycemic state itself [51]. In experimental models, hypoglycemia has been shown to increase vulnerability to AF. Vardas et al. reported that in canine atria AF occurred significantly more often under hypoglycemia rather than hyperglycemia [52]. The atrial refractory period was the shortest under hypoglycemia in the left atrium and the longest under normoglycemia or hyperglycemia in the right atrium [52]. In a streptozotocin-induced diabetic rat model, Saito et al. demonstrated that glucose fluctuations increase the incidence of AF by promoting cardiac fibrosis [53]. Increased ROS levels caused by upregulation of thioredoxin-interacting protein (Txnip) and NADPH oxidase expression could be the underlying mechanism of glucose fluctuations-induced fibrosis [53]. AF as a complication of hypoglycemia has been reported in several cases of diabetic patients [54,55]. Interestingly, in a community-based cohort with ≤ 10 years of follow-up, no significant association was observed between insulin resistance and incident AF [56]. In addition, Huxley et al. did not find any correlation between markers of glucose homeostasis (fasting glucose and insulin levels, HbA1c) and AF onset in subjects without diabetes or prediabetes suggesting that the severity of diabetes and long-term cumulative exposure to hyperglycemia can induce AF but not the prediabetic increased fasting glucose [10]. 11. Upstream therapies for diabetes mellitus related atrial remodeling It is well known that antiarrhythmic drugs have major limitations, including incomplete efficacy and risks of life-threatening proarrhythmic events [57,58]. Ablation procedures are efficient and relatively safe, but the large burden of AF in the population allows application of ablation treatment in only a small number of patients [59]. Atrial remodeling seems to be a major determinant of AF ablation success. McGann et al. hypothesized that late gadolinium enhancement MRI can identify LA wall structural remodeling and stratify patients who are likely or not to benefit from ablation therapy [60]. After multivariate analysis, ablation outcome was best predicted by advanced structural remodeling stage and the presence of DM whereas increased LA volume and persistent AF were not significant predictors [60]. In a very recent study, metformin use was associated with a decreased risk of AF in patients with type 2 DM who were not using other anti-diabetic medications, probably via attenuation
of atrial cell tachycardia-induced myolysis and oxidative stress [61]. However, in another very recent report intensive glycemic control did not affect the rate of new-onset AF [62]. Upstream therapies have recently attracted much attention given their appealing rationale to modulate atrial substrate without having the untoward effects of ion-channel blockers [63–65]. Several agents such as blockers of the renin-angiotensin-aldosterone (RAA) system, statins, antioxidants, n-3 fatty acids, and others may exert beneficial effects in AF although inconsistent results have been published in the literature. A proposed key mechanism of the antiarrhythmic action of RAA inhibitors relates to opposing the arrhythmogenic effects of angiotensin II, which include stimulation of atrial fibrosis and hypertrophy secondary to activation of mitogen-activated protein kinases, uncoupling gap junctions, impaired calcium handling, alteration of ion channel dynamics, activation of mediators of oxidative stress, and promotion of inflammation [66,67]. Several studies indicate that RAA inhibition suppresses the expression of RAGE and connective tissue growth factor (CTGF) as well as AGE formation [68–72]. In streptozotocin-induced diabetic rats Kato et al. demonstrated that treatment with candesartan reduces CTGF expression and effectively suppresses the development of atrial fibrotic deposition [73]. The attenuation of CTGF expression by candesartan may be derived via decreased AGE interaction with RAGE and/or from a direct effect of the drug [73]. Thiazolidinediones (TZDs) belong to a class of insulin sensitizing agents with peroxisome proliferator-activated receptor-c (PPAR-c) activation effects ameliorating insulin resistance in patients with type 2 diabetes [74]. Experimental studies have demonstrated that TZDs prevent atrial electrical and structural remodeling through their antiinflammatory and antioxidant properties [75–79]. The possible targets of PPAR-c agonists include transforming growth factor-b (TGF-b), tumor necrosis factor-a (TNF-a), atrial natriuretic peptide (ANP), superoxide dismutase (SOD), malondialdehyde (MDA), NADPH oxidase subunits, and voltage-dependent Ca2+ currents [80]. In the clinical setting, anecdotal evidence indicated a remarkable improvement of paroxysmal atrial fibrillation (AF) in 2 diabetic patients after treatment with rosiglitazone [81]. In a large population study of 12,605 patients with type 2 diabetes Chao et al. investigated the possible association between TZD use and development of new-onset AF [82]. During a mean followup of 5 years, TZD use was associated with a 31% decreased risk of newonset AF after adjustment for age, underlying diseases, and baseline medications [82]. Moreover, Gu et al. reported that pioglitazone improved the maintenance of sinus rhythm and reduced the reablation rate in patients with paroxysmal AF and type 2 DM after catheter ablation [83]. Further largescale randomized trials with long-term follow-up are needed in order to evaluate the potential role of TZDs for AF prevention in patients with diabetes [84]. Probucol, a lipid-lowering drug that has potent antioxidant effects may favorably affect atrial remodeling [85]. In an experimental model probucol decreased the C-reactive protein rise and attenuated atrial oxidative stress caused by atrial tachypacing [86]. In addition, probucol effectively inhibited atrial nerve growth factor-beta upregulation, attenuated atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and reduced the inducibility and duration of AF [86]. In another experimental study, probucol effectively attenuated atrial structural remodeling and apoptosis [87]. Moreover, Fu et al. investigated the effects of probucol on atrial structural and electrical remodeling in alloxan-induced diabetic rabbits demonstrating that probucol significantly reduces left atrial interstitial fibrosis and AF inducibility [88]. Remarkably, it was indicated that its inhibitory effects on oxidative stress, nuclear factor-κΒ (NF-κB), TGF-β, and TNF-α over-expression contribute to its anti-remodeling effects [88]. Other potential upstream therapies targeting atrial structural remodeling, inflammation and oxidative stress, such as statins [89], n-3 polyunsaturated fatty acids [90], antioxidant agents including vitamin C and E, N-acetylcysteine, and xanthine oxidase inhibitors [91,92], have been proposed as novel therapeutic interventions in the management of
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AF but their specific role in the setting of diabetes is uncertain. Further studies are needed in order to evaluate the potential role of these agents in the primary and secondary prevention of AF in diabetic patients. 12. Conclusion DM is one of the most important risk factors for the initiation and perpetuation of AF. Pathophysiological mechanisms implicated in AF occurrence in diabetic patients include autonomic remodeling, electrical, electromechanical and structural remodeling, oxidative stress, connexin remodeling, and glycemic fluctuations. DM related atrial fibrosis results in prolongation of atrial activation time and cycle length, and local reduction of atrial electrogram voltages, thus contributing to the development of the arrhythmia. Upstream therapies with antioxidant and antiinflammatory effects such as ACEI/ARBs, TZDs, and probucol may play an important role in the prevention and treatment of AF in this setting. 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