- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Submit a Manuscript
- Subscription Information
- Table of Contents
The Scientific World Journal
Volume 2013 (2013), Article ID 209428, 6 pages
Mechanism of and Therapeutic Strategy for Atrial Fibrillation Associated with Diabetes Mellitus
Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou 0086-510630, China
Received 11 January 2013; Accepted 19 February 2013
Academic Editors: Y. Du and Y. Wang
Copyright © 2013 Yubi Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetes mellitus (DM) is one of the most important risk factors for atrial fibrillation (AF) and is a predictor of stroke and thromboembolism. DM may increase the incidence of AF, and when it is combined with other risk factors, the incidence of stroke and thromboembolism may also be higher; furthermore, hospitalization due to heart failure appears to increase. Maintenance of well-controlled blood glucose and low levels of HbA1c in accordance with guidelines may decrease the incidence of AF. The mechanisms of AF associated with DM are autonomic remodeling, electrical remodeling, structural remodeling, and insulin resistance. Inhibition of the renin-angiotensin system is suggested to be an upstream therapy for this type of AF. Studies have indicated that catheter ablation may be effective for AF associated with DM, restoring sinus rhythm and improving prognosis. Catheter ablation combined with hypoglycemic agents may further increase the rate of maintenance of sinus rhythm and reduce the need for reablation.
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disorder and contributes to thromboembolism. The presence of AF is an independent risk factor for thromboembolism; especially stroke in association with AF increases mortality and morbidity, leading to greater disability, longer hospital stays, and worse quality of life [1, 2]. There are approximately 40 million people with diabetes mellitus (DM) and 10 million with AF in China, and morbidity from AF is increasing with the aging population. AF seriously affects people’s health. The abnormal glucose metabolism and DM can facilitate the occurrence and development of AF and are associated with a worse prognosis.
2. DM Is a Strong Risk Factor for AF
2.1. DM Increases the Incidence of AF
AF commonly coexists with cardiovascular risk factors and disorders, which in turn increase the risk of the complications associated with the arrhythmia. The common risk factors for AF are cardiovascular, including hypertension, congestive heart failure, valvular heart disease, and vascular disease. As a cardiovascular risk factor, DM may be associated with the development and progression of AF. Investigators in the VHAH study reported the incidence of AF in patients with DM to be 14.9%, which was significantly higher than that in patients with hypertension but not DM (P < 0.0001). DM is a strong and independent risk factor for the occurrence of AF, with an odds ratio (OR) of 2.13 (P < 0.0001) . The VALUE trial showed that new onset DM could be attributed to a significant increase in the new onset of AF (relative risk (RR) 1.49, P = 0.0031) and a higher risk of developing persistent AF (RR 1.87, P = 0.0014). When patients with new onset DM developed AF, the occurrence of heart failure was much higher (RR 3.56, P < 0.0001) . In Nichols’ 7.2 ± 2.8-year follow-up study, the age- and gender-adjusted incidence of AF in DM patients (9.1/1000 person-years) was greater than that in non-DM patients (6.6/1000 person-years). Sex is an independent risk factor for AF; women with DM have about a 26% increased risk of developing AF . A meta-analysis  of seven prospective cohort studies and four case-control studies included 1,686,097 cases, of which 108,703 had AF. The study indicated that DM was associated with about a 40% increased risk of AF compared with non-DM patients (RR 1.39, P < 0.001). After adjusting for multiple risk factors for AF, the RR of AF in patients with DM was still 1.24, and the population-attributable fraction of AF owing to DM was 2.5%. Among 75-year-old patients, occurrence of AF was associated with long-term hyperglycemia, and it was suggested that proactive screening for DM or prediabetes should be performed in patients with a history of AF more than 5 years .
2.2. DM Increases the Incidence of AF When Accompanied by Other Diseases
DM with hypertension further increased the OR of AF to 3.3, from 0.7 in patients with hypertension only and 2.0 in those with DM only, though this increase had no statistical significance after adjusting for insulin resistance, suggesting that insulin resistance may be the underlying mechanism of AF . The population-attributable fraction of AF owing to metabolic syndrome (hypertension, increased low-density lipoprotein, hypertriglyceridemia, and impaired glucose metabolism) was 22% and the RR was 4.40 in patients with all five components of this syndrome compared with those without the disorder; the more the components, the higher the RR. The multivariate-adjusted RR for impaired glucose tolerance was 1.16. This indicates that the risk of AF increases significantly when DM is combined with other risk factors .
2.3. Poorly Controlled Blood Glucose Increases the Risk of AF
The risk of AF is increased by 3%/year with prolonged DM. Compared with people without DM, the adjusted ORs for DM patients with average HbA1c ≤ 7, 7-8, 8-9, or >9 were 1.06, 1.48, 1.46, and 1.96, respectively , in a prospective cohort study involving 13,025 participants. There was a positive linear association between HbA1c and the risk of AF in patients with or without DM, with hazard ratios of 1.13 and 1.05, respectively. Fasting blood glucose and insulin level were correlated with the risk of AF in DM patients, but not in people without DM. For every 1% increase in HbA1c, the risk of AF increased by 5% in non-DM individuals, but by 13% in those with DM. The risk of AF has also been shown to increase with the duration of DM, high HbA1c levels, and poor blood glucose control .
3. Prognostic Evaluation of DM Patients with AF
AF is a marker of poor prognosis in patients with DM and increases the risk of cardiovascular events and all-cause mortality. Diabetic neuropathy may mask the cardiac symptoms of first-recorded AF, making it asymptomatic, which may increase the risk of further cardiovascular events and mortality . The ADVANCE study showed a 61% (P < 0.0001) increase of multivariate-adjusted all-cause mortality in DM patients with AF during the 4.3-year follow-up period compared with those without AF, and cardiovascular mortality, risk of stroke, and heart failure increased significantly (all P < 0.001). Routine treatment with a fixed combination of perindopril and indapamide reduced blood pressure by 5.3/2.3 mmHg and by 5.9/2.3 mmHg more than placebo in patients with AF, significantly decreasing the risk of cardiovascular events and all-cause mortality. Thus, a comprehensive therapeutic strategy that aggressively targets all cardiovascular risk factors is very important for DM patients with AF .
DM was an independent risk factor for the recurrence of AF in patients with persistent AF who underwent successful synchronization with current cardioversion, over a median follow-up period of 74 days. In patients with DM, the sinus rhythm maintenance rate was 45.2%, which was lower than that of patients without DM (66.8%, P < 0.0001) . A study  reported that even after successful direct current cardioversion in DM patients with persistent AF, there was no significant improvement of endothelial responsiveness to supine shear stress or orthostatic modulation, which may be associated with DM-induced endothelial relaxation-constriction dysfunction. In patients with AF alone or in association with hypertension, endothelial dysfunction improved significantly after successful direct current cardioversion. DM-induced oxidative stress injury may be an underlying mechanism of AF .
4. Underlying Mechanisms of Diabetes-Induced AF
The precise pathophysiologic mechanisms that cause AF in DM patients are unknown . The proposed mechanisms include autonomic remodeling, structural remodeling, electrical remodeling, and insulin resistance. There have been no studies of the role of DM-associated atrial inflammatory reaction and stress reaction in the occurrence of AF.
4.1. Autonomic Remodeling
Cardiac autonomic neuropathy (CAN) is a common complication of DM that significantly increases mortality. Reports of the morbidity from CAN in DM patients are inconsistent, which may be related to variations in the populations studied and the methods used to screen for CAN . The morbidity from CAN was low (2.5%) in patients undergoing primary prevention, but very high (90%) in those with long-term type 1 DM awaiting pancreas transplantation [19, 20]. Based on heart rate variability (HRV) tests and spectral analysis of RR intervals, the morbidity from CAN in type 2 DM (T2DM) was 34.3%. Age, sex, and other risk factors may be associated with the progression of CAN . A recent report showed that CAN was common in patients with T2DM, with a morbidity of 44.3%; CAN was associated with modifiable factors such as carotid lipid deposition, hypertension, dyslipidemia, smoking, poorly controlled glycemia, and microvasculopathy. Management of these risk factors can prevent the occurrence and progression of CAN , which is closely related to the effects of risk factors such as poor glycemic control, a history of hyperglycemia, age-related neural injury, and high blood pressure. Hyperglycemia plays an important role in the pathogenesis of CAN by impairing nerve blood perfusion and activating cellular metabolism and redox-associated biologic pathways.
The autonomic dysfunction in DM patients can be caused by hyperglycemia-related pathophysiologic pathways such as the formation of advanced glycation end products, 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 . Most DM patients have autonomic imbalance—that is, enhanced sympathetic activity and decreased parasympathetic activity—regardless of whether they have DM neuropathy. Well-controlled blood glucose and use of angiotensin converting enzyme inhibitors have a beneficial effect on HRV . A DM rat model established by intravenous injection of streptozotocin indicated that sympathetic stimulation increased the incidence of AF in DM rats but not in controls (P < 0.01). Sympathetic stimulation significantly shortened the effective refractory period (ERP) of atrial cells in both groups, but the heterogeneity of the atrial ERP increased in the DM rats only. Parasympathetic stimulation also increased the incidence of AF via shortening of the atrial ERP in both DM rats and controls. 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. This evidence indicates that cardiac adrenergic nerve stimulation in individuals with DM can lead to AF. The heterogeneity of sympathetic innervation is increased in DM, which suggests that autonomic remodeling may increase susceptibility to AF in this group . Animal studies have indicated that sympathetic nerve remodeling may play an important role in the development and progression of AF in DM patients.
4.2. Electrical and Structural Remodeling
DM cardiomyopathy (i.e., DM-related cardiac structural and functional changes that are not caused by coronary atherosclerosis or hypertension) can lead to left ventricular hypertrophy and increased susceptibility to ischemic injury and the morbidity of heart failure, thereby increasing mortality. Possible pathophysiologic mechanisms of DM cardiomyopathy include myocardial hypertrophy, myocardial lipotoxicity, oxidative stress, cellular apoptosis, interstitial fibrosis, contraction-relaxation dysfunction, impaired myocardial contractile reserve, mitochondrial dysfunction, and disorders of myocardial metabolism . A study employing the genetic T2DM (Goto-Kakizaki) rat model found no difference in ERP between DM and control rats, but the intra-atrial activation time of the DM group was much longer. In a DM rat model, a single premature electrical stimulation induced large numbers of repetitive atrial responses . During catheter ablation, using a three-dimensional mapping system, the activation time of both atria was significantly longer, and the bipolar voltage significantly decreased in a DM group . Maximal P-P interval and the degree of P wave dispersion were significantly increased in prediabetic patients without a history of coronary heart disease, hypertension, or left ventricular hypertrophy, and the latter was positively related to fasting blood glucose level .
Atrial fibrosis is also an important mechanism for cardiac structural and electrical remodeling. In a DM rat model, there are widespread fibrotic deposits in the atria that are prone to the formation of anchoring points for reentry circuits and changes in the forward propagation of fibrillatory wavelets and thus cause atrial fractionated potentials and conduction delay . Oxidative stress may also be involved in the formation of hyperglycemia-associated AF substrates, leading to atrial fibrosis. A study in which atrial tissue was collected from DM patients during coronary artery bypass graft surgery found that mitochondrial dysfunction in the atrial myocardium can cause excessive oxidative stress . In DM rats, the expression of connexin-43 was elevated, whereas its phosphorylation was decreased in the atrial myocardium, which leads to disorders of intercellular electrical coupling and atrial arrhythmia . Advanced glycation end products (AGEs) and AGE receptors (RAGEs) (the AGE-RAGE system) mediate the diffuse interstitial fibrosis of the atrial myocardium in DM rats through upregulation of the expression of growth factors by connective tissue, and cause structural remodeling. AGE inhibitors can downregulate the expression of growth factors and significantly inhibit the progression of DM-induced atrial fibrosis . AGE inhibitors may be used in the upstream therapy of DM-related fibrosis in the future.
4.3. Insulin Resistance
Previous studies have demonstrated that patients with insulin-dependent DM suffer AF attacks while hypoglycemic. Some experts consider the cause of such AF attacks to be fluctuations in glycemia rather than the hyperglycemic state itself . A study has found that blood glucose is significantly elevated during an AF attack and that a high dose of insulin (10 times the daily dose) is required to control it. After successful cardioversion of AF, the insulin dose required is significantly decreased .
5. Therapeutic Strategy
5.1. Anticoagulation Therapy
AF is a major risk factor for stroke and thromboembolism. The mortality, disability rate, and risk of stroke recurrence are all higher in stroke caused by AF than in that due to other causes. The risk of stroke varies among DM patients with AF, and treatment relies on risk evaluation and appropriate anticoagulation therapy. The simplest way to assess the risk of stroke is the CHADS2 scoring system. The European Society of Cardiology Guidelines for the Management of Atrial Fibrillation (2010 ESC) recommended the use of a more appropriate system, the CHA2DS2-VASc. In AF patients with DM, if the risk of major bleeding is low or the benefit/risk ratio is considered high, an oral anticoagulant such as a vitamin K antagonist (VKAs) is the first choice independent of rate control or rhythm control. The dose of VKAs depends on the target intensity INR (International Normalized Ratio) of 2.0–3.0, with a target value of 2.5. New anticoagulants (e.g., Dabigatran etexilate, Apixaban) are alternatives to VKAs .
5.2. Upstream Therapy
Atrial structural remodeling or fibrosis can decrease the conduction speed of the atrial myocardium, which may be the underlying mechanism of DM-related AF. Angiotensin II receptor blockers (ARBs) may play an important role in the upstream therapy of AF through the following mechanisms: decreasing atrial fibrosis and delaying atrial structural remodeling; inhibiting the production and facilitating the degradation of collagen fibers, thereby decreasing the left atrial overload that is the major reason for the development and progression of AF ; modifying the potassium channel current and downregulating the Ito current, the latter of which plays an important role in atrial electrical remodeling ; exerting various effects on the subunits of the potassium channel (e.g., losartan blocks the HERG, KvLQT1, mink, and hKv1.5 subunits) ; regulating L-type and T-type calcium channels and inhibiting the progression of AF substrates [36, 37]; prolonging the ERP and increasing the frequency adaptability of atria; and decreasing the hyperactivity of the sympathetic nerve system caused by angiotensin II . In hypertensive DM patients with paroxysmal AF, the blood pressure lowering effect is similar in both groups. In patients treated with valsartan/amlodipine, the rate of recurrence of AF is significantly decreased compared with that in patients treated with atenolol/amlodipine, especially those given amiodarone or propafenone compared with those who take other or no antiarrhythmic agents .
Several studies indicated thiazolidinedione as a class of peroxisome proliferator-activated receptor- activator, may potentially benefit for AF prevention [40–42], especially pioglitazone, due to attenuate atrial fibrosis, inflammation activation, oxidative stress, and apoptosis in the atrium of experiment models [43–47]. The thiazolidinedione may be a novel upstream therapy for AF in DM patients, but still needs further large-scale randomized, controlled trials with long-term follow-up period to evaluate the potential role of AF prevention .
5.3. Antiarrhythmic Therapy and Catheter Ablation
Antiarrhythmic treatment in AF patients includes rate control and rhythm control; the choice of drug should be individualized. Commonly used antiarrhythmic drugs that control heart rate in AF patients are -blockers, nondihydropyridine calcium channel blockers, and digitalis glycosides. Drugs commonly used to control heart rhythm are amiodarone and dronedarone. After treatment with the full dose of an antiarrhythmic drug, catheter ablation may be of further benefit in the treatment of AF . A large prospective study enrolled 263 patients receiving first-time ablation for encircling pulmonary veins guided by the CARTO system; 31 of these had DM. Although the age, duration of AF, left atrial size, incidence of hypertension, and proportion with underlying heart disease were significantly higher in the DM patients compared with the non-DM patients, the rate of recurrence of AF after first-time ablation was similar in the two groups (32.3% versus 22.4%, P = 0.24). The possibility of an episode of asymptomatic AF caused by DM neuropathy cannot be excluded in this study, so the success rate of the AF ablation may have been overestimated. This study also suggested that the incidence of procedure-associated complications was higher in the DM patients (29% versus 8.2%, P = 0.002). The major complications were hemorrhage and thromboembolism. When hemorrhage was excluded, the incidence of complications was 6.4%. There was an increased tendency to develop cardiac tamponade and thromboembolism in the DM patients; possible reasons include the following: AF is a risk factor for cerebral embolism; DM can cause both prothrombotic and proinflammatory states; and hyperinsulinemia can induce a prothrombotic state that is closely related to metabolic disorders (postprandial hyperglycemia, high levels of free fatty acids, and hypertriglyceridemia) involving platelets, the coagulation cascade, and fibrinolysis . Another study included 70 DM patients with AF (including paroxysmal and persistent AF) and assigned catheter ablation (one ablation procedure without drug treatment) or antiarrhythmic agents randomly. After 1 year of followup, sinus rhythm was maintained in 42.3% and 80% of patients treated with drugs or catheter ablation, respectively (P = 0.001). The Life Quality Scale score was significantly higher in the ablation group than in the drug group; 17.1% of patients developed obvious drug-associated side effects, and the hospitalization rate was significantly higher in the drug treatment group (P = 0.01). The major complication of catheter ablation was puncturing site bleeding. This evidence suggests that catheter ablation can significantly improve the prognosis of DM patients with AF compared with drug treatment alone . Assessment of DM patients with AF 18.8 ± 6.4 months after catheter ablation showed that, though the recurrence rate was higher in patients with glucose metabolism derangement than in those without DM (P = 0.02), it still reached 18.5%, which may be associated with intra-atrial conduction delay and decreased voltage .
Pioglitazone is a commonly prescribed drug in clinical practice with anti-inflammatory and antioxidative effects. In a contrast study, 150 selected T2DM patients with paroxysmal AF were divided into two groups depending on whether pioglitazone was given after catheter ablation. Antiarrhythmic drugs were discontinued in patients who remained in sinus rhythm. After an average 15-month followup, compared with the control group, the rate of maintenance of sinus rhythm was higher (86.3% versus 70.7%, P = 0.03) and the proportion that underwent a second ablation was lower (9.8% versus 24.2%, P = 0.03) among patients treated with pioglitazone. This evidence indicates that, in T2DM with paroxysmal AF, pioglitazone can significantly increase the success rate of catheter ablation and decrease the recurrence of AF. Left atrial size is associated with recurrence of atrial arrhythmia, which can be decreased by both pioglitazone and ARBs .
DM is one of the most important risk factors for the development and progression of AF and can predict the occurrence of stroke and thromboembolism. Long-term anticoagulation therapy with VKAs is recommended in AF patients with DM. DM can increase the incidence of AF, and when it is combined with other risk factors, the incidence of stroke and thromboembolism may be even higher. The incidence and rate of hospitalization due to heart failure may be increased. Maintenance of well-controlled blood glucose and low HbA1c according to guidelines may decrease the incidence of AF. The mechanisms of AF associated with DM are autonomic remodeling, electrical remodeling, structural remodeling, and insulin resistance; there are few studies concerning the role of inflammation and oxidative stress in the pathogenesis of AF. Inhibition of the renin-angiotensin system is expected to be an upstream therapy for this type of AF. Some studies have indicated that catheter ablation may be effective in AF associated with DM, restoring sinus rhythm and improving prognosis. Catheter ablation combined with hypoglycemic agents may further increase the rate of maintenance of sinus rhythm and also reduce the risk of need for reablation.
This work was supported by grants from the Fundamental Research Funds for the Central Universities (no. 21611333), the Science and Technological Program of Guangdong Province (no. 2010-1096-136), the Science and Technological Projects of Guangzhou (no. 2010Y1-C941), and the Key Disciplines’ Funds and Special Research Funds (no. 2012207) of the First Clinical Medical College of Jinan University, Basic Research Expenses of Jinan University.
- T. Watson, E. Shantsila, and G. Y. Lip, “Mechanisms of thrombogenesis in atrial fibrillation: virchow's triad revisited,” The Lancet, vol. 373, no. 9658, pp. 155–166, 2009.
- C. Steger, A. Pratter, M. Martinek-Bregel et al., “Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry,” European Heart Journal, vol. 25, no. 19, pp. 1734–1740, 2004.
- M. R. Movahed, M. Hashemzadeh, and M. Mazen Jamal, “Diabetes mellitus is a strong, independent risk for atrial fibrillation and flutter in addition to other cardiovascular disease,” International Journal of Cardiology, vol. 105, no. 3, pp. 315–318, 2005.
- T. A. Aksnes, R. E. Schmieder, S. E. Kjeldsen, S. Ghani, T. A. Hua, and S. Julius, “Impact of new-onset diabetes mellitus on development of atrial fibrillation and heart failure in high-risk hypertension (from the VALUE Trial),” American Journal of Cardiology, vol. 101, no. 5, pp. 634–638, 2008.
- G. A. Nichols, K. Reinier, and S. S. Chugh, “Independent contribution of diabetes to increased prevalence and incidence of atrial fibrillation,” Diabetes Care, vol. 32, no. 10, pp. 1851–1856, 2009.
- R. R. Huxley, K. B. Filion, S. Konety, and A. Alonso, “Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation,” American Journal of Cardiology, vol. 108, no. 1, pp. 56–62, 2011.
- O. E. Johansen, E. Brustad, S. Enger, and A. Tveit, “Prevalence of abnormal glucose metabolism in atrial fibrillation: a case control study in 75-year old subjects,” Cardiovascular Diabetology, vol. 7, article 28, 2008.
- C. J. Östgren, J. Merlo, L. Råstam, and U. Lindblad, “Atrial fibrillation and its association with type 2 diabetes and hypertension in a Swedish community,” Diabetes, Obesity and Metabolism, vol. 6, no. 5, pp. 367–374, 2004.
- A. M. Chamberlain, S. K. Agarwal, M. Ambrose, A. R. Folsom, E. Z. Soliman, and A. Alonso, “Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study,” American Heart Journal, vol. 159, no. 5, pp. 850–856, 2010.
- S. Dublin, N. L. Glazer, N. L. Smith et al., “Diabetes mellitus, glycemic control, and risk of atrial fibrillation,” Journal of General Internal Medicine, vol. 25, no. 8, pp. 853–858, 2010.
- R. R. Huxley, A. Alonso, F. L. Lopez, et al., “Type 2 diabetes, glucose homeostasis and incident atrial fibrillation: the Atherosclerosis Risk in Communities study,” Heart, vol. 98, no. 2, pp. 133–138, 2012.
- K. Sugishita, E. Shiono, T. Sugiyama, and T. Ashida, “Diabetes influences the cardiac symptoms related to atrial fibrillation,” Circulation Journal, vol. 67, no. 10, pp. 835–838, 2003.
- X. Du, T. Ninomiya, B. De Galan et al., “Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study,” European Heart Journal, vol. 30, no. 9, pp. 1128–1135, 2009.
- H. Soran, N. Younis, P. Currie, J. Silas, I. R. Jones, and G. Gill, “Influence of diabetes on the maintenance of sinus rhythm after a successful direct current cardioversion in patients with atrial fibrillation,” Quarterly Journal of Medicine, vol. 101, no. 3, pp. 181–187, 2008.
- M. Guazzi, S. Belletti, L. Lenatti, E. Bianco, and M. D. Guazzi, “Effects of cardioversion of atrial fibrillation on endothelial function in hypertension or diabetes,” European Journal of Clinical Investigation, vol. 37, no. 1, pp. 26–34, 2007.
- M. Guazzi, S. Belletti, E. Bianco, L. Lenatti, and M. D. Guazzi, “Endothelial dysfunction and exercise performance in lone atrial fibrillation or associated with hypertension or diabetes: different results with cardioversion,” American Journal of Physiology, vol. 291, no. 2, pp. H921–H928, 2006.
- G. Y. H. Lip and G. I. Varughese, “Diabetes mellitus and atrial fibrillation: perspectives on epidemiological and pathophysiological links,” International Journal of Cardiology, vol. 105, no. 3, pp. 319–321, 2005.
- R. Pop-Busui, “Cardiac autonomic neuropathy in diabetes: a clinical perspective,” Diabetes Care, vol. 33, no. 2, pp. 434–441, 2010.
- The Diabetes Control and Complications Trial Research Group, “The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT),” Diabetologia, vol. 41, no. 4, pp. 416–423, 1998.
- W. R. Kennedy, X. Navarro, and D. E. R. Sutherland, “Neuropathy profile of diabetic patients in a pancreas transplantation program,” Neurology, vol. 45, no. 4, pp. 773–780, 1995.
- D. Ziegler, K. Dannehl, H. Muhlen, M. Spuler, and F. A. Gries, “Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses at various stages of diabetic neuropathy,” Diabetic Medicine, vol. 9, no. 9, pp. 806–814, 1992.
- C. Voulgari, M. Psallas, A. Kokkinos, V. Argiana, N. Katsilambros, and N. Tentolouris, “The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes,” Journal of Diabetes and its Complications, vol. 25, no. 3, pp. 159–167, 2011.
- V. Urbančič-Rovan, B. Meglič, A. Stefanovska, A. Bernjak, K. Ažman-Juvan, and A. Kocijančič, “Incipient cardiovascular autonomic imbalance revealed by wavelet analysis of heart rate variability in type 2 diabetic patients,” Diabetic Medicine, vol. 24, no. 1, pp. 18–26, 2007.
- H. Otake, H. Suzuki, T. Honda, and Y. Maruyama, “Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart,” International Heart Journal, vol. 50, no. 5, pp. 627–641, 2009.
- S. Boudina and E. D. Abel, “Diabetic cardiomyopathy, causes and effects,” Reviews in Endocrine and Metabolic Disorders, vol. 11, no. 1, pp. 31–39, 2010.
- T. Kato, T. Yamashita, A. Sekiguchi et al., “What are arrhythmogenic substrates in diabetic rat atria?” Journal of Cardiovascular Electrophysiology, vol. 17, no. 8, pp. 890–894, 2006.
- T. F. Chao, K. Suenari, S. L. Chang et al., “Atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation associated with diabetes mellitus or impaired fasting glucose,” American Journal of Cardiology, vol. 106, no. 11, pp. 1615–1620, 2010.
- T. Karabag, M. Aydin, S. M. Dogan et al., “Prolonged P wave dispersion in pre-diabetic patients,” Kardiologia Polska, vol. 69, no. 6, pp. 566–571, 2011.
- E. J. Anderson, A. P. Kypson, E. Rodriguez, C. A. Anderson, E. J. Lehr, and P. D. Neufer, “Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart,” Journal of the American College of Cardiology, vol. 54, no. 20, pp. 1891–1898, 2009.
- M. Mitašíková, H. Lin, T. Soukup, I. Imanaga, and N. Tribulová, “Diabetes and thyroid hormones affect connexin-43 and PKC-ε expression in rat heart atria,” Physiological Research, vol. 58, no. 2, pp. 211–217, 2009.
- T. Kato, T. Yamashita, A. Sekiguchi et al., “AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat,” Journal of Cardiovascular Electrophysiology, vol. 19, no. 4, pp. 415–420, 2008.
- V. Rigalleau, L. Baillet, M. Hocini, and H. Gin, “Atrial fibrillation can cause major hyperglycemia,” Diabetes and Metabolism, vol. 28, no. 3, pp. 239–240, 2002.
- A. J. Camm, P. Kirchhof, G. Y. Lip, et al., “Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC),” Europace, vol. 12, no. 10, pp. 1360–1420, 2010.
- J. R. Ehrlich, S. H. Hohnloser, and S. Mattel, “Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence,” European Heart Journal, vol. 27, no. 5, pp. 512–518, 2006.
- R. Caballero, E. Delpón, C. Valenzuela, M. Longobardo, and J. Tamargo, “Losartan and its metabolite E3174 modify cardiac delayed rectifier K+ currents,” Circulation, vol. 101, no. 10, pp. 1199–1205, 2000.
- W. C. De Mello, “Intracellular angiotensin II regulates the inward calcium current in cardiac myocytes,” Hypertension, vol. 32, no. 6, pp. 976–982, 1998.
- S. Fareh, A. Bénardeau, B. Thibault, and S. Nattel, “The T-type Ca2+ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs,” Circulation, vol. 100, no. 21, pp. 2191–2197, 1999.
- T. Unger, “Neurohormonal modulation in cardiovascular disease,” American Heart Journal, vol. 139, no. 1, pp. S2–S8, 2000.
- R. Fogari, A. Zoppi, A. Mugellini et al., “Comparative evaluation of effect of valsartan/amlodipine and atenolol/amlodipine combinations on atrial fibrillation recurrence in hypertensive patients with type 2 diabetes mellitus,” Journal of Cardiovascular Pharmacology, vol. 51, no. 3, pp. 217–222, 2008.
- T. Liu, P. Korantzopoulos, G. Li, and J. Li, “The potential role of thiazolidinediones in atrial fibrillation,” International Journal of Cardiology, vol. 128, no. 1, pp. 129–130, 2008.
- T. F. Chao, H. B. Leu, C. C. Huang, et al., “Thiazolidinediones can prevent new onset atrial fibrillation in patients with non-insulin dependent diabetes,” International Journal of Cardiology, vol. 156, no. 2, pp. 199–202, 2012.
- M. W. Anglade, J. Kluger, C. M. White, J. Aberle, and C. I. Coleman, “Thiazolidinedione use and post-operative atrial fibrillation: a US nested case-control study,” Current Medical Research and Opinion, vol. 23, no. 11, pp. 2849–2855, 2007.
- M. Shimano, Y. Tsuji, Y. Inden et al., “Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure,” Heart Rhythm, vol. 5, no. 3, pp. 451–459, 2008.
- O. Kume, N. Takahashi, O. Wakisaka et al., “Pioglitazone attenuates inflammatory atrial fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats,” Heart Rhythm, vol. 8, no. 2, pp. 278–285, 2011.
- A. G. Vaiopoulos, K. Marinou, C. Christodoulides, et al., “The role of adiponectin in human vascular physiology,” International Journal of Cardiology, vol. 155, no. 2, pp. 188–193, 2012.
- G. Li and T. Liu, “The therapeutic strategies of enhancing adiponectin and lowering leptin may be benefit to controlling atrial fibrillation,” Medical Hypotheses, vol. 73, no. 1, p. 122, 2009.
- D. Xu, N. Murakoshi, M. Igarashi, et al., “PPAR-gamma activator pioglitazone prevents age-related atrial fibrillation susceptibility by improving antioxidant capacity and reducing apoptosis in a rat model,” Journal of Cardiovascular Electrophysiology, vol. 23, no. 2, pp. 209–217, 2012.
- T. Liu and G. Li, “Thiazolidinediones as novel upstream therapy for atrial fibrillation in diabetic patients: a review of current evidence,” International Journal of Cardiology, vol. 156, no. 2, pp. 215–216, 2012.
- R. B. Tang, J. Z. Dong, X. P. Liu et al., “Safety and efficacy of catheter ablation of atrial fibrillation in patients with diabetes mellitus—single center experience,” Journal of Interventional Cardiac Electrophysiology, vol. 17, no. 1, pp. 41–46, 2006.
- G. B. Forleo, M. Mantica, L. De Luca et al., “Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy,” Journal of Cardiovascular Electrophysiology, vol. 20, no. 1, pp. 22–28, 2009.
- J. Gu, X. Liu, X. Wang, et al., “Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus,” Europace, vol. 13, no. 9, pp. 1256–1261, 2011.