CARDIAC ELECTROPHYSIOLOGY IN DIABETES

Elettrofisiologia cardiaca nel diabete

Carlo PAPPONE MD, PhD, FACCVincenzo SANTINELLI, MD

Department of Arrhythmology, Villa Maria Cecilia Hospital, Cotignola, Ravenna, ITALY

Address for correspondenceCarlo Pappone, MDVilla Maria Cecilia HospitalVia Corriera 148010 COTIGNOLAcpappone@gvm-vmc.it

Ph +39.0545.217186Fax +39.0545.217108

1

SUMMARY

Patients with diabetes mellitus are at higher risk of cardiac arrhythmias and sudden death. Although

there are several animal and human studies on this topic, the pathophysiology of the increased

electrical vulnerability in diabetes is complex and remain undefined. It is conceivable that an

interplay of several concomitant factors may facilitate the occurrence of arrhythmias.

Atherosclerosis as well as microvascular disease, which are increased in diabetic patients, may

facilitate myocardial ischemia that predisposes to cardiac arrhythmias and sudden death. In

addition, autonomic neuropathy and/or cardiac repolarization abnormalities such as prolonged QT

interval and altered T-waves of the diabetic heart also increases electrical instability. Therefore, all

these factors may simultaneously contribute to create an electrical instability leading to cardiac

arrhythmias and sudden cardiac death. Recently, we have demonstrated that diabetes is the strongest

predictor of AF progression and that diabetic patients frequently have asymptomatic episodes of AF

with silent arrhythmia progression. Another recent study has reported that patients with type 2

diabetes and AF are at substantially higher risk of death of any cause compared with those without

AF. These seminal studies emphasize that AF in diabetic patients should be regarded as a

prognostic marker of adverse outcome and then a prompt aggressive management of all risk factors

is required. In conclusion, diabetes mellitus significantly alters the cardiac electrophysiology

throughout several complex mechanisms greatly contributing to create an electrical instability of the

heart, which may lead to potentially life-threatening arrhythmias and sudden cardiac death.

2

RIASSUNTO

I pazienti con diabete mellito sono a più alto rischio di aritmie cardiache e di morte cardiaca

improvvisa. Nonostante numerosi studi sia nell’animale che nell’uomo, i meccanismi

dell’aumentata vulnerabilità elettrica ventricolare nel diabete rimane ancora da definire e si ritiene

che una concomitanza di più fattori possa facilitarne l’insorgenza. L’ateroscelosi coronarica nonchè

la microangiopatia frequentemente presenti nel diabete mellito, favoriscono l’insorgenza di

ischemia miocardica che predispone ad aritmie cardiache. Inoltre, la disfunzione del sistema

nervoso autonomico sia simpatico che parasimpatico, che spesso si associa al diabete, può

influenzare negativamente la stabilità elettrica del cuore predisponendolo ad aritmie anche maligne.

Bisogna anche tener conto che in corso di diabete si riscontrano comunemente all’ECG anomalie

della ripolarizzazione cardiaca con allungamento dell’intervallo QT/QTc ed alterazione dell’onda T,

fenomeni che notoriamente destabilizzano elettricamente il cuore attraverso una profonda

dispersione dei periodi refrattari con conseguente predisposizione all’aritmogenesi. Sembra quindi

che moltepli fattori, comunemente presenti nel paziente diabetico, contribuiscano con meccanismi

differenti e complessi ad alterare l’elettrofisiologia cardiaca a tal punto da rendere il cuore più

vulnerabile alle aritmie cardiache e alla morte improvvisa. Un recente studio prospettico della

durata di 5 anni ha dimostrato che il diabete è un predittore indipendente di progressione della

fibrillazione atriale e che tale progressione può rimanere silente. Un altro studio prospettico ha

dimostrato che i pazienti con diabete tipo 2 e fibrillazione atriale sono a più alto rischio di morte

rispetto a pazienti diabetici senza fibrillazione atriale. Queste seminali osservazioni dimostrano che

la fibrillazione atriale, così frequentemente osservata nei diabetici e nelle persone anziane, non deve

essere più considerata come un’ aritmia benigna ma come un marker prognostico negativo di morte

improvvisa.

3

Diabetes and cardiac arrhythmias

It is well known that there is a clear correlation between coronary heart disease and type 2 diabetes

mellitus. Diabetes increases the risk of coronary artery disease by a factor of 2- to 4-fold.

Myocardial ischemia is a major complication in the course of diabetes, causing 75% of diabetes-

related deaths. Patients with diabetes also have a higher rate of cardiac arrhythmias, sudden death

and poorer outcomes after myocardial infarction. Compared with a non-diabetic person, a patient

with type 2 diabetes has a 2- to 4-fold risk of dying from myocardial infarction. In addition,

mortality among diabetic patients from a coronary artery incident is rising. In fact more than 65% of

people with diabetes die from heart disease or stroke. Despite evidence-based guidelines for health

care professionals and patients, there is an estimated 20 million people in the United States with

diabetes which at present still represents a significant cause of morbidity and mortality. It has been

reported among diabetic patients a higher incidence of cardiac arrhythmias and sudden cardiac

death. The pathophysiology surrounding this increased electrical vulnerability is multifactorial,

complex, and still remains undefined. It is conceivable that an interplay of different concomitant

factors contribute to the genesis of arrhythmogenesis by altering cardiac electrophysiology. First,

atherosclerosis as well as microvascular disease, which are increased in diabetic patients, may

facilitate the development of myocardial ischemia that predisposes to cardiac arrhythmias. In

addition, autonomic neuropathy is associated with abnormal reflexes and innervation of the diabetic

heart affecting electrical instability. Finally, cardiac repolarization abnormalities manifesting as

prolonged QT/QTc intervals and altered T-waves on the ECG are common in patients with diabetes.

It seems therefore likely that factors such as coronary artery disease, metabolic and ion channel

abnormalities, and autonomic dysfunction may simultaneously contribute to create an electrical

instability leading to cardiac arrhythmias and/or sudden cardiac death. Several studies in both

animals and humans have addressed the arrhythmogeneicity in the diabetic heart. In animal models

of diabetes different functional and structural alterations of the heart have been reported.

Myocardial fibrosis may result in mechanical and electrical sequelae that affect cardiovascular

4

prognosis of patients with diabetes. Fibrosis reduces ventricular compliance and promotes

arrhythmias by causing local delay in the spread of the action potential (1,2). In an animal model of

mild diabetes mellitus, it has been demonstrated an enhanced susceptibility to ventricular

arrhythmias, with increased electrophysiological sensitivity to catecholamines and nonhomogeneous

collagen accumulation affecting local conduction (3). Diabetic patients have regional cardiac

denervation and sympathetic overactivity, which may lead to life-threatening myocardial electrical

instability and potentially fatal tachyarrhythmias. However, extrapolating such experimental studies

to diabetic patients may be difficult since cardiac electrophysiology may be different in animals and

humans. In addition, most studies have been conducted in animals with uncontrolled or poorly

controlled diabetes while in human studies the majority of diabetic patients usually receive an

optimal treatment. Despite these important limitations, important electrophysiologic data from

animal models have been confirmed in human studies. Other animal studies focused on

pathogenesis of diabetic cardiomyopathy, which appears to be multifactorial (autonomic

dysfunction, metabolic derangment, abnormality in ion homeostasis, alterations in structural

proteins, and intersitial fibrosis). Recent studies in humans while confirming many mechanisms

derived from animal studies have provided insights into understanding of increased vulnerability of

the diabetic heart to cardiac arrhythmias, heart failure and sudden death. At present, an important

still debated question is the impact of AF on the already elevated risk of cardiovascular disease,

cerebrovascular events, complications and mortality among patients with diabetes mellitus.

Diabetes mellitus and atrial fibrillation

It is well known that with the aging of the US and international populations the incidence and

prevalence of AF are rising rapidly and AF is a common arrhythmia among diabetic patients. Rising

obesity in most developed and developing countries is associated with a consequent rise of diabetes.

It is estimated that globally the number of adults affected with diabetes mellitus will progressively

increase over time from 135 million in 1995 to 300 million by 2025, and it is projected to increase

to 4.4% in 2030 (4). More than 2.2 million Americans currently have AF, and this number is

5

expected to increase by at least 2.5-fold over the next 50 years. The prevalence of AF varies greatly

according to the population's age and other health problems. It ranges between 4% in primary care

settings to 15% in hospitalised patients (5,6). There are data to suggest that the prevalence of AF in

people with diabetes is about twice that among people without diabetes (7,8) and up to three times

higher in patients with coexistent hypertension. (6). Therefore, diabetes and AF are the world's

fastest growing diseases with an expanding elderly population, the consequences of this epidemic

become increasingly important. In the Manitoba Follow-up Study (9) diabetes was significantly

associated with AF development in the univariate analysis, but multivariate analysis was not able to

demonstrate diabetes as an independent predictor, suggesting that the increased risk of AF in

diabetic men may be due to other factors such as the presence of coronary artery disease, systemic

hypertension, or heart failure. On the contrary, the Framingham Heart Study (10), showed that

diabetes is associated with AF development even after adjustment for age and other variables,

which suggests that diabetes facilitates AF development. Whether and how diabetes facilitates AF

development and/or progression to more persistent forms have not well defined in previous studies.

Several mechanisms have been hypothesized in diabetic patients to explain AF development which

include intra-atrial conduction delay, repolarization abnormalities and/or increased fibrotic

deposition in atria. Other studies have reported that abnormality of the autonomic nervous system

with cardiac autonomic dysfunction including heterogeneous increase in sympathetic innervation

and/or a progressive parasympathetic denervation may also play an important role in facilitating AF

development. New onset self-terminating episodes of AF may start as an electrical disease with

rapidly discharging foci which "trigger" the arrhythmia, but paroxysmal episodes may become more

persistent and progress over the years to permanent AF by involving a diseased atrial substrate.

Only few studies have examined the natural history of AF with its progression and its interaction

with other risk factors such as diabetes over a long-term follow-up period. The results of studies on

natural history of AF have provide evidence that AF represents a heterogeneous disease and that

comorbidities frequently modulate its progression over time with potential complications. A recent

6

retrospective study has reported interesting data on the natural history of the arrhythmia over a 30-

year follow-up period (11). After a young patient with lone AF ages or develops heart failure,

diabetes, or hypertension, thromboembolic risk increases (11). In relatively young patients, AF may

represent primarily an electrophysiological phenomenon while in older patients with comorbidities,

the arrhythmia may be considered as the final common pathway of a vascular inflammatory process

associated with atrial mechanical and/or electrical remodeling (dilatation, stretch, fibrosis, and

electric inhomogeneity), all of which increase the risk of complications. Therefore, an accurate

screening for comorbidities such as diabetes or hypertension is essential in this group. Further

understanding of the underlying pathophysiology of AF progression with associated comorbidities

is required. Finally, preventive strategies to limit both arrhythmia progression and risk of major

complications also require identification of independent predictors of such progression.

Unfortunately, at present there are no prospective long-term follow-up studies assessing predictors

of AF progression over time in a large number of patients. The few available reports have been

mainly based on retrospective follow-up data with a limited number of patients (11). Recently,

important prospective data focused on the understanding of AF progression and predictors of

arrhythmia progression has been provided by our group (12). In this follow-up study, among 106

patients with an initially first detected paroxysmal episode of AF not due to transient causes, about

a half of patients, most of whom without comorbidities “lone AF”, did not experience recurrent AF

after the first episode remaining in stable sinus rhythm over 5 years (12). Our data while confirming

that absence of comorbidities such as diabetes, heart failure, and hypertension is associated with an

excellent outcome up to 5 years, clearly demonstrated that in patients with comorbidities AF

commonly progresses to more persistent forms despite antiarrhythmic drug therapy or electrical

cardioversion. Of note, we observed that in patients with comorbidities early catheter ablation may

limit AF progression to persistent/permanent AF. These findings are important and provide strong

evidence on the key role of comorbidities such as diabetes mellitus in facilitating AF progression. It

is well known that chronic antiarrhythmic drug administration including amiodarone is ineffective

7

in maintaining a stable sinus rhythm in many patients with safety profiles that are less than ideal

considering concomitant comorbidities such as diabetes mellitus. Multivariate analyis demonstrated

that diabetes mellitus is the strongest independent risk factor for AF progression although older age

and heart failure also predicted arrhythmia progression (12). It is well known that in diabetes silent

episodes of paroxysmal AF may be commonly observed, but little is known about their relevance on

arrhythmia progression and complications. Our experience also shows that silent undetected

episodes of paroxysmal AF if not adequately treated may rapidly progress to more persistent forms

and complications as documented by daily transtelefonic ECG recordings (12).

Diabetes, atrial fibrillation and risk of sudden death

Since diabetes and AF both independently increase major serious clinical outcomes and the

presence of both diseases compounds this risk, the understanding of the complex interplay between

diabetes and AF is crucial in developing a therapeutic approach to reduce the risk. General

population studies have demonstrated that the presence of AF is associated with increased risks of

stroke, heart failure, and cardiovascular death (13,14). Diabetes is a metabolic disease which affects

both cardiac structure and function even in the absence of changes in either blood pressure or

coronary artery disease, the so called “diabetic cardiomyopathy” (15-19). Increased heart failure

rates in patients with diabetes persist despite correction for confounding risk factors such as age,

hypertension, obesity, hypercholesterolemia, and coronary artery disease (20). The AF investigators

group (21) reported that diabetes was an independent predictor of stroke with a relative risk of 1.7.

A relation between the number of additional risk factors in patients with AF, including diabetes, and

the presence of echo contrast or reduced flow velocity in left atrial appendage has been reported

(22), indicating that other variables such as hypertension and diabetes may influence the complex

thromboembolic mechanisms. Current guidelines suggest different risk stratification approaches for

stroke prevention among patients with AF, and the presence of diabetes is considered as an

important risk factor. Patients are classified as low, moderate, and high risk according to age,

previous stroke or TIA, and other risk factors, such as hypertension, diabetes, coronary artery

8

disease, and heart failure. However, the importance of diabetes as a risk factor for stroke differs

among the different stratification schemes. In the 2006 guidelines on AF from the ACC/AHA/ESC

task force (23), diabetes is classified as a moderate risk factor together with age >75 years,

hypertension, heart failure, and a left ventricular ejection fraction <35%.

It is well known that patients with diabetes after myocardial infarction are at higher risk of death of

any cause and cardiovascular death. However, it remains unclear whether diabetes increases sudden

cardiac death since thare are conflicting results in the literature. In the Framingham study, diabetes

was associated with higher risk of sudden cardiac death for all ages (almost four-fold), being

significantly higher in women than men diabetic (24). The role of diabetes as a risk factor for

sudden cardiac death in women has been assessed in a long-term study (25), which included 121 

701 women aged between 30 and 55 years followed for > 20 years. Sudden cardiac death occurred

as the first clinical manifestation of heart disease in most women (69%), even if almost all of them

had at least one cardiac risk factor. Diabetes was a very strong risk factor (three-fold increased risk

of sudden death) as compared with hypertension (2.5-fold increased risk), and obesity (1.6-fold

increased risk). Other long-term follow-up studies confirmed the role of diabetes as predictor of

sudden death (26,27,28) . These results based on large long-term follow-up studies provide strong

evidence that diabetes is a risk factor for sudden cardiac death. Another study by Jouven et al.,(28)

reported that higher levels of glycemia are associated with higher risk of sudden cardiac death,

which does not support the ‘dichotomous’ risk approach of comparison between diabetic vs. non-

diabetic patients. Of note, after adjustment for age, systolic blood pressure, presence of heart

disease, and glucose-lowering treatment, even patients with borderline glicemia levels were at

higher risk of sudden cardiac death than those with normoglycemia. Most importantly,

microvascular disease (retinopathy or proteinuria), and female gender increased the risk of sudden

cardiac death in all groups. These findings are clinically important since suggest that risk begins to

increase at glucose levels that are considered fairly normal. It has been previously reported that

high glycemic levels are associated with lower heart rate variability (29), which can be found even

9

in pre-diabetic patients (30). These findings confirm that glucose levels should be considered as a

continuous variable affecting heart rate variability parameters (HRV) and autonomic control of the

heart. The Rochester diabetic neuropathy study (31) by multivariate analysis, which did not include

HRV as a variable, concluded that neither autonomic neuropathy nor QTc are independent

predictors of the risk for sudden cardiac death, whereas kidney dysfunction and atherosclerotic heart

disease are the most important determinants. These observations taken together suggest that a pre-

diabetic stage cann be associated with progressive abnormalities predisposing to sudden cardiac

death. At present, there are no independent predictors of sudden cardiac death in diabetes to identify

patients at higher risk. In a single study, microvascular disease and nephropathy have been

identified as indicators of increased risk of sudden cardiac death in diabetic patients. The reduction

of mortality from sudden cardiac arrest in the setting of coronary heart disease remains a major

challenge, especially among patients with type 2 diabetes. Diabetes is associated with an increased

risk of sudden cardiac arrest, which is due to several factors. Increased extent of coronary

atherosclerosis due to macrovascular disease has been reported in diabetes, but non-coronary

atherosclerotic pathophysiologic processes such as microvascular disease and autonomic

neuropathy also increase the risk. Also, glycemia is known to affect the electrolyte balance,

potassium and calcium channels, as well as the sympathetic activity, all of which are a key role in

the arrhythmogenesis. Recent evidence suggests that higher risk in diabetes is not specific for

sudden cardiac arrest since diabetes also is associated with a similar increase in risk for non-SCA

CHD death and non-fatal myocardial infarction. These findings are in agreement with prior

observations that coronary atherosclerosis is the most important contributor to the higher sudden

cardiac arrest risk associated with diabetes. Previous data demonstrate that both clinically-

recognized microvascular and autonomic neuropathy also are associated with the risk of sudden

cardiac arrest among treated patients with diabetes, after taking into account prior clinically-

recognized heart disease and other risk factors for SCA. Although the prediction of sudden cardiac

arrest in this "high" risk patient population is likely to remain a challenge, as it is in other "high"

10

risk clinical populations, current recommendations for the prevention of sudden cardiac death,

suggest both lifestyle prescriptions and risk factor decrease, to reduce mortality from sudden cardiac

death in diabetes. A recent multicenter international randomized study (ADVANCE-Study)

enrolling 11140 diabetic patients while confirming that AF is relatively common in type 2 diabetes,

has demonstrated for the first time that among patients with type 2 diabetes, those with AF are at

substantially higher risk of death of any cause, cardiovascular death, major cerebrovascular events,

and heart failure, compared with those without AF (32). This study emphasizes that AF identifies

individuals who are likely to obtain greater absolute benefits from blood pressure-lowering

treatment, and then AF in diabetic patients should be regarded as a marker of particularly adverse

outcome and prompt aggressive management of all risk factors. Diabetes has long been recognized

as a risk factor for AF, but its independent contribution to AF has been recently reported in an

observational, age- and sex-matched cohort, longitudinal study of 34,744 patients with and without

diabetes (33). In this population, diabetes was an independent determinant of AF prevalence but

predicted incidence only among women. These findings have potential public health implications

and emphasize the need for further investigation of the mechanistic links between diabetes and AF.

Other analyses have shown that the rising prevalence and incidence of AF cannot be explained by

aging alone (34,35). Recent findings indicate that AF may be relatively common in diabetic patients

and should be regarded as a marker of particularly adverse outcomes, prompting aggressive

management of all risk factors (32). The overlap of diabetes and AF also contributes to a well-

established increased risk of thromboembolic stroke (36). Although diabetes and AF undoubtedly

share common antecedents such as hypertension, atherosclerosis, and obesity (37,38), the

confluence of these two conditions clearly warrants additional study. However, the potential

independent contribution of diabetes to the prevalence and incidence of AF has not been evaluated.

Comparative analyses of the prevalence and incidence of AF in patients with and without diabetes

have shown that AF was 44% more prevalent and 38% more likely to develop when diabetes was

present (39). In this comparative study controlling for other known risk factors such as hypertension

11

and heart failure approximately halved the risk of incident AF (39). Recent studies have provided

evidence of how comorbidities can have important modulatory effects on the progression and

complications of AF (30). Thus far, studies evaluating the specific role of diabetes have been

lacking. In the recent development of a risk score for AF, the Framingham Heart Study did not find

diabetes to be a significant predictor of AF risk (40). This finding is contrary to a previous

Framingham report that found diabetes to be a strong independent risk factor (41). Consistent with

the latter study, the recent study by Nichols et al (39) suggests that in their studied population,

diabetes made a significant contribution to the prevalence and incidence of AF, independently from

hypertension and congestive heart failure. The continuously rising prevalence of diabetes may

further increase the prevalence of AF, which represents the most common arrhythmia. It is

conceivable that prevention and treatment of diabetes will limit the AF burden. Whether

interventions achieving tight glycemic control decrease sudden cardiac death requires further

studies.

12

REFERENCES

1. Chen PS, Chou CC, Tan AY, Zhou S, Fishbein MC, Hwang C, Karagueuzian HS, Lin SF.

The mechanisms of atrial fibrillation. J Cardiovasc Electrophysiol 2006; 17 (suppl 3): S2–

S7.

2. Khan R, Sheppard R. Fibrosis in heart disease: Understanding the role of transforming

growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology. 2006;

118: 10–24.

3. Bakth S, Arena J, Lee W, Torres R, Haider B, Patel BC, Lyons MM, Regan TJ. Arrhythmia

susceptibility and myocardial composition in diabetes. Influence of physical conditioning. J

Clin Invest. 1986; 77: 382–395.

4. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes; estimates for

year 2000 and projections for 2030. Diabetes Care 2004; 21:1047–1053.

5. Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a strong, independent risk

for atrial fibrillation and flutter in addition to other cardiovascular disease. Int J Cardiol

2005; 105:315–318.

6. Ostgren CJ, Merlo J, Ra°stam L, Lindblad U. Atrial fibrillation and its association with type

2 diabetes and hypertension in a Swedish community. Diabetes Obes Metab 2004; 6:367–

374.

7. Asia Pacific Cohort Studies Collaboration. The effects of diabetes on the risks of major

cardiovascular diseases and death in the Asia-Pacific region. The Asia Pacific Cohort

Studies Collaboration. Diabetes Care 2003; 26:360–366.

8. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with

diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;

332:73–78.

13

9. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial

fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J

Med 1995;98:476-484

10. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB,Belanger AJ, Wolf PA, Independent risk

factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study.

JAMA 1994;271:840-844.

11. Jahangir A, Lee V, Friedman PA, Trusty JM, Hodge DO, Kopecky SL, et al. Long-term

progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year

follow-up study. Circulation 2007;115:3050-3056.

12. Pappone C, Radinovic A, Manguso F, Vicedomini G, Ciconte G, Sacchi S, et al. Atrial

fibrillation progression and management: a 5-year prospective follow-up study. Heart

Rhythm. 2008 ;5:1501-7.

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. Friberg J, Scharling H, Gadsbøll N, Truelsen T, Jensen GB, Copenhagen City Heart Study.

Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death

in women versus men (The Copenhagen City Heart Study). Am J Cardiol 2004;94:889–894.

15. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the

Framingham study. Am J Cardiol. 1974;34:29 –34.

16. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Prog Cardiovasc Dis. 1985;27:255–

270.

17. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther. 1994;8:65–73.

18. Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J. 1989; 118:1000 –1012.

19. Boudina S, Abel ED. Diabetic Cardiomyopathy revisited. Circulation 2007;115:3213-3223

20. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study.

JAMA. 1979;241:2035–2038.

14

21. Atrial fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic

therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials .

Arch Intern Med 1994;154:1449-1457.

22. Illien S, Maroto-Jarvinen S, von der Recke G, Hammerstingl C, Schmidt H, Kuntz-Hehner

S, et al. Atrial fibrillation: relation between clinical risk factors and transoesophageal

echocardiographic risk factors for thromboembolism. Heart 2003;89:165-168.

23. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al.ACC/AHA/ESC

guidelines for the management of patients with atrial fibrillation. Eur Heart J 2006;27:1979-

2030.

24. Kannel WB, Wilson PW, D'Agostino RB, Cobb J. Sudden coronary death in women. Am

Heart J 1998;136:205-212.

25. Kannel WB, Wilson PW, D'Agostino RB, Cobb J. Sudden coronary death in women. Am

Heart J 1998;136:205-212.

26. Curb JD, Rodriguez BL, Burchfiel CM, Abbott RD, Chiu D, Yano K. Related articles.

Sudden death, impaired glucose tolerance, and diabetes in Japanese American men.

Circulation 1995;91:2591-2595.

27. Balkau B, Jouven X, Ducimetiere P, Eschwege E. Diabetes as a risk factor for sudden death.

Lancet 1999;354:1968-1969.

28. Jouven X, Lemaitre RN, Rea TD, Sotoodehnia N, Empana JP, Siscovick DS. Diabetes,

glucose level, and risk of sudden cardiac death. Eur Heart J 2005;26:2142-2147.

29. Singh JP, Larson MG, O'Donnell CJ, Wilson PF, Tsuji H, Lloyd-Jones DM, Levy D.

Association of hyperglycaemia with reduced heart rate variability (The Framingham Heart

Study). Am J Cardiol 2000;86:309-312.

30. Singh JP, Larson MG, O'Donnell CJ, Wilson PF, Tsuji H, Lloyd-Jones DM, Levy D.

Association of hyperglycaemia with reduced heart rate variability (The Framingham Heart

Study). Am J Cardiol 2000;86:309-312.

15

31. Suarez GA, Clark VM, Norell JE, Kottke TE, Callahan MJ, O'Brien PC, et al Sudden

cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study. J

Neurol Neurosurg Psychiatry 2005;76:240-245.

32. Du X, Ninomiya T, de Galan B, Abadir E, Chalmers J, Pillai A, et al ; ADVANCE

Collaborative Group on behalf of the ADVANCE Collaborative GroupRisks of

cardiovascular events and effects of routine blood pressure lowering among patients with

type 2 diabetes and atrial fibrillation: results of the ADVANCE study. Eur Heart J. 2009;

30:1128-35.

33. Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed

combination of perindopril and indapamide on macrovascular and microvascular outcomes

in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled

trial. Lancet 2007;370:829-840.

34. Miyaska Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. 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.

35. Wolf PA, Benjamin EJ, Belanger AJ, Kannel WB, Levy D, D'Agostino RB. Secular trends

in the prevalence of atrial fibrillation: The Framingham Study. Am Heart J 1996;131:790-

795.

36. Tsang TS, Petty GW, Barnes ME, O'Fallon WM, Bailey KR, Wiebers DO, et al. The

prevalence of atrial fibrillation in incident stroke cases and matched population controls in

Rochester, Minnesota: changes over three decades. J Am Coll Cardiol 2003;42:93-100.

37. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, et al. Lifitime risk for

development of of atrial fibrillation: The Framingham Study. Circulation 2004;110:1042-

1046

38. Nichols GA, Hillier TA, Brown JB. Progression from newly acquired impaired fasting glusose to

type 2 diabetes. Diabetes Care 2007;30:228-233.

16

39. Nichols GA, Reinier K, Chugh SS. Independent contribution of diabetes to increased

prevalence and incidence of atrial fibrillation. Diabetes Care. 2009;32:1851-1856.

40. Schnabel RB, Sullivan LM, Levy D, Pencina MJ, Massaro JM, D'Agostino RB Sr, et al

Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-

based cohort study. Lancet 2009;373:739-745.

41. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk

factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study

JAMA 1994;271:840-844.

17