Declaration of conflict of interest. None to declare

Declaration of conflict of interest None to declare

Risk management of coronary artery disease Arrhythmias and diabetes Hercules Mavrakis Cardiology Department Heraklion University Hospital Crete, Greece

Diabetes epidemiology It is estimated that diabetes affects about 246 million people world-wide, with an expected 55% increase to 380 million in 2025. Global projections for the number of people with diabetes 2007 and 2025 IDF Atlas, 3rd edn. 2006

Diabetes and cardiovascular disease Hyperglycaemia, insulin resistance, and the consequent cellular shift to an increased oxidative stress carry a high risk for development of co-morbidities and cardiovascular risk factors, mainly: hypertension, lipid disorders, pro-inflammatory state, activation of coagulation and thrombosis. As a consequence, mortality from all forms of cardiovascular disease are two-to eightfold higher in persons with diabetes, and coronary artery disease accounts for 75% of all deaths in such individuals. Malmberg K, et al. Circulation 2000

Diabetes and cardiovascular disease 20 30% of patients with an acute coronary syndrome have diabetes, and as many as 40% have impaired glucose tolerance. Both in-hospital and long-term mortality rates after an acute myocardial infarction are twice as high for patients with diabetes than among those without diabetes. Haffner SM et al. New England J Med 1998

Crucial question Are diabetic patients at increased risk of arrhythmias?

Risk factors for arrhythmogenic substrate Imbalance in autonomic tone Silent ischemia Slowed conduction Heterogeneities in atrial and ventricular repolarization Extent of myocardial damage and scar formation

Cardiac autonomic neuropathy and silent myocardial ischaemia The risk for cardiovascular autonomic neuropathy depends on the duration of diabetes and the degree of glycaemic control. It is caused by injury to the autonomic nerve fibres that innervate the heart and blood vessels. It has been estimated that about 20% of asymptomatic diabetic patients have abnormal cardiovascular autonomic function. The main consequences are: dysfunctional heart rate control, abnormal vascular dynamics and cardiac denervation, exercise intolerance, orthostatic hypotension, silent myocardial ischaemia. Global myocardial blood flow and coronary flow reserve, studied by PET, were subnormal in diabetics with cardiovascular autonomic neuropathy. Cardiovascular autonomic neuropathy may provoke ischaemic episodes by upsetting the balance between myocardial supply and demand.

Diabetes and atrial fibrillation Experimental data In the animal model of diabetes, the occurrence of AF was enhanced by adrenergic activation in diabetic heart, in which the sympathetic innervations was evident. The heterogeneous increase in sympathetic innervations was proved to be associated with the promotion of AF in several studies. The intra atrial conduction delay and fibrotic deposition in atria play a major role in producing atrial tachyarrhythmias in diabetes animal model. Schmid H, et al Diabetes 1999 Olgin JE, et al. Heterogeneous atrial denervation creates substrate for sustained atrial fibrillation. Circulation 1998

Crucial question Are diabetic patients at increased risk of atrial fibrillation?

Diabetes and atrial fibrillation Diabetes is associated with AF and seems to favour the occurrence of the arrhythmia. In the Framingham Heart Study, diabetes was shown to favour new-onset AF in a large cohort of men and women followed-up for 38 years (OR, 1.4 for men and 1.6 for women). Benjamin EJ, et al. The Framingham Heart Study. JAMA 1994

Diabetes and atrial fibrillation The Manitoba Follow-up Study estimated the age-specific incidence of AF in 3983 males, to identify risk factors for the development of this arrhythmia. Diabetes was significantly associated with AF with a relative risk of 1.82 in the univariate analysis. However, in the multivariate model the association with diabetes was not significant, suggesting that the increased risk of AF in diabetic men may depend on the presence of ischaemic heart disease, hypertension, or heart failure. Krahn AD, et al. Am J Med 1995

Development of a Risk Score for Atrial Fibrillation in the Community:The Framingham Heart Study Schnabel R et al Lancet. 2009

Development of a Risk Score for Atrial Fibrillation in the Community:The Framingham Heart Study Age, sex, significant murmur, heart failure, systolic blood pressure, hypertension treatment, body mass index, and PR interval were associated with incident AF Schnabel R et al Lancet. 2009

Independent Contribution of Diabetes to Increased Prevalence and Incidence of Atrial Fibrillation Men Women Atrial fibrillation prevalence was significantly greater among patients with diabetes (3.6 vs. 2.5%, P :0.0001). After full adjustment for other risk factors, diabetes was associated with a 26% increased risk of AF among women (hazard ratio 1.26) but diabetes was not a statistically significant factor among men (1.09). Nichols GA et al. Diabetes Care 2009

Impact of New-Onset Diabetes Mellitus on Development of AF and Heart Failure in High-Risk Hypertension (from the VALUE Trial) Patients with new-onset DM had a significantly higher event rate of newonset AF with a hazard ratio of 1.49 compared with patients without DM, and there was a trend toward more AF in patients with DM at baseline. Patients with new-onset DM and AF had a hazard ratio of 3.56 for heart failure compared with patients with new-onset DM without AF. Aksnes TA et al, Am J Cardiol 2008

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 AF AF No AF No AF After multiple adjustments, AF was associated with a 61% (P:0.0001) greater risk of all-cause mortality and comparable higher risks of cardiovascular death, stroke, and heart failure (all P : 0.001). AF in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors. Du X et al, Eur Heart J 2009

Diabetes and stroke in AF CHADS 2 CHA 2 DS 2 -VAS C Congestive Heart Failure 1 Hypertension 1 Age > 75 years 1 Diabetes Mellitus 1 Prior Stroke or TIA 2 Diabetes is an independent risk factor for stroke with a relative risk of 1.7. The presence of a single moderate risk factor (e.g. diabetes) carries an annual risk of stroke of 1.5% without warfarin.

Approach to thromboprophylaxis in patients with AF Camm et al. ESC AF guidelines 2010 Eur Heart J 2010

Diabetes and atrial fibrillation Conclusions Diabetes has long been recognized as a risk factor for atrial fibrillation, which was subsequently reaffirmed in several studies. However, the potential independent contribution of diabetes to the prevalence and incidence of atrial fibrillation has not been fully evaluated and the confluence of these two conditions clearly warrants additional studies.

Crucial question Are diabetic patients at increased risk of ventricular arrhythmias and sudden death?

Diabetes-Coronary atherosclerosis & SCD

Pathophysiology of SCD in CAD Mechanisms responsible for SCD: Unstable plaque/acute occlusion Chronic closure/ischemic cardiomyopathy

Chronic closure/ischemic cardiomyopathy Substrate intramyocardial reentry due to scar formation compensatory hypertrophy in non-infarcted myocardium progressive ventricular remodeling and neurohormonal abnormalities Triggers & Modulators changes in ANS activity metabolic disturbances electrolyte abnormalities acute volume and/or pressure overload ion channel abnormalities The electrophysiological alterations induced by all these conditions initiate and maintain VT/VF

Diabetes and sudden death Diabetes is associated with an increased risk of SCD, at least in part, from an increased presence and extent of coronary atherosclerosis (macrovascular disease). Diabetes also is associated with microvascular disease and autonomic neuropathy and, these non-coronary atherosclerotic pathophysiologic processes also have the potential to increase the risk of SCD.

Diabetes and sudden death Interestingly, positive association (2 4 fold increase in the risk of SCD) was found in studies with long-term followup (typically >20 years). In the Paris Prospective Study I, a study of middle-aged men free of clinical heart disease working for the city of Paris, the risk of SCD, but not of fatal myocardial infarction, was increased in diabetes when compared with normal subjects. In the Framingham study, diabetes was strongly associated with the incidence of SCD and the association was stronger in women than in men. Jouven X, et al Circulation 1999 Balkau B,et al. Lancet 1999 Kannel WB et al. Am Heart J 1998

Diabetes and sudden death However, in two other prospective studies of middle-aged men from Finland and England (British Heart Regional Study), diabetes and glucose level were not associated with SCD. Several reasons may explain these apparent discrepancies. In the Finnish study, the prevalence of diabetes was low, only 1.5% of study participants. Finally, these two studies had relative short duration of follow-up, 8 and 11 years, respectively. Suhonen O,et al. Acta Med Scand 1988. Wannamethee G, et al. Circulation 1995

Diabetes, glucose level, and risk of sudden cardiac death When compared with no diabetes, progressively higher risk of SCD was observed associated with borderline diabetes (Odds ratio:1.24), diabetes without microvascular disease (OR:1.73), and diabetes with microvascular disease (OR:2.66). Higher glucose levels were also associated with the risk of SCD both in the absence and in the presence of microvascular disease. Jouven X et al, Eur Heart J 2005

Sudden cardiac death after myocardial infarction in patients with type 2 diabetes A total of 3,276 patients were enrolled at the time of acute MI between 1996 and 2005. Among diabetic patients, the incidence of SCD was higher (5.9%) than in nondiabetic patients (1.7%), with a hazard ratio (HR) of 3.8 (P.001) and adjusted HR of 2.3. The incidence of SCD in post-mi type 2 diabetic patients with LVEF>35% is equal to that of nondiabetic patients with LVEF< 35%. Junttila MJ et al, Heart Rhythm 2010

Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study The Rochester Diabetic Neuropathy Study was designed to define the risk factors for sudden cardiac death and the role of diabetic autonomic neuropathy in a population of 462 diabetic patients followed for 15 years. Interestingly, necropsy findings demonstrated that all victims of sudden cardiac death had signs of coronary artery or myocardial disease. Kidney dysfunction and atherosclerotic heart disease are the most important determinants of the risk of SCD while neither autonomic neuropathy nor QTc are independent predictors of the risk for SCD. Suarez GA,J Neurol Neurosurg Psychiatry 2005

Based on available evidence, it seems that: Glucose intolerance, even at a pre-diabetic stage, is associated with progressive development of a variety of abnormalities that adversely affect survival and predispose to SCD. The identification of independent predictors of SCD in diabetic patients has not yet progressed to a stage where it is possible to devise a risk stratification scheme for the prevention of such deaths in diabetic patients. Recommendations: Control of glycaemia even in the pre-diabetic stage is important to prevent the development of the alterations that pre-dispose to SCD. Class I, Level of Evidence C. Microvascular disease and nephropathy are indicators of increased risk of SCD in diabetic patients. Class IIa, Level of Evidence B. Lars Ryden, et al. Eur Heart J 2007

Diabetes and sudden death Conclusions It is unclear whether diabetes alters the incidence of SCD due to mechanisms including autonomic dysfunction arrhythmias perhaps triggered by hypoglycaemia, altered cardiac repolarization, or cardiomyopathy, which may be distinct from the contributions of coronary disease. Current guidelines for managing SCD risk in diabetics acknowledge their increased risk but fall short of specific guidelines, due to a lack of data.

At present no marker has the power to predict patients at high risk in daily care the search continues for the perfect combination of tests currently, the primary technique to determine who is at risk of SCD is the LVEF Heart Rhythm, Vol 5, No 10, October 2008