Trying to prevent diabetic cardiovascular autonomic neuropathy: More questions than answers

The prevalence of diabetes mellitus in the United States has increased dramatically over the past 30 years, to where it now affects *24 million of adults and with that number expected to double by 2050. This greater prevalence includes both type-1 diabetes mellitus (T1DM) and type-2 diabetes mellitus (T2DM), although the latter predominates primarily because of the increase in obesity. Cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients accounting for approximately two-thirds of all deaths. In addition to its tremendous health burden, there is a substantial economic burden with the cost of diagnosis and treatment of cardiovascular complications in diabetic patients estimated to be *$22 billion annually. Although coronary atherosclerosis is the major cause of cardiovascular disease, diabetes mellitus can impair cardiovascular function independent of atherosclerosis. For example, the presence of T2DM is an independent risk factor for developing left ventricular hypertrophy and congestive heart failure and worsens the prognosis for those who develop these conditions. Cardiovascular autonomic dysfunction (CAN) is another often overlooked complication of this disease. It reflects abnormalities in the sympathetic and/or parasympathetic neuronal systems with their relative contributions defining patient symptomatology. The prevalence of CAN ranges from *1% to 90% in T1DM and from *20%-75% in patients with T2DM. The wide ranges reflect both inconsistencies in criteria used to define CAN and variable study design. CAN may be present the time of diagnosis of diabetes and the prevalence increases with age, disease duration, and worsening glycemic control. There are multiple clinical manifestations of CAN including resting tachycardia, impaired heart rate variability, exercise intolerance, abnormal regulation of blood pressure, orthostatic hypotension, and silent myocardial ischemia. Moreover, CAN is associated with impaired diastolic function and has been posited to be a potential contributor to the cardiomyopathy of diabetes mellitus, although direct causality has been difficult to prove. These diverse manifestations of CAN are likely the reasons it is a key contributor to the increase in CV morbidity and mortality associated with diabetes mellitus. The pathogenesis of CAN is likely multifactorial and reflects the yet to be defined proportional contributions of numerous factors such as hyperglycemia-induced neuronal ischemia/injury, neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor deficiency. The importance of hyperglycemia in the pathogenesis of CAN is supported by multi-center trials such as the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Trial demonstrating that intensive glycemic control had persistent beneficial effects on the incidence, severity, and progression of CAN in patients with T1DM. The results in patients with T2DM are less clear but appear to suggest that intensive glycemic control in combination with aggressive CV risk factor modification reduces the prevalence of CAN in patients with microalbuminuria. Despite these encouraging results, there is intense interest in developing therapeutic approaches to reduce the incidence and clinical severity of CAN. Reprint requests: Robert J. Gropler, MD, Division of Radiological Sciences, Cardiovascular Imaging Laboratory, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO 63110; Groplerr@mir.wustl.edu J Nucl Cardiol 2014;21:842–4. 1071-3581/$34.00 Copyright 2014 American Society of Nuclear Cardiology.