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There is no therapy currently available for the treatment of CAN. Therefore, treatment mostly focuses upon management of a number of modifiable risk factors, which can significantly reduce the risk of developing CAN. In the European Diabetes Prospective Complications Study (EURODIAB), which enrolled 1172 patients with type 1 diabetes, the incidence of neuropathy was associated with a poor glycemic control, elevated triglyceride levels, increased body-mass index, smoking, and hypertension (141). Initially, treatment should focus upon improving overall cardiovascular fitness. Indeed, an exercise program has been shown to be able to improve early CAN (142). However, because CAN might impair exercise tolerance (51,57) and mask myocardial ischemia (25,90-92), subjects with CAN should be considered for a cardiac stress study before undertaking an exercise program.

In the Diabetes Control and Complication Trial study, an HbAlc difference of 1.9% decreased the risk of development of confirmed clinical neuropathy (diagnosed by neurological history and physical examination and confirmed by nerve conduction or autonomic function studies at year five) by 60% (17-19). More recently, multifactorial risk factor intervention (primarily glucose, blood pressure, and lipid control) were found to reduce the risk of CAN in type 2 diabetes by 63% (7). The individual contribution of agents, such as angiotensin converting enzyme inhibitors and statins to these salutary effects remains uncertain (143,144). Perhaps, if additional studies confirm an important role for sympathetic activation early in the development of abnormal blood flow regulation and myocardial damage complicating diabetes, consideration should be given to the use of P-AR blockade before the development of hypertension (particularly as newer agents such as carvedilol appear to reduce oxidative stress, microalbumuria, and insulin resistance in subjects with type 2 diabetes [145]). In any event, these studies are highly supportive of the importance of multiple risk factor management in delaying the development and slowing the progress of CAN (and its down-stream consequences) complicating diabetes and may be particularly important in the high-risk patient with established myocardial ischemia in whom CAN appears to further augment risk.

Increased oxidative stress has emerged as a leading candidate in the pathogenesis of experimental diabetic neuropathy, with a direct relationship between measures of oxida-tive stress and the development of nerve blood flow and nerve conduction deficits (146-148). In diabetic rodents, measures of oxidative stress, including increased nerve conjugated dienes (148) and reduced levels of nerve superoxide dismutase (146,149), glutathione peroxidase (150), glutathione (151), and norepinephine (152) are closely associated with the development of neuropathy. In concert, oxidative stress has also been implicated in the development of cardiomyopathy (120,153) and a contributing factor to endothelial dysfunction (154,155) and changes in acute phase reactants (156). Increases in reactive oxygen species can stimulate apoptosis in cardiac myocytes (157,158) potentially resulting in myocardial dysfunction (159). In the heart, chronic oxidative stress might also impair neurotrophism by depleting nerve growth factor (NGF) (160) and may downregulate NGF receptor expression, sensitivity, and transport in the myocardium (160,161) of diabetic rats (162). The chain breaking antioxidant, a-lipoic acid as well as the beta amino acid and endogenous antioxidant taurine (163) may stimulate NGF synthesis (164) and can prevent NGF protein depletion in sciatic nerve (161,163) and myocardium of diabetic rats (162).

Many studies have shown that oxidative stress is increased in subjects with diabetes before the development of diabetic complications (4,165,166), and recently studies have reported that oxidative stress is further increased in the presence of diabetic neuropathy (4,167) including CAN (4). Finally, activation of the aldose reductase pathway impairs antioxidant defense and promotes oxidative stress and has been implicated for many years in the pathogenesis of the chronic complications of diabetes including neuropathy (168,169). Aldose reductase-mediated oxidative stress is multifactorial, mediated by oxidizing the NADP+/NADPH and GSH/GSSG redox couples and by causing the compensatory depletion of taurine (163,169).

In subjects with diabetes and CAN and abnormal LV function measured during maximal bicycle exercise by gated radionuclide ventriculography (but without coronary heart disease), 1-year treatment with the aldose reductase inhibitor zopolrestat was shown to stabilize or reverse these functional deficits (115). In another study, a trend toward improvement of HRV was found after 4 months of oral treatment with a-lipoic acid (800 mg per day) in patients with type 2 diabetes with CAN (170). Most recently, 120 subjects with diabetic neuropathy were administered either a-lipoic acid 600 mg intravenously for 5 days per week for 14 treatments or a placebo. Treatment with a-lipoic acid resulted in significant improvements in total symptom score and in one attribute of nerve conduction, but did not improve quantitative sensory testing or cardiovascular reflex measures of autonomic function (171). These studies suggest that a single inter-ventional therapy might be insufficient to reverse CAN. In order to test the contribution of oxidative stress to the development and progression of CAN complicating diabetes, a 2-year prospective clinical trial is currently in progress exploring the ability of a combination of antioxidant approaches to reverse established cardiac sympathetic denervation assessed using HED and positron emission tomography.

In summary, CAN is a common but frequently overlooked complication of diabetes, with multiple subclinical and clinical cardiac manifestations ranging from impairment of exercise tolerance to sudden cardiac death. The advent of cardiac scintigraphy has allowed direct characterization of cardiac sympathetic dysinnervation complicating diabetes, and should greatly facilitate the elucidation of its metabolic and functional consequences. The salutary effects of multiple risk factor management in preventing the development and/or the progression of CAN underlines the importance of intensification of metabolic control early in the course of diabetes before the development of cardiovascular denervation. For individuals with already established CAN, the ability of combination antioxidant therapy to reinnervate the heart is currently being evaluated.

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