Epidemiology

Difficulties in accurate estimates of the prevalence of CAN reflect a number of factors including variations in the populations studied, the source of the patients within these populations, individual patient characteristics, choice of test utilized, and the diagnostic criteria. In 1988, in order to reduce some of these variabilities, the San Antonio Conference on Diabetic Neuropathy made a number of recommendations, including the choice of tests to be performed as well as recommending that autonomic function data should be standardized by the development of reference ranges in the local population as well as by reporting absolute data (8). As described later, indirect assessment of CAN utilizing more indirect reflex tests tend to yield lower overall estimates of CAN prevalence compared with newer direct scintigraphic methodology.

CAN is usually detected using widely available indirect standardized cardiovascular reflex tests, which evaluate the integrity of complex reflex arcs. These assessments in general, identify abnormalities of cardiovascular innervation in 16-20% of subjects with diabetes (9-15). In the Eurodiab IDDM Complications Study, for example, altered heart rate variability (HRV) was detected in approximately 19% of subjects (14). In another study of more than 600 subjects with type 1 diabetes approximately 25% of subjects had abnormalities of at least two autonomic function tests (16). However, in the diabetes control and complication trial of type 1 diabetes in the primary prevention cohort, deficits of HRV were found less than 2% (17). In subjects with microvascular complications at baseline, this prevalence increased to approximately 6% (18,19). Despite some earlier controversy, it is now widely recognized that type 2 diabetes is also frequently complicated by the development of CAN. In the French multicenter study of type 1 and type 2 diabetes, for example, approximately 25% of subjects had symptoms consistent with autonomic neuropathy (20). CAN was found to be the most common (51 %) diabetes complication with rates of moderate and more severe CAN being higher in type 1 than in type 2 subjects. CAN correlated with diabetes duration and retinopathy and was independently associated with obesity in type 2 diabetes (20). The frequency of parasympathetic CAN has been reported to be 20% at 5 years and 65% at 10 years (21), and sympathetic CAN 7% at 5 years and 24% at 10 years.

Recently, CAN has also been extensively evaluated using more direct, but expensive techniques involving radiolabeled analogs of norepinephrine, which are actively taken up by cardiac sympathetic nerve terminals (see next) (3-6,22-33). These techniques have identified a specific cardiac sympathetic dysinnervation complicating diabetes, and proven useful in not only determining the prevalence of cardiac sympathetic dysinnervation, but have also been utilized to follow its progression and its response to therapeutic intervention. Both [131I] metaiodobenzylguanidine (MIBG) and [11C] metahydroxyephedrine (HED) have been extensively utilized to assess the integrity of cardiac sympathetic innervation.

In cross-sectional studies, LV [123I] MIBG and [11C]-HED retention deficits have been identified in subjects with type 1 and type 2 diabetes even in the absence of

[,3N]-NH3 0

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[11C]-HED

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