The natural history of CAN has been extensively evaluated utilizing standardized cardiovascular reflex tests, and to a much lesser extent utilizing scintigraphic techniques. Comparison of these two methodologies is hindered by the relative difficulty of reflex testing to sensitively detect the progression of sympathetic deficits and the inability of current scintigraphic tracers to safely map human cardiovascular parasympathetic integrity. Abnormalities in the sensitive parasympathetic cardiovascular reflex tests might be present at diagnosis of diabetes (16) even in children (33), but the importance of this abnormality is unclear as clinical symptoms are rare and it might not predict the development of complications. The beneficial effects of improved glycemic control on the progression of peripheral somatic neuropathy (17-19), neuropathic symptoms (34), electrophysiological deficits (18,34), and vibration perception thresholds (18,35) are now beyond dispute. However, the relationship of metabolic control to progression of autonomic dysfunction has been less clear. The inconsistent effects of improved metabolic control on the progression of CAN could reflect a number of factors including the inability of some studies to sufficiently improve HbA1c, too advanced CAN at initiation of the study, insufficient study duration or insensitivity of autonomic testing to detect a change. Scintigraphic studies have also been utilized to directly explore the effect of glucose control on cardiac autonomic function. These techniques have shown that poor glycemic control can result in progression of LV sympathetic dysinnervation, which can be prevented (30) or reversed (31) by the institution of near-euglycemia.
Tests of cardiovascular autonomic function often deteriorate at a faster rate in patients with diabetes compared with age-matched nondiabetic individuals, with beat-to-beat variability reported to decrease at one beat per minute per year (three times the rate of normal subjects) (36). The Valsalva ratio has been reported to decrease at a rate of 0.015 per year in type 1 diabetes, which might be twice that observed in the normal nondiabetic population (37). In a recently reported 14 year prospective study of subjects with type 1 diabetes, autonomic nerve function was also found to progressively deteriorate (38). Additionally, autonomic neuropathy and the presence of abnormal orthostatic diastolic blood pressure were associated with future renal complications (38). However, clinical symptoms of autonomic dysfunction might correlate poorly with changes in reflex tests, might be intermittent, and not progress (3,35).
With the progression of CAN and the development of sympathetic deficits and disabling symptoms such as orthostatic hypotension, a poor prognosis has been reported with up to a 60% 5 year mortality (39). However, other studies have not predicted such a dire outlook, as 90% of asymptomatic subjects with reduced HRV without the presence of symptoms were still alive after 10 years (36). However, the presence of symptoms, (again in particular postural hypotension) was associated with reduced survival (73% alive after 10 years). The precise cause of death in these subjects is controversial: most probably reflect coexistent renal and cardiovascular disease, but a small number of deaths remain unexplained and the potential causes are discussed (see Cardiac Denervation Syndrome).
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