included 29 873 adults aged at least 20 years. 412 of whom were known diabetic patients. Autonomic function was assessed in 43 type 1 and 202 type 2 diabetic patients using the standard deviation of HRV at rest, expiration/inhalation (E/l) ratio from a single deep breath, and Valsalva ratio. The overall prevalence of abnormal results in one or more of the three tests was 20.9% in type 1 patients and 15.8% in type 2 patients. Since this study did not include control subjects, the reported prevalence of autonomic dysfunction is difficult to interpret. The definition of one abnormality (<2.5th percentile of normal range) among three tests might yield one abnormal test result in up to 7.5% of a control population. Hence, the specificity of the test battery and the prevalence of CAN in that study were relatively low.
In the Pittsburgh Epidemiology of Diabetes Complications Study [62] autonomic neuropathy was evaluated in 168 type 1 diabetic subjects aged 25-34 years, representing 71% of those who were eligible. Cardiovascular autonomic function tests included the E/l ratio and mean circular resultant (MCR) to deep breathing. 30:15 ratio to standing, and Valsalva ratio. The results of the E/I ratio and MCR were significantly associated with the hypertension status, LDL and HDL cholesterol, and gender. The prevalence of autonomic symptoms, ranging from 0 to 8%, was relatively low except for hypoglycemia unawareness, which was present in 26% of the patients. However, this study neither reported the prevalence of abnormal test results nor did it take into account treatment with drugs that potentially influence autonomic function. Orthostatic hypotension, defined as a systolic blood pressure fall of at least 30 mmHg, was noted in 3.4% of the patients.
In a clinic-based multicenter study (DiaCAN) we have found prevalence rates of borderline CAN (2 out of 7 indices abnormal) or definite CAN (>3 out of 7 indices abnormal) of 8.5% and 16.8% respectively among 647 unselected type 1 diabetic patients, and 12.2% and 22.1% respectively in 524 type 2 diabetic patients [31]. The percentage of type 1 diabetic patients with definite CAN was identical with the 16.6% rate observed in 506 patients randomly selected from four hospital diabetic clinics in Bristol [63]. In that study CAN was diagnosed by HRV responses during rest and in response to a single deep breath. Valsalva maneuver, and standing, and was defined by abnormal test results in at least two of these four tests. In the EURODIABIDDM Complications Study [64], among the total of 3250 patients studied. 19.3% (range among centers: 7.8-51.8%) had abnormal HRV and 5.9% (range: 0-14.5%) had postural hypotension. In a Japanese clinic-based cohort of 886 type 2 diabetic patients the prevalence of orthostatic hypotension was 7% [65].
Since particularly in type 2 diabetes the actual onset of the disease may often be preceded by a long period of unrecognized metabolic abnormality, it appears likely that neural dysfunction can be detected at the time of diagnosis of diabetes. Two studies have reported the frequency of neuropathy in type 2 diabetic patients who were examined within four weeks following the diagnosis of the disease. Lehtinen et al. [66] evaluated 132 patients aged 45-64 years in the district of Kuopio University Central Hospital and 142 controls randomly selected from the population registers. The rates of abnormal E/l ratio were 6.3% and 1.4%, respectively. A similar study was performed by Ratzmann et al. [34] in 95 newly diagnosed type2 diabetic patients who were representative of the East Berlin community. The prevalence of abnormal maximum/minimum heart rate during deep breathing was 7.3%.
In a clinic-based study we determined the prevalence of CAN in 120 healthy subjects and 130 newly diagnosed type 1 diabetic patients within 3-49 days after the initiation of insulin treatment with stable mean blood glucose levels. The prevalence of CAN defined by the strict criterion of at least three abnormal tests out of six was 7.7% in the patients and 0 in the controls. Two abnormal tests out of six were found in an additional 9.2% of the patients but in only 1.7% of the controls [67].
Thus, CAN cannot be generally regarded as a late complication of diabetes, but it should be borne in mind that subclinical cardiovascular autonomic dysfunction may be detected even in newly diagnosed type 1 diabetic patients if sensitive indices of spectral analysis are applied in conjunction with tests based on standard analysis of HRV.
Incidence an d Natural History
Only a few studies have evaluated the natural history of CAN in inception cohorts. Töyry et al. [68] followed 133 newly diagnosed type 2 diabetic patients and 144 control subjects over 10 years in Kuopio, Finland. CAN was assessed by the E/l ratio as an index of parasympathetic activity and the systolic blood pressure drop on standing as a measure of sympathetic activity. The prevalence of “parasympathetic neuropathy” rose from 5% in diabetic patients vs 2% in controls at baseline to 65% vs 28% after 10 years, while the prevalence of “sympathetic neuropathy” increased from 7% vs 6% at five years to 24% vs 9% after 10 years. Poor glycemic control and high insulin levels were significant predictors of the development of CAN [68]. Moreover, the presence of CAN at five years was an independent risk factor for the development of stroke after 10 years [69]. Clinic-based studies in patients with variable duration of type 2 diabetes showed a gradual increase in the prevalence of AFT score abnormalities from 41% at baseline to 64% after four years [70], and worsening of the AFT score in 57% of the patients after five years of follow-up [71].
There are no population-based studies including inception cohorts at the time of diagnosis of type 1 diabetes. In a clinic-based study we have shown that the natural evolution of abnormal HRV during the first five years following diagnosis of type 1 diabetes is clearly related to the degree of glycemic control [72]. The rates of abnormalities in HRV at five years were 5% in well-controlled patients and 23% in those who were poorly controlled. In type 1 diabetic children the prevalence of abnormal HRV at rest increased from 27% at the time of diagnosis to 56% after 10 years, but abnormal HRV during deep breathing changed only from 12% to 14% [73].
In longer-term teenage type 1 diabetic patients Young et al. [53] found an increase in the rates of abnormal HRV from 19% to 28% within 20-35 months in poorly controlled type 1 diabetic teenagers. Sampson and colleagues [74] noted a relatively slow decline in HRV of about 1 beat/min per year, approximately three times faster than in healthy subjects [39], over a decade in patients with initially normal HRV. Postural hypotension was persistent, but did not deteriorate in the majority of patients. In contrast, a six-year study has reported the relatively rapid development of postural hypotension in a small group of long-term diabetic patients, which was preceded by a decrease in E/l ratio [75]. In two recent studies in type 1 diabetic patients, AFTs and autonomic symptoms and signs had not changed after 5 and 9 years, respectively [76,77]. In a prospective study over 10-11 years, CAN has been shown to predict future deterioration in glomerular filtration rate in type 1 diabetic patients. It has been hypothesized that nocturnal rise in intraglomerular
