The recognition of alterations in cardiac autonomic function in asymptomatic Type I insulin-dependent diabetic (IDDM) individuals has been facilitated by the development of standardized cardiovascular reflex tests from which inferences about autonomic integrity are drawn. Recent experimental and clinical evidence points to the existence of a left ventricular structural and functional impairment associated with diabetes mellitus that raises the possibility that early in IDDM disease progression the cardiovascular dysfunction detected by standard diagnostic tests may be due to cardiac pathology rather than autonomic neuropathy. This revision of a proposed 4-year study will extend our previous NHLBI- funded work in evaluating autonomic mediation of dynamic cardiovascular function and noninvasive diagnostic approaches for assessing diabetic neuropathy. We will study healthy and IDDM (of more than 10 years duration) men and women (n=130 of 144 recruited), 18-55 years old. IDDM subjects with abnormal and normal autonomic function will be classified using a standard battery of autonomic integrity tests. Group assignment using the standard classification method will be compared with an alternative autonomic classification method that is based on a quantitative clustering technique. Echocardiographic evaluation of left ventricular structure and function will be performed. Then autonomic contribution to the cardiovascular response to orthostatic challenge will be noninvasively assessed using: l) selective pharmacologic blockade; 2) V-hat, a quantitative index of parasympathetic cardiac neural input; 3) systolic time interval estimates of sympathetic myocardial input; and 4) measures of hemodynamic function (heart rate, blood pressure, cardiac output, peripheral resistance). Subjects will be tested under four conditions: placebo, 13-sympathetic blockade, parasympathetic blockade, and combined 13-sympathetic and parasympathetic blockade. The comprehensive assessment of hemodynamic function during rest and postural adjustment (head-up and head-down tilt) in each of the pharmacologic blockade conditions will provide information about the autonomic contribution to hemodynamic regulation in IDDM individuals. The degree of autonomic blockade will be assessed pharmacologically. These data together with the information derived from the echocardiographic left ventricular assessment will yield information regarding IDDM disease progression in relation to the sensitivity and specificity of the standard and alternative IDDM classification methods.
