Circadian Patterns of Heart Rate Variability, Fibrinolytic Activity, and Hemostatic Factors in Type I Diabetes Mellitus With Cardiac Autonomic Neuropathy Doron Aronson, MD, Larry A. Weinrauch, MD, John A. D’Elia, MD, Geoffrey H. Tofler, MD, and Andrew J. Burger, MD Diabetes mellitus is associated with a marked increase in the risk of coronary events but with an altered circadian distribution that demonstrates an absent morning peak and higher infarction rate during the evening hours. To elucidate the mechanism of this phenomenon, the circa- dian pattern of heart rate variability was evaluated in 22 type I diabetic patients with diabetic autonomic neu- ropathy in conjunction with circadian changes of fibrino- lytic and hemostatic factors. The circadian pattern (6 A.M. to 10 P.M. vs 10 P.M. to 6 A.M.) of 3 indexes of parasym- pathetic tone was evaluated using 24-hour heart rate variability analysis. The high-frequency power (3.0  0.2 vs 3.3  0.2 ms 2 ,p  0.08) and the percentage of RR intervals with >50 ms variation (0.47  0.18 vs 0.69  0.33 ms, p  0.52) demonstrated no significant circadian variation. The square root of mean squared differences of successive RR intervals showed a small but significant increase during nighttime (8.5  0.7 vs 9.7  1.1 ms, p  0.02). Fibrinolytic activity was significantly lower at 8 A.M. than at 4 P.M. (166.4  12.5 to 200.2  9.3 mm 2 ,p  0.0003), but with a low amplitude. Plas- minogen activator inhibitor 1 showed no circadian vari- ation. Factor VII and fibrinogen demonstrated a signifi- cant reduction from 8 A.M. to 4 P.M., but both peak and nadir values were elevated. The von Willebrand factor was markedly elevated with no circadian variation. Thus, diabetic autonomic neuropathy is associated with a loss of both the nocturnal predominance of parasym- pathetic activity and a prothrombotic state that persists throughout the day. These abnormalities may attenuate the relative protection from coronary events during the afternoon and nighttime. 1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;84:449 – 453) I n diabetic patients, the circadian distribution of myocardial infarction is altered, resulting in a lower morning peak and a higher percentage of infarctions during the evening hours. 1–6 It has been suggested that the blunted morning surge of myocardial infarction results from altered sympathovagal balance, espe- cially in the subgroup of patients with cardiac auto- nomic neuropathy (CAN). 7 Diabetes is associated with several hematologic and rheologic abnormalities that may predispose to intraluminal thrombosis. 8 The importance of these abnormalities is emphasized by the results of the angioscopic observations demon- strating that diabetic patients with unstable angina have a higher incidence of intracoronary thrombus formation associated with plaque ulceration than non- diabetic patients. 9 Whether an abnormal circadian pat- tern of thrombotic potential also contributes to the altered diurnal distribution of myocardial infarction in diabetic patients is currently unknown. The current study assesses the circadian behavior of the endoge- nous fibrinolytic activity, plasminogen activator inhib- itor 1 (PAI-1), von Willebrand factor antigen, factor VII antigen, and fibrinogen in diabetic patients with autonomic neuropathy. METHODS Patients: The study group consisted of 22 type I diabetic patients who were recruited from a larger group of patients enrolled as part of a multicenter study. The study compared the effects of a program of stringent 3 to 4 insulin injections per day with the effects of the same insulin regimen with the addition of weekly intravenous insulin infusion therapy. The institutional review board approved the study for hu- man research, and all subjects gave informed consent. Criteria for exclusion from the study were: (1) causes of neuropathy other than diabetes (e.g., chronic alcohol abuse, vitamin B12 deficiency, hypothyroid- ism, drug-induced neuropathy) and significant neuro- logic disease (e.g., Parkinson’s disease, epilepsy, re- cent stroke); (2) coronary artery disease with clinically apparent angina or congestive heart failure; (3) creat- inine clearance 30 ml/min; and (4) use of medica- tions with potential influence on autonomic function (e.g., - and -adrenergic and parasympathetic antag- onists and agonists) except for angiotensin-converting enzyme inhibitors. The latter were used in patients with concomitant diabetic nephropathy. The diagnosis of autonomic neuropathy was based on the response to a standardized battery of cardio- From the Division of Cardiology, Beth Israel Deaconess Medical Center, Joslin Diabetes Center, and the Royal North Shore Hospital, Sydney, Australia. Manuscript received March 1, 1999; revised manuscript received April 5, 1999 and accepted April 7. Address for reprints: Andrew J. Burger, MD, Beth Israel Deaconess Medical Center, West Campus Noninvasive Cardiology Laboratory, Baker-3, 1 Deaconess Road Boston, Massaschusetts. E-mail: aburger @caregroup.harvard.edu. 449 ©1999 by Excerpta Medica, Inc. All rights reserved. 0002-9149/99/$–see front matter The American Journal of Cardiology Vol. 84 August 15, 1999 PII S0002-9149(99)00331-8