Cardiovascular Autonomic Neuropathy Due to Diabetes Mellitus: Clinical Manifestations, Consequences, and Treatment

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Cardiovascular Autonomic Neuropathy Due to Diabetes Mellitus: Clinical Manifestations, Consequences, and Treatment
First Published Online July 12, 2005
Received April 6, 2005.
Accepted July 5, 2005.
Raelene E. Maser and M. James Lenhard
Journal of Clinical Endocrinology & Metabolism

Department of Medical Technology (R.E.M.), University of Delaware, Newark, Delaware 19716; Diabetes and Metabolic Research Center (R.E.M., M.J.L.), Research Institute, Christiana Care Health Services, Newark, Delaware 19713; and Diabetes and Metabolic Diseases Center (M.J.L.), Christiana Care Health Services, Wilmington, Delaware 19801

Address all correspondence and requests for reprints to: Raelene E. Maser, Ph.D., Department of Medical Technology, 305F Willard Hall Education Building, University of Delaware, Newark, Delaware 19716. E-mail: rmaser@UDEL.EDU.

Abstract

Context: The aim of this article was to review the importance of the clinical identification of persons with cardiovascular autonomic neuropathy (CAN) and discuss potential treatment interventions.

Evidence Acquisition: A MEDLINE search was conducted for articles published during the last 20 yr. In addition, subsequent references of retrieved articles were reviewed. Search strategies included using key terms such as CAN, heart rate variability, orthostatic hypotension, and diabetes mellitus.

Evidence Synthesis: CAN is a common form of diabetic autonomic neuropathy and causes abnormalities in heart rate control as well as central and peripheral vascular dynamics. The clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, painless myocardial ischemia, and increased risk of mortality. CAN contributes to morbidity, mortality, and reduced quality of life for persons with diabetes. The American Diabetes Association has recently published a statement that provides guidelines for prevention, detection, and management of neuropathy, including CAN, for healthcare providers who care for patients with diabetes. Algorithms for the evaluation and treatment of the patient with CAN, even if the patient is asymptomatic, are provided in this review.

Conclusions: Once CAN is identified in a patient with diabetes, healthcare providers may consider altering the prescribed exercise regimen, increasing surveillance for cardiac ischemia, carefully reexamining the list of prescribed medications, and aggressively treating cardiovascular risk factors (e.g. hypertension) that may be associated with the development of CAN.

Introduction

THE AUTONOMIC NERVOUS system modulates the electrical and contractile activity of the myocardium via the interplay of sympathetic and parasympathetic activity (1). An imbalance of autonomic control is implicated in the pathophysiology of arrhythmogenesis (1). Cardiovascular autonomic neuropathy (CAN), a common form of autonomic dysfunction found in patients with diabetes mellitus, causes abnormalities in heart rate control, as well as defects in central and peripheral vascular dynamics. Individuals with parasympathetic dysfunction have a high resting heart rate most likely because of vagal neuropathy that results in unopposed increased sympathetic outflow. Persons with a combined parasympathetic/sympathetic dysfunction have slower heart rates. With advanced nerve dysfunction, heart rate is fixed. Thus, it is apparent that the determination of heart rate itself is not a reliable diagnostic sign of CAN. Reduction in variability of heart rate is the earliest indicator of CAN. Clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension (OH), asymptomatic ischemia, painless myocardial infarction (MI), and increased risk of mortality (2). A recent publication by the American Diabetes Association highlighted the significance of diabetic neuropathy by issuing a statement for healthcare professionals that provides guidelines for prevention, detection, and management of neuropathy (3). In light of the statement by the American Diabetes Association, we discuss in this overview the clinical manifestations, consequences of, and therapeutic strategies for CAN in diabetic patients.

Clinical Manifestations of Cardiovascular Autonomic Dysfunction

Exercise intolerance

In diabetic individuals with CAN, exercise tolerance is limited as a result of impaired parasympathetic/sympathetic responses that would normally enhance cardiac output and result in directing peripheral blood flow to skeletal muscles (4). Reduced ejection fraction, systolic dysfunction, and decreased diastolic filling, potentially as a result of CAN, also limit exercise tolerance (4). For diabetic persons likely to have CAN, it has been suggested that cardiac stress testing should be performed before beginning an exercise program (5). When discussing exercise instructions and goals with patients with CAN, healthcare providers need to emphasize that the use of heart rate is an inappropriate gauge of exercise intensity because maximal heart rate is depressed in persons with CAN (6). Recently it has been shown that percentage of heart rate reserve, an accurate predictor of percentage of VO2 reserve, can be used to prescribe and monitor exercise intensity in diabetic individuals with CAN (7). An alternate method for monitoring intensity of physical activity is the Rating of Perceived Exertion scale (7, 8). The Rating of Perceived Exertion scale, which uses the subjective feelings of intensity of the individual, can be used in clinical settings where maximal heart rate is not easily measured.

Intraoperative cardiovascular lability

There is a 2- to 3-fold increase in cardiovascular morbidity and mortality intraoperatively for patients with diabetes (9). Studies have demonstrated that the induction of anesthesia causes a greater degree of decline in heart rate and blood pressure in diabetic patients compared with nondiabetic individuals (10) and that hemodynamic stability, in the intraoperative period, depends on the severity of autonomic dysfunction (11). Patients with severe autonomic dysfunction have a high risk of blood pressure instability (11, 12), and intraoperative blood pressure support is needed more often in those with greater impairment (10). Intraoperative hypothermia (13), which may decrease drug metabolism and affect wound healing, and impaired hypoxic-induced ventilatory drive (14) have also been shown to be associated with the presence of CAN. Although one study failed to detect any association with abnormal hemodynamics during anesthesia in patients with diabetic CAN and coronary artery disease (15), noninvasive diagnostic methods assessing autonomic function allow identification of at-risk patients preoperatively and may better prepare the anesthesiologist for potential hemodynamic changes.

Orthostatic hypotension

A change from lying to standing normally results in activation of a baroreceptor-initiated, centrally mediated sympathetic reflex, resulting in an increase in peripheral vascular resistance and cardiac acceleration (9). OH is characterized by a defect in this reflex arc, resulting in signs and symptoms such as weakness, faintness, dizziness, visual impairment, and syncope. Although the absolute fall in blood pressure is arbitrary, OH is usually defined as a fall in blood pressure [i.e. >20–30 mm Hg for systolic or >10 mm Hg for diastolic (16, 17)] in response to postural change, from supine to standing.

Painless myocardial ischemia

Inability to detect ischemic pain can impair the recognition of myocardial ischemia or MI. The mechanisms of painless myocardial ischemia are, however, complex and not fully understood. Altered pain thresholds, subthreshold ischemia not sufficient to induce pain, and dysfunction of the afferent cardiac autonomic nerve fibers have all been suggested as possible mechanisms (18). A recent investigation that used positron emission tomography to measure regional cerebral blood flow as an index of regional neuronal activation has shown that impaired afferent signaling resulting from autonomic dysfunction is associated with failed signal transmission from the thalamus to the frontal cortex (19). Although evidence for a mechanistic link between diabetes and painless myocardial ischemia may not include autonomic dysfunction as some have suggested (20), it is hard to ignore the results of the Detection of Ischemia in Asymptomatic Diabetics study (21). In the Detection of Ischemia in Asymptomatic Diabetics study of 1123 patients with type 2 diabetes, cardiac autonomic dysfunction was a strong predictor of ischemia (21). A meta-analysis of 12 studies also demonstrated a consistent association between CAN and the presence of painless myocardial ischemia (2). The Mantel-Haenszel estimate for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with a 95% confidence interval of 1.53–2.51 (P < 0.001; n = 1468 total subjects) (2). Thus, patients with CAN warrant more careful attention. Cardiovascular autonomic function testing may be an important component in the risk assessment of diabetic patients with coronary artery disease (21).

Increased risk of mortality

Impaired autonomic control of heart rate is linked to increased risk of mortality. Reduced parasympathetic function or increased sympathetic activity may provide the propensity for lethal arrhythmias (22). In a recent meta-analysis of 15 studies among individuals with diabetes, CAN was found to be significantly associated with subsequent mortality when autonomic dysfunction was defined as the presence of two or more abnormalities of tests of heart rate variability (HRV) [i.e. pooled relative risk was 3.45 (95% confidence interval, 2.66–4.47; P < 0.001)] (23). The stronger association observed in studies defining CAN by the presence of two or more abnormalities may be due to more severe autonomic dysfunction in these individuals, specificity of assessment modalities, or a higher frequency of other comorbid complications.

Copyright © 2005 by The Endocrine Society

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