Diabetic Autonomic Neuropathy

Aaron I. Vinik, MD, PhD.; Roy Freeman, MB, ChB.; Tomris Erbas, MD


Semin Neurol. 2003;23(4) 

In This Article

Cardiovascular Autonomic Neuropathy

Cardiovascular autonomic neuropathy is a common form of autonomic neuropathy, causing abnormalities in heart rate control and central and peripheral vascular dynamics. Cardiovascular autonomic neuropathy has been linked to postural hypotension, exercise intolerance, enhanced intraoperative cardiovascular lability, increased incidence of asymptomatic ischemia, myocardial infarction, and decreased likelihood of survival after myocardial infarction. Cardiovascular autonomic neuropathy occurs in ~17% of patients with type 1 diabetes and 22% of those with type 2. An additional 9% of type 1 patients and 12% of type 2 patients have borderline dysfunction.[22] In a review of several epidemiological studies among individuals with diabetes, the 5-year mortality rate is five times higher for individuals with cardiovascular autonomic neuropathy than for individuals without cardiovascular autonomic involvement.[1,6] The stronger association observed in studies defining cardiovascular autonomic neuropathy by the presence of two or more abnormalities may be due to more severe autonomic dysfunction in these patients or a higher frequency of other comorbid complications that contributed to their higher mortality risk.[23]

An increased resting heart rate is observed frequently in diabetic patients most likely due to the vagal cardiac neuropathy that results in unopposed cardiac sympathetic activity. The tachycardia may be followed by a decrease in heart rate and, ultimately, a fixed heart rate due to progressive dysfunction of the cardiac sympathetic nervous system. Heart rate variability is considered the earliest indicator and most frequent finding in symptomatic cardiovascular autonomic dysfunction. Cardiovascular autonomic neuropathy leads to a reduced cardiac ejection fraction and systolic dysfunction and decreased diastolic filling.[24] Limited exercise tolerance is due to impaired sympathetic and parasympathetic responses that normally augment cardiac output and redirect peripheral blood flow to skeletal muscles. Exercise tolerance is also reduced by a reduced ejection fraction, systolic dysfunction, and decreased diastolic filling. A prolonged corrected QT interval and QT dispersion (the difference between the longest and shortest QT interval) indicates an imbalance between right and left sympathetic innervation.[25] Diabetic patients with a regional sympathetic imbalance and QT interval prolongation may be at greater risk for arrhythmias. Regional myocardial autonomic denervation and altered vascular responsiveness in diabetic autonomic neuropathy may predispose to malignant arrhythmogenesis and sudden cardiac death.

Diabetic patients have a high rate of coronary heart disease, which may be asymptomatic owing to autonomic neuropathy.[26,27] Silent ischemia is significantly more frequent in patients with than in those without autonomic neuropathy (38% versus 5%). The cause of silent myocardial ischemia in diabetic patients is controversial. It is clear, however, that a reduced appreciation for ischemic pain can impair timely recognition of myocardial ischemia or infarction and thereby delay appropriate therapy. In nondiabetic patients, acute myocardial infarction has a circadian variation with a significant morning peak. The characteristic diurnal variation in the onset of myocardial infarction is altered in diabetic patients, with a lower morning peak and a higher percentage of infarction during evening hours. The blunted morning surge of incidence of myocardial infarction results from altered sympathovagal balance in patients with cardiac autonomic neuropathy. Mortality rates after a myocardial infarction are also higher for diabetic patients than for nondiabetic patients.[28] This may be due to autonomic insufficiency, increasing the tendency for development of ventricular arrhythmia and cardiovascular events after infarction.

Orthostatic hypotension, another sign of autonomic neuropathy, is a fall in systolic blood pressure of greater than 30 mm Hg upon standing. In patients with diabetes, orthostatic hypotension is usually due to damage to the efferent sympathetic vasomotor fibers, particularly in the splanchnic vasculature. In addition, there is a decrease in cutaneous, splanchnic, and total vascular resistance that occurs in the pathogenesis of this disorder. Normally, in response to postural change there is an increase in plasma norepinephrine. For individuals with orthostatic hypotension, there may be a reduction in this response relative to the fall in blood pressure. Diminished cardiac acceleration and cardiac output, particularly in association with exercise, may also be important in the presentation of this disorder. Patients with orthostatic hypotension typically present with lightheadedness and presyncopal symptoms. Symptoms such as dizziness, weakness, fatigue, visual blurring, and neck pain also may be due to orthostatic hypotension. Many patients, however, remain asymptomatic despite significant falls in blood pressure.[1]

Cardiovascular Autonomic Function Tests

In the early 1970s, Ewing et al proposed five simple noninvasive cardiovascular reflex tests (Valsalva maneuver, heart rate response to deep breathing, heart rate response to standing up, blood pressure response to standing up, and blood pressure response to sustained handgrip) that have been applied successfully.[29] Today, sensitive and early assessment of cardiovascular autonomic neuropathy is possible by means of noninvasive autonomic function tests, including power spectral analysis of a series of successive R-R intervals (frequency domain analyses).[30,31] This can be performed on short R-R sequences (e.g., 7 minute) or on 24-hour electrocardiogram recordings. The heart rate power spectrum is typically divided into two frequency bands: low (0.04 to 0.15 Hz) and high (0.15 to 0.4 Hz). The high-frequency region is generally considered a marker of vagal activity, whereas the low-frequency component is influenced by both sympathetic and vagal activity.[32]

The association of mortality and cardiovascular autonomic dysfunction indicates that individuals with abnormal autonomic function tests are candidates for close surveillance. Thus it has been recommended that a baseline determination of cardiovascular autonomic function be performed upon diagnosis in type 2 diabetes and within 5 years of diagnosis for those with type 1 diabetes, followed by a yearly repeat test.[4] In addition, the presence of autonomic dysfunction should alert the health care professional to search for associated risk factors of cardiovascular disease and implementation of an intense program to reduce these factors and thereby reduce the risk of mortality.[23]


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