A number of largely clinic-based prospective studies have demonstrated increased mortality among diabetic patients with symptomatic CAN or those with abnormal cardiovascular reflex tests. Their major findings are summarized in Table 3.8 [68,74,117,119 128]. The overall mortality rates over periods up to 10 years were about 26% in diabetic patients with CAN compared with 4% in those without evidence of CAN. However, it must be kept in mind that autonomic dysfunction may also be found in the absence of diabetes as a consequence of common cardiovascular diseases such as coronary artery disease, myocardial infarction, and heart failure. It has been shown that reduced HRV is an independent indicator of poor prognosis in these patients [129]. Since cardiovascular diseases represent the major cause of death in diabetic patients [130], the impact of diabetes and, for example, coronary sclerosis on the autonomic nervous system may overlap in a number of patients to such a degree that CAN may at least not be the only factor responsible for the increased mortality [127]. On the other hand, there is evidence that CAN contributes to the poor prognosis in diabetic patients as an independent factor [122].
The mechanisms by which CAN leads to the increased mortality remain a matter of debate, but two hypotheses have been suggested [123,131]. A number of studies have shown an association between CAN and QT interval prolongation, and a recent metaanalysis revealed a 2.3-fold increased risk of CAN in diabetic patients showing a prolonged QT interval [132], leading to the speculation that, in analogy to the QT prolongation encountered in the idiopathic long QT syndrome, which is characterized by recurrent episodes of syncope or cardiac arrest due to torsades de pointes [133], CAN might also predispose patients to malignant ventricular arrhythmias and sudden death. A recent five-year study from Italy showed a considerably increased risk of mortality in type 1 diabetic patients with QTc prolongation (odds ratio: 24.6 [95% CI: 6.5-92.9]) which requires further confirmation [128]. Although the studies listed in Table 3.8 were not sufficiently large to allow unequivocal conclusions regarding an increased incidence of sudden death in CAN, recent evidence indicates an important role of the autonomic nervous system in triggering sudden death in both nondiabetic and diabetic subjects with low HRV. A marked decrease in HRV in nondiabetic patients with coronary artery disease was present immediately before the onset of the ST shift precipitating ischemic sudden death, suggesting that sympathovagal imbalance may trigger fatal arrhythmias during acute myocardial ischemia [134]. HRV was also diminished in nondiabetic survivors of sudden death not associated with coronary artery disease, indicating that abnormal autonomic activity may trigger malignant arrhythmia independently of coronary artery disease [135]. In subjects with inducible ventricular tachycardia (VT), 42% of whom were diabetic, HRV was markedly lower than in those without evidence of VT [136]. In unselected patients a 2.6-fold higher relative risk of sudden death within two years (after adjustment for age, left ventricular dysfunction, and history of myocardial infarction) was observed among patients with reduced HRV than in those with normal HRV. Among the subjects who died suddenly. 9.3% were diabetic, whereas only 3.5% of the patients who survived had diabetes [137]. The Zutphen Study [138] recently showed that low HRV predicts mortality from all causes in the general population. The population-based Honolulu Heart Program demonstrated that orthostatic hypotension defined as a drop in systolic blood pressure of at least 20 mmHg or in diastolic blood pressure of at least 10 mmHg predicts four-year all-cause mortality in a cohort of 3522 elderly Japanese-American men aged 71-93. Four-year age-adjusted mortality rates were 57 and 39 per 1000 person-years in men with and without orthostatic hypotension, respectively [139].
The second hypothesis for the explanation of the increased mortality in CAN suggests that impaired central control of respiration rather than abnormal cardiovascular reflexes contributes to the poor prognosis [131]. This view is supported by studies reporting an increased prevalence of sleep apnea and nocturnal oxygen desaturation in diabetic patients with CAN [140,141]. Several studies have demonstrated impaired ventilatory responses to progressive hypercapnia or hypoxemia in CAN [142–144]. This impairment is not due to peripheral factors such as abnormal lung function or diaphragmatic muscle alterations, but to defective central control of respiration. This last suggestion is supported by the finding that naloxone, a specific opioid antagonist, produced no increase in CO2 response in diabetic patients with CAN, in contrast to healthy subjects. However, a lack of effect of naloxone on CO2 response was also observed in diabetic patients without CAN [143]. Hence, the question remains open as to whether the altered central control of respiration is specific to CAN or is rather a feature of diabetes itself. To complicate matters even more, an increased hypercapnic drive, indicating an exaggerated response of the central drive due to removal of the sympathetic inhibition, was recently found in patients with CAN and orthostatic hypotension [144].
There is little information available on the prognostic significance of the other manifestations of autonomic neuropathy. Diabetic gastroparesis diagnosed by scintigraphy was not associated with a poor prognosis in two studies performed over 3-5 and 9-14 years, respectively [145,