Cardiovascular Autonomic Neuropathy

Role of Vagosympathetic Impairment in Insulin Resistance

Obesity is a major determinant of CAN in T2DM patients. Data suggest that cardiac autonomic dysfunction may occur in obese individuals before diabetes. In obese patients, cardiac vagal tests more often show impairment in those with the metabolic syndrome, and the impairment is more commensurate with the severity of perturbations of the components of the syndrome. In individuals with the metabolic syndrome, increased activity of the sympathetic nervous system was found to be associated with several of the components of the metabolic syndrome, including elevated blood pressure (BP). However, whether this disorder contributes to the development of the metabolic syndrome or is a consequence of it remains still a matter of debate. Because cardiac autonomic dysfunction may occur in individuals with only one or two metabolic abnormalities without insulin resistance, cardiac autonomic dysfunction is suggested to precede insulin resistance in the metabolic syndrome. This hypothesis is strongly supported by a recent demonstration that the progression to T2DM is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition. Indeed, vagal depression and sympathetic predominance might contribute to insulin resistance and depression of insulin secretion. Several findings support this hypothesis. In obese normotensive patients, central fat distribution is associated with higher sympathetic activity. Glucose usage has been found to correlate negatively with the low frequency–to–high frequency ratio (LF/HF) on spectral analysis of heart rate (HR) variations, which means that glucose usage was reduced when sympathetic activity was relatively higher. We reported that in obese patients with vagal cardiac impairment, insulin levels correlated negatively with glucose oxidation rate (indirect calorimetry), suggesting a more severe insulin resistance that may again result from sympathetic overactivity.

Effects of Insulin and Glucagon-like Peptide 1 on Autonomic Activity

Hyperinsulinemia subsequent to insulin resistance may also modulate autonomic activity and induce changes in hemodynamic parameters. Insulin may increase HR slightly, as shown during hyperinsulinemic euglycemic clamps in healthy individuals. ^, HR elevation results from both vagal depression ^, and cardiac sympathetic activation as indicated by increased muscle sympathetic nerve activity (MSNA), ^, plasma catecholamines, and in some studies LF/HF ratio (an index for relative sympathetic predominance). Sympathoexcitatory effects of insulin result from a central nervous action and possibly from baroreflex activation secondary to insulin-induced peripheral vasodilation. However, during insulin clamp the shift in the cardiac autonomic activity toward sympathetic predominance was reported to be lower in obese than in lean individuals and in insulin-resistant patients, suggesting that chronic hyperinsulinemia may prevent further enhancement of cardiac sympathetic tone during an acute rise in insulin.

In addition, recent data suggest that the incretin hormone glucagon-like peptide 1 (GLP-1) may also play a role in this context. Regarding the effects of GLP-1 on autonomic activity, both the acute and chronic administration of central long-lasting GLP-1 receptor agonist exendin-4 was shown to reduce HF and LF powers of HR variations and to inhibit neurotransmission to cardiac vagal neurons. GLP-1, administered peripherally or centrally, also increases sympathetic activity in rats. Further studies on the effects of GLP-1 on autonomic activity need to be performed in diabetic and obese patients to determine the role of GLP-1 in these populations.

Thus, insulin and GLP-1 are able to induce vagal depression and sympathetic activation (see Fig. 29-1 ). Both hormones may potentially affect BP with effects that might differ depending on the presence of hypertension, cardiac autonomic impairment, and endothelium function.

Vagosympathetic Imbalance and Hemodynamic Changes

Sympathetic activity was found to be greater and baroreflex sensitivity more severely impaired in individuals with obesity and hypertension than in those with either obesity or hypertension alone and similarly for individuals with the metabolic syndrome and hypertension, suggesting that sympathetic overactivity may contribute to hypertension. Vagal impairment and/or sympathetic overactivity may also contribute to resting sinus tachycardia.

At advanced stages of diabetic CAN sympathetic activity is depressed, which may induce orthostatic hypotension (OH). Postprandial hypotension may also occur as a result of meal-induced splanchnic vasodilation while sympathetic response is blunted ( Fig. 29-2 ).

Prevalence and Correlates of Cardiovascular Autonomic Neuropathy

In clinical studies including both T1DM and T2DM patients, the prevalence of confirmed CAN (defined by at least two abnormal cardiovascular autonomic reflex test [CART] results) was approximately 20%. ^, However, prevalence rates increased with age and diabetes duration (up to 35% in T1DM and 65% in T2DM patients with longstanding diabetes). Glycemic control and the presence of microvascular complications (polyneuropathy, retinopathy, nephropathy) are other correlates of CAN. A contributing role of several cardiovascular risk factors (high BP or hypertension, smoking, dyslipidemia, overweight or obesity in T2DM, large waist circumference, high insulin levels in T2DM, and cardiovascular disease) has also been reported. The influence of overweight and obesity is supported by the high prevalence of impaired cardiac vagal activity in nondiabetic obese patients and the finding of an inverse correlation between HR variability and body weight in the general population. This suggests that cardiac autonomic dysfunction precedes the onset of T2DM and might play a role in metabolic disorders.

Cardiovascular Autonomic Neuropathy as a Predictor of Cardiovascular Morbidity and Mortality

CAN is a risk marker for all-cause and cardiac mortality, stroke, coronary events, silent myocardial ischemia (SMI), heart failure, arrhythmia, sudden death, and nephropathy progression. A meta-analysis of 15 longitudinal studies, which included 2900 patients followed for 1 to 16 years, showed that the diagnosis of CAN based on at least two abnormal CART results determined a relative risk of mortality of 3.45 (95% confidence interval 2.66-4.47; P < 0.001). Subsequent studies including the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial confirmed the independent predictive value of CAN for all-cause and cardiovascular mortality (still predictive after adjustment for cardiovascular risk factors). The presence of OH, a clinical manifestation of severe CAN, impaired the prognosis and was associated with a higher mortality risk than the increase in risk associated with vagal cardiac test abnormalities. Prolongation of the QT interval corrected for HR (QTc), which may result from CAN, is also an independent predictor of all-cause and cardiovascular mortality.