Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events

Abstract

Autonomic nervous system (ANS) imbalance manifesting as cardiac autonomic neuropathy in the diabetic population is an important predictor of cardiovascular events. Symptoms and signs of ANS dysfunction, such as resting heart rate elevations, diminished blood pressure responses to standing, and altered time and frequency domain measures of heart rate variability in response to deep breathing, standing, and the Valsalva maneuver, should be elicited from all patients with diabetes and prediabetes. With the recognition of the presence of ANS imbalance or for its prevention, a rigorous regime should be implemented with lifestyle modification, physical activity, and cautious use of medications that lower blood glucose. Rather than intensifying diabetes control, a regimen tailored to the individual risk of autonomic imbalance should be implemented. New agents that may improve autonomic function, such as SGLT2 inhibitors, should be considered and the use of incretins monitored. One of the central mechanisms of dysfunction is disturbance of the hypothalamic cardiac clock, a consequence of dopamine deficiency that leads to sympathetic dominance, insulin resistance, and features of the metabolic syndrome. An improvement in ANS balance may be critical to reducing cardiovascular events, cardiac failure, and early mortality in the diabetic population.

Keywords: cardiac autonomic neuropathy; cardiovascular event prediction; diabetes; dopamine deficiency; heart rate variability; insulin resistance; parasympathetic; sympathetic.

FIGURE 1

Schematic of dopamine – clock interactions in the regulation of fuel metabolism. Figure illustrates the hypothalamic clock with decreased suprachiasmic nuclear (SCN) early morning peak of dopamine activity and enhanced activity of the paraventricular nucleus (PVN), which increase autonomic tone and the paraventricular nucleus to raise levels of corticotrophin releasing hormone (CRH). The consequences include activation of the sympathetic nervous system (SNS) hypothalamic and glucose sensitization reducing parasympathetic (vagal drive) to the liver and resistance to both leptin and insulin. CRH, corticotrophin releasing hormone; eNOS, endothelial nitric oxide synthase; FFAs, free fatty acids; NPY, neuropeptide Y; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; SNS, sympathetic nervous system; TGs, triglycerides; VMH, ventromedial hypothalamus (Raskin and Cincotta, 2016).