Diabetes-Induced Cardiac Autonomic Neuropathy: Impact on Heart Function and Prognosis

Abstract

Cardiovascular autonomic neuropathy (CAN) is a severe complication of the advance stage of diabetes. More than 50% of diabetic patients diagnosed with peripheral neuropathy will have CAN, with clinical manifestations including tachycardia, severe orthostatic hypotension, syncope, and physical exercise intolerance. Since the prevalence of diabetes is increasing, a concomitant increase in CAN is expected and will reduce quality of life and increase mortality. Autonomic dysfunction is associated with reduced baroreflex sensitivity and impairment of sympathetic and parasympathetic modulation. Various autonomic function tests are used to diagnose CAN, a condition without adequate treatment. It is important to consider the control of glucose level and blood pressure as key factors for preventing CAN progression. However, altered biomarkers of inflammatory and endothelial function, increased purinergic receptor expression, and exacerbated oxidative stress lead to possible targets for the treatment of CAN. The present review describes the molecular alterations seen in CAN, diagnosis, and possible alternative treatments.

Keywords: cardiac autonomic neuropathy; diabetes; endothelium dysfunction; inflammation; oxidative stress.

Figure 1

Evolution of symptoms of cardiac autonomic neuropathy (CAN) in diabetes. Patients display reduced variability in heart rate and resting tachycardia in the early phase of parasympathetic dysfunction, which underlie the reduced exercise tolerance and the increased arrhythmogenesis. Later stages of CAN involve sympathetic denervation and cause hemodynamic dysregulation and silent myocardial ischemia. Source: Own authorship.

Figure 2

Pathophysiological factors underlying the development and aggravation of diabetic cardiac autonomic neuropathy (DCAN). AGE, advanced glycation end-products; RAGE, receptor for advanced glycation end-products; GlcNAc, N-acetyl glucosamine; PARP, poly(ADP-ribose) polymerase; PKC, protein kinase C; NOX, reduced nicotinamide adenine dinucleotide phosphate oxidase; GSH, reduced glutathione; IL, interleukin; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β; IKKβ, inhibitor of nuclear factor kappa B kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase. Source: Own authorship.

Figure 3

Pharmacological strategies for management of main causes and symptoms of diabetic cardiac autonomic neuropathy (DCAN). ACE, angiotensin-converting enzyme; GLP-1R, receptor for glucagon-like peptide-1; SGLT-2, sodium/glucose cotransporter 2; AR, aldose reductase. Source: Own authorship.