Cardiac autonomic neuropathy in patients with diabetes mellitus

Abstract

Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.

Keywords: Autonomic; Cardiac; Cardiac autonomic neuropathy; Cardiovascular; Diabetes mellitus; Diabetic cardiomyopathy; Dysfunction; Heart rate variability; Neuropathy; Parasympathetic; Postural hypotension; Spectral analysis; Sympathetic.

Figure 1

Summary of the mechanisms that relate hyperglycaemia to microvascular complications in patients with diabetes. PKC: Protein kinase C; AGE: Advanced glycation end-products; PARP: Poly ADP-ribose polymerase; GAPDH: Glyceraldehyde-3 phosphate dehydrogenase; GSH: Glutathione; NADH: Nicotinamide adenine dinucleotide; TGF-β: Transforming growth factor; VEGF: Vascular endothelial growth factor; PAI-1: Plasminogen activator inhibitor-1; eNOS: Endothelial nitric oxide synthase; IL-1: Interleukin 1; TNF-α: Tumour necrosis factor-α; VCAM-1: Vascular cell adhesion molecule 1.

Figure 2

Natural progression of CAN and correlation with clinical signs and symptoms. CAN: Cardiac autonomic neuropathy; LV: Left ventricle.

Figure 3

Current recommendations on screening for cardiac autonomic neuropathy. CAN: Cardiac autonomic neuropathy; DM: Diabetes mellitus.