Cardiovascular autonomic neuropathy in diabetes: Pathophysiology, clinical assessment and implications

Abstract

Cardiovascular autonomic neuropathy (CAN) is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier, even before diabetes is diagnosed. CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers, which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control. The entire mechanism is still not elucidated, but several aspects of the pathophysiology of CAN have already been described, such as the production of advanced glycation end products, reactive oxygen species, nuclear factor kappa B, and pro-inflammatory cytokines. This microvascular complication is an important risk factor for silent myocardial ischemia, chronic kidney disease, myocardial dysfunction, major cardiovascular events, cardiac arrhythmias, and sudden death. It has also been suggested that, compared to other traditional cardiovascular risk factors, CAN progression may have a greater impact on cardiovascular disease development. However, CAN might be subclinical for several years, and a late diagnosis increases the mortality risk. The duration of the transition period from the subclinical to clinical stage remains unknown, but the progression of CAN is associated with a poor prognosis. Several tests can be used for CAN diagnosis, such as heart rate variability (HRV), cardiovascular autonomic reflex tests, and myocardial scintigraphy. Currently, it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV, which is a non-invasive test with a lower operating cost. Therefore, considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes, the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition.

Keywords: Cardiovascular autonomic neuropathy, Cardiac autonomic neuropathy, Diabetes mellitus, Heart rate variability, Sympathetic autonomic nervous system, Parasympathetic autonomic nervous system

Core Tip: Cardiovascular autonomic neuropathy (CAN) is an important risk factor for cardiovascular events. However, CAN may be subclinical for several years, worsening its potential contribution to increased mortality due to late diagnosis. Even during the subclinical stage, CAN could be detected through reduction in heart rate variability, a non-invasive test. Therefore, considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes, the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality impact from this long-lasting condition.