Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet

Abstract

The burden of diabetic cardiovascular autonomic neuropathy (CAN) is expected to increase due to the diabetes epidemic and its early and widespread appearance. CAN has a definite prognostic role for mortality and cardiovascular morbidity. Putative mechanisms for this are tachycardia, QT interval prolongation, orthostatic hypotension, reverse dipping, and impaired heart rate variability, while emerging mechanisms like inflammation support the pervasiveness of autonomic dysfunction. Efforts to overcome CAN under-diagnosis are on the table: by promoting screening for symptoms and signs; by simplifying cardiovascular reflex tests; and by selecting the candidates for screening. CAN assessment allows for treatment of its manifestations, cardiovascular risk stratification, and tailoring therapeutic targets. Risk factors for CAN are mainly glycaemic control in type 1 diabetes mellitus (T1DM) and, in addition, hypertension, dyslipidaemia, and obesity in type 2 diabetes mellitus (T2DM), while preliminary data regard glycaemic variability, vitamin B12 and D changes, oxidative stress, inflammation, and genetic biomarkers. Glycaemic control prevents CAN in T1DM, whereas multifactorial intervention might be effective in T2DM. Lifestyle intervention improves autonomic function mostly in pre-diabetes. While there is no conclusive evidence for a disease-modifying therapy, treatment of CAN manifestations is available. The modulation of autonomic function by SGLT2i represents a promising research field with possible clinical relevance.

Keywords: Autonomic nervous system; Cardiovascular system; Diabetic neuropathies; Diagnosis; Epidemiology; Glucagon-like peptide-1 receptor; Hypotension, orthostatic; Prognosis; Sodium-glucose transporter 2 inhibitors; Therapeutics.

Fig. 1. Mechanisms of sympathetic overactivity in insulin resistant conditions and obstructive sleep apnoea syndrome (OSAS). Sympathetic overactivity in insulin resistant conditions is attributed to an insulin-driven sympathetic activation through a peripheral mechanism at play in acute conditions (insulin causes endothelial-dependent vasodilatation resulting in baroreflex-mediated sympathetic activation), and a central mechanism mainly present in chronic conditions of hyperinsulinemia (insulin operates in the paraventricular nucleus of hypothalamus and the arcuate nucleus). Moreover, insulin-induced carotid body overactivity has been demonstrated in animal models of insulin resistance (insulin receptors have been found on carotid bodies) [18]. A role of carotid chemoreceptors in a long-term insulin-mediated increase in sympathetic activity in humans has been also suggested [19]. Comorbid OSAS leads to chemoreflex upregulation due to nocturnal chronic intermittent hypoxia and arousals, therefore fostering sympathetic activation. Modified from Greco et al. [19] with permission from Bentham Science Publishers. CNS, central nervous system.

Fig. 2. Multiple factors in the relationship between metabolic syndrome and autonomic dysfunction. In addition to obstructive sleep apnoea syndrome (OSAS) with its consequences including microbiota perturbation [19], other factors in metabolic syndrome able to cause autonomic dysfunction are: obesity (also independently of dysglycemia) [24], liver steatosis [20], leptin (as a sympathetic activator) [19], and inflammation and neuroinflammation at hypothalamic level [2122]. Most of these components of metabolic syndrome have a bidirectional relationship with autonomic dysfunction, for example with respect to the autonomic regulation of the immune system and inflammation [23]. The end result of this complex system can be the exacerbation of metabolic derangements at different levels [1924], as well as of cardiovascular effects. IFG-IGT, impaired fasting glucose and/or impaired glucose tolerance; NAFLD, non-alcoholic fatty liver disease.

Fig. 3. Multifactorial pathogenesis of nondipping in diabetes. In addition to the central role of autonomic derangement, insulin resistance in type 2 diabetes mellitus and diabetes-associated obstructive sleep apnoea syndrome (OSAS) can induce chemoreflex upregulation and baroreflex impairment, and reinforce sympathetic overactivity. In advanced cardiovascular autonomic neuropathy (CAN), orthostatic hypotension can favour nondipping through postural changes in blood volume and supine hypertension. Moreover, there is documentation that the fluid redistribution from the extra to the intravascular compartment in the presence of proteinuria, the mechanism of compensatory nocturnal pressure-natriuresis in salt-sensitive hypertension and in renal failure, the sleep loss so common in diabetes, and even the neuropathic pain may act as contributory factors. Adapted from Spallone [77], with permission from Springer Nature.

Fig. 4. (A) Clinical effectiveness of cardiovascular autonomic neuropathy (CAN) diagnosis in clinical forms of CAN and (B) the awareness of CAN for the therapeutic strategy in asymptomatic forms of CAN. QTi, QT interval; BP, blood pressure; ANS, autonomic nervous system.

Fig. 5. Interaction between sodium glucose transporter 2 inhibitor (SGLT2i) and sympathetic nervous system. NE, norepinephrine; T2DM, type 2 diabetes mellitus; BP, blood pressure; MSNA, muscle sympathetic nerve activity.

Fig. 6. Glucagon-like peptide 1 receptor agonists (GLP1-RAs) and autonomic nervous system. HR, heart rate; HRV, heart rate variability; SNS, sympathetic nervous system; MSNA, muscle sympathetic nerve activity; T2DM, type 2 diabetes mellitus; BP, blood pressure; GLP-1 R, glucagon-like peptide 1 receptor.