An explicative review on Diabetic Cardiac Autonomic Neuropathy: From pathophysiology to the era of gene therapy

Diabetic Cardiac Autonomic Neuropathy (DCAN) is a prevalent and severe yet underdiagnosed complication of diabetes characterized by progressive injury to autonomic nerve fibers that regulate cardiovascular functions. This multifactorial disorder contributes significantly to morbidity and mortality due to arrhythmias, silent myocardial ischemia, and sudden cardiac death. DCAN onset is often insidious, with early stages marked by subclinical autonomic dysfunction detectable through heart rate variability and reflex testing. The pathogenesis involves chronic hyperglycemia-induced oxidative stress, mitochondrial dysfunction, and microvascular damage, compounded by genetic predispositions and complex epigenetic and epitranscriptomic modifications affecting gene expression in autonomic nerves. Notably, non-coding RNAs such as long non-coding RNAs (lncRNAs) play critical roles in diabetic neuropathy (DN) pathophysiology by modulating inflammatory and neurodegenerative pathways. Current management remains focused on stringent glycemic control, comprehensive cardiovascular risk reduction, lifestyle modifications, and symptom-targeted pharmacotherapies. Despite these measures, effective disease-modifying treatments are limited, underscoring the need for novel therapeutic approaches. This review synthesizes DCAN's molecular pathology, and genetic advances, highlighting innovative CRISPR and gene therapy strategies poised to revolutionize its diagnosis and treatment.