Remodeling of the Intracardiac Ganglia During the Development of Cardiovascular Autonomic Dysfunction in Type 2 Diabetes: Molecular Mechanisms and Therapeutics

Abstract

Type 2 diabetes mellitus (T2DM) is one of the most significant health issues worldwide, with associated healthcare costs estimated to surpass USD 1054 billion by 2045. The leading cause of death in T2DM patients is the development of cardiovascular disease (CVD). In the early stages of T2DM, patients develop cardiovascular autonomic dysfunction due to the withdrawal of cardiac parasympathetic activity. Diminished cardiac parasympathetic tone can lead to cardiac arrhythmia-related sudden cardiac death, which accounts for 50% of CVD-related deaths in T2DM patients. Regulation of cardiovascular parasympathetic activity is integrated by neural circuitry at multiple levels including afferent, central, and efferent components. Efferent control of cardiac parasympathetic autonomic tone is mediated through the activity of preganglionic parasympathetic neurons located in the cardiac extensions of the vagus nerve that signals to postganglionic parasympathetic neurons located in the intracardiac ganglia (ICG) on the heart. Postganglionic parasympathetic neurons exert local control on the heart, independent of higher brain centers, through the release of neurotransmitters, such as acetylcholine. Structural and functional alterations in cardiac parasympathetic postganglionic neurons contribute to the withdrawal of cardiac parasympathetic tone, resulting in arrhythmogenesis and sudden cardiac death. This review provides an overview of the remodeling of parasympathetic postganglionic neurons in the ICG, and potential mechanisms contributing to the withdrawal of cardiac parasympathetic tone, ventricular arrhythmogenesis, and sudden cardiac death in T2DM. Improving cardiac parasympathetic tone could be a therapeutic avenue to reduce malignant ventricular arrhythmia and sudden cardiac death, increasing both the lifespan and improving quality of life of T2DM patients.

Keywords: autonomic dysfunction; intracardiac ganglia; sudden cardiac death; type 2 diabetes mellitus; ventricular arrhythmia.

Figure 1

A schematic diagram of the anatomy and physiology of cardiac parasympathetic innervation of the heart. GPA: ganglionic parasympathetic axon, GPN: ganglionic parasympathetic neuron, ACh: acetylcholine, MCR: muscarinic cholinergic receptor, nAChR: nicotinic acetylcholine receptor. Figure was created in BioRender.com.

Figure 2

Cellular and Molecular Mechanisms Driving Cardiac Vagal Postganglionic Parasympathetic Neuronal Dysfunction in T2DM. AGE: Advanced glycation end product, ROS: reactive oxygen species, CVP: cardiac vagal postganglionic. Figure was created in BioRender.com.