Anthony J. Evans

Malignant ventricular arrhythmias (VAs), such as ventricular tachycardia and ventricular fibrillation, are the cause of approximately half a million deaths per year in the United States, which is a common lethal event in heart disease, such as hypertension, catecholaminergic polymorphic ventricular tachycardia, takotsubo cardiomyopathy, long-QT syndrome, and progressing into advanced heart failure. A common characteristic of these heart diseases, and the subsequent development of VAs, is the overactivation of the sympathetic nervous system. Current treatments for VAs in these heart diseases, such as β-adrenergic receptor blockers and cardiac sympathetic ablation, aim at inhibiting cardiac sympathetic overactivation. However, these treatments do not translate into becoming efficacious as long-term suppressors of ventricular tachycardia/ventricular fibrillation events. As a key regulatory component in the heart, cardiac postganglionic sympathetic neurons residing in the stellate ganglia (SGs) release neurotransmitters (such as norepinephrine and NPY [neuropeptide Y]) to perform their regulatory role in dictating cardiac function. Growing evidence from animal experiments and clinical studies has demonstrated that the remodeling of the SG may be intimately involved in malignant arrhythmogenesis. This identifies the SG as a key potential therapeutic target for the treatment of malignant VAs in heart disease. Therefore, this review summarizes the role of SG in ventricular arrhythmogenesis and updates the novel targeting of SG for clinical treatment of VAs in heart disease.

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.