Cardiac Neurobiology of Arrhythmia in Human Cell Models: Novel Therapeutic Targets

ABSTRACT

Heightened sympathetic drive (dysautonomia) is a hallmark of several cardiovascular diseases including SARS-CoV-2. It is also a powerful prognostic predictor for arrhythmia and sudden cardiac death, especially in patients with channelopathies (long QT syndrome-LQTS, and catecholaminergic polymorphic ventricular tachycardia-CPVT). However, little is known about the molecular targets underlying this dysautonomia. We have identified a novel pathway using a combination of single cell and bulk RNAseq, neurochemistry, FRET imaging and single cell electrophysiology. This pathway involves impairment of cyclic nucleotide coupled phosphodiesterases (PDE) linked to enhanced intracellular calcium transients and exocytosis from rat sympathetic neurons. In particular, the adaptor protein Nos1-ap, Pde2A, and Ace2 are associated with sympathetic hyperexcitability. These proteins are also conserved in human stellates from patients with LQTS and CPVT, although their role in neuronal-myocyte cellular function is unknown. We have developed a unique human iPSC sympathetic-cardiac co-culture model for target discovery in LQTS and CPVT. The lecture will highlight the use of gene manipulation of these proteins to determine their role in driving abnormal transmission and arrhythmia.