Associate Professor University of Oxford, United Kingdom
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that can lead to life-threatening arrhythmias and sudden cardiac death, particularly in young individuals. Stress-induced activation of the sympathetic nervous system is viewed as the primary driver, yet the molecular mechanisms governing neuronal-cardiac signalling in CPVT remain incompletely understood. Existing studies often rely on animal models that don’t fully recapitulate the human phenotype. To address this, we developed hiPSC-derived cardiomyocytes (CMs) and sympathetic neurons (SNs) from patients with CPVT and their isogenic controls in both 2D co-cultures and 3D microtissue platforms. The 3D models, fabricated with an innovative droplet-printing technique, mimic the complex tissue architecture and electrophysiological properties of human neuronal-cardiac interactions. Our 2D co-culture studies revealed that CPVT hiPSC-CMs and SNs exhibit abnormal calcium signalling, increased cAMP levels, heightened excitability, and enhanced norepinephrine release from CPVT hiPSC-SNs, leading to disrupted electrophysiological activity. Using 3D microtissues, we further contextualized neuronal-cardiac interactions in a physiologically relevant setting, demonstrating that CPVT SNs exacerbate arrhythmogenic phenotypes in healthy CMs. Single-cell RNA sequencing identified critical transcriptomic changes, suggesting novel therapeutic targets for regulating neuronal-cardiac signalling. Advancements in 3D extracellular matrix design enhanced tissue integration and functionality. These findings provide new insights into the pathophysiology of CPVT and highlight the potential of targeting sympathetic excitability as a therapeutic strategy to personalized treatments.
Funding Source: British Heart Foundation SP/F/22/150027
