Human‐derived cardiac‐neural microtissues reveal catecholaminergic polymorphic ventricular tachycardia is also a disease of the sympathetic neuron

Abstract Sudden cardiac death in young individuals with structurally normal hearts represents a critical unresolved clinical challenge and typically occurs in patients with inherited arrhythmia syndromes due to cardiac channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) can cause fatal arrhythmias triggered by adrenergic stimulation. Therapeutic interventions primarily target cardiac myocytes (CMs) despite robust clinical evidence demonstrating the life‐saving efficacy of cardiac sympathetic denervation. To understand this therapeutic paradox, we developed human induced pluripotent stem cell (hiPSC)‐derived CMs and sympathetic neurons (SNs) from healthy individuals and CPVT patients to investigate neurocardiac interactions using two‐ and three‐dimensional microtissue models. We tested the hypothesis that CPVT is also a disease of the autonomic nervous system and observed that CPVT hiPSC‐derived SNs had enhanced calcium transients, elevated cyclic adenosine monophosphate levels, and hyperexcitability, similar to diseased cardiomyocytes. Critically, co‐culturing diseased neurons with healthy CMs induced arrhythmogenic activity, establishing that neuronal dysfunction directly triggers cardiac arrhythmias. Multielectrode array recordings, optical mapping and single‐cell RNA sequencing revealed dysregulated neurotransmitter pathways and identified druggable molecular targets within SNs. These findings may explain why surgically interrupting sympathetic nerves helps CPVT patients and identify the nervous system as a therapeutic target. They further suggest that CPVT is more than a disease of the CM and should be re‐defined as a neuro‐cardiac disorder that paves the way for neuromodulation therapy. image Key points Sympathetic nerve overactivity is pro‐arrhythmic and a key contributor to ventricular tachycardia and sudden cardiac death in patients with cardiac channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) sympathetic neurons (SNs) exhibit enhanced calcium transients, elevated cAMP levels, and hyperexcitability that directly trigger arrhythmias in healthy cardiomyocytes. Novel human induced pluripotent stem cell‐derived cardiac‐neural microtissue models reveal CPVT is also a neurological disorder involving dysfunctional neurocardiac interactions. Single‐cell RNA sequencing identifies dysregulated neurotransmitter pathways in SNs, providing new therapeutic targets for neuromodulation therapy.