Listen to your heart and its sympathetic nerves in CPVT

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterised by bidirectional ventricular tachycardia triggered by adrenergic stress, leading to potentially fatal ventricular arrhythmias. The heart appears structurally normal, and the baseline ECG typically shows no distinctive features, although bradycardia may sometimes be observed. Patients often experience syncope induced by exercise or emotional stress; in some cases, the first sign may be sudden cardiac death. The primary treatment for CPVT is β-blockade therapy, which has demonstrated efficacy. In cases where β-blockade is ineffective or intolerable, flecainide or left cardiac sympathetic denervation is considered as adjunctive treatment. Additionally, an implantable cardioverter-defibrillator is also used in some cases for the prevention of sudden death (Priori et al., 2021). In this edition of The Journal of Physiology, Li and colleagues challenge the notion that CPVT is a disorder exclusively of cardiomyocytes and suggest it also involves sympathetic neurons and, critically, their interactions. Consequently, it was suggested that CPVT should be redefined as a neurocardiac disorder (Li et al., 2026). The authors utilise human-induced pluripotent stem cell models to generate ventricular cardiomyocytes and sympathetic neurons from control and CPVT patients. The investigation made use of three RYR2 variants, two of which were derived from CPVT patients (S2246L and F2483I), while the third, R4497C, was introduced into a control induced pluripotent stem cell (iPSC) line. Additionally, an isogenic control for S2246L was created via CRISPR editing to correct the mutation. They employ 2D culture to evaluate the electrical phenotypes of neurons and cardiomyocytes, and co-culture to examine the synaptic influences on the electrical phenotypes of cardiomyocytes. Impressively, 3D droplet-printed microtissues were established and studied with optical mapping to capture network dynamics and calcium waveforms. Cardiomyocytes and neurons derived from CPVT patients both exhibit dysregulated calcium signalling, leading to a proarrhythmic phenotype. The surprising finding is that CPVT neurons can also induce a proarrhythmic phenotype when co-cultured with non-disease cardiomyocytes. Although this scenario does not occur naturally, it demonstrates why left cardiac sympathetic denervation is effective in CPVT cases and indicates that gene therapy for CPVT, which is under development (Priori et al., 2021), should consider neuronal input to CPVT, as repairing the heart alone may not be sufficient, and targeting presynaptic mechanisms may be required to minimise breakthrough events while on β-blockade therapy. CPVT1 and CPVT2 are caused by autosomal dominant pathogenic variants in RYR2 and CASQ2, respectively. Furthermore, less common forms of CPVT are associated with variants in additional calcium-handling genes, including CALM1-3, TRDN and TECRL. The majority of CPVT cases are attributable to pathogenic variants in RYR2. Because CPVT is an inherited arrhythmia syndrome, genetic testing is recommended as part of patient management. The coding sequence of RYR2 (NM_001035.3) contains 14,901 nucleotides that encode a 4967-amino-acid protein known as the ryanodine receptor (RyR2). Given its size, many RYR2 variants are to be expected. Identifying these RYR2 variants in clinical genetic testing is straightforward, but determining the pathogenicity of these RYR2 missense variants is challenging. This is evidenced by the fact that 3817 out of 4491 missense RYR2 variants are classified as Variant of Uncertain Significance (VUS) in ClinVar, a database that aggregates human genetic variants and their interpretations related to human diseases. These VUSs have been a clinical challenge since genetic sequencing has become more affordable and has improved in accuracy. A proportion of these variants may be benign; however, only for those RYR2 VUSs with functional validation are more likely to be reclassified as likely pathogenic. This principle has been demonstrated in the context of cardiac channelopathies, such as long QT syndrome (O'Neill et al., 2024) or Brugada syndrome (O'Neill et al., 2025), where not all variants identified in these patients are necessarily causal. This study offers a practical functional platform relevant to the pathophysiology of CPVT, which can be utilised to demonstrate the pathogenicity of RYR2 variants detected in CPVT patients. Nevertheless, notable limitations include financial and temporal constraints, which pose significant hurdles for translation into the clinic. Clinically, β-blockers are considered the first-line therapy in CPVT; however, dose escalation may be limited by intolerance. Alternative pharmacological agents have been investigated for the treatment of CPVT (Priori et al., 2021), but as highlighted by Li and colleagues, CPVT is also a disease of the sympathetic neuron; therefore, adjunctive pharmacotherapy targeting presynaptic mechanisms may help minimise breakthrough events while patients are on β-blockade therapy. Targeting the M-current, as identified by Li and colleagues, represents a promising avenue for developing a new pharmacological agent focused on presynaptic mechanisms. For example, BHV-7000, a Kv7.2/7.3 activator currently in Phase 2/3 clinical trials for refractory focal epilepsy, could be repurposed to assess its efficacy in CPVT patients (https://clinicaltrials.gov/study/NCT06132893, 2023). It was reported to be well-tolerated in healthy volunteers, but its full side-effect profile is not yet definitive and will depend on Phase 2/3 outcomes. The human iPSC-based neurocardiac platform developed by Li and colleagues is well-suited as a preclinical model for testing pharmacological agents in a disease-relevant context, especially as CPVT is being redefined as a neurocardiac disorder. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. Sole author. C.A.N. is supported by a Medical Research Future Fund: Genomics Health Futures Mission grant (MRF2016760).