Metabolic stress exacerbates Ca²⁺ dysregulation and arrhythmias in catecholaminergic polymorphic ventricular...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the sarcoplasmic reticulum (SR) calcium (Ca²⁺) release channel RyR2 or its accessory proteins, including calsequestrin-2 (CASQ2). RyR2 dysfunction or leak is the hallmark feature of CPVT and directly triggers arrhythmias. Despite this electrical instability, CPVT hearts are typically anatomically normal and lack pathological remodelling. Therefore, we hypothesized that introducing additional stressors, such as metabolic stress, would worsen cardiac arrhythmias and potentially trigger pathological remodelling. To test this hypothesis, metabolic stress was introduced by crossbreeding a CPVT model of CASQ2^-/- mice with the Akita mouse, a genetic model of diabetes that also lacks cardiac remodelling. We found that dysregulation of myocyte Ca²⁺ handling was exacerbated in Akita-CASQ2^-/- cells, which exhibited slower Ca²⁺ transient decay kinetics and increased arrhythmogenic Ca²⁺ waves. Akita-CASQ2^-/- mice also displayed more severe arrhythmias, diastolic dysfunction, and cardiac hypertrophy, but without evidence of fibrosis, cell death, or worsened metabolic dysfunction. Finally, mitochondrial reactive oxygen species production was increased in Akita-CASQ2^-/- cardiomyocytes, which may contribute to the more severe pathological phenotype. Overall, our results suggest that metabolic stress can aggravate dysregulated myocyte Ca²⁺ handling and promote cardiac dysfunction in CPVT hearts.