RyR2-Mediated Ca2+ Leak Drives Progressive Arrhythmogenic Cardiomyopathy

In RyR2-V2475F rabbits, chronic RyR2 gain-of-function produces spontaneous ventricular tachyarrhythmias, sudden cardiac death, and progressive RV-dominant fibrofatty cardiomyopathy resembling human ACM.

• Why it matters: It is unknown whether persistent RyR2 Ca2+ leak can connect electrical instability to the structural remodeling that defines arrhythmogenic cardiomyopathy.
• What they did: Rabbits carrying the severe gain-of-function RyR2-V2475F mutation were followed with longitudinal cardiac phenotyping, continuous ECG monitoring, cellular electrophysiology and Ca2+ imaging, histopathology, biochemical assays, and snRNA-seq; ent-verticilide was given continuously for two months.
• The result: Malignant ventricular arrhythmias preceded overt remodeling and were linked to early spontaneous Ca2+ release and early afterdepolarizations; selective RyR2 inhibition reduced ventricular tachycardia burden and preserved RV contraction and LV filling during progression.

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