Abstract Body (Do not enter title and authors here): Background: Hypertrophic cardiomyopathy (HCM) due to genetic variants in sarcomere genes is associated with severe diastolic dysfunction and a high risk of atrial fibrillation (AF). We previously reported that inhibiting RyR2 diastolic calcium leak improves cardiac function in ischemic cardiomyopathy and suppresses AF in PitX2+/- mice. Here, we use a specific RyR2 modulator, ent-verticilide, to test the hypothesis that RyR2 calcium leak contributes mechanistically to diastolic dysfunction and atrial myopathy in HCM.
Methods: The effect of ent-verticilide treatment on AF risk was assessed using a well-established murine HCM model (troponin T I79N mice). Mice were treated with vehicle or ent-verticilide between 12 and 24 weeks. Left atrial (LA) size and diastolic function were assessed by echocardiography. Fibrosis was assessed by qRT-PCR and histology. AF risk was determined using a published transesophageal pacing protocol in 20-week-old wild-type (wt) and TnT-I79N mice in a randomized crossover design to assess the acute effect of ent-verticilide.
Results: Compared to non-transgenic littermates, TnT-I79N mice exhibit cardinal features of non-obstructive HCM: age-dependent progressive diastolic dysfunction, LA enlargement, and increased gene expression of fibrotic markers (Fig 1). Chronic treatment with ent-verticilide (from 12 to 24 weeks of age) prevented LA enlargement, LA fibrosis, and diastolic function (Fig 1). Atrial myocytes isolated from 20-week-old I79N mice exhibit increased RyR2 diastolic calcium leak, which was suppressed by ent-verticilide (Fig. 2). Administration of ent-verticilide (10 mg/kg IP) 15 min before pacing significantly reduced the incidence of AF induction in TnT-I79N (Fig 3).
Conclusions: In a genetic mouse model of thin filament HCM, RyR2 calcium leak contributes mechanistically to diastolic dysfunction and atrial remodeling, which can be prevented by a selective RyR2 inhibitor.
Clinical implication: These results support using RyR2 modulation for improving diastolic dysfunction and reducing AF risk in HCM.