Abstract Body: Background: Hypertrophic cardiomyopathy (HCM) stands as the most common inherited cardiomyopathy. This condition is marked by a significant risk of sudden cardiac death (SCD) among younger individuals, with ventricular arrhythmias being the primary factor behind SCD.

Hypothesis: Inflammation is still a debate in HCM hearts, remaining the challenge to confirm the role of low-grade inflammation in ventricular arrhythmias in this disease.

Objective: We sought to examine the mechanism of ventricular arrhythmias in an HCM mouse model.

Methods: A preclinical model of HCM (cTnI^Gly146, heterozygous) was characterized, while FVB/N mice served as controls. Five-month-old mice were evaluated by echocardiogram, in vivo electrophysiological studies, ex vivo whole-heart high-resolution optical mapping, fluorescent staining, and histology. Hearts from both groups were used for bulk RNAseq and western blot. A different cohort of HCM mice was treated daily for three weeks with an inflammasome inhibitor (MCC950, 10 mg/kg) or vehicle, and thoroughly phenotyped at the endpoint.

Results: HCM mice presented increased interventricular septum, ejection fraction, and diastolic dysfunction compared to controls. Pulmonary congestion was observed, as evidenced by the augmented lung weight and pulmonary index. Surface ECG studies revealed electrical remodeling, with prolonged QRS complex duration and QTc interval in HCM mice compared to controls. Moreover, HCM mice presented higher inducibility to ventricular tachycardia (5/8) than controls (0/6). Optical mapping studies revealed slower conduction velocity in HCM mice compared to controls, and increased ventricular fibrosis was seen by histology. Bulk RNAseq exposed an elevated activation of the NLRP3 inflammasome pathway. The NLRP3 inflammasome activator, Txnip, was upregulated in HCM’s samples. Besides, the thioredoxin activity was reduced, the mitoROS production increased, and a higher expression of mature IL-1β in the left ventricle of HCM mice. NLRP3 inflammasome inhibition treatment decreased cardiac hypercontractility, diastolic dysfunction, and cardiac fibrosis. Furthermore, inflammasome inhibition prevented the occurrence of ventricular tachycardia.

Conclusion: NLRP3 inflammasome is activated in HCM in a mitoROS-Txnip-dependent way, driving low-grade inflammation. Treatment with a NLRP3 inflammasome inhibitor reversed the disease traits and prevented ventricular arrhythmias.