Activation Of Camkii Signaling Pathway Contributes To The Pathogenesis Of Genetic Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent form of genetic cardiomyopathy associated with ventricular arrhythmia and sudden cardiac death. To date, several pathogenic variants of sarcomeric protein genes have been identified in genetic HCM. However, the mechanisms by which specific mutations cause the hallmark phenotypes of HCM remain largely unresolved. There is a major unmet need for a better understanding of disease mechanisms in order to predict individuals at risk for sudden cardiac death and design mechanism-based therapeutics. Methods: We modeled HCM in vitro using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from HCM patients with a history of ventricular arrhythmias and sudden cardiac death harboring a heterozygous mutation in the Tropomyosin 1 gene (TPM1, c.107 A>G). We studied the functional and molecular consequences of the TPM1 mutation in iPSC-CMs to determine the molecular mechanism of HCM pathogenesis. Results: In mutant cardiomyocytes we observed impaired mechanical relaxation, aberrant intracellular calcium cycling and increased incidence of delayed after-depolarizations when compared to isogenic controls, recapitulating the HCM phenotype in vitro . Genome wide transcriptional profiling revealed a significant enrichment of genes associated with calcium dysregulation and the activation of the Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) pathway in mutant cardiomyocytes. Conversely, pharmacological inhibition of CaMKII pathway rescued the arrhythmic phenotype of mutant cardiomyocytes in vitro . Conclusions: Taken together, our data suggest a mechanistic link between the activation of CaMKII signaling pathway and the pathogenesis of sarcomeric HCM. These results provide a better understanding of the arrhythmogenic signaling pathway associated with the HCM phenotype and could potentially lead to mechanism-based targeted therapeutics for genetic HCM patients.