(CCSP008) THE ROLE OF MICRORNAS IN HYPERTROPHIC CARDIOMYOPATHY: INSIGHTS FROM PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELL CARDIOMYOCYTES AND MYOCARDIAL TISSUE

Background: Hypertrophic cardiomyopathy (HCM) is an inherited disease characterized by thickening of the heart muscle. It is the leading cause of sudden cardiac death among young adults and athletes. Although mutations in sarcomeric proteins, such as myosin binding protein C (MYBPC3) and β-myosin heavy chain (MYH7), have been observed in HCM, the mechanisms by which cardiomyocytes (CM) undergo hypertrophy remain unclear. MicroRNAs (miRNAs) are regulators of gene expression that may influence disease progression; however, there is a paucity of data published regarding miRNA expression in HCM. Induced pluripotent stem cells (iPSCs) have been used to model many cardiovascular diseases, including HCM. However, profiles of expressed miRNAs have yet to be identified. Therefore, by determining the differential expression of miRNAs in patients with HCM, we have the potential to develop diagnostic tools and therapeutic targets to monitor patients with HCM.

METHODS AND RESULTS: We performed an unbiased screen using a microarray from NanoString Technologies that contained 798 miRNAs to identify differentially expressed miRNAs in induced pluripotent stem cell (iPSC)-CM and myocardial tissues derived from healthy donors and HCM patients with MYBPC3 and MYH7 mutations (Table 1, 2). There were no significant differences in donor characteristics between MYBPC3 and MYH7 iPSC-CM and myocardial tissue donors. There were 516 and 183 miRNAs downregulated in iPSC-CM and tissues with MYBPC3 and MYH7 mutations, respectively, while 42 and 27 miRNAs were upregulated (Figure 1). Additionally, 15 and 19 differentially expressed miRNAs in the MYBPC3 and MYH7 samples, respectively, were identified to target genes implicated in HCM. These findings are currently being validated using qPCR. Interestingly, significant discrepancies in miRNA expression patterns between cells and tissues in MYH7 samples were observed, suggesting that additional validation is necessary when modelling HCM using some iPSC lines. In contrast, MYBPC3 samples had similar expression patterns in both cells and tissues, validating the fidelity of the MYBPC3 iPSC-CM and their use for future work.

Conclusion: This work represents the first attempt to comprehensively assess miRNA expression patterns in iPSC-CMs derived from patients with HCM with additional validation from primary myocardial tissue, the current gold standard. While iPSCs have revolutionized disease modeling, not all iPSC lines are created equal, and in vitro models need further validation from tissue sources. Ultimately, investigating the role of miRNAs could provide insights into gene expression regulation in HCM and allow for miRNAs as therapeutic targets to mitigate disease progression and improve patient outcomes.