Interrogating Diastolic Dysfunction Using a Novel Stem Cell Model of Restrictive Cardiomyopathy

Background: Diastolic dysfunction is an important cause of morbidity and mortality in both children and adults. Unfortunately, investigation of new therapies is limited by a lack of in vitro models of diastolic dysfunction. Idiopathic Restrictive Cardiomyopathy (RCM) is a serious genetic condition in which children have an isolated defect in myocardial relaxation. Though some of the genetic lesions have been identified, there is still an incomplete understanding of the mechanisms that lead to diastolic dysfunction in this condition. I hypothesize that cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from patients with RCM will provide an in vitro model of diastolic dysfunction and will allow elucidation of cellular and molecular pathways involved in myocardial relaxation.

Methods: Patients with RCM and a known pathogenic sarcomeric mutation were identified through speaking with providers in our heart failure and cardiac transplant program. hiPSCs were derived from patient blood samples and differentiated into cardiomyocytes. Isogenic controls were generated using CRISPR-mediated homologous directed repair. Calcium handling, contraction kinetics, and resting tension of RCM hiPSC-CMs were compared to control hiPSC-CMs on substrates with defined stiffness using high-throughput quantitative imaging techniques.

Results: Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from patients with RCM will provide an in vitro model of diastolic dysfunction and will allow elucidation of cellular and molecular pathways involved in myocardial relaxation.

Conclusion: RCM hiPSC-CMs represent a novel model of diastolic dysfunction that can be interrogated on a high-throughput platform. We plan to use these cells to perform proteome-scale functional screens, providing a novel opportunity to discover previously unknown contributors to diastolic dysfunction.