Abstract

Sudden cardiac death in the young is devastating. Advances in genetics have associated mutations in the contractile sarcomere apparatus of cardiomyocytes with hypertrophic cardiomyopathy, the most frequent cause of sudden cardiac death in the young. Currently, it is challenging to predict genotype-phenotype relationships in hypertrophic cardiomyopathy due to its incomplete disease penetrance. For example, different patients from the same family with identical genomic variants develop different symptoms. Non-genetic, environmental factors such as blood pressure are critical in heart function and disease. Therefore, understanding how mechanical factors contribute to phenotypes in diseases like hypertrophic cardiomyopathy is critical for developing effective therapeutics. Promising approaches in tissue engineering and stem cell biology have significantly improved the structural and functional maturity of the engineered heart tissue derived from human induced pluripotent stem cells, which can be served as a complementary method to traditional mouse models. However, limited studies have been performed to investigate the mechanical effects on engineered heart tissue physiology. Here, a mechanical induced in vitro micro-heart muscle model has been developed to investigate how mechanical resistance in combination with genetic mutations trigger hypertrophic cardiomyopathy structural and functional pathophysiology. In this work, it was found that mechanical loading induced by material stiffness trigger early structure defects in micro-heart muscle derived from human induced pluripotent stem cells with a hypertrophic cardiomyopathy mutation. This led to micro-scale sarcomere structural defects, contractile dysfunction, causing impaired energetics and cellular hypertrophy. There was also profound dysregulation of calcium handling; studies with drug probes revealed that this was caused by excessive calcium intake rather than either sarcoplasmic reticulum calcium ATPase dysfunction or defective buffering of calcium by cardiac myofilaments. These studies illustrate the importance of physiologically relevant engineered tissue models to study inherited disease mechanisms with induced pluripotent stem cell technology.

Committee Chair

Nathaniel Huebsch

Committee Members

Guy Genin, Jonathan Silva, Jessica Wagenseil, Jianjun Guan,

Degree

Doctor of Philosophy (PhD)

Author's Department

Mechanical Engineering & Materials Science

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

Summer 8-15-2022

Language

English (en)

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