Elucidating the Role of Biomechanical Strain in Atrial Physiology and Arrhythmias

Yale University, New Haven CT

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT MOTIVATION: The burden of atrial fibrillation (AF) and its clinical consequences, which include stroke, heart failure, and decreased quality of life, are expected to increase dramatically over the next several decades. Despite this, few disease-modifying therapies exist, and symptomatic treatments are limited by side effects. Leveraging fundamental discoveries in cardiac tissue biomechanics, this proposal takes a novel approach to arrhythmia pathogenesis, uncovering biophysical mechanisms that underlie healthy atrial function and pathological, pro-arrhythmic remodeling. Motivated by a desire to accurately model atrial physiology and pathology, we use human induced pluripotent stem cell (hiPSC)-derived engineered heart tissue (EHT) and an electro-mechanical bioreactor to delineate “healthy” vs “diseased” mechanical loading. AIMS: In Aim 1, physiologically-inspired biomechanical strain is applied to atrial EHTs to improve their functional maturity at the gene expression, contractile, and electrophysiological level. Successful completion of this aim will broadly increase the applicability of engineered heart tissue for atrial disease modeling. In Aim 2, a substrate for atrial arrhythmias will be induced by imposing pathological mechanical strain on atrial EHTs. These abnormal mechanical strains are directly inspired by clinical imaging findings. Notably, abnormal mechanical loading of tissue causes contractile dysfunction, along with upregulation of pathological remodeling genes, such as αSMA and calmodulin kinase. This suggests that a common, mechanosensitive pathway may be an attractive upstream target for novel AF therapies. TRAINING: To enable these investigations, the applicant will pursue new learning in stem cell biology, engineered heart tissue development, in vitro electrophysiology, and electron microscopy. The training plan, overseen by two co-sponsors in complementary fields (biomedical engineering/muscle physiology and electrophysiology), will emphasize acquisition of new scientific knowledge and expertise; rigor, reproducibility, and generalizability of in vitro disease models; clinical correlations; and professional development. The proposal will leverage cutting-edge technology and expertise at Yale University and Yale School of Medicine, and fully support the applicant’s future career goal. RELEVANCE: AF affects millions of Americans, and 10% of those over 80. The public/health/relevance of this project lies in addressing the morbidity and mortality of this condition through novel mechanisms. Motivated by a lack of disease-modifying therapies, the proposal highlights the importance of biological pathways regulated by tissue-level biomechanical cues which may provide avenues for developing more effective therapeutics.