MECHANISMS AND PROCESSES UNDERLYING THE REVERSIBILITY OF HYPOCONTRACTILITY-INDUCED DILATED CARDIOMYOPATHY

Abstract

Dilated cardiomyopathy (DCM) is a progressive heart disease driven by inherited mutations that impair cardiomyocyte contractility, ultimately leading to systolic dysfunction, dilation, and fibrosis. Current therapies, such as angiotensin inhibitors, β-blockers, and left ventricular assist devices (LVADs), are largely palliative and do not address the primary defect in myocyte force generation. Myosin activators have emerged as a promising new class of small molecules that can directly augment contractility at the myofilament level; however, despite encouraging preclinical data, clinical trials have yielded only modest functional improvements for patients. This gap highlights a longstanding assumption in the field that correcting the cardiomyocyte defect alone should be sufficient to reverse disease. Given that DCM often progresses over years to decades before diagnosis, it remains unclear whether targeted myocyte therapies can reverse established remodeling. This dissertation interrogates this assumption by defining how cardiomyocyte hypocontractility shapes fibroblasts behavior, ECM mechanics, and ultimately, the capacity of the heart to recover. Using transgenic mouse models and engineered heart tissues, we first demonstrate that fibroblasts act as early mechanosensitive rheostats that detect impaired myocyte tension and initiate changes in the ECM. Hypocontractile cardiomyocytes triggered the emergence of a hyperproliferative fibroblast state and increased myocardial stiffness well before the emergence of overt fibrosis. Importantly, conditional deletion of p38 in fibroblasts prevented fibroblast proliferation, ECM remodeling, and myocyte eccentric hypertrophy, demonstrating that interrupting fibroblast signaling halts DCM progression even when the myocyte defect persists. Next, we examined whether restoring myocyte contractility after disease onset is sufficient for recovery. While genetic suppression of the sarcomeric mutation fully restored cardiomyocyte structure, function, and chromatin accessibility, it did not reverse ECM stiffness or reduce fibroblast number. Persistent fibrosis and fibroblast survival limited whole-organ functional recovery. Full phenotypic reversal was achieved when myocyte correction was paired with an inhibitor of ECM crosslinking, revealing that non-myocyte adaptations impose a durable barrier to reverse remodeling. Finally, developmental studies demonstrated that transient myocyte correction during the postnatal period delayed DCM onset and attenuated remodeling, underscoring the importance of injury timing in determining recovery potential. Together, this body of work demonstrates that: 1) fibroblasts and fibrosis are central drivers of DCM progression, 2) adaptations within these compartments are far less amenable to reversal than cardiomyocyte dysfunction, and 3) early-life myocyte hypocontractility shapes the long-term severity of DCM, suggesting that pathological fibroblast and ECM states may be installed during the postnatal window. More broadly, this work can be used to help design new combinational therapeutic strategies and contextualize the performance of emerging myosin activators as they begin clinical trials for efficacy.