The Margulies Lab examines mechanisms of myocardial remodeling to identify targets for therapeutic interventions. Many of our inquiries are initiated by multilevel examinations of explanted human heart tissues obtained at the time of transplantation or organ donation to permit insights into both the heterogeneity of myocardial adaptations to disease and identification of dominant mechanisms and responses. The Margulies lab has a longstanding focus on load-dependent myocardial remodeling with current studies focusing on mechanisms of load-dependent maturation, mechanical memory and pathological myocardial hypertrophy. In addition, the lab is actively engaged in studies examining regulation of contractility by microtubules and other cytoskeletal elements, cardiotoxicity associated with VEGF-anti-angiogenic tyrosine kinase inhibitors, disease-associated shifts in cardiac metabolism, mechanisms of inherited cardiomyopathies, advanced myocardial phenotyping using digital pathology and machine learning techniques, and integrated genomic inquiries designed to identify molecular mechanisms of myocardial pathology. Increasingly, complementary use of primary human cardiac myocytes, iPSC-derived cardiac myocytes and engineered cardiac microtissues are employed as versatile tools to balance human relevance and mechanistic clarity to advance these inquiries. Our work also includes, strategic patient-based proof-of-concept studies.