Unraveling Endothelial-CardiomyocyteCrosstalk in Cardiomyopathy: An Integrated Multimodal Approach

/Abstract Cardiomyopathy is known to affect the myocardium and is associated with either mechanical and/or electrical dysfunction that can lead to ventricular hypertrophy or dilatation. These cardiomyopathies can affect people of all ages and can be either inherited or acquired, where inherited cardiomyopathies are due to mutations that alter the genes that control cardiac function and acquired due to associated co-morbidities such as diabetes or exposure to chemotherapeutic agents. Endothelial (EC) dysfunction has been shown to play an important role in the development and progression of cardiomyopathy, however the molecular mechanisms by which it imparts cardiac (CM) dysfunction remains elusive. The long-term goal of this proposal is to study and understand the pathogenesis of cardiac dysfunction via the lens of the endothelium. The endothelium is a critical component of the cardiovascular system that forms a protective barrier for CMs and releases paracrine factors to maintain CM health and function. Despite impressive progress, little attention has been given to the potential importance of cell-to-cell signaling between ECs and CMs. This knowledge gap impedes our comprehensive understanding of organ dysfunction at a multi- cellular level. With the knowledge that dysfunctional ECs can have a negative impact on CM function, we need a better understanding of the integral role of ECs in the development of myocardial injury. By utilizing a multidisciplinary approach that integrates human iPSCs, bioengineering tools, single-cell ‘omics’, and animal models of cardiomyopathy, we intend to decipher the EC-CM crosstalk. This research program focuses on two major forms of cardiomyopathy, inherited due to mutations, or acquired following exposure to chemotherapy. The proposal aims to provide important insights and map the role of endothelial cells in the development of cardiac dysfunction and define the mechanisms by which they cause cardiomyopathy. Accordingly, the data, methods and animal models generated from this R35 initiative can be useful for all HLBS investigators interested in targeting the endothelium to improve cardiac function. Project Number: 1R35HL183578-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Nazish Sayed | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $770,000 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 RCCS-M (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R35HL18357801