Myocardial tissue architecture in heart failure: implications on physiology and fitness

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 DESCRIPTION (provided by applicant): Heart failure (HF) represents a major threat to cardiovascular health in the United States, with nearly 550,000 new cases and over $37 billion in costs annually. Existing metrics of HF severity (e.g., natriuretic peptides, echocardiography, functional class) do not reveal an understanding of cellular disruption in the form of fibrosis/hypertrophy that lead to deleterious whole-organ structural changes termed "LV remodeling." In turn, adverse LV remodeling is associated with impaired cardiac performance, poorer cardiorespiratory fitness, and deceased survival in HF, making it an important therapeutic target in HF. Tissue phenotypes (diffuse interstitial fibrosis, myocyte hypertrophy, apoptosis) have been associated with prognosis, HF progression, and reverse LV remodeling in HF. Unfortunately, these myocardial tissue phenotypes are poorly understood in vivo in patients, owing to an inability to non-invasively phenotype the heart. The aim of this application is to develop novel cardiac magnetic resonance (CMR) markers of myocardial remodeling in HF and to investigate their association with exercise hemodynamics and novel RNA physiologic biomarkers of fibrosis/hypertrophy. In his preliminary work, the PI has developed and validated CMR techniques to quantify cardiomyocyte size (by intracellular lifetime of water, τic) and interstitial fibrosis (by extracellular volume fraction, ECV) in patients and animal models of hear disease. He has also demonstrated that CMR fibrosis may be associated with novel RNA biomarkers that are mechanistically involved in fibrosis in LV remodeling. In this application, the PI will identify a tissue signature of LV remodeling in multiple human HF subtypes and its association with circulating extracellular RNAs (Aim 1). He will extend these observations to physiology, investigating the relationship between CMR tissue markers, fitness and exercise hemodynamic indices (Aim 2). Finally, he will investigate the association of CMR tissue signatures with progressive LV remodeling over time in chronic HF using serial CMR (Aim 3). To accomplish these goals, he has assembled a unique mentoring team consisting of senior CMR investigators (Michael Jerosch-Herold, PhD; Warren Manning, MD), basic scientists (Anthony Rosenzweig, MD; Saumya Das, MD, PhD), and a HF physiologist (Gregory Lewis, MD). As part of his training, the PI will enrich his expertise in human CMR imaging, RNA biology, and exercise testing as a platform for future research, and will establish important ongoing collaborations in the field of translational HF research. The PI will obtain further statistical training in clinical research via the Harvard School of Public Health (MPH degree), and will be integral to the HF research mission of his home institution, the Beth Israel Deaconess Medical Center. The long-term goal of the PI is to establish an independent research career in translational imaging-HF research, focusing on early stages of disease for targeted therapy. This project addresses an NHLBI mission by affording an innovative, novel method for assessing HF severity that might improve early identification of advanced HF, for which there remain limited options.