R35HL166565

Intersection of Obesity and Heart Failure with Preserved Ejection Fraction - This project will elucidate the biological mechanisms by which obesity alters the myocardium in patients with heart failure and a preserved ejection fraction (HFPEF) to ultimately derive sorely needed precision-guided therapies.

HFPEF currently represents more than half of all heart failure worldwide. Its prevalence is rising, morbidity and mortality are substantial, and yet we still have very few effective therapies. It is a major unmet medical need and a disease priority for the NIH.

One of the factors that has made it difficult to treat is a major transformation over the past two decades. Most patients are now obese, many severely, with diabetes and metabolic syndrome also very common. This obesity-metabolic syndrome (OMS-HFPEF) phenotype has altered disease manifestations and progression and worsened prognosis. Yet our knowledge of the underlying myocardial pathobiology effects from obesity are limited.

Johns Hopkins has established a dedicated clinical HFPEF center that obtains detailed phenotyping of HFPEF patients, the majority being OMS-HFPEF, African American, and female. The phenotyping includes obtaining myocardial biopsies that have already provided novel insights into cellular and molecular features.

Our recent studies revealed less fibrosis than predicted, and that fat metabolism and glucose metabolism seem both to be depressed in OMS-HFPEF, pairing abnormalities found in HF with reduced EF and obesity/diabetes respectively, in essence a worst of both worlds that limits fuel flexibility. Yet unlike HFREF, oxidative phosphorylation seems enhanced particularly in obese patients. We also find a strong inverse correlation between obesity and calcium-stimulated myofilament function – being very depressed in OMS-HFPEF ± diabetes, hypertension, or LV hypertrophy. Obesity is thus a major driver for fundamental changes in HFPEF.

This R35 program dissects metabolic and sarcomeric dysregulation in OMS-HFPEF, starting with analysis of human myocardial tissues, and testing abnormalities in animal models that have both marked OMS and cardiac hemodynamic stress. Models are benchmarked to pair with human molecular/cellular pathobiology, rather than only organ level physiology as historically done.

Our metabolic studies will determine the fuel substrates used by OMS-HFPEF heart, where bottlenecks in fuel metabolism occur, how these may be circumvented, and what the impact is. We will also investigate which metabolites are formed that can impact epigenetics (histone modifications) to alter gene programs controlling metabolism and other key cellular functions. Major interest is on Krebs cycle intermediates such as citrate, succinate, and fumarate, and polyamines, that can impact histone methylation and acetylation.

Our myocyte studies will determine how obesity depresses sarcomere function, find the protein(s) and structural changes involved, their causes, and prove causality.

Lastly, we will test therapies to improve metabolic flexibility and sarcomere performance in OMS-HFPEF that can lead to precision-guided medicines for this common phenotype.

The Johns Hopkins University

THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS; FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS; AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Baltimore, Maryland 212051832 United States

Single Zip Code

NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional) (RFA-HL-23-004)

Amendment Since initial award the End Date has been shortened from 12/31/30 to 12/31/29 and the total obligations have increased 526% from $648,077 to $4,059,151.