Heart Failure with Preserved Ejection Fraction: Mechanisms and Novel Therapeutics
Abstract
Heart failure (HF), a set of conditions in which the heart does not pump sufficiently to meet the body s needs, affects more than 3 million Americans each year and is growing in incidence and prevalence as the average age of the population increases. HF with preserved ejection fraction (HFPEF) accounts for approximately 50% of HF worldwide and, unlike other conditions that cause HF, has no treatments or devices that alter disease symptoms or course. As a distinct clinical syndrome refractory to routine medical approaches, HFPEF represents a critical unmet medical need. Despite some similarity to other conditions that lead to HF, the basic mechanisms that underlie development of HFPEF are not understood. Cardiosphere-derived cells (CDCs), a population of stem cells derived from heart tissue, are being developed as a candidate cell type for regenerative therapy. They have shown preliminary therapeutic potential, but the mechanisms these cells use to promote healing and reduce disease symptoms are unknown. The unifying challenge of this Focused Program Award proposal is to discover the mechanisms underlying HFPEF and determine whether crucial mechanistic pathways can be effectively targeted by CDC therapy. Five labs at the Cedars-Sinai Heart Institute, Los Angeles, CA, and one at the Ralph H. Johnson Department of Veterans Affairs (VA) Medical Center, Charleston, SC, will collaborate on five complementary but synergistic projects aimed at understanding HFPEF and determining the therapeutic potential of CDCs. Three projects (1-3) will utilize the Dahl salt-sensitive rat model developed by the Principal Investigator (PI). This animal model, when fed a high-salt diet, develops hypertension and other hallmark characteristics of HFPEF, faithfully recapitulating features of human disease. In Project 1, the PI Eduardo Marbán, MD, PhD, will determine whether the beneficial effects of CDCs are mediated through bodies secreted from cells called exosomes. In Project 2, Joshua I. Goldhaber, MD, will uncover the roles of calcium in HFPEF disease processes and assess changes due to CDC treatment. In Project 3, Robin Shaw, MD, PhD and TingTing Hong, MD, PhD, will identify proteins that change in abundance due to HFPEF and CDC treatment. The fourth project, directed by Jennifer Van Eyk, PhD, will use both rat and human tissue specimens to identify biochemical markers that may help predict clinical responses to CDC treatment. The fifth project, directed by Michael R. Zile, MD, is a clinical trial of CDCs in Veterans with HFPEF. This work will determine whether CDC treatment improves clinical functional status, including exercise tolerance and heart function. The proposed collaborative work using the reproducible HFPEF model, combined with human studies, has the potential to define underlying mechanisms of action of CDC therapy and lead to the development of treatments for patients with HFPEF. The proposed work addresses Topic Areas "Cardiovascular Health" and "Women s Heart Disease," as HFPEF affects women more than men by almost 2:1. HF is the leading cause of hospitalizations nationally. Disability and frequent hospitalization are hallmarks of the disease, and associated comorbidities include hypertension, diabetes, and obesity. The 5-year mortality rate for HFPEF is approximately 60%. A cell therapy that stops damage and promotes cardiac regeneration has the potential to halt or reverse disease in millions of HFPEF patients worldwide. Military Relevance: HF is the leading cause of hospitalizations nationally, and Veterans hospitals are no exception. Indeed, HFPEF affects Veterans more frequently than civilians, and rates of hospital admission and re-admission for Veterans are higher than the general public. Female Veterans may have even greater risk for HFPEF, as they have an increased number of medical conditions and higher rates of mental illness, which may contribute to risk. Consistent with this, a signif
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610592
Entities
People
- Eduardo Marban
Organizations
- Cedars-Sinai Medical Center
- United States Army