Human Cardiac Microtissues to Study Sex-Dependent Genetic Determinants of Heart Failure
Abstract
Congestive heart failure (CHF) is a condition in which the heart is incapable of efficiently pumping enough blood and nutrients to satisfy the demands of other organ systems. This leads to impaired function of nearly every organ system in the human body, and for patients this translates to difficulty breathing, fatigue, and eventually death unless new therapies are developed. The cost to the US healthcare system to treat CHF is currently a staggering $37 billion annually, and annual increases in this cost are predicted to accelerate. Compared to a prevalence of 2% of civilians, CHF affects 2.6% of US military. By 2030, it s estimated that 1 in 28 military Veterans will have CHF, many of whom will be women. Among CHF patients, women have an increased risk for, and a higher mortality rate from, a prevalent form of heart failure classified as heart failure with preserved ejection fraction, or HFpEF. HFpEF is associated with distinct pathological changes that include thickening of the walls, decreased chamber size, and impaired relaxation of the heart. Why women have higher rates of this form of CHF remains unclear. There is strong evidence that genetic factors and not hormones are critical for the increased risk of HFpEF for women, since the vast majority of HFpEF women are post-menopausal, when hormonal changes become similar to men. Moreover, the American Heart Association does not support hormone replacement therapy for preventing cardiovascular diseases like HFpEF because of increased morbidity and mortality. Therefore, there is a significant need to determine the non-hormonal basis of sex-based differences in HFpEF to develop new mechanistic insights and therapeutic targets for women with HFpEF. In this Discovery Award project, the 2016 Peer Reviewed Medical Research Program topic area of Women s Heart Disease will be addressed by creating the first human in vitro cardiac tissue model of HFpEF to identify sex-specific mechanisms that increase risk for women. How female and male cardiac tissues respond differently to factors that induce HFpEF in patients will be investigated, such as by increased mechanical load and two chemical inducers of thickening of the heart. The hypothesis being tested is that genetic factors, especially the number of X chromosomes, play a direct, critical role in sex-based differences in cardiac function, which is supported by expression data from male and female human cardiac cells. Finally, how changes in gene dosage of FHL1, which is an X chromosome gene that is increased in females and regulates cardiac structure and function in mouse models, impacts human cardiac HFpEF models, will be tested. It is anticipated that insights from this sex-specific human cardiac tissue model of HFpEF will lead to discovery of new therapeutic targets for heart failure especially relevant to women.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710163
Entities
People
- John M Hinson
Organizations
- United States Army
- University of Connecticut Health Center