HFpEF Susceptibility in Women: The Role of Inflammation

PROJECT SUMMARY/ABSTRACT Heart failure (HF) is an important public health concern, affecting over 6 million individuals in the United States alone. HF with preserved ejection fraction (HFpEF) is now the leading form of HF and the prevalence continues to rise. HFpEF remains a therapeutic challenge, given our limited understanding of causal and

contributing factors, clinical heterogeneity within HFpEF subphenotypes, and lack of available therapies. HFpEF is far more prevalent in women than men, driven in part by sex differences in cardiac structure and remodeling, adaptations to physiologic stress, and comorbidity burden. Emerging data support the role of

systemic inflammation in the pathogenesis of HFpEF and sex differences in immune response have led many to hypothesize that inflammation is an important driver of the female susceptibility to HFpEF. A better understanding of these sex differences may offer critical insights into disease pathogenesis, particularly in light

of recent evidence highlighting potential therapeutic benefit of sacubitril/valsartan preferentially in women with HFpEF. To date, investigations of inflammation in HFpEF have been limited to downstream markers of inflammation. Eicosanoids are small bioactive lipids that regulate the upstream initiation of systemic

inflammation in humans. Advanced methods using mass spectrometry now allow for the rapid and accurate quantification of >150 upstream eicosanoid mediators. We will leverage this state-of-the-art technology to provide a more detailed understanding of how biologic sex differences in upstream eicosanoid pathways

contribute to HFpEF risk and disease progression. In Aim 1, we will examine sex differences in the association of circulating eicosanoids with clinical antecedents of HFpEF as well as incident HFpEF in the community. In Aim 2, we will evaluate the association of eicosanoid analytes with cardiac and extra-cardiac responses to

exercise in men and women with clinical HFpEF. In Aim 3, we will conduct a prospective observational study to investigate the changes in inflammatory profiles and endothelial cell inflammation as ascertained by eicosanoid metabolites and endothelial cell gene expression profiling through the menopausal transition in women and

age-matched men at risk for developing HFpEF. The overarching goal of this proposal is to evaluate the hypothesis that sex differences in systemic inflammation may account for observed differences in HFpEF risk and disease manifestations in men and women. This research will be accomplished in the setting of a

comprehensive career development program designed to provide Dr. Lau, an early career investigator, with the skills needed to become an independent physician-scientist in women’s cardiovascular (CV) health. Her long- term career goal is to identify biologic sex differences that contribute to CV risk and disease in order to refine

prevention and therapeutic strategies for women with CV disease. This proposal brings together a unique interdisciplinary advisory team of experts in the fields of metabolomics, gene expression profiling, women’s health, and advanced biostatistics that will guide the candidate in her transition to scientific independence.