HFpEF Susceptibility in Women: The Role of Inflammation

女性 HFpEF 易感性：炎症的作用

• 批准号: 10595021
• 负责人: Emily Lau
• 金额: $ 19.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595021
• 关键词: Advisory Committees; Affect; Age; Anti-Inflammatory Agents; Biometry; Cardiac; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Career Mobility; Clinical; Communities; Complex; Data; Development; Disease; Disease Progression; EFRAC; Eicosanoids; Endothelial Cells; Endothelium; Exercise; Female; Future; Gene Expression Profiling; Goals; Heart failure; Heterogeneity; Hospitals; Human; Immune response; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Knowledge; Light; Lipids; Mass Spectrum Analysis; Mediator; Mentorship; Methods; Molecular; Morbidity - disease rate; Nested Case-Control Study; Obesity; Observational Study; Outcome; Pathogenesis; Pathway interactions; Patients; Perimenopause; Phenotype; Physicians; Physiological; Postmenopause; Predisposition; Premenopause; Prevalence; Prevention; Program Development; Public Health; Research; Research Personnel; Research Proposals; Risk; Role; Scientist; Sex Differences; Stress; Structure; Symptoms; Techniques; Technology; Therapeutic; Time; United States; Validation; Venous; Woman; Women' s Health; Work; biological sex; cardiometabolic risk; cardiovascular health; cardiovascular risk factor; career; career development; clinical heterogeneity; cohort; comorbidity; design; disease heterogeneity; effective therapy; endothelial dysfunction; exercise intolerance; hemodynamics; improved; inflammatory marker; insight; longitudinal, prospective study; men; metabolomics; mortality; novel; patient oriented research; preservation; prospective; response; sex; skills; systemic inflammatory response; transcriptomics; valsartan

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.

项目总结/文摘

项目成果

Sex differences in heart failure with preserved ejection fraction: From traditional risk factors to sex-specific risk factors.

• DOI: 10.1177/17455057221140209
• 发表时间: 2022-01
• 期刊: WOMENS HEALTH
• 影响因子: 2.4
• 作者: Kaur, Gurleen;Lau, Emily
• 通讯作者: Lau, Emily

Reply: Previous Pregnancies and Heart Failure Prognosis.

答复：既往妊娠史和心力衰竭预后。

• DOI: 10.1016/j.jacc.2022.06.012
• 发表时间: 2022
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Lau,EmilyS;Ho,JenniferE
• 通讯作者: Ho,JenniferE

A Women in Medicine Trainees' Council: a model for women trainee professional development.

女性医学实习生委员会：女性实习生职业发展的典范。

• DOI: 10.1093/postmj/qgad018
• 发表时间: 2023
• 期刊: Postgraduate medical journal
• 影响因子: 5.1
• 作者: Warner,ASofiaC;Ufere,NnekaN;Patel,NaomiJ;Lau,EmilyS;Uchida,AmikoM;Hills-Dunlap,Kelsey;Bromberg,GabrielleK;Cunningham,ElizabethA;Tagerman,MichelleD;Mills,GabrielleG;Palamara,Kerri;Rigotti,NancyA;Burnett-Bowie,Sherri-Ann
• 通讯作者: Burnett-Bowie,Sherri-Ann

Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long?

• DOI: 10.1161/circulationaha.122.061559
• 发表时间: 2023-02-14
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Cho, Leslie;Kaunitz, Andrew M.;Lindley, Kathryn J.
• 通讯作者: Lindley, Kathryn J.

Infertility and Subclinical Antecedents of Heart Failure With Preserved Ejection Fraction in the Framingham Heart Study.

弗雷明汉心脏研究中不孕症和保留射血分数的心力衰竭的亚临床前因。

• DOI: 10.1016/j.cardfail.2023.10.482
• 发表时间: 2024
• 期刊: Journal of cardiac failure
• 影响因子: 6
• 作者: Zhou,JoyceC;Zhao,Yunong;Bello,Natalie;Benjamin,EmeliaJ;Ramachandran,VasanS;Levy,Daniel;Cheng,Susan;Murabito,JoanneM;Ho,JenniferE;Lau,EmilyS
• 通讯作者: Lau,EmilyS