HFpEF Susceptibility in Women: The Role of Inflammation

项目摘要/摘要 心力衰竭是一个重要的公共卫生问题，在美国有600多万人受到影响 独自一人。射血分数保留的心力衰竭(HFpEF)是目前心力衰竭的主要形式， 继续上升。HFpEF仍然是一个治疗挑战，因为我们对因果关系和 影响因素，HFpEF亚型的临床异质性，以及缺乏可用的治疗方法。 HFpEF在女性中比男性更常见，部分原因是心脏结构和心脏结构的性别差异 重塑，对生理压力的适应，以及共病负担。新兴数据支持 在HFpEF发病机制中的全身炎症和免疫反应的性别差异导致了许多 假设炎症是女性对HFpEF易感性的重要驱动因素。更好的 了解这些性别差异可能会为疾病的发病机制提供关键的见解，特别是在 最新证据表明，萨舒比利/valsartan优先用于 HFpEF。到目前为止，对HFpEF炎症的研究仅限于下游标志物。 发炎。二十烷基类化合物是一种小的生物活性脂类，调节系统性红斑狼疮的上游启动。 人类的炎症。现在使用质谱学的先进方法允许快速和准确地 &gt；150上游二十烷类介体的量化。我们将利用这一最先进的技术来 提供更详细的关于上游二十烷类生物性别差异的理解 增加HFpEF风险和疾病进展。在目标1中，我们将检查该协会中的性别差异 循环二十烷类化合物与HFpEF的临床前驱以及社区中的HFpEF事件。在……里面 目的2，我们将评估二十烷类化合物与心脏和心脏外反应的相关性。 临床HFpEF的男性和女性的运动。在目标3中，我们将进行一项前瞻性观测研究，以 研究二十烷类化合物所确定的炎症模式和内皮细胞炎症的变化 更年期妇女代谢产物和血管内皮细胞基因表达谱 年龄匹配的男性有患HFpEF的风险。这项提案的首要目标是评估 假设全身炎症中的性别差异可能解释观察到的HFpEF风险差异 以及男性和女性的疾病表现。这项研究将在一个 全面的职业发展计划，旨在为刘博士，一名早期职业调查员，提供 成为女性心血管(CV)健康领域的独立内科科学家所需的技能。她长长的- 学期的职业目标是确定导致简历风险和疾病的生物性别差异，以求细化 预防和治疗女性心血管疾病的策略。这项提议汇集了一个独特的 代谢组学、基因表达谱、女性 健康和先进的生物统计学将指导候选人向科学独立过渡。

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.