Cardiac Perfusion, Structure, and Function across the Primary Aldosteronism Spectrum

项目摘要/摘要 射血分数保留的心力衰竭(HFpEF)是一种日益流行的疾病，与多个 合并症，包括高血压。部分由于其异质性，在HFpEF进行的临床试验 到目前为止，很大程度上令人失望，尽管NHLBI资助的螺内酯TOPCAT试验是一种矿质皮质激素 受体(MR)拮抗剂，有良好的效果。这促使NIH和行业正在进行的几项试验 HFpEF中的MR拮抗剂。然而，MR拮抗剂治疗HFpEF的机制仍然存在。 人们对此知之甚少。MR表达于心肌细胞、血管内皮细胞和平滑肌细胞。 这些部位MR的激活会导致炎症、氧化应激、内皮功能障碍和纤维化。 -所有涉及HFpEF的通路。原发性醛固酮增多症(PA)是引起高血压和 使用MR拮抗剂治疗的不成比例的心血管风险，其靶向是潜在的 病理生理学：肾素非依赖性的醛固酮的产生，但长期激活MR PA被认为是罕见的，最近在高达15%-20%的明显的“原发性”高血压患者中发现了PA，并有 严重程度从亚临床到显性的连续变化，与血压和对MR的反应性平行 拮抗剂：称为“亚临床PA”这些数据表明，MR拮抗剂的作用扩大为精确度 在适当的患者中进行治疗。鉴于其在高血压中的流行，亚临床PA可能是一种 HFpEF发病机制不明，并确定最佳MR治疗的患者亚组 对抗者。目前的建议旨在评估亚临床PA与HFpEF风险的关系 并利用生理成像技术探讨其发病机制。具体目标1是对两者进行评估 心脏结构和功能的横断面关系及与心脏结构和功能的纵向关系 NHLBI社区动脉粥样硬化风险(ARIC)队列中的亚临床PA和事件HFpEF。特定的 AIM 2利用导师建立的肾上腺和心脏PET注册表来调查两者之间的关系 在PA和心肌血流储备(血管功能障碍和心血管风险的标志)之间，通过 评估MR拮抗剂的效果。这项研究将在一个全面的职业生涯中完成 旨在为布朗博士提供成为一名独立内科科学家的技能的发展计划。 她的长期职业目标是成为一名独立的、由R01资助的内科科学家，专注于了解 心力衰竭风险的潜在生物学和激素机制，使用生理成像工具识别 并表征亚临床表型，这些表型可用于丰富有反应的患者群体 临床试验，并最终确定心力衰竭预防的靶点。一支优秀的指导团队和 由醛固酮和血管生物学领域的知名科学家组成的咨询委员会 最先进的心血管成像、心血管临床试验以及流行病学和生物统计学方法将 指导候选人在获奖期内向科学独立性过渡。

PROJECT SUMMARY/ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is a growing epidemic associated with multiple comorbidities, including hypertension. In part because of its heterogeneity, clinical trials in HFpEF have been largely disappointing to date, though the NHLBI-funded TOPCAT trial of spironolactone, a mineralocorticoid receptor (MR) antagonist, had promising results. This has prompted several ongoing NIH and industry trials of MR antagonists in HFpEF. However, the mechanisms through which MR antagonists may treat HFpEF remain poorly understood. The MR is expressed in cardiomyocytes and vascular endothelial and smooth muscle cells. Activation of the MR at these sites causes inflammation, oxidative stress, endothelial dysfunction, and fibrosis – all pathways implicated in HFpEF. Primary aldosteronism (PA) is a cause of both hypertension and disproportionate cardiovascular risk that is treated with MR antagonists, which target the underlying pathophysiology: renin-independent production of aldosterone that chronically activates the MR. Though considered rare, PA has recently been identified in up to 15-20% of apparently “essential” hypertension, with a continuum of severity ranging from subclinical to overt, paralleling blood pressure and responsiveness to MR antagonists: termed ‘subclinical PA.’ These data suggest an expanded role for MR antagonists as precision therapy in the appropriate patients. Given its prevalence in hypertension, subclinical PA may be an unrecognized mechanism of HFpEF pathogenesis and identify a patient subgroup best treated with MR antagonists. The current proposal aims to evaluate the relationship between subclinical PA and HFpEF risk and to probe the mechanism of risk using physiologic imaging techniques. Specific Aim 1 is to evaluate both the cross-sectional relationship with cardiac structure and function and the longitudinal relationship between subclinical PA and incident HFpEF in the NHLBI Atherosclerosis Risk in Communities (ARIC) cohort. Specific Aim 2 leverages the mentors’ established Adrenal and Cardiac PET registries to investigate the relationship between PA and myocardial flow reserve, a marker of vascular dysfunction and cardiovascular risk, by evaluating the effect of an MR antagonist. This research will be accomplished within a comprehensive career development plan designed to provide Dr. Brown with the skills to become an independent physician-scientist. Her long-term career goal is be an independent, R01-funded physician-scientist focused on understanding the underlying biological and hormonal mechanisms of heart failure risk, using physiologic imaging tools to identify and characterize subclinical phenotypes that can be leveraged to enrich for responsive patient populations in clinical trials, and ultimately to identify targets for heart failure prevention. An outstanding mentoring team and advisory committee of established scientists in the fields of aldosterone and vascular biology, HFpEF, state-of- the-art cardiovascular imaging, cardiovascular clinical trials, and epidemiological and biostatistical methods will guide the candidate’s transition to scientific independence over the course of the award period.