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

项目总结/摘要 射血分数保留性心力衰竭（HFpEF）是一种日益增长的流行病，与多种射血分数相关。 合并症，包括高血压。部分由于其异质性，HFpEF的临床试验已被 尽管NHLBI资助的TOPCAT对盐皮质激素安体舒通（spironolactone）的试验 受体（MR）拮抗剂，有希望的结果。这促使NIH和工业界进行了几项试验， HFpEF中的MR拮抗剂。然而，MR拮抗剂治疗HFpEF的机制仍然存在， 不太了解。MR在心肌细胞、血管内皮细胞和平滑肌细胞中表达。 这些部位的MR激活导致炎症、氧化应激、内皮功能障碍和纤维化 - 所有与HFpEF有关的通路。原发性醛固酮增多症（PA）是高血压和高血压的原因之一。 使用MR拮抗剂治疗的不成比例的心血管风险，其靶向基础 病理生理学：不依赖于肾素的醛固酮产生，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”高血压中被确定， 严重程度从亚临床到明显，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拮抗剂作为精密度的扩展作用 在适当的患者中进行治疗。考虑到其在高血压中的患病率，亚临床PA可能是一种 HFpEF发病机制尚未被认识，并确定最佳MR治疗的患者亚组 对手。目前的建议旨在评估亚临床PA和HFpEF风险之间的关系 并利用生理成像技术探讨其危险机制。具体目标1是评估两者 与心脏结构和功能的横截面关系以及与心脏结构和功能之间的纵向关系 NHLBI动脉粥样硬化风险社区（ARIC）队列中的亚临床PA和事件HFpEF。具体 目标2利用导师已建立的肾上腺和心脏PET登记研究来调查 PA和心肌血流储备之间的关系，血管功能障碍和心血管风险的标志物， 评价MR拮抗剂的作用。这项研究将在一个全面的职业生涯中完成 发展计划旨在提供布朗博士的技能，成为一个独立的物理学家，科学家。 她的长期职业目标是成为一名独立的，R 01资助的医生科学家，专注于了解 心力衰竭风险的潜在生物学和激素机制，使用生理成像工具来识别 并表征亚临床表型，这些表型可用于富集反应性患者群体， 临床试验，并最终确定心力衰竭预防的目标。优秀的指导团队， 醛固酮和血管生物学领域知名科学家咨询委员会，HFpEF，国家 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间过渡到科学独立。

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.