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

原发性醛固酮增多症谱系的心脏灌注、结构和功能

• 批准号: 10448000
• 负责人: Jenifer Michelle Brown
• 金额: $ 19.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448000
• 关键词: Adrenal Glands; Adult; Advisory Committees; Aldosterone; Ammonia; Atherosclerosis Risk in Communities; Award; Biological; Biology; Biostatistical Methods; Blood Pressure; Blood Vessels; Blood capillaries; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Coronary Arteriosclerosis; Cross-Sectional Studies; Data; Development; Development Plans; Diabetes Mellitus; Disease Outcome; EEF2 gene; EFRAC; Echocardiography; Endothelium; Epidemic; Epidemiologic Methods; Epidemiology; Essential Hypertension; Extracellular Matrix; Failure; Fibrosis; Functional Imaging; Functional disorder; Funding; General Population; Goals; Heart; Heart Diseases; Heart failure; Heterogeneity; High Prevalence; Hormonal; Hospitalization; Hyperaldosteronism; Hypertension; Imaging Device; Imaging Techniques; Industry; Inflammation; Intervention; Investigation; Ischemia; Kidney; Lead; Left Ventricular Remodeling; Measures; Mediating; Medicine; Mentors; Microvascular Dysfunction; Mineralocorticoid Receptor; Myocardial; Myocardial perfusion; National Heart, Lung, and Blood Institute; Obesity; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phenotype; Physicians; Positron-Emission Tomography; Precision therapeutics; Prevalence; Prevention; Production; Receptor Activation; Registries; Renin; Research; Risk; Risk Factors; Role; Scientist; Severities; Site; Smooth Muscle; Smooth Muscle Myocytes; Spironolactone; Structure; Symptoms; Syndrome; Techniques; Treatment Failure; United States National Institutes of Health; Vascular Diseases; Vascular Endothelium; Vascular blood supply; Ventricular Dysfunction; Ventricular Remodeling; Work; antagonist; atherosclerosis risk; cardiovascular disorder risk; cardiovascular effects; cardiovascular imaging; cardiovascular risk factor; career; career development; clinical epidemiology; cohort; comorbidity; design; endothelial dysfunction; epidemiology study; eplerenone; heart imaging; imaging biomarker; improved; improved outcome; insight; longitudinal analysis; modifiable risk; mortality; novel; patient population; patient response; patient subsets; preservation; prognostic; skills; targeted treatment; translational scientist; treatment response

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.

项目概要/摘要 射血分数保留的心力衰竭（HFpEF）是一种日益流行的疾病，与多种疾病相关 合并症，包括高血压。部分由于其异质性，HFpEF 的临床试验已经开展 尽管 NHLBI 资助的螺内酯（一种盐皮质激素）的 TOPCAT 试验迄今为止基本上令人失望 受体（MR）拮抗剂，取得了有希望的结果。这促使 NIH 和行业正在进行多项试验 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 MR 的激活会导致炎症、氧化应激、内皮功能障碍和纤维化 – HFpEF 涉及的所有途径。原发性醛固酮增多症 (PA) 是高血压和高血压的病因 使用 MR 拮抗剂治疗的不成比例的心血管风险，该拮抗剂针对潜在的 病理生理学：不依赖肾素产生醛固酮，长期激活 MR。尽管 PA 被认为是罕见的，最近在高达 15-20% 的明显“原发性”高血压中被发现，其中 严重程度从亚临床到明显的连续性，与血压和 MR 反应平行 拮抗剂：称为“亚临床 PA”。这些数据表明 MR 拮抗剂作为精确性的扩大作用 对适当的患者进行治疗。鉴于其在高血压中的患病率，亚临床 PA 可能是一种 尚未认识的 HFpEF 发病机制，并确定最适合 MR 治疗的患者亚组 对手。当前提案旨在评估亚临床 PA 与 HFpEF 风险之间的关系 并利用生理成像技术探讨风险机制。具体目标 1 是评估 与心脏结构和功能的横截面关系以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。具体的 目标 2 利用导师已建立的肾上腺和心脏 PET 登记来调查这种关系 PA 与心肌血流储备之间的关系，心肌血流储备是血管功能障碍和心血管风险的标志， 评估 MR 拮抗剂的效果。这项研究将在全面的职业生涯中完成 旨在为布朗博士提供成为独立医师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 资助的医师科学家，专注于了解 心力衰竭风险的潜在生物和激素机制，使用生理成像工具来识别 并表征亚临床表型，可用于丰富有反应的患者群体 临床试验，并最终确定预防心力衰竭的目标。优秀的导师团队和 由醛固酮和血管生物学、HFpEF、现状领域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 在获奖期间指导候选人过渡到科学独立。