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

基本信息

批准号：
10609914
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
项目类别：
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/10609914
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 Chronic Kidney Failure Clinical Clinical Research Clinical Trials Coronary Arteriosclerosis Cross-Sectional Studies Data Dedications Development Development Plans Diabetes Mellitus Disease Outcome EEF2 gene EFRAC Echocardiography Endothelium Epidemic Epidemiologic Methods Epidemiology Essential Hypertension Exclusion Extracellular Matrix 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 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 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 clinical translation 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

项目摘要

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.

项目摘要/摘要心力衰竭和保留的射血分数（HFPEF）是一种与多种相关的流行病合并症，包括高血压。部分原因是其异质性，HFPEF的临床试验一直是尽管NHLBI资助的螺旋藻酮的TOPCAT试验，迄今为止，迄今为止令人失望接收者（MR）拮抗剂有希望的结果。这促使了几项正在进行的NIH和行业试验 HFPEF的拮抗剂先生。但是，MR拮抗剂可以治疗HFPEF的机制仍然存在理解不佳。 MR在心肌细胞和血管内皮和平滑肌细胞中表达。在这些部位激活MR会引起感染，氧化应激，内皮功能障碍和纤维化 - HFPEF中实现的所有途径。原发性醛固酮主义（PA）是高血压和 MR拮抗剂治疗的心血管风险不成比例，该风险针对基础病理生理学：醛固酮非肾素非依赖性产生，该醛固酮长期激活MR。尽管被认为是罕见的，最近在多达15-20％的“本质”高血压中发现了PA，严重程度的连续体从亚临床到明显的，平行的血压和对MR的反应性拮抗剂：称为“亚临床PA”。这些数据表明MR拮抗剂的作用扩大为精确适当患者的治疗。鉴于其在高血压方面的患病率，亚临床PA可能是 HFPEF发病机理的未识别机制，并确定最佳用MR治疗的患者亚组对手。当前的建议旨在评估亚临床PA和HFPEF风险之间的关系并使用生理成像技术探测风险的机理。具体目标1是评估与心脏结构和功能的横截面关系以及之间的纵向关系 NHLBI动脉粥样硬化风险（ARIC）队列中的NHLBI动脉粥样硬化风险中的亚临床PA和入射HFPEF。具体的 AIM 2利用导师既定的肾上腺和心脏宠物登记处进行调查在PA和心肌流量储备（血管功能障碍和心血管风险的标记）之间评估MR拮抗剂的效果。这项研究将在全面的职业中完成开发计划旨在为布朗博士提供成为独立的身体科学家的技能。她的长期职业目标是一个独立的R01资助的身体科学家，专注于理解使用生理成像工具来识别心力衰竭风险的生物学和骑马机制并表征可以利用的亚临床表型，以丰富反应迅速的患者人群临床试验，并最终确定预防心力衰竭的目标。一个杰出的心理团队， HFPEF的醛固酮和血管生物学领域成熟科学家的咨询委员会艺术的心血管成像，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整个奖项期间向科学独立的过渡。