Genetic determinants of aldosterone escape in heart failure

描述(由申请人提供)：心力衰竭影响了500多万美国人，是老年人住院的主要原因。肾素-血管紧张素-醛固酮系统(RAAS)在心力衰竭的发生发展中起着核心作用。血管紧张素转换酶(ACE)抑制剂是抑制RAAS的基石疗法；然而，尽管继续接受ACE抑制剂治疗，部分患者的醛固酮水平仍会上升。考虑到醛固酮对液体容量和心脏重构的有害影响，这种现象被称为醛固酮逃逸，可能会产生重要的后果。关于调节醛固酮分泌的蛋白质的基因是否会影响醛固酮逃逸的风险，数据有限。本研究的重点是确定在心力衰竭患者接受血管紧张素转换酶抑制剂治疗期间，血管紧张素转换酶基因、醛固酮合成酶基因(CYP11B2)、心钠素基因(NPPA基因)和P-糖蛋白基因(ABCB1基因)是否与醛固酮逃逸有关。这项研究的长期目标是确定在心力衰竭中，基因型别是否能预测对醛固酮拮抗剂的反应。这项研究将检验ACE、CYP11B2、NPPA和/或ABCB1基因与心力衰竭中的醛固酮逃逸相关的假设。我们的具体目标是(1)通过比较ACE I/D、CYP11B2 T-344C、NPPA C-664G和T2238C以及ABCB1 C3435T等位基因频率，确定ACE、CYP11B2、NPPA和/或ABCB1基因是否与心力衰竭患者的醛固酮逃逸有关；(2)通过评估血管紧张素转换酶抑制剂治疗的心力衰竭患者循环中的醛固酮与血管紧张素II和心房利钠肽浓度之间的相关性，来研究循环中的醛固酮与血管紧张素II和心房利钠肽浓度之间的相关性，以确定ACE抑制剂治疗的心力衰竭患者中循环中的醛固酮水平&GT；150pg/ml与心钠素浓度之间的相关性，以确定ACE、CYP11B2、NPPA和/或ABCB1基因是否与心力衰竭患者的醛固酮逃逸有关。这项拟议的研究很重要，因为深入了解遗传因素对醛固酮逃逸的影响最终可能导致预测哪些患者尽管接受了标准治疗，但仍有可能面临由醛固酮介导的疾病进展的风险，在这些患者中，拮抗醛固酮的额外治疗可能特别有益。 公共卫生相关性：心力衰竭是老年人住院治疗的最常见原因。醛固酮是一种促进心力衰竭发展和进展的荷尔蒙。这项研究旨在确定一个人的基因构成是否会影响他或她尽管接受标准的心力衰竭治疗，其醛固酮水平升高的风险。

DESCRIPTION (provided by applicant): Heart failure affects over 5 million Americans and is the leading cause for hospitalization in the elderly. The renin-angiotensin-aldosterone system (RAAS) plays a central role in heart failure development and progression. Angiotensin converting enzyme (ACE) inhibitors are cornerstone therapy to suppress the RAAS; however, aldosterone levels rise in a subset of patients despite continued ACE inhibitor treatment. This phenomenon, known as aldosterone escape, may have important consequences given the deleterious effects of aldosterone on fluid volume and cardiac remodeling. There are limited data on whether genes for proteins that regulate aldosterone secretion influence the risk for aldosterone escape. The focus of this proposal is to determine whether the genes for ACE, aldosterone synthase (CYP11B2), atrial natriuretic peptide (NPPA), and p- glycoprotein (ABCB1) contribute to aldosterone escape during ACE inhibitor therapy in heart failure. The long-term goal of this line of investigation is to determine whether genotype is predictive of response to aldosterone antagonists in heart failure. This study will test the hypothesis that the ACE, CYP11B2, NPPA, and/or ABCB1 genes are associated with aldosterone escape in heart failure. Our specific aims are (1) to determine whether the ACE, CYP11B2, NPPA, and/or ABCB1 genes are associated with aldosterone escape in heart failure by comparing ACE I/D, CYP11B2 T-344C, NPPA C-664G and T2238C, and ABCB1 C3435T genotype frequencies between heart failure patients with a circulating aldosterone level >150 pg/ml despite ACE inhibitor treatment and those with a lower level; and (2) to examine the mechanism underlying genetic associations with aldosterone escape by estimating the correlation between circulating aldosterone and both angiotensin II and atrial natriuretic peptide concentrations in ACE inhibitor-treated heart failure patients. The proposed study is important because insight into genetic contributions to aldosterone escape could ultimately lead to the ability to predict which patients are at risk for aldosterone-mediated disease progression despite standard therapy, in whom the additional therapy to antagonize aldosterone might be particularly beneficial. PUBLIC HEALTH RELEVANCE: Heart failure is the most common cause for hospitalization in the elderly. Aldosterone is a hormone that promotes heart failure development and progression. This study aims to determine whether a person's genetic makeup affects his or her risk for elevated aldosterone levels despite standard therapy in heart failure.