Genetic determinants of aldosterone escape in heart failure

描述（由申请人提供）：心力衰竭影响超过500万美国人，是老年人住院的主要原因。肾素-血管紧张素-醛固酮系统（RAAS）在心力衰竭的发生和进展中起着重要作用。血管紧张素转换酶（ACE）抑制剂是抑制RAAS的基础治疗;然而，尽管持续ACE抑制剂治疗，但部分患者的醛固酮水平仍会升高。这种现象，称为醛固酮逃逸，可能有重要的后果，醛固酮对液体容量和心脏重塑的有害影响。关于调节醛固酮分泌的蛋白质基因是否影响醛固酮逃逸的风险，数据有限。该建议的重点是确定ACE、醛固酮合成酶（CYP 11B 2）、心房利钠肽（NPPA）和P-糖蛋白（ABCB 1）基因是否有助于心力衰竭患者在ACE抑制剂治疗期间的醛固酮逃逸。这项研究的长期目标是确定基因型是否能预测心力衰竭患者对醛固酮拮抗剂的反应。本研究将检验ACE、CYP 11B 2、NPPA和/或ABCB 1基因与心力衰竭中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、CYP 11B 2 T-344 C、NPPA C-664 G和T2238 C，确定ACE、CYP 11B 2、NPPA和/或ABCB 1基因是否与心力衰竭中的醛固酮逃逸相关，在循环醛固酮水平>150 pg/ml的心力衰竭患者中，ml;（2）通过评估ACE抑制剂治疗的心力衰竭患者中循环醛固酮与血管紧张素II和心钠素浓度之间的相关性，研究与醛固酮逃逸相关的潜在遗传机制。这项拟议的研究很重要，因为深入了解醛固酮逃逸的遗传贡献可能最终导致预测哪些患者尽管接受标准治疗仍有醛固酮介导的疾病进展的风险，其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的最常见原因。醛固酮是一种促进心力衰竭发展和进展的激素。这项研究的目的是确定一个人的基因组成是否影响他或她的风险升高醛固酮水平，尽管标准治疗心力衰竭。

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.