Natriuretic Peptides, Genes, and Diastolic Heart Failure

描述（由申请人提供）： 血浆利钠肽水平在左心室肥厚（LVH）患者中显著升高，LVH是舒张性心力衰竭（DHF）的关键前体之一。然而，使用基因敲除小鼠的实验表明，利钠肽缺乏（而不是过量）导致进行性LVH。这一明显的矛盾现象可以通过利钠肽的重要反调节功能来解释，利钠肽是在心房和心室壁应激时分泌的。在实验模型中，利钠肽对心脏有两种旁分泌作用：增强的增肌作用和抑制心肌细胞肥大和纤维化。 据推测，利钠肽的缺乏有助于人类LVH和DHF的发展。两个临床相关的方法来检验这一假设是检查的影响，利钠肽轴的遗传变异对左心室的结构和功能，并研究这些肽的急性管理的影响。本研究有3个具体目的：（1）采用多变量分析方法，检测利钠肽基因多态性对血浆利钠肽水平和左室肥厚的影响;（2）采用比例风险模型，检测利钠肽基因变异和利钠肽水平与心力衰竭事件的关系;（3）应用血流动力学和超声心动图评价外源性B型利钠肽对DHF患者心肌功能的影响。前两个目标将通过研究一个具有广泛临床、超声心动图和遗传特征的大型社区队列（Frachial Heart研究）来解决。目标3将在一家大型转诊医院的心导管实验室和冠心病监护室进行。这些研究的目的是阐明利钠肽及其基因在心室重塑和舒张功能障碍中的作用，以期确定更具体的治疗和预防充血性心力衰竭的策略。 这项研究和相关的职业发展活动将为候选人提供遗传流行病学，血液动力学和心室功能的非侵入性评估，生物标志物的使用和临床试验方面的具体培训。这些技能中的每一项都对候选人成为一名专注于心力衰竭的独立临床研究者的长期目标至关重要。

DESCRIPTION (provided by applicant): Plasma natriuretic peptide levels are markedly elevated in individuals with left ventricular hypertrophy (LVH), one of the key precursors of diastolic heart failure (DHF). However, experiments using gene knockout mice indicate that natriuretic peptide deficiency (not excess) leads to progressive LVH. This apparent paradox is explained by the important counter-regulatory function of the natriuretic peptides, which are secreted in response to atrial and ventricular wall stress. In experimental models, natriuretic peptides have two paracrine effects on the heart: enhanced lusitropy and inhibition of myocyte hypertrophy and fibrosis. It is hypothesized that deficiency of natriuretic peptides contributes to the development of LVH and DHF in humans. Two clinically relevant approaches to testing this hypothesis are to examine the impact of genetic variations in the natriuretic peptide axis on left ventricular structure and function and to study the effects of acute administration of these peptides. The proposed research has 3 specific aims: (1) to examine the influence of selected polymorphisms in natriuretic peptide genes on plasma natriuretic peptide levels and LVH, using multivariable analyses; (2) to examine the association of genetic variation in natriuretic peptides and natriuretic peptide levels with incident heart failure, using proportional hazards models; (3) to assess the effects of exogenous B-type natriuretic peptide on myocardial function in patients with DHF, using serial hemodynamic and echocardiographic assessments. The first 2 aims will be addressed by studying a large, community-based cohort (Framingham Heart Study) with extensive clinical, echocardiographic, and genetic characterization. Aim 3 will be carried out in the cardiac catheterization laboratory and coronary care unit of a large, referral hospital. The goal of these studies is to elucidate the role of the natriuretic peptides and their genes in ventricular remodeling and diastolic dysfunction, in the hopes of identifying more specific strategies for treating and preventing congestive heart failure. This research and the associated career development activities will provide the candidate with specific training in genetic epidemiology, the hemodynamic and non-invasive assessment of ventricular function, the use of biomarkers, and clinical trials. Each of these skills will be critical to the candidate's long-term goal of becoming an independent clinical investigator with a focus on heart failure.