Natriuretic Peptides, Genes, and Diastolic Heart Failure

描述(由申请人提供)： 左心室肥厚(LVH)是舒张性心力衰竭(DHF)的关键先兆之一，其血浆钠尿肽水平显著升高。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)会导致进行性左心室肥厚。这一明显的悖论是由钠尿肽的重要反调节功能解释的，钠尿肽是在房室壁应激时分泌的。在实验模型中，利钠肽对心脏有两种旁分泌作用：增强肌张力和抑制心肌细胞肥大和纤维化。据推测，钠尿肽缺乏在人类左心室肥厚和DHF的发生中起作用。检验这一假说的两种临床相关方法是检查利钠肽轴基因变异对左心室结构和功能的影响，以及研究急性应用这些多肽的效果。这项拟议的研究有3个具体目标：(1)使用多变量分析，检测利钠肽基因的特定多态对血浆利钠肽水平和左心室肥厚的影响；(2)使用比例风险模型，检查利钠肽和利钠肽水平的遗传变异与心力衰竭事件的关系；(3)使用系列血流动力学和超声心动图评估，评估外源性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广泛的临床、超声心动图和基因特征的大型社区队列(弗雷明翰心脏研究)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护理病房进行。这些研究的目的是阐明利钠肽及其基因在心室重构和舒张期功能障碍中的作用，以期找到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应聘者提供遗传流行病学、血流动力学和非侵入性心功能评估、生物标记物的使用和临床试验方面的专门培训。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员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.