Natriuretic Peptide System as Therapy in Human Preclinical LV Dysfunction

本项目的主要目的是促进我们对利钠肽系统(NPS)在调节临床前左心功能不全患者的室、肾和体液功能中的整合生物学的理解，并评价BNP作为临床前心功能不全的一种有效策略的慢性多肽治疗。具体地说，我们将重点介绍临床前左室收缩功能障碍(PSD)和临床前左室舒张功能障碍(PDD)。我们的研究认识到，充血性心力衰竭(CHF)的人数继续上升，尽管最近在治疗显性症状性CHF方面取得了进展，但死亡率和发病率仍然很高，延缓进展到终末期CHF的可能性有限。研究表明，40%-50%的CHF病例主要是由于舒张期功能异常。需要了解生物学和确定临床前左心功能不全的有效治疗方法，现在是努力延缓CHF进展的优先事项。认识和治疗临床期左撇子的重要性 心功能不全已被比作肿瘤学领域公认的策略，其中强调临床前疾病的识别和治疗已被采用。利钠肽(NPs)是一类结构相似但遗传上不同的多肽，具有扩张血管、利钠、抑制肾素和促血管生成等功能。急性多肽联合脑利钠肽(BNP)输注已被FDA批准为治疗急性失代偿性充血性心力衰竭的一种治疗策略。本申请的具体目的如下：1)在正常对照、人类PSD和PDD中，确定急性SQ BNP对急性钠负荷所致的心、肾和体液综合反应的作用。2)明确慢性服用SQ BNP对人PSD的心、肾和体液功能的影响，以及对急性钠负荷的综合反应。3)明确慢性服用SQ BNP对人PDD心、肾、体液功能的影响以及对急性钠负荷的综合反应。研究将在罗切斯特梅奥诊所圣玛丽医院的综合临床研究中心(GCRC)进行。这个项目将促进我们对临床前左心功能不全的心肾和体液生理学的理解，并确定慢性多肽的疗效。 使用BNP进行治疗。

The broad objective of this project is to advance our understanding of the integrative biology of the natriuretic peptide system (NPS) in the regulation of ventricular, renal and humoral function in human preclinical left ventricular dysfunction and to evaluate chronic peptide therapy with BNP as an effective strategy in preclinical ventricular dysfunction. Specifically, we will focus on human preclinical left ventricular systolic dysfunction (PSD) and human preclinical left ventricular diastolic dysfunction (PDD). Our studies recognize that the number of persons with congestive heart failure (CHF) continues to rise and despite recent advances in the treatment of overt symptomatic CHF, mortality and morbidity remain high and the potential for retarding progression to terminal CHF is limited. Studies have established that 40-50% of incident CHF cases are due primarily to abnormal diastolic function. The need to understand the biology and to identify effective therapy for preclinical left ventricular dysfunction is now a priority in efforts to delay the progression of CHF. The importance of recognizing and treating preclinical left ventricular dysfunction has been likened to well recognized strategies in the field of oncology where an emphasis on recognition and treatment of preclinical disease has been adapted. The natriuretic peptides (NPs) are a family of structurally similar but genetically distinct peptides with vasodilating, natriuretic, renin inhibiting and lusitropic properties. Acute peptide therapy with brain natriuretic peptide (BNP) infusion has recently been approved by the FDA as a therapeutic strategy for the treatment of acute human decompensated CHF. The Specific Aims of this application are as follows: 1) Define in normal controls, human PSD and PDD the actions of acute SQ BNP on the integrated ventricular, renal and humoral response to acute sodium loading. 2) Define in human PSD the actions of chronic administration of SQ BNP on ventricular, renal and humoral function and the integrated response to acute sodium loading. 3) To define in human PDD the actions of chronic administration of SQ BNP on the ventricular, renal and humoral function and the integrated response to acute sodium loading. Studies will be will be performed in the General Clinical Research Center (GCRC) at St Mary's Hospital, Mayo Clinic, Rochester. This project will advance our understanding of the integrated cardiorenal and humoral physiology of preclinical left ventricular dysfunction and defines the efficacy of chronic peptide therapy with BNP.