Human Cardiorenal Syndrome

描述(申请人提供)：这项新申请的广泛目标是促进我们对人类心脏肾综合征(CRS)的病理生理机制的理解，特别强调利尿剂治疗、肾素-血管紧张素-醛固酮系统(RAAS)和环状3-5-鸟苷一磷酸(CGMP)途径之间的生物相互作用。肾功能不全是慢性心力衰竭(CHF)常见的进行性并发症，尽管人们越来越多地认识到心肾联合功能不全(CRS)的常见表现，但其潜在的病理生理机制尚不清楚，对其适当的处理缺乏共识。CRS可分为两大类：1)代偿性充血性心力衰竭肾功能受损；2)失代偿性充血性心力衰竭伴肾功能恶化。利尿剂对缓解充血是有效和必要的，然而最近的报告表明，利尿剂对心力衰竭的进展有潜在的有害影响。我们证明了血管紧张素II受体(AT1)的阻断可以防止利尿剂对肾脏的不利影响。环鸟苷酸(CGMP)是利钠肽(NP)系统和一氧化氮系统(NO)的第二信使。这两种体液系统在平衡血管收缩和钠保留激素(如血管紧张素II)以保护充血性心力衰竭的肾功能方面都很重要。为了解决这些与人类CRS相关的问题，我们将利用广泛的临床设施、患者群体和我们位于梅奥诊所的NIH资助的普通临床研究中心(GCRC)进行人体研究，这使得我们提议的研究具有高度的可行性和重要的临床意义。我们的具体目标如下：目的1：明确减少速尿剂量对代偿性充血性心力衰竭伴肾功能不全患者和无肾功能不全代偿性充血性心力衰竭患者的心肾和体液功能的影响。其次，对两组的体液激活进行界定。目的2：明确慢性AT1受体阻断与血管紧张素转换酶抑制增加相比，慢性阻断AT1受体对心肾功能和体液功能的调节作用。目的：明确失代偿性充血性心力衰竭合并慢性肾功能衰竭患者在存在和不存在急性PDE-V抑制的情况下小剂量静脉滴注BNP对改善肾功能的肾脏作用。 公共卫生相关性 慢性心力衰竭在美国是一个主要的健康问题，尽管最近在治疗方面取得了进展，但结果仍然很差，特别是在那些患有肾衰竭的患者中。这项研究应该有助于应对这一健康挑战。

DESCRIPTION (provided by applicant): The broad objective of this new application is to advance our understanding of the pathophysiological mechanisms of human Cardiorenal Syndrome (CRS) with a specific emphasis upon the biological interaction between diuretic therapy, the renin-angiotensin-aldosterone-system (RAAS) and cyclic 3_- 5_-guanosine monophosphate (cGMP) pathway. Renal dysfunction is a common and progressive complication of chronic heart failure (CHF) and despite growing recognition of the frequent presentation of combined cardiac and renal dysfunction, or CRS, its underlying pathophysiology is not well understood, with a lack of consensus as to its appropriate management. The CRS can be classified into 2 broad categories: 1) patients with compensated CHF and impaired renal function; and 2) patients with decompensated CHF and worsening renal function. Diuretics are effective and necessary to relieve congestion in CHF however recent reports have suggested potential deleterious effects on the progression of CHF. We demonstrated that angiotensin II receptor (AT1) blockade prevented the detrimental renal effects of diuretics. Cyclic GMP (cGMP) is the second messenger of both the natriuretic peptide (NP) system and the nitric oxide system (NO). Both of these humoral systems are important in balancing the vasocontricting and sodium retaining hormones such as the angiotensin II to preserve renal function in CHF. To address these issues related to human CRS, we will pursue human studies taking advantage of the extensive clinical facilities, patient populations and our NIH funded General Clinical Research Center (GCRC) at the Mayo Clinic, which makes our proposed research highly feasible and of significant clinical importance. Our Specific Aims are as follows: Aim 1: To define the effects of decreasing the furosemide dose on cardiorenal and humoral function in humans with compensated CHF and renal dysfunction and also in humans with compensated CHF without renal dysfunction. Secondly, to define the humoral activation in both groups.. Aim 2: Define in humans with compensated CHF and renal dysfunction, the modulating actions of chronic AT1 receptor blockade on cardiorenal and humoral function as compared to increased ACE inhibition. Aim 3: Define in hospitalized decompensated CHF patients with CRS, the renal actions of low dose intravenous infusion of BNP in the presence and absence of acute PDE V inhibition in improving renal function. PUBLIC HEALTH RELEVANCE Chronic heart failure is a major health problem in the US and despite recent advances in the treatment, the outcome remains poor, especially in those patients with renal failure as well. This research should aid in addressing this health challenge.