Human Cardiorenal Syndrome

项目摘要 当前申请的广泛目标是加深我们对2种主要临床表型的了解 射血分数保留的心力衰竭（HFpEF）：1）HFpEF伴容量超负荷， 慢性肾脏疾病（HFpEF-CKD）和2）HFpEF伴运动诱导的呼吸困难（HFpEF-EI），以阐明 病理生理机制的差异，以确定生物标志物来区分两种临床 表型，并开发新的治疗个性化的治疗。50%的心力衰竭患者 (HF)保存EF。HFpEF的病理生理异质性很大，从慢性肾功能衰竭， 没有FDA批准的用于HFpEF（LVEF>55%）的治疗，其 可能是由于异质性的潜在病理生理原因。最近，NHLBI研究 HFpEF工作组的优先事项强调需要对HFpEF患者进行表型分析，以便 将患者分为表型同质的亚群，以了解病理生理学 机制和促进个性化治疗。沙库巴曲/缬沙坦是双重血管紧张素受体 (AT1)阻滞剂和脑啡肽酶（NEP）抑制剂，已被批准用于治疗HFrEF。但 PARAGON研究未能证明HFpEF患者的显著临床获益。这可能是因为NP 在HFpEF的某些亚组中非常低，因此否定了NEP抑制的作用，因此， 沙库巴曲/缬沙坦有效地作为AT 1阻滞剂发挥作用，之前已证明其无益 在HFpEF中。因此，我们假设，内源性NP水平（特别是ANP）在那些有 与CKD和血管外液体超负荷患者相比，运动引起的呼吸困难。因此，那些 HFpEF-EI可能对沙库巴曲/缬沙坦无反应，但对外源性NPs给药有反应， HFpEF-CKD患者由于内源性NP增加而对沙库巴曲/缬沙坦有反应。MANP是一本小说 马约诊所设计的颗粒鸟苷酸环化酶A（pGC-A）受体激活剂， ANP促进尿钠排泄，抑制醛固酮生成，cGMP活性增强，半衰期延长。我们 具体目的：具体目的1：对HFpEF-CKD和HFpEF-EI进行高清晰度表型分型，定义 对急性盐水容量扩张（VE）的不同心肾和体液反应具体目标2： 确定沙库巴曲/缬沙坦对脑啡肽酶和血管紧张素受体抑制剂对心肾功能的影响， HFpEF-CKD和HFpEF-EI对急性VE的体液反应。具体目标3：确定 MANP对HFpEF-CKD和HFpEF-EI中急性VE的心肾和体液反应的影响。 我们提出的研究的影响是高的，因为它将促进我们的知识的综合心肾和 HFpEF-CKD和HFpEF-EI患者的体液生理学，并测试新的诊断和治疗方法 针对HFpEF-CKD和HFpEF-EI的特异性策略，从而推进HFpEF的精准医学方法。

PROJECT SUMMARY The broad objective of the current application is to advance our understanding of 2 major clinical phenotypes of heart failure with preserved ejection fraction (HFpEF): 1) HFpEF with volume overload in the presence of chronic kidney diseases (HFpEF-CKD) and 2) HFpEF with exercise induced (HFpEF-EI) dyspnea, to elucidate the differences in the pathophysiological mechanisms, to identify biomarkers to differentiate the two clinical phenotypes and to develop novel therapies for individualization of treatment. 50% of patients with heart failure (HF) have preserved EF. Pathophysiological heterogeneity in HFpEF is substantial, ranging from chronic kidney diseases, diabetes, obesity, hypertension, etc. There is no FDA approved therapy for HFpEF (LVEF>55%) which may be due to the heterogeneous underlying pathophysiological causes. Recently, the NHLBI Research Priorities for HFpEF Working Group emphasized the need for phenotyping of patients with HFpEF so as to classify patients into phenotypically homogeneous subpopulations, to understand pathophysiological mechanisms and to facilitate individualization of treatment. Sacubatril/valsartan is a dual angiotensin receptor (AT1) blocker and neprilysin (NEP) inhibitor which is approved for management of HFrEF. However, the PARAGON Study failed to demonstrate significant clinical benefit in HFpEF patients. This may be because NP are very low in some subgroups of HFpEF, thus negating the actions of NEP inhibition and therefore, Sacubatril/valsartan effectively functions as an AT1blocker, which has previously been shown to be not beneficial in HFpEF. Therefore, we hypothesized that the endogenous NP levels (specifically ANP) are low in those with exercise induced dyspnea as compared to those with CKD and extravascular fluid overload. Hence, those with HFpEF-EI may not respond to Sacubatril/valsartan but will respond to exogenous NPs administration, while those with HFpEF-CKD will respond to Sacubatril/valsartan due to increased endogenous NPs. MANP is a novel particulate-guanylyl-cyclase A (pGC-A) receptor activator designed at the Mayo Clinic which is more potent than ANP in promoting natriuresis, inhibiting aldosterone with greater activation of cGMP and longer half-life. Our Specific Aims: Specific Aim 1: To perform high definition phenotyping of HFpEF-CKD and HFpEF-EI, defining the differential cardiorenal and humoral response to acute saline volume expansion (VE) Specific Aim 2: To determine the effects of neprilysin and angiotensin receptor inhibition with Sacubatril/valsartan on the cardiorenal and humoral response to acute VE in HFpEF-CKD and HFpEF-EI. Specific Aim 3: To determine the effects of MANP on the cardiorenal and humoral response to acute VE in HFpEF-CKD and HFpEF-EI. The impact of our proposed studies is high as it will advance our knowledge of the integrated cardiorenal and humoral physiology in patients with HFpEF-CKD and HFpEF-EI, and to test novel diagnostic and therapeutic strategies specific for HFpEF-CKD and HFpEF-EI, thus advancing a precision medicine approach in HFpEF.