Human Cardiorenal Syndrome

项目总结 目前应用的主要目标是促进我们对两种主要临床表型的理解 心衰伴保留射血分数(HFpEF)：1)心衰伴容量超负荷 慢性肾病(HFpEF-CKD)和2)HFpEF伴运动性呼吸困难(HFpEF-EI)，以阐明 在病理生理机制上的差异，找出生物标记物来区分两种临床 表型，并开发个体化治疗的新疗法。50%的心力衰竭患者 (Hf)保存了EF。HFpEF的病理生理异质性很大，从慢性肾脏到慢性肾脏。 疾病、糖尿病、肥胖、高血压等。FDA没有批准的治疗HFpEF(LVEF&GT；55%)的方法。 可能是由于不同的潜在病理生理原因所致。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 将患者分为表型相同的亚群，以了解病理生理学 这是一种新的治疗方法和机制，并有助于个体化治疗。Sacubatril/valsartan是一种双重血管紧张素受体 (AT1)阻滞剂和Neprilysin(NEP)抑制剂，被批准用于HFrEF的管理。然而， Paragon研究未能证明HFpEF患者有显著的临床益处。这可能是因为NP 在HFpEF的某些亚群中非常低，因此否定了NEP抑制的作用，因此， 萨库巴特利/valsartan有效地起到了AT1受体阻滞剂的作用，这在以前已经被证明是无益的 在HFpEF中。因此，我们假设内源性NP水平(特别是ANP)在那些患有高血压的人中是低的 运动性呼吸困难与慢性肾脏病和血管外液体超负荷的患者相比。因此，那些拥有 HFpEF-EI对沙丁胺醇/valsartan可能无反应，但对外源性NPs给药有反应，而 患有HFpEF-CKD的患者将因内源性NPs增加而对Sacubatril/valsartan产生反应。《MANP》是一部小说 梅奥诊所设计的PGC-A受体激活剂比 ANP具有促钠、抑制醛固酮的作用，具有较大的cGMP活性和较长的半衰期。我们的 具体目标：具体目标1：对HFpEF-CKD和HFpEF-EI进行高清表型鉴定，定义 急性生理盐水扩容(VE)特异性心肾和体液反应的差异性目标2 沙丁胺醇/血管紧张素受体拮抗剂对心肾的影响 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患者急性VE心肾和体液反应的影响 我们建议的研究的影响很大，因为它将促进我们对心脏和肾脏综合功能的了解 HFpEF-CKD和HFpEF-EI患者的体液生理，并测试新的诊断和治疗方法 针对HFpEF-CKD和HFpEF-EI的策略，从而推动了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.