Human Cardiorenal Syndrome

人类心肾综合症

• 批准号: 10544510
• 负责人: HORNG H CHEN
• 金额: $ 39.71万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544510
• 关键词: Acute; Aldosterone; Angiotensin Receptor; Annexin A1; Atrial Natriuretic Factor; Attenuated; Blood Vessels; Cardiac; Cardiorenal syndrome; Cardiovascular system; Categories; Chronic Kidney Failure; Classification; Clinic; Clinical; Cyclic GMP; Data; Diabetes Mellitus; Dyspnea; EFRAC; Edema; Exercise; Extracellular Matrix; FDA approved; Fluid overload; Funding; Half-Life; Heart failure; Heterogeneity; Homeostasis; Hour; Human; Hypertension; Kidney; Left Ventricular Ejection Fraction; Liquid substance; Lung; National Heart, Lung, and Blood Institute; Natriuresis; Natriuretic Peptides; Neprilysin; Obesity; Particulate; Patients; Peripheral; Phenotype; Physiological; Physiology; Plasma; Pump; Receptor Inhibition; Renal function; Research Priority; Resistant Hypertension; Rest; Saline; Secondary to; Sodium; Stress; Stress Tests; Stretching; Subgroup; Symptoms; System; Testing; Ventricular; atrial natriuretic factor receptor A; biomarker identification; clinical phenotype; design; first-in-human; heart function; human study; improved; individualized medicine; inhibitor; knowledge integration; non-compliance; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; personalized medicine; pre-clinical; precision medicine; preservation; pressure; response; subcutaneous; valsartan; working group

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.

项目概要 当前应用的主要目标是增进我们对两种主要临床表型的理解 射血分数保留的心力衰竭 (HFpEF)：1) 存在容量超负荷的 HFpEF 慢性肾脏病 (HFpEF-CKD) 和 2) HFpEF 伴运动诱发 (HFpEF-EI) 呼吸困难，以阐明 病理生理机制的差异，以确定区分两种临床的生物标志物 表型并开发个体化治疗的新疗法。 50%的患者患有心力衰竭 (HF)保留了EF。 HFpEF 的病理生理学异质性很大，从慢性肾病 疾病、糖尿病、肥胖、高血压等。 FDA 没有批准治疗 HFpEF (LVEF>55%) 的疗法 可能是由于潜在病理生理原因的异质性。近日，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 机制并促进个体化治疗。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。然而， PARAGON 研究未能证明 HFpEF 患者具有显着的临床益处。这可能是因为NP 在 HFpEF 的某些亚组中非常低，从而否定了 NEP 抑制的作用，因此， Sacubatril/valsartan 可有效发挥 AT1 阻滞剂的作用，此前已被证明无益 在 HFpEF 中。因此，我们假设患有以下疾病的人的内源性 NP 水平（特别是 ANP）较低： 与 CKD 和血管外液体超负荷的患者相比，运动引起的呼吸困难。因此，那些具有 HFpEF-EI 可能对 Sacubatril/valsartan 没有反应，但对外源 NP 给药有反应，而 由于内源性 NP 增加，HFpEF-CKD 患者会对 Sacubatril/valsartan 产生反应。 《MANP》是一部小说 颗粒鸟苷酸环化酶 A (pGC-A) 受体激活剂由 Mayo Clinic 设计，比 ANP 可促进尿钠排泄，抑制醛固酮，并具有更大的 cGMP 激活和更长的半衰期。我们的 具体目标： 具体目标 1：对 HFpEF-CKD 和 HFpEF-EI 进行高清表型分析，定义 对急性盐水扩容 (VE) 的不同心肾和体液反应 具体目标 2： 确定 Sacubatril/valsartan 抑制脑啡肽酶和血管紧张素受体对心肾功能的影响 HFpEF-CKD 和 HFpEF-EI 中急性 VE 的体液反应。具体目标 3：确定效果 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很大，因为它将增进我们对综合心肾和心血管疾病的了解。 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 的特定策略，从而推进 HFpEF 的精准医疗方法。