Avoiding (Heart) Failure: Physiologic-Based Targeting of the RAAS to Treat Subclinical HFpEF among PWH

避免（心）力衰竭：基于生理学的 RAAS 靶向治疗感染者中的亚临床 HFpEF

• 批准号: 10084314
• 负责人: Suman Srinivasa
• 金额: $ 84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084314
• 关键词: Affect; Aldosterone; Angiotensin II Receptor; Angiotensin Receptor; Attention; Biological Markers; Blood Vessels; Brain natriuretic peptide; Cardiac; Cardiomyopathies; Cardiovascular system; Chronic; Chronic Disease; Clinical; Coupled; Data; Deposition; Development; Disease; Disease model; EFRAC; Echocardiography; Endocrinology; FDA approved; Failure; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Functional disorder; GDF15 gene; General Population; HIV; Health; Heart Atrium; Heart Diseases; Heart failure; Hormonal; Hormones; Hypertrophy; Image; Imaging Techniques; Immunologics; Impairment; Individual; Inflammation; Inflammatory; Insulin Resistance; Knowledge; Left; Left Ventricular Ejection Fraction; Left Ventricular Hypertrophy; Left ventricular structure; Link; Liver; Macrophage Activation; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Metabolic; Metabolic Diseases; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial dysfunction; Myocardium; Natriuresis; Natriuretic Peptides; Neprilysin; Patients; Persons; Pharmacology; Phenotype; Physiological; Physiology; Placebos; Population; Prevalence; Public Health; Randomized Controlled Trials; Relaxation; Renin-Angiotensin-Aldosterone System; Research Personnel; Risk; Science; Structure; System; Testing; Therapeutic; Time; Tissue Inhibitor of Metalloproteinase-1; Vasodilation; Ventricular Remodeling; Visceral; base; cardiometabolism; cardioprotection; cardiovascular health; coronary fibrosis; extracellular; heart disease risk; heart function; immune activation; improved; indexing; inhibitor/antagonist; insight; monocyte; mortality; myocardial damage; novel; novel therapeutics; patient population; preservation; pressure; sudden cardiac death; systemic inflammatory response; tissue injury; treatment strategy; valsartan

Project Summary: Heart disease is a leading cause of non-communicable disease-related morbidity and mortality in the well-treated HIV population, and heart failure with preserved ejection fraction (HFpEF) is rising in prevalence. There are no FDA-approved therapeutics directed at HFpEF that effectively reduce morbidity and mortality in HIV or the general population, which highlights an expanding population of patients with a significant unmet clinical need. Early changes in myocardial structure and function are well-recognized among asymptomatic persons with HIV (PWH), affecting 50-60% of the population. The exact mechanism precipitating antecedent myocardial dysfunction, related to altered relaxation and increased stiffness and filling pressures of the left ventricle, and subsequent progression to symptomatic HFpEF in HIV is unclear. Myocardial inflammation and fibrosis are postulated to be substantial mediators of HFpEF and are mechanistically relevant among PWH whom demonstrate chronic systemic inflammation and immune activation and metabolic disease regardless of immunological control. Rigorous hormonal testing from our group among PWH show increased renin-angiotensin-aldosterone system (RAAS) activation is relation to reduced natriuretic peptide (NP) and increased inflammation and monocyte/macrophage activation. NPs have cardioprotective effects, and relatively reduced NPs could impair activities related to natriuresis, vasodilation, myocyte hypertrophy, and fibroblast proliferation, altering stability of the myocardium. We further postulate relatively reduced NP, a phenotype shown in highly metabolic groups and now demonstrated for the first time in HIV, may allow permissive RAAS activation leading to downstream inflammation and myocardial damage. We aim to investigate the cardiac phenotype associated with reduced NP among PWH compared to uninfected individuals utilizing advanced CV imaging techniques (cardiac MRI, cardiac TTE) and circulating myocardial biomarkers to comprehensively assess myocardial inflammation, structure, and function. This novel proposal represents a substantial departure from the typically well-studied HF patients with relatively higher NP and may uncover a large class of newly-identified inflammatory-prone or metabolically-deranged patients deserving of more clinical attention in the HF realm. We will also determine the effect of sacubitril/valsartan, a dual angiotensin II receptor antagonist and neprilysin inhibitor, vs. placebo on longitudinal changes in myocardial inflammation, structure and function among PWH in a 6-month randomized controlled trial. These studies apply a novel concept in studying PWH, among whom we postulate a therapy to simultaneously increase NP and decrease RAAS activation may be beneficial for heart disease based on unique RAAS-NP physiology in HIV. These studies led by an early stage investigator and team of experts in HIV-associated CVD, CV imaging, HFpEF phenotyping, CV biomarker science, and CV endocrinology will provide key insight on two neurohormonal systems critical to CV health, RAAS-NP, and test whether targeted manipulation of these systems can reduce subclinical HFpEF risk in HIV.

心脏病是非传染性疾病相关发病率的主要原因， 接受良好治疗的HIV人群的死亡率和射血分数保留的心力衰竭（HFpEF）正在上升 in prevalence流行.没有FDA批准的针对HFpEF的治疗方法可以有效降低发病率 和死亡率在艾滋病毒或一般人群，这突出了不断扩大的患者群体， 严重未满足的临床需求。心肌结构和功能的早期变化是公认的， 无症状艾滋病毒感染者（PWH），影响50-60%的人口。沉淀的确切机制 先前的心肌功能障碍，与舒张功能改变、僵硬度和充盈压增加有关， 左心室，随后进展为症状性HFpEF的HIV尚不清楚。心肌 炎症和纤维化被认为是HFpEF的主要介质，并且在机制上是相关的 在表现出慢性全身性炎症、免疫激活和代谢疾病的PWH中， 不管免疫控制如何。我们小组对威尔斯亲王医院进行的严格激素测试显示， 肾素-血管紧张素-醛固酮系统（RAAS）的激活与尿钠肽（NP）的减少有关， 增加炎症和单核细胞/巨噬细胞活化。纳米颗粒具有心脏保护作用， 减少的NPs可损害与尿钠排泄、血管舒张、肌细胞肥大和成纤维细胞相关的活动， 增殖改变心肌的稳定性我们进一步假设相对减少的NP， 在高代谢群体中表现出来，现在首次在艾滋病毒中得到证实，可能允许允许RAAS 激活导致下游炎症和心肌损伤。我们的目标是研究心脏 与使用晚期CV的未感染个体相比，PWH中NP降低相关的表型 成像技术（心脏MRI，心脏TTE）和循环心肌生物标志物，以全面 评估心肌炎症、结构和功能。这一新的提案代表了一个实质性的 与典型的研究充分的具有相对较高NP的HF患者不同， 新发现的易患炎症或代谢紊乱的患者值得更多的临床关注， HF领域。我们还将确定沙库巴曲/缬沙坦，一种双重血管紧张素II受体拮抗剂， 和脑啡肽酶抑制剂与安慰剂对心肌炎症、结构和功能的纵向变化的影响 在一项为期6个月的随机对照试验中，这些研究在PWH的研究中应用了一个新的概念， 其中，我们假设同时增加NP和减少RAAS激活的治疗可能是 基于HIV中独特的RAAS-NP生理学，这些研究由早期的 HIV相关CVD、CV成像、HFpEF表型分型、CV生物标志物研究者和专家团队 科学和CV内分泌学将提供对CV健康至关重要的两个神经激素系统的关键见解， RAAS-NP，并测试这些系统的靶向操作是否可以降低HIV亚临床HFpEF风险。