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: 9927067
• 负责人: Suman Srinivasa
• 金额: $ 87.4万
• 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/9927067
• 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; 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.

项目摘要：心脏病是与疾病无关的发病率和 经过良好治疗的艾滋病毒人群的死亡率以及保留的射血分数（HFPEF）的心力衰竭正在上升 在患病率中。没有针对HFPEF的FDA批准的治疗剂可有效降低发病率 艾滋病毒或普通人群的死亡率，这突出了患有A的患者人群不断扩大 明显未满足的临床需求。心肌结构和功能的早期变化在 无症状的艾滋病毒（PWH）患者影响了50-60％的人口。确切的机制沉淀 先例心肌功能障碍，与放松的改变和增加的刚度和充满压力有关 左心室以及随后在艾滋病毒中症状HFPEF的进展尚不清楚。心肌 炎症和纤维化被认为是HFPEF的实质介质，并且机械上相关 在PWH中表现出慢性全身炎症和免疫激活和代谢疾病 无论免疫控制如何。 PWH中我们组的严格激素测试显示了 肾素 - 血管紧张素 - 醛固酮系统（RAAS）激活与降低的脂肪肽（NP）和 炎症和单核细胞/巨噬细胞激活增加。 NP具有心脏保护作用，相对较 减少的NP可能会损害与Natriuresis，血管舒张，肌细胞肥大和成纤维细胞有关的活动 增殖，改变心肌的稳定性。我们进一步假设相对降低的NP，一种表型 在高度代谢组中显示，现在在HIV中首次证明，可以允许RAAS 激活导致下游炎症和心肌损伤。我们旨在调查心脏 与使用晚期CV的未感染个体相比，与PWH中NP减少相关的表型 成像技术（心脏MRI，心脏TTE）和循环心肌生物标志物全面 评估心肌炎症，结构和功能。这个小说的提议代表了一个实质性的 偏离NP相对较高的典型良好研究的HF患者，可能会发现大量的HF患者 新发现的易发性炎症或代谢性患者应受到更多临床关注 HF领域。我们还将确定sacubitril/valsartan（双重血管紧张素II受体拮抗剂）的效果 和Neprilysin抑制剂，与安慰剂有关心肌炎症，结构和功能的纵向变化 在6个月的随机对照试验中的PWH中。这些研究在研究PWH时应用了一个新颖的概念， 在其中，我们假设一种同时增加NP并减少RAAS激活的疗法可能是 基于HIV中独特的RAAS-NP生理学对心脏病有益。这些研究以早期阶段领导 HIV相关CVD，CV成像，HFPEF表型，CV生物标志物的研究人员和专家团队 科学和简历内分泌学将为两个对简历健康至关重要的神经激素系统提供关键见解， RAAS-NP，并测试对这些系统的有针对性操纵是否可以降低艾滋病毒中的亚临床HFPEF风险。