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: 10323258
• 负责人: Suman Srinivasa
• 金额: $ 84.24万
• 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/10323258
• 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; 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; antagonist; base; cardiac magnetic resonance imaging; cardiometabolism; cardioprotection; cardiovascular health; coronary fibrosis; extracellular; heart disease risk; heart function; immune activation; improved; indexing; inhibitor; 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.

项目摘要：心脏病是非传染性疾病相关发病率和发病率的主要原因