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

项目摘要：心脏病是导致非传染性疾病相关发病率和 在接受良好治疗的艾滋病毒人群中，死亡率和心力衰竭保留射血分数(HFpEF)正在上升 在流行方面。目前还没有FDA批准的针对HFpEF的有效降低发病率的疗法 以及艾滋病毒或普通人群的死亡率，这突显了艾滋病患者人数的不断扩大。 重大的未得到满足的临床需求。心肌结构和功能的早期变化是公认的 无症状的艾滋病毒携带者(PWH)，影响50%-60%的人口。沉淀的确切机制 先前的心肌功能障碍，与舒张性改变、僵硬和充盈压增加有关 在HIV中，左心室以及随后进展为有症状的HFpEF的情况尚不清楚。心肌 炎症和纤维化被认为是HFpEF的重要介质，并且在机制上是相关的 在表现为慢性全身炎症和免疫激活以及代谢性疾病的PWH中 而不考虑免疫控制。我们组在PWH中进行的严格激素测试显示增加了 肾素-血管紧张素-醛固酮系统(RAAS)的激活与降钠尿肽(NP)和 炎症增加，单核/巨噬细胞活化。NPS具有心脏保护作用，并且相对 NPs减少可能会损害与钠尿、血管扩张、心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NP相对减少，这是一种表型 在高代谢组中显示，现在首次在HIV中显示，可能允许RAAS 激活导致下游炎症和心肌损伤。我们的目标是调查心脏 与使用晚期CV的未感染个体相比，PWH患者中NP降低的表型 影像技术(心脏MRI、心脏TTE)和循环心肌生物标志物 评估心肌炎症、结构和功能。这一新颖的建议代表了一项实质性的 与典型的研究充分的心力衰竭患者相比，他们的NP相对较高，可能发现一大类 新发现的易发炎或代谢紊乱的患者值得临床更多关注 高频领域。我们还将确定血管紧张素II受体双重拮抗剂萨舒比利/伐沙坦的作用。 Neprilysin抑制剂与安慰剂对心肌炎症、结构和功能纵向变化的比较 在一项为期6个月的随机对照试验中。这些研究应用了一个新的概念来研究PWH， 在这些患者中，我们假设一种同时增加NP和降低RAAS活性的治疗方法可能是 基于HIV中独特的RAAS-NP生理学，有益于心脏病。这些研究由早期阶段领导 HIV相关心血管疾病、心血管成像、HFpEF表型、心血管生物标记物的研究人员和专家团队 科学和心血管内分泌学将提供对心血管健康至关重要的两个神经激素系统的关键洞察， RAAS-NP，并测试这些系统的靶向操作是否可以降低HIV的亚临床HFpEF风险。

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.