Clinical and immunologic factors underlying heart failure with preserved ejection fraction among persons with HIV in South Africa

前提：艾滋病毒相关的心血管疾病是临床发病率的重要原因，也是成功衰老的障碍 在艾滋病毒携带者(PWH)中。到目前为止，艾滋病毒-心血管疾病的研究一直强调缺血的冠状动脉 疾病。然而，全球近80%的心血管疾病负担存在于发展中国家，70%的艾滋病毒感染者 流行于撒哈拉以南非洲(SSA)，心力衰竭(HF)是主要的心血管疾病表现。 来自高收入国家(HIC)的数据证实，慢性艾滋病毒疾病会增加风险 用于治疗心功能不全和临床心衰。我们已经证明了南非(SA)的无症状PWH 与未感染的对照组相比，CMR患者的弥漫性心肌纤维化程度更大，代表结构性 可能增加射血分数(HFpEF)保留的心衰风险的变化。这些发现支持我们的 假设在SA中接受抗逆转录病毒治疗的PWH患者发生心力衰竭的风险将增加，并将主要表现为 HFpEF。虽然已经提出了统一的HFpEF的发病机制，但其发病机制仍很复杂。 受共病的终末器官疾病的影响。这激发了人们试图将 基于并存条件的HFpEF临床“表型群”。与HIC相比， 合并疾病(例如肥胖、高血压)和其他危险因素(例如结核分枝杆菌、 物质使用)在南非这样的中低收入国家有所不同。SA中PWH独特的危险因素分析 然后将导致不同的HFpEF表型群和潜在心脏结构的变化。 方法：我们建议登记PWH和非感染对照，利用超声心动图来判定心衰。 亚组，然后确定PWH与HFpEF的队列，以更详细地研究临床和生物因素。 目标人群包括居住在南非开普敦郊外卡耶利沙镇的年龄较大的患者 ≥40年和ART与病毒抑制(如果与艾滋病毒一起生活)。标准化临床超声心动图(ECHO) 将被用来判断心衰状态，心脏磁共振(CMR)将被用来表征 心衰患者心肌纤维化的损伤类型。我们的建议包括以下具体目标： 目的1：评估SA患者心功能不全所致心力衰竭的患病率，以及HIV治疗的效果。 目的：确定慢性阻塞性肺疾病患者≥40岁的临床表型组(S)在慢性阻塞性肺疾病中的临床表型。 目的3：探讨免疫学因素对PWH患者心肌纤维化和HFpEF风险的影响。 研究和对健康的影响：该提案针对的是艾滋病毒-心血管疾病领域未得到满足的大量需求。艾滋病病毒 相关的心衰在临床上是一个重大的挑战，来自HIC的数据不能充分代表LMIC 莎拉。此外，HFpEF可由异质性病理引起，而HIV疾病可能会影响HFpEF的风险 根据潜在的风险，通过多条途径。我们的提案将决定HFpEF的负担 在PWH中，开发POC方法来识别有风险的人，并识别临床和生物学特征 这可能是在全球范围内的艾滋病毒-心血管疾病临床试验中的目标，该地区是大多数艾滋病毒流行的地区。

Premise: HIV associated CVD is a significant cause of clinical morbidity and a barrier to successful aging among persons living with HIV (PWH). To date, HIV-CVD research has emphasized ischemic coronary heart disease. However, nearly 80% of the global CVD burden exists in developing nations and 70% of the HIV epidemic exists in sub-Saharan Africa (SSA) where heart failure (HF) is the predominant CVD manifestation. Data from high income countries (HIC) has established that chronic HIV disease contributes to increased risk for ventricular dysfunction and clinical HF. We have shown that asymptomatic PWH in South Africa (SA) have greater diffuse myocardial fibrosis by CMR, when compared to uninfected controls, representing structural changes that may increase risk for HF with preserved ejection fraction (HFpEF). These findings support our hypothesis that risk for HF will be increased among PWH taking ART in SA, and will manifest predominantly as HFpEF. Unifying mechanistic features of HFpEF have been proposed but the pathogenesis is heavily influenced by the presence of co-morbid end-organ diseases. This has motivated attempts to characterize clinical `phenogroups' of HFpEF based on the profile of comorbid conditions. When compared to HICs, the relative frequencies of co-morbid conditions (e.g., obesity, hypertension) and other risk factors (e.g., mTB, substance use) differs in low-to-middle income countries like SA. The unique risk factor profiles of PWH in SA will then result in distinct HFpEF phenogroups and changes to underlying cardiac structure. Approach: We propose to enroll PWH and uninfected controls, utilize echocardiography to adjudicate HF subgroups, and then identify a cohort of PWH with HFpEF to study clinical and biologic factors in greater detail. The target population includes patients living in Khayelitsha township, outside of Cape Town, SA, who are age ≥40 years and on ART with viral suppression (if living with HIV). Standardized clinical echocardiogram (ECHO) will be used to adjudicate HF status and cardiac magnetic resonance (CMR) will be used to characterize the injury pattern of cardiac fibrosis among those with HF. Our proposal includes following specific aims: Aim 1: Estimate the prevalence of HF due to ventricular dysfunction in SA, as well as the effect of treated-HIV. Aim 2: Determine the clinical phenogroup(s) that define HFpEF among PWH on ART, age ≥40, in SA. Aim 3: Explore immunologic factors that may contribute to myocardial fibrosis and HFpEF risk in PWH. Research and Health Implications: This proposal targets a large unmet need in the HIV-CVD field. HIV associated HF is a clinically significant challenge, and data from HIC do not adequately represent LMIC like SA. In addition, HFpEF can result from heterogeneous pathologies, and HIV disease may influence HFpEF risk through multiple pathways depending on underlying risk. Our proposal will determine the burden of HFpEF among PWH, develop POC approaches for identifying those at risk, and identify clinical and biologic features that may be targeted in HIV-CVD clinical trials within a global region where most of the HIV epidemic resides.