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

结论：HIV相关的CVD是临床发病率的重要原因，也是成功衰老的障碍 艾滋病毒感染者（PWH）。迄今为止，HIV-CVD研究强调缺血性冠心病 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%的艾滋病负担存在于发展中国家。 流行病存在于撒哈拉以南非洲（SSA），其中心力衰竭（HF）是主要的CVD表现。 来自高收入国家的数据表明，慢性艾滋病毒疾病会增加风险 心室功能障碍和临床心力衰竭。我们已经证明，南非（SA）的无症状PWH 与未感染对照组相比，CMR显示弥漫性心肌纤维化程度更高，代表结构性 可能增加射血分数保留性心力衰竭（HFpEF）风险的变化。这些发现支持了我们的 假设在SA中接受ART的PWH中HF风险将增加，并将主要表现为 HFpEF。已经提出了HFpEF的统一机制特征，但其发病机制严重不足。 受共病终末器官疾病的影响。这促使人们试图描述 基于共病状况的HFpEF临床“表型组”。与HIC相比， 共病状况的相对频率（例如，肥胖，高血压）和其它危险因素（例如，mTB， 在低收入到中等收入国家，如南非，药物使用情况不同。SA中PWH的独特危险因素谱 然后将导致不同的HFpEF表型群和潜在心脏结构的变化。 方法：我们建议入组PWH和未感染的对照组，利用超声心动图判定HF 亚组，然后确定一组PWH与HFpEF，以更详细地研究临床和生物学因素。 目标人群包括居住在南非开普敦外Khayelitsha镇的年龄 年龄≥40岁且正在接受抗逆转录病毒治疗（如果感染艾滋病毒）。标准化临床超声心动图 将用于判定HF状态，心脏磁共振（CMR）将用于表征 HF患者心脏纤维化损伤模式。我们的建议包括以下具体目标： 目的1：评估SA患者因心室功能不全导致HF的患病率，以及HIV治疗的影响。 目的2：确定SA中年龄≥40岁接受ART的PWH中定义HFpEF的临床表型组。 目的3：探讨PWH患者心肌纤维化和HFpEF发生的免疫因素。 研究和健康的影响：这项建议的目标是在艾滋病毒-心血管疾病领域的一个大的未满足的需求。艾滋病毒 相关HF是一项具有临床意义的挑战，HIC的数据不能充分代表LMIC， SA.此外，HFpEF可能由异质性病理引起，HIV疾病可能影响HFpEF风险 通过多种途径，取决于潜在的风险。我们的建议将确定HFpEF的负担 在威尔斯亲王医院中，发展概念验证方法，以识别高危病人，并识别临床和生物特征 在全球大部分HIV流行地区的HIV-CVD临床试验中可能会有针对性。

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.