Mechanisms of Cardiac Dysfunction in HIV and the Effect of Statins

7.项目总结/摘要 当代艾滋病毒感染者（PLWH）的心力衰竭相对风险增加约2.5倍 与对照组比较。PLWH中心力衰竭的主要类型是心力衰竭， 射血分数（HFpEF）。这种类型的心力衰竭通常发生在舒张功能障碍之前，舒张功能障碍是心脏病患者的一种状况。 心脏的左心室变硬，导致舒张延迟和充盈压增加。 在PLWH中，舒张功能障碍的患病率非常高：43%。一旦舒张功能障碍 如果进展为明显的HFpEF，则不存在良好的治疗选择。因此，存在着强有力的必要性，以测试合理的， 安全的策略，可以保护舒张功能，并防止进展到明显的心力衰竭， 有两个关键过程可能有助于舒张期高血压的发展， 艾滋病病毒的功能障碍第一种是心肌纤维化，这是一种过量胶原蛋白沉积在心肌中的情况。 心肌结构间隙第二种是心肌脂肪变性，在这种情况下，甘油三酯 异位沉积在心肌细胞内。心肌纤维化和心肌脂肪变性均增加 在PLWH中，与舒张功能障碍有关。我们假设PLWH没有明显的心力衰竭，他汀类药物 治疗将减少心肌纤维化和心肌脂肪变性的进展， 功能我们的主要假设是他汀类药物抑制全身免疫激活和炎症 将转化为减少原位心肌炎症，进而减少心肌纤维化。我们还将 检验他汀类药物改善脂质代谢的作用将导致异位脂肪减少的替代假设 沉积在心脏。心脏磁共振成像/磁共振波谱（MRI/MRS） 代表了一个黄金标准的方法来测试我们的假设。我们提出了一个观察性的心脏 基于MRI/MRS的研究，CARDIAC-MR，结合正在进行的匹伐他汀与安慰剂的随机试验 （暂不执行）。我们将从8个REPRIEVE研究中心共入组130名年龄在40-75岁之间、无已知心力衰竭的PLWH。 在REPRIEVE之外，我们将在入组和24个月时安排额外的研究访视。在这些访问中， 参与者将接受心脏MRI/MRS以及靶向代谢和免疫表型分析。我们的工作 将回答与HIV心力衰竭预防相关的科学问题，否则将不会得到解决 在缓刑。如果我们证实了他汀类药物阻止心肌纤维化和/或脂肪的进展的假设， 在PLWH中，我们将发现第一个有效的策略来保护艾滋病毒感染者的心脏功能。即使在 他汀类药物对纤维化/脂肪无效的病例，我们对易患 心功能不全将有助于确定未来针对艾滋病毒心力衰竭预防的有针对性的策略。 鉴于心力衰竭是一种高度病态的、与年龄相关的合并症，PLWH特别容易受到影响， 我们的工作将对改善艾滋病毒感染者的生活有重要的临床意义。

7. Project Summary/Abstract Contemporary cohorts of people living with HIV (PLWH) have a ~ 2.5-fold increased relative risk of heart failure versus matched controls. The predominant type of heart failure among PLWH is heart failure with a preserved ejection fraction (HFpEF). This type of heart failure is typically preceded by diastolic dysfunction, a condition in which the left ventricle of the heart stiffens, resulting in delayed relaxation and increased filling pressures. Among PLWH, the prevalence of diastolic dysfunction is strikingly high: 43%. Once diastolic dysfunction has progressed to overt HFpEF, no good therapeutic options exist. Thus, strong imperatives exist to test rational, safe strategies which may preserve diastolic function and prevent progression to overt heart failure among aging PLWH on ART. There are two key processes which likely contribute to the development of diastolic dysfunction in HIV. The first is myocardial fibrosis, a condition in which excess collagen is deposited in the myocardial structural space. The second is myocardial steatosis, a condition in which triglycerides are ectopically deposited within cardiomyocytes. Myocardial fibrosis and myocardial steatosis are both increased among PLWH, in relation to diastolic dysfunction. We postulate that PLWH without overt heart failure, statin therapy will reduce the progression of myocardial fibrosis and myocardial steatosis, preserving cardiac function. Our primary hypothesis is that statin effects to dampen systemic immune activation and inflammation will translate to reduced in situ myocardial inflammation and, in turn, reduced myocardial fibrosis. We will also test an alternate hypothesis that statin effects to improve lipid metabolism will result in reduced ectopic fat deposition in the heart. Cardiac magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) represents a gold-standard approach with which to test our hypotheses. We propose an observational cardiac MRI/MRS-based study, CARDIAC-MR, integrated with an ongoing randomized trial of pitavastatin vs. placebo (REPRIEVE). From 8 REPRIEVE sites, we will co-enroll 130 PLWH aged 40-75 without known heart failure. Outside of REPRIEVE, we will orchestrate additional study visits at entry and 24 months. At these visits, participants will undergo cardiac MRI/MRS, as well as targeted metabolic and immune phenotyping. Our work will answer scientific questions relevant to heart failure prevention in HIV which will not otherwise be addressed in REPRIEVE. If we confirm our hypothesis that statins forestall progression of myocardial fibrosis and/or fat among PLWH, we will have found the first effective strategy to preserve cardiac function in HIV. Even in the case of null statin effects on fibrosis/fat, our baseline characterization of pathologic pathways predisposing to cardiac dysfunction will help identify future targeted strategies geared toward heart failure prevention in HIV. Given that heart failure is a highly morbid, age-related comorbidity to which PLWH are particularly vulnerable, our work will have significant clinical implications to improve the lives of at-risk individuals aging with HIV.