Mechanisms of Cardiac Dysfunction in HIV and the Effect of Statins

7.项目摘要/摘要 当代艾滋病毒携带者(PLWH)患心力衰竭的相对风险增加约2.5倍 与配对的对照组。在PLWH中，心力衰竭的主要类型是心力衰竭并保留 射血分数(HFpEF)。这种类型的心力衰竭通常先于舒张期功能障碍，这种情况在 这会导致心脏左室僵硬，导致延迟松弛和充盈压力增加。 在PLWH中，舒张期功能障碍的患病率高得惊人：43%。一旦舒张期功能障碍 进展到明显的HFpEF，没有好的治疗选择。因此，存在着测试理性的强烈必要性， 可保留舒张期功能和防止进展为明显心力衰竭的安全策略 关于ART的老化的PLWH。有两个关键的过程可能有助于舒张期的发展。 艾滋病患者的功能障碍。第一种是心肌纤维化，在这种情况下，过量的胶原蛋白在心脏 心肌结构间隙。第二种是心肌脂肪变性，这是一种甘油三酯 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，与舒张期功能障碍有关。我们假设PLWH没有明显的心力衰竭，他汀类药物 治疗将减缓心肌纤维化和心肌脂肪变性的进展，保护心脏 功能。我们的主要假设是他汀类药物可以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 验证另一种假设，即他汀类药物改善脂肪代谢的作用将导致异位脂肪减少 在心脏中沉积。心脏磁共振成像/磁共振波谱(MRI/MRS) 代表了检验我们假设的黄金标准方法。我们提出了一种观察性心脏 基于MRI/MRS的研究，心脏磁共振，与正在进行的匹伐他汀与安慰剂的随机试验相结合 (缓刑)。从8个缓解点中，我们将联合登记130名年龄在40-75岁之间且无心力衰竭的PLWH患者。 除了缓期外，我们将安排在入境时和24个月内进行额外的考察访问。在这些访问中， 参与者将接受心脏MRI/MRS以及有针对性的代谢和免疫表型鉴定。我们的工作 将回答与艾滋病毒心力衰竭预防相关的科学问题，否则这些问题不会得到解决 缓期执行。如果我们证实他汀类药物可以阻止心肌纤维化和/或脂肪进展的假设 在PLWH中，我们将发现第一个有效的策略来保护HIV患者的心功能。即使是在 他汀类药物对纤维化/脂肪的无效作用，我们对易患 心功能障碍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、与年龄相关的并发症，PLWH特别容易受到这种疾病的影响， 我们的工作将对改善艾滋病毒高危人群的生活具有重要的临床意义。

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.