Mechanisms of Cardiac Dysfunction in HIV and the Effect of Statins

HIV 心脏功能障碍的机制和他汀类药物的作用

• 批准号: 9906261
• 负责人: Tomas G Neilan
• 金额: $ 65.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906261
• 关键词: Address; Aging; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Clinical; Collagen; Deposition; Detection; Development; Diagnosis; EFRAC; Enrollment; Fatty acid glycerol esters; Fibrosis; Functional disorder; Future; Gold; HIV; HIV diagnosis; Hand; Heart; Heart Rate; Heart Ventricle; Heart failure; Histology; Imaging Techniques; Immune; Impairment; In Situ; Individual; Inflammation; Left ventricular structure; Lipids; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Metabolic; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Participant; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Placebos; Prevalence; Prevention; Process; Relative Risks; Relaxation; Risk; Risk Behaviors; Risk Factors; Site; Stroke; Structure; Symptoms; Techniques; Testing; Therapeutic; Translating; Triglycerides; Viral Load result; Visit; Work; age related; aged; base; cardiogenesis; cardiometabolic risk; co-infection; cohort; comorbidity; coronary fibrosis; extracellular; heart function; heart preservation; immune activation; improved; innovation; lipid metabolism; mortality; non-invasive imaging; preservation; pressure; prevent; randomized trial

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.

7. 项目总结/摘要 当代 HIV 感染者 (PLWH) 人群发生心力衰竭的相对风险增加约 2.5 倍 与匹配的对照相比。 PLWH 心力衰竭的主要类型是保留功能的心力衰竭。 射血分数（HFpEF）。这种类型的心力衰竭通常先发生舒张功能障碍，这是一种疾病 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惊人地高：43%。一旦出现舒张功能障碍 进展为明显的 HFpEF，不存在良好的治疗选择。因此，存在着强烈的必要性来检验理性， 可以保留舒张功能并防止进展为明显心力衰竭的安全策略 接受抗逆转录病毒治疗的老年感染者。有两个关键过程可能有助于舒张压的发展 HIV 功能障碍。第一个是心肌纤维化，这是一种过量的胶原蛋白沉积在心肌中的病症。 心肌结构空间。第二种是心肌脂肪变性，甘油三酯在这种情况下 异位沉积在心肌细胞内。心肌纤维化和心肌脂肪变性均加重 在 PLWH 中，与舒张功能障碍有关。我们假设没有明显心力衰竭的 PLWH，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，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 测试另一个假设，即他汀类药物改善脂质代谢的作用将导致异位脂肪减少 沉积于心。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。我们建议观察性心脏 基于 MRI/MRS 的研究 CARDIAC-MR，与正在进行的匹伐他汀与安慰剂的随机试验相结合 （缓刑）。我们将在 8 个 REPRIEVE 站点中共同招募 130 名年龄在 40-75 岁之间且无已知心力衰竭的 PLWH。 除 REPRIEVE 之外，我们将在入职时和 24 个月内安排额外的研究访问。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分析。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，否则这些问题将无法解决 在缓刑中。如果我们证实我们的假设，即他汀类药物可以阻止心肌纤维化和/或脂肪的进展 在艾滋病病毒感染者中，我们将找到第一个保护艾滋病毒心脏功能的有效策略。即使在 他汀类药物对纤维化/脂肪无效的情况下，我们的病理途径的基线特征易于 心功能障碍将有助于确定未来预防艾滋病毒心力衰竭的有针对性的策略。 鉴于心力衰竭是一种发病率很高、与年龄相关的合并症，感染者特别容易罹患， 我们的工作将对改善感染艾滋病毒的高危人群的生活具有重大的临床意义。

项目成果

Reply: Immunosuppression Does Not Reduce Antitumor Efficacy.

答复：免疫抑制不会降低抗肿瘤功效。

• DOI: 10.1016/j.jacc.2018.06.005
• 发表时间: 2018
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Mahmood,SyedS;Sullivan,RyanJ;Reynolds,KerryL;Neilan,TomasG
• 通讯作者: Neilan,TomasG

Case-control study of heart rate abnormalities across the breast cancer survivorship continuum.

乳腺癌生存过程中心率异常的病例对照研究。

• DOI: 10.1002/cam4.1916
• 发表时间: 2019
• 期刊: Cancer medicine
• 影响因子: 4
• 作者: Groarke,JohnD;Mahmood,SyedS;Payne,David;Ganatra,Sarju;Hainer,Jon;Neilan,TomasG;Partridge,AnnH;DiCarli,MarceloF;Jones,LeeW;Mehra,MandeepR;Nohria,Anju
• 通讯作者: Nohria,Anju