Cardiac Energy Metabolism and Diastolic Dysfunction in PLWH

今天，接受抗逆转录病毒治疗的艾滋病毒感染者(PLWH)寿命更长，但 慢性病的发病率明显高于未感染艾滋病毒的人群。今天，多达50%的PLWH已经被 据报道有左室舒张功能障碍(DD)，这与心房颤动有关，运动 不耐受，以及进展为射血分数保留的心力衰竭(HFpEF)。负责任的人 现代PLWH人群中DD及其进展的机制尚不清楚，但我们的 初步研究表明，心脏能量代谢受损可能是与之前 向副署长报告危险因素。ATP对于正常的心肌细胞松弛是绝对必要的，而且相当可观 临床前数据和我们使用31P磁共振波谱(MRS)的试点临床研究表明 “能量肌病”是PLWH中DD的基础。此外，尽管联合使用，炎症仍会增加 ART和病毒抑制在PLWH中，并已知损害线粒体功能。我们建议在这里研究一下 心脏高能磷酸盐代谢、原因及其与左心舒张功能不全的关系 (DD)和PLWH的DD进展。中心假说是心肌线粒体能量代谢是 即使在治疗良好的PLWH中也会受到损害，并促进PLWH中DD的发展和进展 超声心动图评估包括心脏重构和HFpEF在内的DD的后果增加 循环中的心力衰竭生物标志物、心力衰竭症状和运动能力下降。具体的 目标是1)使用31P确定静息和运动时心肌能量异常的范围和程度 PLWH的MRS/MRI，2)探讨心肌线粒体和能量异常的相关因素 在PLWH中，包括PLWH独有的(艺术史和累积病毒史)和其他更常见的 在PLWH(炎症增加，免疫激活，胰岛素抵抗，心脏纤维化，和/或更高的心脏 肌肉脂肪)，以及3)以确定观察到的心肌能量的功能后果 PLWH的变化，特别是DD的存在和进展。这些研究将利用这些专业知识， 资源，并在约翰霍普金斯大学建立PLWH队列，收集新的心脏能量、舒张压 功能、定量运动耐量和生物标记物数据。这些研究的结果将带来新的 对PLWH心肌能量-线粒体异常类型、程度及影响因素的认识 在PLWH中普遍存在，与心肌线粒体能量代谢受损关系最密切，以及 功能性后果，最重要的是舒张期功能障碍。这些研究，描述了 以及似乎是心肌和骨骼肌“线粒体病”的功能后果 PLWH有望提供新的途径来更好地了解PLWH中DD的病理生理机制并建议选择 并设计代谢策略，以减少艾滋病毒疾病相关功能疾病对个人和社会的影响 这一重要且不断增长的人口正在减少。

People living with HIV infection (PLWH) on ART live longer today but the incidence and prevalence of chronic diseases is significantly higher that it is in those without HIV. As many as 50% of PLWH today have been reported to have left ventricular diastolic dysfunction (DD), which is associated with atrial fibrillation, exercise intolerance, and the progression to heart failure with preserved ejection fraction (HFpEF). The responsible mechanisms for DD and its progression in contemporary PLWH populations are poorly understood but our preliminary studies suggest that impaired cardiac energy metabolism may be a central factor linking previously reported risk factors to DD. ATP is absolutely required for the normal myocellular relaxation and considerable pre-clinical data and our pilot clinical studies using 31P magnetic resonance spectroscopy (MRS) suggest an “energetic myopathy” as a basis for the DD in PLWH. In addition, inflammation is increased despite combined ART and viral suppression in PLWH and is known to impair mitochondrial function. We propose here to examine cardiac high energy phosphate metabolism, its causes, and its relationship to left ventricular diastolic dysfunction (DD) and DD progression in PLWH. The central hypothesis is that cardiac mitochondrial energy metabolism is impaired even in well-treated PLWH, and promotes the development and progression of DD in PLWH as well as the consequences of DD including cardiac remodeling and HFpEF assessed with echocardiography, increased circulating heart failure biomarkers, heart failure symptoms and decreased exercise performance. The specific aims are 1) to define the scope and extent of myocardial energetic abnormalities at rest and exercise using 31P MRS/MRI in PLWH, 2) to probe the factors underlying cardiac muscle mitochondrial and energetic abnormalities in PLWH, including those unique to PLWH (ART history and cumulative viral history) and others more common in PLWH (increased inflammation, immune activation, insulin resistance, cardiac fibrosis, and/or higher cardiac muscle lipids by MRI), and 3) to determine the functional consequences of observed cardiac muscle energetic changes in PLWH, particularly the presence and progression of DD. The studies will leverage the expertise, resources, and established PLWH cohorts at Johns Hopkins and collect novel cardiac energetic, diastolic function, quantitative exercise tolerance and biomarker data. The results of these studies will deliver novel understandings of the type and extent of myocardial energetic-mitochondrial abnormalities in PLWH, the factors prevalent in PLWH that are most closely related to impaired cardiac mitochondrial-energetic metabolism, and the functional consequences, most importantly diastolic dysfunction. These studies, characterizing the presence and functional consequences of what appears to be a “mitochondriopathy” of cardiac and skeletal muscle in PLWH promise new avenues to better understand the pathophysiology of DD in PLWH and suggest the selection and design of metabolic strategies to reduce the personal and societal impact of HIV disease-related functional decline in this important and growing population.