Cardiac Energy Metabolism and Diastolic Dysfunction in PLWH

感染者的心脏能量代谢和舒张功能障碍

基本信息

批准号：
10479599
负责人：
ROBERT G WEISS
金额：
$ 55.96万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10479599
关键词：
ATP Synthesis Pathway Acceleration Activities of Daily Living Age Atrial Fibrillation Biological Markers Body mass index Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Chronic Chronic Disease Clinical Clinical Research Creatine Kinase Data Development Diastolic blood pressure Diastolic heart failure Disease EFRAC Echocardiography Energy Metabolism Ethnic Origin Exercise Exercise Tolerance Fibrosis Frequencies Functional disorder Future General Population Glucose Intolerance HIV HIV Infections Heart Heart Diseases Heart failure Hypertension Impairment Incidence Individual Inflammation Insulin Resistance Left Left Ventricular Dysfunction Link Lipids Longitudinal Studies Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Mechanics Medicine Metabolic Metabolism Mitochondria Modeling Muscle Muscle Mitochondria Myocardial Myocardium Myopathy Outcome Patients Performance Persons Pilot Projects Population Prevalence Public Health Questionnaires Race Reaction Recording of previous events Relaxation Reporting Research Personnel Resources Rest Risk Factors Severities Skeletal Muscle Symptoms Techniques Technology Testing Therapeutic Intervention Time Tissues United States National Institutes of Health Ventricular Viral Viremia Walking Woman cardiometabolism cohort coronary fibrosis design effective therapy exercise intolerance experience factor A functional decline heart metabolism immune activation improved in vivo indexing inhibitor inorganic phosphate insight men middle age mortality novel pre-clinical preservation preventive intervention prospective randomized trial sex systemic inflammatory response

项目摘要

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.

如今，接受抗逆转录病毒治疗的艾滋病毒感染者 (PLWH) 的寿命更长，但艾滋病毒的发病率和患病率如今，50% 的感染者患有慢性疾病，其患病率明显高于未感染艾滋病毒的人。据报道患有左心室舒张功能障碍（DD），这与心房颤动、运动有关不耐受，以及进展为射血分数保留的心力衰竭（HFpEF）。 DD 的机制及其在当代 PLWH 人群中的进展尚不清楚，但我们的研究初步研究表明，心脏能量代谢受损可能是导致先前症状的一个核心因素。据报道，DD 的危险因素是正常的肌细胞松弛所必需的，而且相当大。临床前数据和我们使用 31P 磁共振波谱 (MRS) 进行的试点临床研究表明 “能量性肌病”是 PLWH DD 的基础此外，尽管合并了炎症，但炎症仍增加。已知 PLWH 中的 ART 和病毒抑制会损害线粒体功能。心脏高能磷酸代谢、其原因及其与左心室舒张功能障碍的关系 (DD) 和 PLWH 的 DD 进展核心假设是心脏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 的发生和进展以及 DD 的后果，包括通过超声心动图评估的心脏重塑和 HFpEF，增加循环心力衰竭生物标志物、心力衰竭症状和运动能力下降。目的是 1) 使用 31P 定义静息和运动时心肌能量异常的范围和程度 PLWH 中的 MRS/MRI，2) 探讨心肌线粒体和能量异常的潜在因素在 PLWH 中，包括 PLWH 特有的情况（ART 史和累积病毒史）和其他更常见的情况 PLWH（炎症增加、免疫激活、胰岛素抵抗、心脏纤维化和/或更高的心脏通过 MRI 测量肌肉脂质），以及 3）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，这些研究将利用专业知识，资源，并在约翰霍普金斯大学建立了 PLWH 队列，并收集新的心脏能量、舒张功能这些研究的结果将提供新颖的功能、定量运动耐量和生物标志物数据。了解 PLWH 心肌能量线粒体异常的类型和程度、影响因素普遍存在于 PLWH 中，与心脏线粒体能量代谢受损最密切相关，并且这些研究描述了功能后果，最重要的是舒张功能障碍。以及心肌和骨骼肌“线粒体病”的功能后果 PLWH 承诺提供新的途径来更好地了解 PLWH 中 DD 的病理生理学并建议选择和设计代谢策略，以减少艾滋病毒疾病相关功能对个人和社会的影响这一重要且不断增长的人口数量的下降。