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.

患有艾滋病毒感染的人（PLWH）对艺术的寿命更长，但事件和流行率在没有艾滋病毒的患者中，慢性疾病明显更高。今天多达50％的PLWH是据报道，与房颤有关 intlerance，以及保留的射血分数（HFPEF）的心力衰竭进展。负责 DD的机制及其在当代PLWH种群中的发展知之甚少，但是我们初步研究表明，心脏能量代谢受损可能是以前连接的核心因素报告了DD的风险因素。正常的心肌松弛和相当大的ATP是绝对必需的使用31p磁共振光谱（MRS）的临床前数据和我们的试验临床研究表明 “充满活力的肌病”是PLWH中DD的基础。此外，炎症增加了目的地 PLWH中的ART和病毒抑制作用，已知会损害线粒体功能。我们在这里提议检查心脏高能磷酸代谢，其原因及其与左心舒张功能障碍的关系 PLWH中的（DD）和DD进展。中心假设是心脏线粒体能量代谢是即使在经过良好培训的PLWH中也受到损害，并促进了DD在PLWH中的发展和发展 DD的后果包括心脏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，心力衰竭症状和改善运动表现。具体目的是1）定义休息时心肌能量异常的范围和程度，并使用31p进行运动 PLWH中的MRS/MRI，2）探测心肌线粒体和能量异常的因素在PLWH中，包括PLWH独有的人（艺术史和累积病毒史）和其他更常见的在PLWH中（炎症增加，免疫激活，胰岛素抵抗，心脏纤维化和/或心脏更高 MRI）和3）确定观察到的心肌能量的功能后果 PLWH的变化，尤其是DD的存在和进展。研究将利用专业知识，资源，并在约翰·霍普金斯（Johns Hopkins）建立了PLWH队列，并收集了新颖的心脏充满活力，舒张期功能，定量运动耐受性和生物标志物数据。这些研究的结果将带来新颖对PLWH中心肌能量异常异常的类型和程度的理解，这些因素在PLWH中普遍与心脏线粒体 - 能源新陈代谢受损最密切相关的PLWH和功能后果，最重要的是舒张功能障碍。这些研究，表征存在以及似乎是心脏和骨骼肌的“线粒体病”的功能后果 PLWH保证新途径可以更好地了解PLWH中DD的病理生理学，并建议选择并设计代谢策略，以减少与艾滋病毒疾病相关功能的个人和社会影响这个重要和不断增长的人口下降。