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

• 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
• 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

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.

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 慢性病患者的死亡率明显高于未感染艾滋病毒的人。今天，多达50%的艾滋病毒携带者 据报道，左心室舒张功能障碍（DD），这是与房颤，运动 不耐受和进展为射血分数保留的心力衰竭（HFpEF）。负责 DD的机制及其在当代PLWH人群中的进展尚不清楚，但我们的研究表明， 初步的研究表明，心脏能量代谢受损可能是与先前的心脏病相关的一个中心因素。 向DD报告风险因素。ATP对于正常的肌细胞松弛是绝对必需的， 临床前数据和我们使用31 P磁共振波谱（MRS）的初步临床研究表明， “能量性肌病”作为PLWH DD的基础。此外，炎症增加，尽管结合 ART和病毒抑制PLWH，并已知损害线粒体功能。我们在此建议审查 心脏高能磷酸盐代谢及其与左室舒张功能障碍的关系 (DD)和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中也会受损，并促进PLWH中DD的发展和进展， DD的后果包括心脏重塑和超声心动图评估的HFpEF， 循环心力衰竭生物标志物、心力衰竭症状和运动能力下降。具体 目的是：1）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潜在因素 在PLWH中，包括PLWH特有的那些（ART史和累积病毒史）和其他更常见的 在PLWH中（炎症增加、免疫活化、胰岛素抵抗、心脏纤维化和/或更高的心脏功能）， 通过MRI测量肌肉脂质），以及3）确定观察到的心肌能量代谢的功能后果。 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，并在约翰霍普金斯建立PLWH队列，并收集新的心脏能量，舒张 功能、定量运动耐量和生物标志物数据。这些研究的结果将提供新颖的 了解PLWH中心肌能量线粒体异常的类型和程度， 在PLWH中普遍存在，与心脏能量代谢受损最密切相关， 最重要的是舒张功能障碍。这些研究表明， 以及心脏和骨骼肌“线粒体病”的功能后果 PLWH承诺新的途径，以更好地了解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的个人和社会影响， 这一重要且不断增长的人口的下降。