Pericardial fat, inflammation, and structural heart disease in HIV

描述(由申请人提供)：与未感染艾滋病毒的对照人群相比，慢性艾滋病毒感染患者患动脉粥样硬化性血管疾病(包括心肌梗死和中风)的风险增加。脂肪组织功能障碍--包括内脏和心包脂肪肥大--可能是危险的重要因素。与已知的血管风险相比，在当前有效的联合ART时代，对内在心肌疾病或心力衰竭风险的了解较少。成像和生物标记物识别早期结构性心脏病和预测心力衰竭风险的能力在普通人群中是一个密集的研究领域，但在艾滋病毒感染人群中很少被研究。此外，在撒哈拉以南非洲，非艾滋病合并症的影响可能更大，尽管在这种情况下，对接受抗逆转录病毒治疗的患者进行的心血管疾病研究很少。这项拟议的K23研究计划的总体目标是使用生物标记物和非侵入性成像来识别患有早期结构性心脏病的艾滋病毒感染患者，并了解这些变化的机制，以便能够适当地针对风险降低疗法，并在未来开发新的预防策略。该项目旨在开发一种新的“心包脂肪评分”，在艾滋病临床试验小组的一项研究中，对360名患者进行为期3年的纵向研究，以预测心脏代谢风险。在一项对300名受试者的横断面研究中，我们将调查在俄亥俄州克利夫兰和乌干达坎帕拉，HIV感染者与年龄、性别和吸烟相匹配的HIV非感染者对照，心包脂肪是否发生改变。此外，我们还将调查心包脂肪和平均衰减是否与炎症和心脏应激的生物标记物或左心室收缩和舒张期功能的敏感指标相关。这些研究将提供一个全面的观点，说明脂肪组织、炎症、免疫激活和心脏应激的生物标记物与美国和撒哈拉以南非洲地区接受抗逆转录病毒治疗的艾滋病毒感染者的早期结构性心脏病之间的关系。这些队列将在未来对艾滋病毒的心功能和事件心力衰竭风险的纵向研究中进行跟踪。这位名叫朗格内克的私人侦探是一位杰出的候选人，他正在寻求成为艾滋病毒/艾滋病心血管并发症领域的国际公认的临床医生和调查员。他在目前和以前的研究导师的指导下，在顶级艾滋病毒/艾滋病和心血管杂志上发表文章，有着坚实的记录。他还拥有在乌干达进行临床研究的四年经验。作为一名专注于非侵入性心血管成像的心脏病专家，他处于独特的地位，能够为NHLBI艾滋病工作组战略计划(2012年9月)中概述的研究目标做出贡献。Longenecker博士得到了凯斯西储大学和大学医院心血管医学部的强有力的机构支持。他将保证75%的受保护研究时间和访问丰富的校园资源，这将确保成功过渡到独立资助的研究人员。他的雄心勃勃的培训计划包括：1)他的主要导师Grace McComsey博士以及三名心脏病学合作导师、一名生物统计学家和一组合作者的高质量指导；2)基础免疫学课程工作，重点是慢性艾滋病毒感染；2)临床研究设计和统计方面的强化培训；3)多地点跨学科团队科学经验；以及4)整合临床护理和研究项目的现场经验。

DESCRIPTION (provided by applicant): Patients with chronic HIV-infection are at increased risk for atherosclerotic vascular disease including myocardial infarction and stroke compared to HIV-uninfected control populations. Adipose tissue dysfunction-including visceral and pericardial lipohypertrophy-may be an important contributor of risk. Compared to what is known about vascular risk, less is known about intrinsic myocardial disease or risk of heart failure in the current era of effective combination ART. The ability of imaging and biomarkers to identify early structural heart disease and prognosticate heart failure risk is an area of intense investigation i the general population, but has been scarcely investigated in the HIV-infected population. Furthermore, the impact of non-AIDS comorbidities may be greater in sub-Saharan Africa, though few studies of CVD have been conducted in patients on ART in this setting. The overall objective of this proposed K23 research plan is to use biomarkers and non-invasive imaging to identify HIV-infected patients with early structural heart disease and to understand the mechanisms of these changes, so that risk-reduction therapies can be appropriately targeted and novel preventive strategies may be developed in the future. This project aims to develop a novel "pericardial fat score" that will predict cardiometabolic risk in a 3 year longitudinal cohor of 360 patients in an AIDS Clinical Trials Group study. In a cross-sectional study of 300 subjects, we will investigate whether pericardial fat is altered in HIV-infected subjects compared to age-, gender-, and smoking-matched HIV uninfected controls in Cleveland, Ohio and Kampala, Uganda. We will additionally investigate whether pericardial fat and mean attenuation correlate with biomarkers of inflammation and cardiac stress or sensitive measures of left ventricular (LV) systolic and diastolic function. These studies will provide a comprehensive view of how adipose tissue, inflammation, immune activation, and biomarkers of cardiac stress relate to early structural heart disease among HIV- infected subjects on ART in the United States and sub-Saharan Africa. These cohorts will be followed in future longitudinal studies of cardiac function and incident heart failure risk in HIV. The PI, Dr. Longenecker, is an exceptional candidate who is seeking to become an internationally recognized clinician-investigator in the field of cardiovascular complications of HIV/AIDS. He has a solid track record of publishing in top-tier HIV/AIDS and cardiovascular journals with his current and prior research mentors. He also has four years of experience conducting clinical research in Uganda. As a cardiologist with a focus in non-invasive cardiovascular imaging, he is uniquely positioned to contribute to the research goals outlined in the NHLBI's AIDS Working Group strategic plan (September 2012). Dr. Longenecker has strong institutional support from Case Western Reserve University and the Division of Cardiovascular Medicine at University Hospitals. He will have guaranteed 75% protected research time and access to a wealth of campus resources that will ensure a successful transition to independently funded investigator. His robust training plan includes: 1) high quality mentorship from his primary mentor, Dr. Grace McComsey, as well as three cardiology co-mentors, a biostatistician, and a group of collaborators; 2) coursework in fundamental immunology with a focus on chronic HIV infection; 2) intensive training in clinical research design and statistics; 3) experience in multi-site interdisciplinary team science; and 4) Field experience in integrating clinical care and research programs.