Pericardial fat, inflammation, and structural heart disease in HIV

描述（由申请人提供）：与未感染HIV的对照人群相比，慢性HIV感染患者发生动脉粥样硬化性血管疾病（包括心肌梗死和卒中）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一个重要的风险因素。与已知的血管风险相比，在当前有效联合ART的时代，对内源性心肌疾病或心力衰竭风险的了解较少。成像和生物标志物识别早期结构性心脏病和急性心力衰竭风险的能力是普通人群中密集调查的一个领域，但在HIV感染人群中几乎没有调查。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ART患者进行的CVD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志物和非侵入性成像来识别患有早期结构性心脏病的HIV感染患者，并了解这些变化的机制，以便能够适当地针对降低风险的治疗方法，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”，以预测艾滋病临床试验组研究中360例患者的3年纵向队列中的心脏代谢风险。在一项300例受试者的横断面研究中，我们将调查在俄亥俄州的克利夫兰和乌干达的坎帕拉，与年龄、性别和吸烟匹配的未感染HIV的对照组相比，HIV感染受试者的心包脂肪是否发生了改变。我们还将研究心包脂肪和平均衰减是否与炎症和心脏应激的生物标志物或左心室（LV）收缩和舒张功能的敏感指标相关。这些研究将提供一个全面的观点，脂肪组织，炎症，免疫激活和心脏应激的生物标志物如何与美国和撒哈拉以南非洲接受ART的HIV感染受试者的早期结构性心脏病相关。这些队列将在未来的艾滋病毒心脏功能和突发心力衰竭风险的纵向研究中进行随访。主要研究者Longenecker博士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国际公认的临床研究者。他与现任和前任研究导师一起在顶级艾滋病毒/艾滋病和心血管期刊上发表了可靠的记录。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，他具有独特的优势，可以为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博士拥有凯斯西储大学和大学医院心血管医学部的强大机构支持。他将保证75%的研究时间受到保护，并获得丰富的校园资源，这将确保成功过渡到独立资助的研究人员。他强大的培训计划包括：1）来自他的主要导师Grace McComsey博士以及三位心脏病学共同导师，一位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，重点是慢性HIV感染; 2）临床研究设计和统计学的强化培训; 3）多中心跨学科团队科学的经验;（4）临床护理与研究项目整合的现场经验。

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.