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.
We and others have demonstrated that patients with chronic HIV-infected are at increased risk for atherosclerotic vascular disease and heart failure. Our proposed investigations 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 insights will lead to the development of novel heart failure prevention strategies in these populations.