This proposal is a training and research program devised to facilitate Dr. Hossein Bahrami's transition to an independent investigator studying the inflammatory pathways involved in pathogenesis of cardiovascular disease (CVD), with a particular emphasis on HIV-infected patients. Dr. Bahrami is a cardiologist with advanced degrees in epidemiology and biostatistics and significant experience conducting clinical research. The project aims to provide him with additional skills and knowledge required to achieve his long-term goal of studying the mechanisms and risk factors involved in development and progression of CVD in HIV-infected patients in order to develop new diagnostic, preventive, and therapeutic methods. The immediate training objectives are focused on consolidating his expertise in: (1) advanced cardiac imaging; and (2) immunological pathways of inflammation with special focus on cardiovascular disease and HIV infection. The career development plan includes close mentorship by an advisory committee consisting of carefully selected experts, didactic courses and workshops in principals of imaging, HIV immunology, faculty development, intramural conferences and seminars, and participation in national and professional meetings. The Advisory Committee offers significant expertise in cardiac imaging, HIV infection, immunology, and clinical research. The primary mentor, Dr. Michael McConnell, and the Advisory Committee will closely monitor his progress toward independence and will provide him with the guidance and the resources to guarantee his success. The proposed study leverages the extensive resources available at Stanford University to address an important public health issue, which makes it directly relevant to the NIH mission. While HIV infection continues to be a major public health problem, affecting 34 million people worldwide, successful control of the infection with antiretroviral therapy has changed the portrait of the infection from a fatal diseas to a chronic medical condition. Therefore, chronic conditions such as cardiovascular disease (CVD) increasingly become the major health concerns for these patients. It has been shown that HIV-infected patients are at higher risk of CVD, particularly myocardial fibrosis (MF) and coronary artery disease. However, the mechanisms involved in this increased risk are not clear. Of particular interest are the roles of activated monocytes, T-cells, and the possible role of CMV infection in this process. The proposed clinical study uses state-of-the-art technologies (cardiac MRI and Cytometry by Time-Of-Flight (CyTOF)), to investigate structural and functional abnormalities of the myocardium and coronary arteries and their relationship to measures of inflammation and immune cell activation in HIV infected patients. The central hypothesis is that chronic inflammation, including CMV infection, increases the risk of myocardial and coronary diseases in HIV infected patients.
The Specific Aims driven from that central hypothesis include: (1) determining clinical inflammatory factors that contribute to myocardial fibrosis and coronary disease in a cohort of treated HIV patients and matched controls; and (2) determining the phenotypes of monocytes and T cells in the HIV patients that correlate with presence of myocardial fibrosis and coronary disease.
For Aim 1, the applicant will perform myocardial and coronary MRI exams on HIV-positive patients in a well-characterized cohort at Stanford, plus matched uninfected controls, to analyze the association of the MRI findings with clinical and serum markers of inflammation, independent of ART and traditional risk factors.
For Aim 2, Dr. Bahrami will analyze pro-inflammatory cellular phenotypes (monocytes and T cells) as well as phenotypic and functional immune profiling of CMV-specific T cells in HIV patients and uninfected controls using CyTOF, which can simultaneously detect up to 42 markers. He will then analyze the relationship of CyTOF findings of immune activation, both general and CMV-specific, with the MRI measures of MF and coronary disease. These innovative and important clinical studies, utilizing state-of-the-art technologies on a well- characterized cohort, will illuminate the mechanisms leading to increased risk of CVD in HIV patients. In addition, considering HIV infection as an exaggerated state of inflammation, the findings of this study can also lead to further understanding of the role of inflammation in CVD in the general population. Achieving the proposed aims will provide strong support and guidance for developing preventive and therapeutic measures to reduce chronic inflammation in HIV-infected patients. It will also enable us to better identify HIV patients who are at higher risk for CVD. Furthermore, these studies and the described career development plan will provide a springboard for launching Dr. Bahrami's independent physician-scientist career and obtaining R01 funding.
While HIV infection continues to be a major public health problem, successful control of the infection with medical therapy has made chronic conditions such as cardiovascular diseases major health concerns for HIV infected patients. Although it is shown that HIV infected patients are at higher risk of cardiovascular diseases, the mechanisms involved in this increased risk are not clear. By studying the mechanisms leading to increased risk of cardiovascular diseases in HIV patients, the proposed study guides development of preventive and therapeutic measures to reduce cardiovascular diseases in these patients and ultimately protect and improve their health, which is one of NIH's missions.
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