This proposal describes a 4-year training program designed to develop Dr. Dominic Chow as an independent investigator in the field of cardiovascular autonomic research related to human immunodeficiency virus type 1 (HIV-1). His long term goal is to study the pathogenesis of cardiovascular disease (CVD) in HIV disease. Dr. Chow is an internist and pediatrician specializing in HIV medicine at the University of Hawaii. Findings from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial funded by the NIAID, NIH which assessed the safety and efficacy of antiretroviral structured treatment interruption (STI) strategies in a multi-center trial of 5,472 participants, showed increased morbidity and mortality from CVD in those who interrupted antiretroviral therapy (ART) compared to those who continued to utilize ART. One hypothesis to explain this relatively prompt (within months) increase in CVD risk associated with STI is that viremia induced by discontinuation of ART leads to an increase in cardiovascular autonomic dysfunction in a population already vulnerable to autonomic dysfunction. Cardiovascular autonomic dysfunction in the general population has been associated with increased arrhythmia, cardiomyopathy and acute myocardial infarction. Thus, the candidate's hypothesis is that the presence of viremia leads to increased cardiovascular autonomic dysfunction. A prospective study involving 3 groups of patients as they undergo alterations in their ART is proposed to test the critical components of this hypothesis.
The specific aims are 1) to assess and correlate autonomic function by indirect testing [cardiovagal, adrenergic, and quantitative sudomotor axon reflex (QSART) tests] to the presence or absence of plasma HIV RNA in the 3 groups of subjects undergoing changes in ART, 2) to assess and compare autonomic (sympathetic) function by direct testing [muscle sympathetic nerve activity (MSNA)] in the presence or absence of plasma HIV RNA, 3) to determine if the relationship of plasma catecholamines (dopamine, noradrenaline and adrenaline) and inflammatory markers [C-reactive protein and tumor necrosis factor] are elevated with sympathetic activity and presence or absence of plasma HIV RNA, and 4) to determine if the relationship between sympathetic activity and flow-mediated brachial artery dilation (a marker of endothelial function and early atherosclerosis development) are inversely correlated with respect to the presence or absence of plasma HIV RNA. The career development plan proposed here incorporates mentoring and a patient-oriented research experience that will provide the foundation for comprehensive clinical research. The significance of this work will be to understand the interrelationships between the autonomic nervous system and the development of CVD in HIV disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL088981-04
Application #
8107519
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Scott, Jane
Project Start
2008-09-19
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$144,990
Indirect Cost
Name
University of Hawaii
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
McIntosh, Roger C; Chow, Dominic C; Lum, Corey J et al. (2017) Reduced functional connectivity between ventromedial prefrontal cortex and insula relates to longer corrected QT interval in HIV+ and HIV- individuals. Clin Neurophysiol 128:1839-1850
Zungsontiporn, Nath; Tello, Raquel R; Zhang, Guangxiang et al. (2016) Non-Classical Monocytes and Monocyte Chemoattractant Protein-1 (MCP-1) Correlate with Coronary Artery Calcium Progression in Chronically HIV-1 Infected Adults on Stable Antiretroviral Therapy. PLoS One 11:e0149143
Chow, Dominic C; Kagihara, Jamie M; Zhang, Guangxiang et al. (2016) Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy. HIV Clin Trials 17:114-22
Chow, Dominic; Kohorn, Lindsay; Souza, Scott et al. (2016) Atazanavir use and carotid intima media thickness progression in HIV: potential influence of bilirubin. AIDS 30:672-4
Chow, Dominic; Young, Rebekah; Valcour, Nicole et al. (2015) HIV and coronary artery calcium score: comparison of the Hawaii Aging with HIV Cardiovascular Study and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts. HIV Clin Trials 16:130-8
Parikh, Nisha I; Gerschenson, Mariana; Bennett, Kara et al. (2015) Lipoprotein concentration, particle number, size and cholesterol efflux capacity are associated with mitochondrial oxidative stress and function in an HIV positive cohort. Atherosclerosis 239:50-4
O-charoen, Pichaya; Ndhlovu, Lishomwa C; Gangcuangco, Louie Mar A et al. (2014) Albuminuria is associated with elevated acute phase reactants and proinflammatory markers in HIV-infected patients receiving suppressive combination antiretroviral therapy. AIDS Res Hum Retroviruses 30:1185-91
Chow, Dominic; Nakamoto, Beau; So, Edison et al. (2013) Rates of autonomic dysfunction in HIV patients receiving antiretroviral therapy. J Neurovirol 19:511-2
Nakamoto, Beau K; Shikuma, Cecilia M; Ogata-Arakaki, Debra et al. (2013) Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder. J Neurovirol 19:601-5
Lin, Chunrong; Grandinetti, Andrew; Shikuma, Cecilia et al. (2013) The effects of extended release niacin on lipoprotein sub-particle concentrations in HIV-infected patients. Hawaii J Med Public Health 72:123-7

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