HIV, COCAINE, AND REGIONAL LV DYSFUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV, Cocaine, and Regional LV Dysfunction ABSTRACT 1. Background 1.1. Cocaine Abuse and Its Effect on the Cardiovascular System Cardiac abnormalities reported among asymptomatic cocaine abusers include echocardiographic left ventricular (LV) hypertrophy and segmental wall motion abnormalities. Electrocardiograms may reveal increased QRS voltage, ST-T changes, and pathologic Q waves. Episodes of ST elevation may be seen during Holter monitoring. Reports of cocaine-induced myocarditis and cardiomyopathy have been reviewed. Experimental studies and clinical case reports suggest that cocaine may cause lethal arrhythmias. Cocaine prolongs repolarization by a depressant effect on potassium current and may generate early after depolarizations. Numerous reports also suggest that cocaine abuse may precipitate (LV) dysfunction. However, rigorous investigation of cocaine cardiotoxicity in humans by controlled clinical trials has proved difficult. Differences in route of administration, drug purity, and other factors may also contribute to the cardiotoxic effects of cocaine. Cocaine use was also found to be associated with LV hypertrophy. 1.2. HIV Infection and Its Effect on the Cardiovascular System Clinical manifestations of HIV-related cardiac disease are similar to those symptoms of cardiac disease from other causes. The most common cardiac complication-a dilated cardiomyopathy-will produce typical signs of congestive heart failure. Endocarditis will result in fever, murmurs, and embolic phenomena. Similarly, disseminated Kaposi's sarcoma and congestive heart failure would lead one to investigate more closely the possibility of metastatic cardiac disease. In addition, specific noncardiac symptoms may suggest an underlying cardiac pathology. For example, central nervous system toxoplasmosis with concomitant cardiomyopathy may suggest cardiac toxoplasmosis. In summary, the cardiovascular complications of HIV infection have 2 aspects. The first is complications arising from HIV infection itself (and/or its immunosuppressive effects and/or the effects of opportunistic infections); the second aspect is treatment-related metabolic abnormalities, which will be addressed later. 2. Rationale for the Proposed Study 1. The prevalence rate of heart failure continues to rise in this country, despite the decline in death rates due to cardiovascular disease in general. Most studies indicate coronary artery disease as the main determinant of heart failure, responsible for more than 50% of all cases in the United States; however, asymptomatic LV dilatation and global dysfunction have been directly linked to the eventual development of symptomatic heart failure in several clinical and epidemiologic studies. Nevertheless, the mechanisms by which etiologic and risk factors interact to determine sub-clinical cardiac failure is unknown. 2. Although several studies on HIV, cocaine, and LV dysfunction have been published, no systematic evaluation of the relationships between these factors has been conducted. Because protease inhibitors may adversely affect the development of LV dysfunction and regimens containing protease inhibitors have become standard therapy, a prospective, well-designed study is urgently needed to provide critical information in this area. 3. Blacks have a high mortality rate from cardiovascular diseases. Black HIV-infected cocaine users are underserved and understudied. 4. This study will systematically evaluate the impact of both HIV and cocaine abuse on regional and global LV dysfunction in black men and women who are HIV-infected and use cocaine, with the use of inexpensive imaging methods in conjunction with demographic, cocaine-use, and biochemical investigations. This study has the potential to provide critical information about the impact of HIV, cocaine use, and protease inhibitors on the development of LV dysfunction. 5. This study will investigate whether plasma cytokines are etiologically associated with LV dysfunction, and whether HIV and associated therapeutic regimens interact with cocaine abuse to induce and accelerate cardiomyopathy. 3. Study Design This study will enroll 400 black men and women who are HIV-positive, but free of cardiac symptoms, aged 25 to 45 years from the study cohorts established by the research team at the Infectious Disease Program, the Department of Epidemiology, the Johns Hopkins University. This study will also enroll 400 HIV-negative black men and women (200 cocaine(+) and 200 cocaine(-)). After screening to determine eligibility, 100 HIV(+), cocaine(+), and protease inhibitors(+); 100 HIV(+), cocaine(+). and protease inhibitors(-); 100 HIV(+), cocaine(-), and protease inhibitors(+); 100 HIV(+), cocaine(-), and protease inhibitors(-); 200 HIV(-) and cocaine(+); and 200 HIV(-) and cocaine(-) will be recruited into this study. During the baseline visit, the study subjects will be interviewed for cocaine use behavior and cardiovascular risk information. The following examinations will also be performed at baseline: physical examinations, electrocardiography, and echocardiography. Biochemical tests to be performed include lipid profile (total serum cholesterol, triglyceride, HDL, LDL), C-reactive protein and cytokines (TNF-?, IL-1?, and IL-6). For HIV negatives, ELISA and Western Blot will be performed to confirm HIV seronegativity. For HIV positives, viral load and CD4 count will be measured (the ALIVE study will recruit all HIV positives identified from this study and get viral load and CD4 count tested). All above-mentioned examinations and tests will be repeated 2 years later. The study subjects will be followed up for at least 2 years. 4. Study Population African Americans residing inner-city of Baltimore. 5. Outcome measures 5.1. Echocardiogram basic parameters 5.1.1.1. Basic Parameters 1. M-mode and 2-D echocardiogram: Dimensions: - Aorta: annulus diameter. - Left Ventricle: end-diastolic volume, end-systolic volume, ejection fraction (%), LV wall thickness, septum thickness, LV mass. - Left atrium: dimension. - Right ventricle: wall thickness, minor dimension. - Pulmonary artery: main PA dimension - Inferior Vena Cava: diameter. - Left ventricular segmental wall motion: 2. Doppler echocardiogram: - LV inflow: E velocity, A velocity, E/A ratio, IVRT (isovolumic relaxation time), DT (deceleration time). - RV inflow: E velocity. - RA filling (SVC, HV): systole, diastole. - LA filling (pulmonary vein): systole, diastole, atrial reversal - Cardiac valves: stenosis, regurgitation. 3. Color Doppler M-mode: Speed of propagation (slope of the black to red transition at the leading edge of the E-wave) 4. Doppler tissue imaging: Left ventricular motion velocities and times (intraventricular septum: basilar, middle, apical; posterior wall: basilar, middle, apical) 5.1.1.2. Secondary index from basic echocardiogram measurements LV pump function: - Fractional shortening. - Ejection Fraction - Rate-corrected velocity of circumferential fiber shorting. LV shape: - End-diastolic long-axis ratio LV geometry: - LV mass - Relative wall thickness (RWT) Contractility at endocardium layer: - Stress-velocity index - Stress-shortening index Contractility at mid-wall layer: - Stress-velocity index - Stress-shortening index Ventricular preload: - Functional preload index Ventricular after-load: Blood pressure. 5.2. Follow-up of Cardiovascular Events With the study subjects' consent, information regarding their visits and hospitalizations will be obtained. Throughout the study, the database will be updated with details of hospital and outpatient visits, along with interventions, to account for key events related to cardiovascular diseases, including death.