IAS 2007: Sydney, Australia; July 22-25

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The Body PRO Covers: The 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention

Insight Into the Burden of Coronary Artery Disease in HIV-Infected Patients

July 24, 2007

Starting with Keith Henry's letter to The Lancet in 19981 reporting two cases of myocardial infarction in young men on protease inhibitors (PIs), multiple studies, such as those from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study group2 and the Kaiser Permanente database,3 have reported an increased risk of myocardial infarction and endothelial dysfunction in patients on highly active antiretroviral therapy (HAART) and PIs. Despite the recognition of this risk for almost a decade, little is known about the underlying histopathology, distribution and severity of coronary artery lesions.

To better understand the histopathology of coronary artery disease (CAD) in HIV-infected individuals, Robert Micheletti and colleagues from the CARE program at the University of California, Los Angeles, studied the hearts of 66 patients who expired with advanced AIDS and compared them with the hearts from 19 HIV-uninfected controls.4

All individuals were younger than 55 years of age. Arteries were dissected at 3-mm intervals and histologically graded to determine the extent of luminal stenosis, the lipid content of atherosclerotic plaques and the extent of intimal calcification (graded on a scale from 0 to 3). Available charts were reviewed for relevant medical histories, antiretroviral therapies and risk factors for CAD.

In comparison with the HIV-uninfected controls, the 66 HIV-infected patients tended to be older (43 versus 39 years of age), and a higher proportion were male (86% versus 63%). Although a greater percentage of those with HIV infection had used cocaine, smoked and were hypertensive and fewer were overweight, none of these values were statistically significantly different from the values for control patients. However, it is important to note that the HIV-infected patients had died with advanced AIDS and were extensively HAART experienced.

The HIV-infected patients had greater stenosis per artery segment (35% versus 21%), more lipid content per atherosclerotic plaque (25% versus 11%) and a greater percentage of segments with the highest grade of stenosis (22% versus 9%) compared with HIV-uninfected individuals, not controlling for age and sex.

In addition, 35% of HIV-infected patients had severe luminal narrowing of 75% or more in at least one coronary artery compared with 16% of HIV-uninfected controls. Also among HIV-infected patients, 6% of artery segments were complicated by plaque fissure, hemorrhage or thrombus compared with 0% of artery segments from HIV-uninfected controls.

Detailed Location and Severity of Lesions Found in HIV-Infected Patients
Heart RegionMean Narrowing per Artery, % (+ SD)Arteries With > 75% Stenosis, n/N (%)Vessel Sections With Grade 2/3 Calcification, n/N (%)Mean Intimal Lipid Content, % (+ SD)
LM26.8 (+ 21.5)2/65 (3.1)20/66 (30.3)25.6 (+ 24.9)
LAD50.5 (+ 26.0)17/66 (25.8)40/66 (60.6)37.0 (+ 27.0)
LCX37.4 (+ 25.3)7/66 (10.6)20/66 (30.3)29.0 (+ 27.7)
RCA43.3 (+ 24.9)10/66 (15.2)23/66 (34.8)34.5 (+ 28.9)

LAD = left anterior descending; LCX = left circumflex; LM = left main; RCA = right coronary artery; SD = standard deviation.

After controlling for age and sex differences between HIV-infected patients and HIV-uninfected controls, the odds of at least 75% stenosis were found to be three-fold higher in the presence of HIV infection (P = .03, one-sided test). Older age and male sex were also significant predictors of at least 75% stenosis, with respective odds ratios of 1.07 and 10.08 (both P values < .001).

HIV seropositivity was associated with high-grade (i.e., grade 2 or 3) atherosclerotic calcification (odds ratio: 2.44; P = .08, one-sided test), as well as greater lipid content in atherosclerotic plaques (11% additive increase; P = .02, one-sided test).

The HIV-infected population was analyzed separately from controls to determine whether any HIV-specific factors were associated with more severe atherosclerosis. In a multivariate analysis, only older age and hypertension were significant predictors of atherosclerosis.

The duration of HIV infection, use of HAART, use of PI therapy, CD4+ cell count and viral load were not associated with more severe atherosclerosis in the multivariate analysis, although higher CD4+ cell counts and lower viral loads did predict more severe atherosclerosis in the univariate analysis.

In addition to these findings, the investigators observed two patterns of dystrophic calcification not previously described in the medical literature. The first, calcification of the internal elastic lamina of the coronary artery was associated with older age in all individuals and with a low CD4+ cell count in HIV-infected individuals. The second, calcium oxalate crystals in atherosclerotic plaques were found in three chronically ill, HIV-infected patients with no renal disease. Both of these findings are pending publication.

This is the first moderately sized study to examine at a histological level the lesions associated with the increased risk of myocardial infarction among HIV-infected individuals that has been reported in multiple case series and cohort studies. This study suggests young to middle-aged HIV-infected patients have a burden of CAD that may result in clinically significant luminal narrowing, heavy calcification and high lipid content in plaques -- characteristics that have been associated with plaque rupture and sudden cardiac death. The evidence also suggests that the odds of severe CAD may be increased for HIV-infected individuals compared with HIV-uninfected controls, even though the pattern of disease is similar between the two populations. Despite these findings, it is important to note that this small study of highly treatment-experienced patients found no evidence to suggest that HAART or specific measures of HIV disease increase the risk for significant atherosclerotic disease in HIV-infected patients.

CAD is a serious risk for HIV-infected patients, and understanding the types of lesions likely to occur and in whom they are likely to occur will certainly improve our day-to-day practice of HIV medicine. Although larger, better controlled studies are still needed to ferret out the risk of atherosclerosis in the setting of HIV infection, the risk associated with specific therapies and the pathogenesis of atherosclerosis and dystrophic calcified lesions in those with HIV infection, this excellent paper helps build the foundation for understanding CAD in the HAART era.


  1. Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery disease with protease inhibitors [letter]. Lancet. May 2, 1998;351(9112):1328.

  2. Friis-Møller N, Reiss P, El-Sadr W, et al, and the D:A:D Study Group. Exposure to PI and NNRTI and risk of myocardial infarction: results from the D:A:D Study. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colo. Abstract 144.

  3. Klein D, Hurley L, Silverberg M, Horberg M, Quesenberry C, Sidney S. Surveillance data for myocardial infarction hospitalizations among HIV+ and HIV- Northern Californians: 1994-2006. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 807.
    View poster: Download PDF

  4. Micheletti R, Fishbein G, Currier J, Singer E, Fishbein M. Coronary artery disease in HIV-infected patients. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB065.

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