Inflammatory cytokines may contribute to endothelial dysfunction in people with untreated HIV

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A study published in the December 15th edition of the Journal of Acquired Immune Deficiency Syndromes has provided further insight into the relationship between HIV and heart disease by examining factors associated with endothelial activation. The study found higher than normal endothelial activation levels in HIV-positive people who are not taking antiretroviral therapy, but there was no evidence of an association between endothelial activation and lipoatrophy, which other researchers have suggested may be a risk factor for heart disease in HIV-positive people.

The cross-sectional observational study, conducted in the United States, utilised four arms: HIV-positive people who are taking antiretroviral therapy and who have lipoatrophy (N = 82); HIV-positive people who are taking antiretroviral therapy and who do not have lipoatrophy (N = 50); HIV-positive people who are not taking antiretroviral therapy (N = 20); and healthy controls (N = 30). The healthy control arm was group-matched with the HIV-positive antiretroviral-naive arm in regard to age and body mass index.

When the two HIV-positive arms taking antiretroviral therapy were combined and compared to the control arm, endothelial activation markers in the two groups were similar. On the other hand, the HIV-positive study participants who were not taking antiretroviral therapy had higher levels of endothelial activation markers than either of the other two groups, an indication that uncontrolled HIV replication may have a detrimental effect on endothelial functioning.

Glossary

biomarker

Genes, proteins or chemicals that can act as signals for certain diseases.

lipoatrophy

Loss of body fat from specific areas of the body, especially from the face, arms, legs, and buttocks.

cardiovascular

Relating to the heart and blood vessels.

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

cytokines

Chemical "messengers" exchanged between immune cells that affect the function of the immune system. Interleukins such as IL-2 are a particular type of cytokine.

Endothelial tissue lines the heart and blood vessels, and damage to the tissue results in enhanced endothelial activation. The consequent narrowing of the arteries, known as atherosclerosis, is an underlying cause of heart attack, stroke and other major health problems.

There are many unanswered questions about the mechanisms behind heart disease in HIV-positive people, and it is difficult to determine how various factors relate to each other. HIV itself appears to have harmful cardiovascular effects, while some of the antiretroviral medicines used to treat HIV may increase the risk of heart disease as well.

The study measured endothelial activation using three biomarkers: soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM), and von Willebrand factor (vWF). The antiretroviral-naive group had significantly higher levels of sVCAM-1 and vWF than the antiretroviral-treated group (both p ≤ 0.05). The antiretroviral-naive group had significantly higher levels of all three biomarkers than the healthy control group (sICAM-1 and sVCAM-1, p ≤ 0.05; vWF, p ≤ 0.01).

The study examined the relationship between inflammatory cytokines and endothelial dysfunction in HIV-positive people as well. One inflammatory cytokine biomarker, soluble tumor necrosis factor receptor-II (sTNFR-II), was found to correlate with all three endothelial activation biomarkers in the antiretroviral-treated group (sICAM-1, p = 0.006; sVCAM-1, p

The researchers note, “These observations suggest a role of inflammation in the enhanced endothelial activation present in HIV and may explain the detrimental effect on [cardiovascular disease] incidence seen with the … SMART study.” They are referring to a treatment-interruption study that was stopped early because people in the treatment-interruption arm were found to be at greater risk for heart disease than people in the continuous-treatment arm.

The endothelial activation study also found that levels of myeloperoxidase (MPO), an enzyme associated with heart disease in the general population, were higher among HIV-positive study participants than among healthy controls. The HIV-positive groups had correlations between MPO levels and sTNFR-II, and between MPO levels and two endothelial activation biomarkers, but the control group did not. “The determinant of MPO levels and its relationship with other CVD risks may be different in the HIV-positive population and deserves further investigation,” the researchers state.

The researchers conclude that lipoatrophy was unrelated to endothelial activation in their study population because no correlations were found between limb fat and endothelial activation biomarkers, and because endothelial activation biomarkers were similar in the lipoatrophy-antiretroviral study arm and the non-lipoatrophy-antiretroviral study arm.

HIV duration, CD4 cell count, lipid levels, glucose levels, and specific antiretroviral regimens were all found to be unrelated to endothelial activation and inflammatory cytokine levels.

While the potential cardiovascular impact of antiretroviral therapy is still being investigated, the existing evidence does not argue in favour of discontinuing treatment or delaying the initiation of treatment because of concerns about heart disease. A high HIV viral load appears to pose a much greater risk to cardiovascular health, and also is likely to bring on life-threatening opportunistic infections. HIV-positive people are encouraged to monitor their cardiovascular health carefully, especially if they have other risk factors for heart disease.

References

Ross AC et al. Endothelial activation markers are linked to HIV status and are independent of antiretroviral therapy and lipoatrophy. J Acquir Immune Defic Syndr 49: 499 – 506, 2008.