Protease inhibitors and cardiovascular outcomes in patients with HIV-1

Holmberg, Scott D.; Moorman, Anne C.; Williamson, John; Tong, Tony C.; Ward, Douglas J.; Wood, Kathy; Greenberg, Alan E.; Janssen, Robert S.

doi:10.1016/s0140-6736(02)11672-2

Cited by 452 publications

(252 citation statements)

References 3 publications

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“…However, PIs have been associated with a rare but potentially fatal and specific prolonged QT interval, a cardiotoxicity that leads to TdP [30,31] . Over the past four years, the Food and Drug Administration (FDA) has issued warnings that ritonavir boosted with lopinavir or saquinavir may cause prolongation of the QTc and PR intervals.…”

Section: Discussionmentioning

confidence: 99%

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

et al. 2015

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Aim: Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K + channels expressed in HEK293 cells. Methods: hERG K + currents were detected using whole-cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K + channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy. Results: Application of ATV (0.01-30 μmol/L) concentration-dependently decreased hERG K + currents with an IC 50 of 5.7±1.8 μmol/L. ATV (10 μmol/L) did not affect the activation and steady-state inactivation of hERG K + currents. Compared with the wild type hERG K + channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K + currents. Overnight treatment with ATV (0.1-30 μmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core-glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane. Conclusion: ATV directly blocks hERG K + channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane.

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Section: Discussionmentioning

confidence: 99%

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

et al. 2015

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“…[4][5][6]9,10,29,30 Therefore, the study of mechanisms involved in HAART-associated cardiovascular mortality may be relevant for the development of new drugs to treat HIV infection. In this study, we showed for the first time that HAART decreases the circulating levels of TIMP-1 by approximately 65%, thus increasing pro-MMP-9/TIMP-1 ratios by 34%.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 However, HAART has also been associated with the development of metabolic complications, including dyslipidemia, insulin resistance and altered fat distribution, and with the increased concern regarding enhanced cardiovascular risk. [3][4][5][6][7][8][9][10] Indeed, endothelial dysfunction can be caused by the virus itself and by protease inhibitors, and the thymidine analogs (zidovudine and stavudine) may increase superoxide production, thus affecting the endothelial function. 11 Although the increased cardiovascular risk associated with HAART is probably because of adverse metabolic alterations that are known risk factors for cardiovascular diseases, other mechanisms may also be involved.…”

Section: Introductionmentioning

confidence: 99%

A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients

et al. 2009

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We examined whether two functional polymorphisms (g.À1562C4T and g.À90(CA)14-24) in the matrix metalloproteinase (MMP)-9 gene or MMP-9 haplotypes affect the circulating levels of pro-MMP-9 and pro-MMP-9/TIMP-1 (tissue inhibitor of metalloproteinase-1) ratios in AIDS patients, and modulate alterations in these biomarkers after highly active antiretroviral therapy (HAART). We studied 82 patients commencing HAART. Higher pro-MMP-9 concentrations and pro-MMP-9/TIMP-1 ratios were found in CT/TT patients compared with CC patients. HAART decreased pro-MMP-9 levels and pro-MMP-9/TIMP-1 ratios in CT/TT patients, it did not modify pro-MMP-9 levels and it increased pro-MMP-9/TIMP-1 ratios in CC patients. The g.À90(CA)14-24 polymorphism, however, produced no significant effects. Moreover, we found no significant differences in HAARTinduced changes in plasma pro-MMP-9, TIMP-1 and pro-MMP-9/TIMP-1 ratios when different MMP-9 haplotypes were compared. These findings suggest that the g.À1562C4T polymorphism affects pro-MMP-9 levels in patients with AIDS and modulates the alterations in pro-MMP-9 levels caused by HAART, thus possibly affecting the risk of cardiovascular complications.

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“…hypertension, diabetes or increased plasma homocysteine levels) might be at raised risk of developing coronary artery disease because of accelerated atherosclerosis. Conflicting data exist, however, on the relationship between HAART and incidence of acute coronary syndromes, such as unstable angina or myocardial infarction, among HIV-infected patients receiving PI-containing HAART [85][86][87][88][89] . Differences in the study design, selection of patients and statistical analyses might explain this disparity.…”

Section: Haart-associated Coronary Artery Diseasementioning

confidence: 99%