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Canadian Journal of Cardiology

Coronary Artery Disease Manifestations in HIV: What, How, and Why

  • Arjun Sinha
    Affiliations
    Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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  • Matthew J. Feinstein
    Correspondence
    Corresponding author: Dr Matthew J. Feinstein, Assistant Professor of Medicine and Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, Illinois 60611, USA. Tel.: +1 312 503 8153; fax: +1-312-908-9588.
    Affiliations
    Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    Search for articles by this author
Published:December 04, 2018DOI:https://doi.org/10.1016/j.cjca.2018.11.029

      Abstract

      Understanding why persons with human immunodeficiency virus (HIV) have accelerated atherosclerosis and its sequelae, including coronary artery disease (CAD) and myocardial infarction, is necessary to provide appropriate care to a large and aging population with HIV. In this review, we delineate the diverse pathophysiologies underlying HIV-associated CAD and discuss how these are implicated in the clinical manifestations of CAD among persons with HIV. Several factors contribute to HIV-associated CAD, with chronic inflammation and immune activation likely representing the primary drivers. Increased monocyte activation, inflammation, and hyperlipidemia present in chronic HIV infection also mirror the pathophysiology of plaque rupture. Furthermore, mechanisms central to plaque erosion, such as activation of toll-like receptor 2 and formation of neutrophil extracellular traps, are also abundant in HIV. In addition to inflammation and immune activation in general, persons with HIV have a higher prevalence than uninfected persons of traditional cardiovascular risk factors, including dyslipidemia, hypertension, insulin resistance, and tobacco use. Antiretroviral therapies, although clearly necessary for HIV treatment and survival, have had varied effects on CAD, but newer generation regimens have reduced cardiovascular toxicities. From a clinical standpoint, this mix of risk factors is implicated in earlier CAD among persons with HIV than uninfected persons; whether the distribution and underlying plaque content of CAD for persons with HIV differs considerably from uninfected persons has not been definitively studied. Furthermore, the role of cardiovascular risk estimators in HIV remains unclear, as does the role of traditional and emerging therapies; no trials of CAD therapies powered to detect clinical events have been completed among persons with HIV.

      Résumé

      Il est nécessaire de comprendre pourquoi les personnes infectées par le virus de l’immunodéficience humaine (VIH) souffrent d’athérosclérose accélérée et de ses séquelles, y compris la coronaropathie et l’infarctus du myocarde, afin d’être en mesure de dispenser des soins appropriés à une population nombreuse et vieillissante de personnes vivant avec le VIH. Dans cet article de synthèse, nous distinguons les diverses physiopathologies sous-jacentes des coronaropathies associées au VIH et nous analysons leur rôle dans les manifestations cliniques des coronaropathies chez les personnes vivant avec le VIH. Plusieurs facteurs contribuent à la coronaropathie associée au VIH dont, probablement au premier chef, l’inflammation chronique et l’activation du système immunitaire. L’activation accrue des monocytes, l’inflammation et l’hyperlipidémie observées dans l’infection à VIH chronique reflètent également la physiopathologie de la rupture des plaques. De plus, les mécanismes jouant un rôle central dans l’érosion des plaques, notamment l’activation du récepteur de type Toll-2 et la formation de pièges extracellulaires des neutrophiles, sont très présents dans l’infection à VIH. En plus de l’inflammation et de l’activation du système immunitaire en général, les personnes vivant avec le VIH présentent une prévalence plus élevée de facteurs de risque cardiovasculaire que les personnes non infectées, y compris la dyslipidémie, l’hypertension, l’insulinorésistance et le tabagisme. Les thérapies antirétrovirales, malgré leur nécessité évidente pour le traitement et la survie des personnes infectées par le VIH, ont eu différents effets sur la coronaropathie, mais les schémas thérapeutiques plus récents présentent une toxicité cardiovasculaire moindre. D’un point de vue clinique, ce mélange de facteurs de risque joue un rôle dans la survenue plus précoce de la coronaropathie chez les personnes infectées par le VIH que dans la population non infectée; il n’a pas encore été déterminé si les caractéristiques de distribution et de contenu des plaques sous-jacentes de la coronaropathie chez les personnes vivant avec le VIH diffèrent considérablement de celles observées chez les personnes non infectées. De surcroît, le rôle des estimateurs du risque cardiovasculaire dans l’infection par le VIH demeure imprécis, tout comme celui des traitements classiques et des traitements émergents; aucun essai clinique sur le traitement des coronaropathies ayant la puissance nécessaire pour déceler des événements cliniques n’a été réalisé dans la population infectée par le VIH.
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      References

        • Rodger A.J.
        • Lodwick R.
        • Schechter M.
        • et al.
        • INSIGHT SMART, ESPRIT Study Groups
        Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population.
        AIDS. 2013; 27: 973-979
        • Palella Jr., F.J.
        • Baker R.K.
        • Moorman A.C.
        • et al.
        Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.
        J Acquir Immune Defic Syndr. 2006; 43: 27-34
        • Feinstein M.J.
        • Bahiru E.
        • Achenbach C.
        • et al.
        Patterns of cardiovascular mortality for HIV-infected adults in the United States: 1999 to 2013.
        Am J Cardiol. 2016; 117: 214-220
        • Sullivan P.S.
        • Jones J.S.
        • Baral S.D.
        The global north: HIV epidemiology in high-income countries.
        Curr Opin HIV AIDS. 2014; 9: 199-205
        • Triant V.A.
        • Lee H.
        • Hadigan C.
        • Grinspoon S.K.
        Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease.
        J Clin Endocrinol Metab. 2007; 92: 2506-2512
        • Durand M.
        • Sheehy O.
        • Baril J.G.
        • Lelorier J.
        • Tremblay C.L.
        Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec's public health insurance database.
        J Acquir Immune Defic Syndr. 2011; 57: 245-253
        • Freiberg M.S.
        • Chang C.C.
        • Kuller L.H.
        • et al.
        HIV infection and the risk of acute myocardial infarction.
        JAMA Intern Med. 2013; 173: 614-622
        • Seecheran V.K.
        • Giddings S.L.
        • Seecheran N.A.
        Acute coronary syndromes in patients with HIV.
        Coron Artery Dis. 2017; 28: 166-172
        • Mirza F.S.
        • Luthra P.
        • Chirch L.
        Endocrinological aspects of HIV infection.
        J Endocrinol Invest. 2018; 41: 881-899
        • Bourgi K.
        • Wanjalla C.
        • Koethe J.R.
        Inflammation and metabolic complications in HIV.
        Curr HIV/AIDS Rep. 2018; 15: 371-381
        • Veloso S.
        • Escote X.
        • Ceperuelo-Mallafre V.
        • et al.
        Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy.
        Cytokine. 2012; 58: 253-260
        • Armah K.A.
        • Chang C.C.
        • Baker J.V.
        • et al.
        Veterans Aging Cohort Study (VAC) Project Team. Prehypertension, hypertension, and the risk of acute myocardial infarction in HIV-infected and -uninfected veterans.
        Clin Infect Dis. 2014; 58: 121-129
        • Fahme S.A.
        • Bloomfield G.S.
        • Peck R.
        Hypertension in HIV-infected adults: novel pathophysiologic mechanisms.
        Hypertension. 2018; 72: 44-55
        • Riddler S.A.
        • Smit E.
        • Cole S.R.
        • et al.
        Impact of HIV infection and HAART on serum lipids in men.
        JAMA. 2003; 289: 2978-2982
        • Phillips A.N.
        • Carr A.
        • Neuhaus J.
        • et al.
        Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial.
        Antivir Ther. 2008; 13: 177-187
        • Mdodo R.
        • Frazier E.L.
        • Dube S.R.
        • et al.
        Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys.
        Ann Intern Med. 2015; 162: 335-344
        • Rahmanian S.
        • Wewers M.E.
        • Koletar S.
        • et al.
        Cigarette smoking in the HIV-infected population.
        Proc Am Thorac Soc. 2011; 8: 313-319
        • Okeke N.L.
        • Chin T.
        • Clement M.
        • Chow S.C.
        • Hicks C.B.
        Coronary artery disease risk reduction in HIV-infected persons: a comparative analysis.
        AIDS Care. 2016; 28: 475-482
        • Henry K.
        • Melroe H.
        • Huebsch J.
        • et al.
        Severe premature coronary artery disease with protease inhibitors.
        Lancet. 1998; 351: 1328
        • Behrens G.
        • Schmidt H.
        • Meyer D.
        • Stoll M.
        • Schmidt R.E.
        Vascular complications associated with use of HIV protease inhibitors.
        Lancet. 1998; 351: 1958
        • Coplan P.M.
        • Nikas A.
        • Japour A.
        • et al.
        Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors.
        AIDS Res Hum Retroviruses. 2003; 19: 449-455
        • Friis-Moller N.
        • Reiss P.
        • Sabin C.A.
        • et al.
        Class of antiretroviral drugs and the risk of myocardial infarction.
        N Engl J Med. 2007; 356: 1723-1735
        • Friis-Moller N.
        • Sabin C.A.
        • Weber R.
        • et al.
        Combination antiretroviral therapy and the risk of myocardial infarction.
        N Engl J Med. 2003; 349: 1993-2003
        • Thienemann F.
        • Sliwa K.
        • Rockstroh J.K.
        HIV and the heart: the impact of antiretroviral therapy: a global perspective.
        Eur Heart J. 2013; 34: 3538-3546
        • Lang S.
        • Mary-Krause M.
        • Cotte L.
        • et al.
        Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4.
        Arch Intern Med. 2010; 170: 1228-1238
        • Lundgren J.D.
        • Babiker A.G.
        • Gordin F.
        • et al.
        Initiation of antiretroviral therapy in early asymptomatic HIV infection.
        N Engl J Med. 2015; 373: 795-807
        • Baker J.V.
        • Sharma S.
        • Achhra A.C.
        • et al.
        INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) START (Strategic Timing of Antiretroviral Treatment) Study Group. Changes in cardiovascular disease risk factors with immediate versus deferred antiretroviral therapy initiation among HIV-positive participants in the START (Strategic Timing of Antiretroviral Treatment) Trial.
        J Am Heart Assoc. 2017; 6
        • Duprez D.A.
        • Neuhaus J.
        • Kuller L.H.
        • et al.
        Inflammation, coagulation and cardiovascular disease in HIV-infected individuals.
        PLoS One. 2012; 7: e44454
        • Tabib A.
        • Greenland T.
        • Mercier I.
        • Loire R.
        • Mornex J.F.
        Coronary lesions in young HIV-positive subjects at necropsy.
        Lancet. 1992; 340: 730
        • Post W.S.
        • Budoff M.
        • Kingsley L.
        • et al.
        Associations between HIV infection and subclinical coronary atherosclerosis.
        Ann Intern Med. 2014; 160: 458-467
        • Lo J.
        • Abbara S.
        • Shturman L.
        • et al.
        Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men.
        AIDS. 2010; 24: 243-253
        • Boccara F.
        • Mary-Krause M.
        • Teiger E.
        • et al.
        Prognosis of Acute Coronary Syndrome in HIV-infected patients (PACS) Investigators. Acute coronary syndrome in human immunodeficiency virus-infected patients: characteristics and 1 year prognosis.
        Eur Heart J. 2011; 32: 41-50
        • Zanni M.V.
        • Abbara S.
        • Lo J.
        • et al.
        Increased coronary atherosclerotic plaque vulnerability by coronary computed tomography angiography in HIV-infected men.
        AIDS. 2013; 27: 1263-1272
        • O'Dwyer E.J.
        • Bhamra-Ariza P.
        • Rao S.
        • et al.
        Lower coronary plaque burden in patients with HIV presenting with acute coronary syndrome.
        Open Heart. 2016; 3: e000511
        • Hanna D.B.
        • Lin J.
        • Post W.S.
        • et al.
        Association of macrophage inflammation biomarkers with progression of subclinical carotid artery atherosclerosis in HIV-infected women and men.
        J Infect Dis. 2017; 215: 1352-1361
        • Kearns A.
        • Gordon J.
        • Burdo T.H.
        • Qin X.
        HIV-1-associated atherosclerosis: unraveling the missing link.
        J Am Coll Cardiol. 2017; 69: 3084-3098
        • Quillard T.
        • Franck G.
        • Mawson T.
        • Folco E.
        • Libby P.
        Mechanisms of erosion of atherosclerotic plaques.
        Curr Opin Lipidol. 2017; 28: 434-441
        • Delgado-Rizo V.
        • Martinez-Guzman M.A.
        • Iniguez-Gutierrez L.
        • et al.
        Neutrophil extracellular traps and its implications in inflammation: an overview.
        Front Immunol. 2017; 8: 81
        • Quillard T.
        • Araujo H.A.
        • Franck G.
        • et al.
        TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion.
        Eur Heart J. 2015; 36: 1394-1404
        • Franck G.
        • Mawson T.
        • Sausen G.
        • et al.
        Flow perturbation mediates neutrophil recruitment and potentiates endothelial injury via TLR2 in mice: implications for superficial erosion.
        Circ Res. 2017; 121: 31-42
        • Henrick B.M.
        • Yao X.D.
        • Rosenthal K.L.
        HIV-1 structural proteins serve as PAMPs for TLR2 heterodimers significantly increasing infection and innate immune activation.
        Front Immunol. 2015; 6: 426
        • Cerrato E.
        • Calcagno A.
        • D'Ascenzo F.
        • et al.
        Cardiovascular disease in HIV patients: from bench to bedside and backwards.
        Open Heart. 2015; 2: e000174
        • Lopez M.
        • San Roman J.
        • Estrada V.
        • et al.
        Endothelial dysfunction in HIV infection--the role of circulating endothelial cells, microparticles, endothelial progenitor cells and macrophages.
        AIDS Rev. 2012; 14: 223-230
        • Becker A.C.
        • Sliwa K.
        • Stewart S.
        • et al.
        Acute coronary syndromes in treatment-naive black South Africans with human immunodeficiency virus infection.
        J Interv Cardiol. 2010; 23: 70-77
        • Sliwa K.
        • Carrington M.J.
        • Becker A.
        • et al.
        Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study cohort.
        Eur Heart J. 2012; 33: 866-874
        • Crea F.
        • Camici P.G.
        • Bairey Merz C.N.
        Coronary microvascular dysfunction: an update.
        Eur Heart J. 2014; 35: 1101-1111
        • Lerman A.
        • Holmes D.R.
        • Herrmann J.
        • Gersh B.J.
        Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both?.
        Eur Heart J. 2007; 28: 788-797
        • Sinha A.
        • Ma Y.
        • Scherzer R.
        • et al.
        Role of T-cell dysfunction, inflammation, and coagulation in microvascular disease in HIV.
        J Am Heart Assoc. 2016; 5
        • Hsue P.Y.
        • Giri K.
        • Erickson S.
        • et al.
        Clinical features of acute coronary syndromes in patients with human immunodeficiency virus infection.
        Circulation. 2004; 109: 316-319
        • D'Ascenzo F.
        • Cerrato E.
        • Biondi-Zoccai G.
        • et al.
        Acute coronary syndromes in human immunodeficiency virus patients: a meta-analysis investigating adverse event rates and the role of antiretroviral therapy.
        Eur Heart J. 2012; 33: 875-880
        • Peyracchia M.
        • De Lio G.
        • Montrucchio C.
        • et al.
        Evaluation of coronary features of HIV patients presenting with ACS: The CUORE, a multicenter study.
        Atherosclerosis. 2018; 274: 218-226
        • D'Ascenzo F.
        • Cerrato E.
        • Appleton D.
        • et al.
        Prognostic indicators for recurrent thrombotic events in HIV-infected patients with acute coronary syndromes: use of registry data from 12 sites in Europe, South Africa and the United States.
        Thromb Res. 2014; 134: 558-564
        • Crane H.M.
        • Paramsothy P.
        • Drozd D.R.
        • et al.
        Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) Cohort. Types of Myocardial infarction among human immunodeficiency virus-infected individuals in the United States.
        JAMA Cardiol. 2017; 2: 260-267
        • Ren X.
        • Trilesskaya M.
        • Kwan D.M.
        • et al.
        Comparison of outcomes using bare metal versus drug-eluting stents in coronary artery disease patients with and without human immunodeficiency virus infection.
        Am J Cardiol. 2009; 104: 216-222
        • Boccara F.
        • Cohen A.
        • Di Angelantonio E.
        • et al.
        French Italian Study on Coronary Artery Disease in AIDS Patients (FRISCA-2). Coronary artery bypass graft in HIV-infected patients: a multicenter case control study.
        Curr HIV Res. 2008; 6: 59-64
        • Feinstein M.J.
        • Mitter S.S.
        • Yadlapati A.
        • et al.
        HIV-related myocardial vulnerability to infarction and coronary artery disease.
        J Am Coll Cardiol. 2016; 68: 2026-2027
        • Feinstein M.J.
        • Poole B.
        • Engel Gonzalez P.
        • et al.
        Differences by HIV serostatus in coronary artery disease severity and likelihood of percutaneous coronary intervention following stress testing.
        J Nucl Cardiol. 2018; 25: 872-883
        • Aberg J.A.
        • Gallant J.E.
        • Ghanem K.G.
        • et al.
        Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America.
        Clin Infect Dis. 2014; 58: e1-e34
        • Feinstein M.J.
        • Achenbach C.J.
        • Stone N.J.
        • Lloyd-Jones D.M.
        A systematic review of the usefulness of statin therapy in HIV-infected patients.
        Am J Cardiol. 2015; 115: 1760-1766
        • Egan G.
        • Hughes C.A.
        • Ackman M.L.
        Drug interactions between antiplatelet or novel oral anticoagulant medications and antiretroviral medications.
        Ann Pharmacother. 2014; 48: 734-740
        • Lang S.
        • Mary-Krause M.
        • Cotte L.
        • et al.
        French Hospital Database on HIV-ANRS CO4. Increased risk of myocardial infarction in HIV-infected patients in France, relative to the general population.
        AIDS. 2010; 24: 1228-1230
        • Womack J.A.
        • Chang C.C.
        • So-Armah K.A.
        • et al.
        HIV infection and cardiovascular disease in women.
        J Am Heart Assoc. 2014; 3: e001035
        • Fitch K.V.
        • Srinivasa S.
        • Abbara S.
        • et al.
        Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women.
        J Infect Dis. 2013; 208: 1737-1746
        • Volpe M.
        • Uglietti A.
        • Castagna A.
        • et al.
        Cardiovascular disease in women with HIV-1 infection.
        Int J Cardiol. 2017; 241: 50-56
        • Feinstein M.J.
        Cardiovascular disease risk assessment in HIV: navigating data-sparse zones.
        Heart. 2016; 102: 1157-1158
        • Feinstein M.J.
        • Nance R.M.
        • Drozd D.R.
        • et al.
        Assessing and refining myocardial infarction risk estimation among patients with human immunodeficiency virus: a study by the Centers for AIDS Research Network of Integrated Clinical Systems.
        JAMA Cardiol. 2017; 2: 155-162
        • Triant V.A.
        • Perez J.
        • Regan S.
        • et al.
        Cardiovascular risk prediction functions underestimate risk in HIV infection.
        Circulation. 2018; 137: 2203-2214
        • Friis-Moller N.
        • Ryom L.
        • Smith C.
        • et al.
        • D:A:D study group
        An updated prediction model of the global risk of cardiovascular disease in HIV-positive persons: The Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study.
        Eur J Prev Cardiol. 2016; 23: 214-223
        • Lo J.
        • Lu M.T.
        • Ihenachor E.J.
        • et al.
        Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial.
        Lancet HIV. 2015; 2: e52-e63