Diastolic dysfunction is associated with myocardial viral load in simian immunodeficiency virus-infected macaques

Objective:To establish the relationship between HIV-induced cardiac diastolic dysfunction, immune responses, and virus replication in the heart using the simian immunodeficiency virus (SIV)/macaque model. Design:Cardiac diastolic dysfunction is common in HIV-infected individuals including asymptomatic patients and those treated with combination antiretroviral therapy. SIV-infected macaques develop cardiac dysfunction, serving as a useful model to establish mechanisms underlying HIV-induced cardiac dysfunction. To understand the relationship between functional cardiac impairment, viral replication in the heart, and associated host inflammatory responses, cardiac function was evaluated in SIV-infected macaques and functional decline was correlated with features of the host immune response and the extent of viral replication in both the myocardium and plasma. Methods:Cardiac function was evaluated longitudinally in 22 SIV-infected and eight uninfected macaques using mitral inflow and tissue Doppler echocardiography. Myocardial macrophage populations were evaluated by CD68 and CD163 immunostaining. SIV RNA levels in both myocardium and plasma were measured by qRT-PCR. Results:Echocardiographic abnormalities developed in SIV-infected macaques that closely resembled diastolic dysfunction reported in asymptomatic HIV-infected individuals. Although CD68 and CD163 were upregulated in the myocardium of SIV-infected animals, neither macrophage marker correlated with functional decline. SIV-induced diastolic dysfunction was strongly correlated with extent of SIV replication in the myocardium, implicating virus or viral proteins in the initiation and progression of cardiac dysfunction. Conclusion:This study demonstrated a strong correlation between cardiac functional impairment and extent of SIV replication in the myocardium, suggesting that persistent viral replication in myocardial macrophages induces cardiomyocyte damage manifest as diastolic dysfunction.

[1]  N. Reinsch,et al.  Prevalence of Cardiac Diastolic Dysfunction in HIV-Infected Patients: Results of the HIV-HEART Study , 2010, HIV clinical trials.

[2]  Jeffrey N. Martin,et al.  Impact of HIV Infection on Diastolic Function and Left Ventricular Mass , 2010, Circulation. Heart failure.

[3]  J. Clements,et al.  Coordinated Regulation of SIV Replication and Immune Responses in the CNS , 2009, PloS one.

[4]  Chalak O Berzingi,et al.  P38 MAP Kinase Inhibitor Prevents Diastolic Dysfunction in Rats Following HIV gp120 Injection In vivo , 2009, Cardiovascular Toxicology.

[5]  Youxi Yuan,et al.  CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120 , 2008, Cardiovascular Toxicology.

[6]  A. Cohen,et al.  Subclinical cardiac abnormalities in human immunodeficiency virus-infected men receiving antiretroviral therapy. , 2008, The American journal of cardiology.

[7]  K. Mansfield,et al.  Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFα , 2008, AIDS.

[8]  B. Mayosi.  Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa , 2007, Heart.

[9]  D. Vittecoq,et al.  Cytokines in HIV-associated cardiomyopathy. , 2007, International journal of cardiology.

[10]  K. Mansfield,et al.  Phenotypic variation in myocardial macrophage populations suggests a role for macrophage activation in SIV-associated cardiac disease. , 2007, AIDS research and human retroviruses.

[11]  R. Hajjar,et al.  CXCR4 modulates contractility in adult cardiac myocytes. , 2006, Journal of molecular and cellular cardiology.

[12]  Thomas Unger,et al.  Quantitative real-time RT-PCR data analysis: current concepts and the novel “gene expression’s CT difference” formula , 2006, Journal of Molecular Medicine.

[13]  J. Clements,et al.  From mice to macaques--animal models of HIV nervous system disease. , 2006, Current HIV research.

[14]  S. Westmoreland,et al.  CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. , 2006, The American journal of pathology.

[15]  R. Pandey,et al.  Cardiac dysfunction in human immunodeficiency virus (HIV) infected patients in India. , 2006, International journal of cardiology.

[16]  G. Bárbaro.  HIV-associated myocarditis. , 2005, Heart failure clinics.

[17]  S. Prabhu.  Cytokine-Induced Modulation of Cardiac Function , 2004, Circulation research.

[18]  G. Bárbaro.  Pathogenesis of HIV-associated heart disease , 2003, AIDS.

[19]  J. Clements,et al.  Searching for clues: tracking the pathogenesis of human immunodeficiency virus central nervous system disease by use of an accelerated, consistent simian immunodeficiency virus macaque model. , 2002, The Journal of infectious diseases.

[20]  M. Bukrinsky,et al.  Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Clements,et al.  The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. , 2002, The Journal of infectious diseases.

[22]  D. Vlahov,et al.  Use of HIV protease inhibitors is associated with left ventricular morphologic changes and diastolic dysfunction. , 2002, Journal of acquired immune deficiency syndromes.

[23]  V. Perry,et al.  Accumulation of β‐Amyloid Precursor Protein in Axons Correlates with CNS Expression of SIV gp41 , 2002 .

[24]  T. K. van den Berg,et al.  Rat macrophages: membrane glycoproteins in differentiation and function , 2001, Immunological reviews.

[25]  S. Lipshultz,et al.  Pathogenesis of HIV‐Associated Cardiomyopathy , 2001, Annals of the New York Academy of Sciences.

[26]  M. Graves,et al.  Essential role of HIV type 1-infected and cyclooxygenase 2-activated macrophages and T cells in HIV type 1 myocarditis. , 2001, AIDS research and human retroviruses.

[27]  R. Shannon.  SIV cardiomyopathy in non-human primates. , 2001, Trends in cardiovascular medicine.

[28]  E. Pujol,et al.  Ventricular mass and diastolic function in patients infected by the human immunodeficiency virus , 2000, Heart.

[29]  Z. Xie,et al.  HIV gp120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-kappaB activation. , 2000, American journal of physiology. Heart and circulatory physiology.

[30]  R. Raddino,et al.  Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. , 2000, The Journal of infection.

[31]  M. Simon,et al.  Dilated cardiomyopathy associated with simian AIDS in nonhuman primates. , 2000, Circulation.

[32]  J. Clements,et al.  High Viral Load in the Cerebrospinal Fluid and Brain Correlates with Severity of Simian Immunodeficiency Virus Encephalitis , 1999, Journal of Virology.

[33]  G. Barbarini,et al.  Intensity of myocardial expression of inducible nitric oxide synthase influences the clinical course of human immunodeficiency virus-associated cardiomyopathy. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS (GISCA). , 1999, Circulation.

[34]  K. Shannon,et al.  Infection of human fetal cardiac myocytes by a human immunodeficiency virus-1-derived vector. , 1998, Circulation research.

[35]  L. Seghers,et al.  Assessment of ventricular diastolic function in AIDS patients from Congo: a Doppler echocardiographic study , 1998, Heart.

[36]  V. Stone,et al.  Cardiac manifestations of HIV/AIDS: a review of disease spectrum and clinical management. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[37]  F. Rocha Gonçalves,et al.  Left ventricular dysfunction in human immunodeficiency virus (HIV)-infected patients. , 1998, International journal of cardiology.

[38]  J. Clements,et al.  Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV. , 1997, The American journal of pathology.

[39]  G. Barbarini,et al.  Early impairment of systolic and diastolic function in asymptomatic HIV-positive patients: a multicenter echocardiographic and echo-Doppler study. The Gruppo Italiano Per lo Studio Cardiologico dei Pazienti Affetti da AIDS. , 1996, AIDS research and human retroviruses.

[40]  A. Herskowitz.  Cardiomyopathy and other symptomatic heart diseases associated with HIV infection. , 1996, Current opinion in cardiology.

[41]  D. Vlahov,et al.  Prevalence and incidence of left ventricular dysfunction in patients with human immunodeficiency virus infection. , 1993, The American journal of cardiology.

[42]  W. Grody,et al.  Infection of the heart by the human immunodeficiency virus. , 1990, The American journal of cardiology.

[43]  A. Van Tosh,et al.  Unsuspected cardiac abnormalities in the acquired immune deficiency syndrome. An echocardiographic study. , 1989, Chest.

[44]  N. Reichek,et al.  Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. , 1989, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[45]  D. Chernoff,et al.  Cardiac manifestations of human immunodeficiency virus infection: a two-dimensional echocardiographic study. , 1989, Journal of the American College of Cardiology.

[46]  R. Virmani,et al.  Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome. , 1988, Journal of the American College of Cardiology.

[47]  D. Kass,et al.  Determination of left ventricular end-systolic pressure-volume relationships by the conductance (volume) catheter technique. , 1986, Circulation.

[48]  F. Boccara,et al.  Prevalence of dilated cardiomyopathy in HIV-infected African patients not receiving HAART: a multicenter, observational, prospective, cohort study in Rwanda. , 2007, Current HIV research.

[49]  H. Kan,et al.  iPLA2 inhibitor blocks negative inotropic effect of HIV gp120 on cardiac myocytes. , 2006, Journal of molecular and cellular cardiology.

[50]  J. Yamate,et al.  In vivo responses of macrophages and myofibroblasts in the healing following isoproterenol-induced myocardial injury in rats , 2005, Virchows Archiv.

[51]  H. Kan,et al.  p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes. , 2004, American journal of physiology. Cell physiology.

[52]  O. Smiseth.  Assessment of ventricular diastolic function. , 2001, Canadian Journal of Cardiology.

[53]  D. Chemla,et al.  Left ventricular diastolic function in asymptomatic and symptomatic human immunodeficiency virus carriers: an echocardiographic study. , 1995, European heart journal.

[54]  E. Döpp,et al.  The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in rat recognized by monoclonal antibodies ED1, ED2 and ED3. , 1985, Advances in experimental medicine and biology.