title: Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFalpha.
abstract: OBJECTIVE
  To investigate a role for endogenous myocardial cytokine production in the development of HIV-associated cardiomyopathy.
  
  
  METHODS
  Cardiomyopathy is a late-stage sequela of HIV infection. Although pathogenesis of this condition in HIV infection is poorly defined, inflammatory cytokines are recognized for their detrimental effects on myocardial structure and function. HIV infection is characterized by chronic immune activation and inflammatory cytokine dysregulation. As the myocardium itself is a rich potential source of inflammatory cytokines, HIV-mediated cytokine dysregulation may be an important contributor to development of HIV cardiomyopathy. An antigenic stimulation protocol conducted in the simian immunodeficiency virus (SIV) model of HIV infection was used to study the effects of endogenous cytokine production on myocardial structure and function.
  
  
  METHODS
  Twenty-six rhesus monkeys were assigned to treatment groups for a 35-day study. Animals were SIV-infected; SIV-infected and treated with killed Mycobacterium avium complex bacteria (MAC); SIV-infected, MAC-treated, and given the TNFalpha antagonist etanercept; or uninfected and MAC-treated. All animals were subjected to weekly echocardiographic studies. Hearts were collected for further evaluation at euthanasia.
  
  
  RESULTS
  SIV-infected, MAC-treated animals developed significant systolic dysfunction [left ventricular ejection fraction (LVEF) decline of 19 +/- 2%] and ventricular chamber dilatation [left ventricular end-diastolic diameter (LVEDD) increase of 26 +/- 6%] not seen in other groups. Concurrent treatment with etanercept prevented development of these changes, implicating a causative role of myocardial TNFalpha.
  
  
  CONCLUSIONS
  SIV-infected animals develop exaggerated myocardial pathology on stimulation with the ubiquitous environmental agent MAC. These responses are TNFalpha-dependent and may play a significant role in the development of cardiomyopathy in HIV infection.
authors.affiliation: University of Massachusetts, Graduate School of Biomedical Sciences, Worcester, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.forename: Keith G
authors.initials: KG
authors.lastname: Mansfield
authors.forename: Angela A L
authors.initials: AA
authors.lastname: Carville
authors.forename: George G
authors.initials: GG
authors.lastname: Sokos
authors.forename: Dongling
authors.initials: D
authors.lastname: Xia
authors.forename: Christine B
authors.initials: CB
authors.lastname: Pearson
authors.forename: Richard P
authors.initials: RP
authors.lastname: Shannon
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D018450:Disease Progression; D000068800:Etanercept; D007074:Immunoglobulin G / Q000627:therapeutic use; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D020382:Interleukin-18 / Q000097:blood; D008253:Macaca mulatta; D008297:Male; D015269:Mycobacterium avium Complex / Q000276:immunology*; D015270:Mycobacterium avium-intracellulare Infection / Q000150:complications / Q000276:immunology / Q000821:virology; D009206:Myocardium / Q000737:chemistry / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors
chemical_list: D000942:Antigens, Bacterial; D015415:Biomarkers; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D000068800:Etanercept