Clinical course of cardiomyopathy in HIV-infected patients with or without encephalopathy related to the myocardial expression of tumour necrosis factor-alpha and nitric oxide synthase.
ABSTRACT To define whether the development of encephalopathy influences the clinical course of HIV-associated cardiomyopathy (HIV-DCM) in relation to the myocardial expression of tumour necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS).
University hospitals and AIDS centres.
115 HIV-infected patients with echocardiographic diagnosis of HIV-associated cardiomyopathy (34 with encephalopathy and 81 without encephalopathy) were followed for a mean of 24 +/- 3.2 months. All patients underwent endomyocardial biopsy for determination of myocardial immunostaining intensity of TNF-alpha and iNOS. Cerebrospinal fluid (CSF) from patients with encephalopathy was examined for the presence of viruses. Patients underwent clinical examination every 3 months and echocardiographic examination every 6 months. The intensity of TNF-alpha and iNOS immunostaining was also evaluated on postmortem cerebral tissue of patients who died of congestive heart failure (CHF).
A greater impairment of echocardiographic parameters was observed in patients with HIV-associated cardiomyopathy after development of encephalopathy. These parameters tended to worsen progressively during the follow-up period and were inversely correlated with HIV-1 viral load, CD4 cell count, mini mental status score and the intensity of myocardial and cerebral TNF-alpha and iNOS staining. CSF specimens were available in 29 patients with encephalopathy. HIV-1 sequences were detected in CSF of all these patients with cytomegalovirus sequences in two. The mortality rate for CHF was greater among patients with encephalopathy (73% versus 12%).
The development of encephalopathy has an adverse effect on the clinical course of HIV-associated cardiomyopathy. In the relationship between cardiomyopathy and encephalopathy, the activation of iNOS by TNF-alpha may have a significant pathogenetic role in HIV disease.
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ABSTRACT: The HIV-1 accessory protein Tat has been found to exert profound effects on vascular cell behavior. Recently, Tat has been found to activate the c-Jun amino-terminal kinase (JNK1, SAPK) MAP kinase in lymphoid cells. We found that purified Tat rapidly activated JNK1 in human umbilical vein endothelial cells and ECV-304 cells, and coculture of ECV-304 cells with Tat-transfected HeLa cells resulted in persistent activation of JNK1. In addition, lower doses of Tat potentiated TNFalpha-induced JNK1 activation, although higher doses paradoxically diminished JNK1 activation by TNFalpha. Treatment of ECV-304 cells with Tat acutely increased intracellular oxidant levels, and Tat-induced oxidant activity was decreased by two structurally distinct NADPH oxidase inhibitors, diphenylene iodonium and apocynin. Both oxidase inhibitors and the thiol antioxidant N-acetyl cysteine decreased Tat-induced JNK1 activation in parallel with reduction in oxidant levels. Activation of JNK1 by Tat was also inhibited by cytochalasin B, suggesting that Tat signaling was dependent upon intact cytoskeletal function. Indeed, JNK1 activation by Tat was associated with actin microfilament rearrangement. We conclude that HIV Tat may cause acute and persistent activation of the JNK MAP kinase through activation of a specific oxidase.Virology 08/2001; 286(1):62-71. · 3.28 Impact Factor
- Journal of the Royal Society of Medicine 09/2001; 94(8):384-90. · 2.02 Impact Factor
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ABSTRACT: The role of macrophage activation, traffic, and accumulation on cardiac pathology was examined in twenty-three animals. Seventeen animals were SIV-infected, 12 were CD8-lymphocyte depleted, and the remaining 6 were uninfected controls (2 CD8-lymphocyte depleted, 4 non-depleted). None of the uninfected controls had cardiac pathology. One of five (20%) SIV-infected, non-CD8 lymphocyte depleted animals had minor cardiac pathology with increased numbers of macrophages in ventricular tissue compared to controls. Seven of the twelve (58%) SIV-infected, CD8-lymphocyte depleted animals had cardiac pathology in ventricular tissues, including macrophage infiltration and myocardial degeneration. The extent of fibrosis (measured as the percentage of collagen per tissue area), was increased 41% in SIV-infected, CD8-lymphocyte depleted animals with cardiac pathology compared to animals without pathological abnormalities. The number of CD163+ macrophage increased significantly in SIV-infected, CD8-lymphocyte depleted animals with cardiac pathology compared to ones without pathology (1.66 fold) and controls (5.42 fold). The percent of collagen (percentage of collagen per total tissue area) positively correlated with macrophage numbers in ventricular tissue in SIV-infected animals. There was an increase of BrdU+ monocytes in the heart during late SIV infection, regardless of pathology. These data implicate monocyte/macrophage activation and accumulation in the development of cardiac pathology with SIV infection.AIDS research and human retroviruses 02/2014; · 2.18 Impact Factor