Cytokines in HIV-associated cardiomyopathy.
Among the multiple cardiac manifestations occurring in HIV-infected patients, cardiomyopathy is one of the most challenging. Its incidence has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART). Also, its pathogenesis remains relatively unclear. Although several studies demonstrated the presence of HIV genome in the heart of patients, more recent developments found that viral infection plays an indirect role only, as well as they recognized the contribution of proinflammatory cytokines in the progression of the disease. Experimental studies on animals and cultured myocytes have established the signalling pathway triggered by proinflammatory cytokines in heart failure and cardiomyopathy. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 promote expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes through activation of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappaB (NFkappaB). TNF-alpha and high concentrations of NO also induce cardiomyocyte apoptosis by TNF type 1 receptor activation. This biological framework, which is also involved in progression of cardiomyopathy in humans, is more pronounced in HIV-infected patients, in whom proinflammatory cytokines TNF-alpha, IL-1 and IL-6 are increased, resulting in an enhanced expression of cardiac iNOS, especially in patients with a low CD4 T cell count. This may account for the worse outcome of heart failure in HIV-infected patients. However, there are only few data today to support future therapeutic implications of cytokines antagonism in treatment of HIV-infected patients with cardiomyopathy. Whether modulation of TNF production or selective inhibition of p38 MAPK pathway could be useful approaches remains uncertain.
Monsuez
Jean-Jacques
JJ
AP-HP, Hôpital Paul Brousse, Department of Internal Medicine and Infectious Diseases, Université Paris-Sud 11, Faculté de Médecine, de Bicêtre, France 94804 Villejuif, France. jean-jacques.monsuez@rmb.aphp.fr
Escaut
Lelia
L
Teicher
Elina
E
Charniot
Jean-Christophe
JC
Vittecoq
Daniel
D
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004279:DNA, Viral / Q000502:physiology; D015658:HIV Infections / Q000150:complications* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics
D016207:Cytokines; D004279:DNA, Viral