title: Sustained white cell cytokine activation in idiopathic dilated cardiomyopathy despite haemodynamic improvement with medical therapy.
abstract: Cytokine production in idiopathic dilated cardiomyopathy (IDC) may depend on neurohumoral stimulation, haemodynamic impairment or auto-antibody production. We aimed to ascertain the impact of haemodynamic improvements with standard medical therapy and neurohumoral blockade on white cell tumour necrosis factor- alpha (TNF-alpha ) production in patients with IDC. Twenty-seven patients with IDC and NYHA class I to IV heart failure but without evidence of oedema, reduced peripheral perfusion, or elevated plasma endotoxin concentrations were evaluated for indicators of cytokine activation. Plasma TNF-alpha concentrations were raised (p < 0.001) in patients prior to commencement of medical therapy as compared to controls (n = 27). In addition, endotoxin-free cultured whole blood TNF-alpha production was enhanced (p < 0.02) in the patients. Although plasma TNF-alpha tended to decrease, excessive whole blood TNF-alpha production remained unaltered following marked improvements in haemodynamics and functional class (increase in absolute left ventricular ejection fraction = 8.7 +/- 2.6%, p < 0.01, 37% in NYHA functional class I after therapy) with six to 12 months of medical therapy (diuretic, angiotensin converting enzyme inhibitor and beta-blocker). Against a role for neurohumoral substances in promoting excessive white cell TNF-alpha synthesis the angiotensin II receptor antagonist, losartan, failed to modulate white cell TNF- alpha production in patients with IDC. We concluded that white cell TNF-alpha overproduction is sustained in patients with IDC despite haemodynamic improvement with standard medical therapy and blockade of angiotensin II receptors. These data suggest that mechanisms other than haemodynamic impairment and neurohumoral activation contribute to excess white cell TNF-alpha production in IDC.
authors.affiliation: Cardiovascular Pathophysiology Research Unit, School of Physiology, University of the Witwatersrand, Chris Hani-Baragwanath Hospital, South Africa.
authors.forename: Richard
authors.initials: R
authors.lastname: Brooksbank
authors.forename: Angela
authors.initials: A
authors.lastname: Woodiwiss
authors.forename: Karen
authors.initials: K
authors.lastname: Sliwa
authors.forename: Dawn
authors.initials: D
authors.lastname: Deftereos
authors.forename: Mohammed R
authors.initials: MR
authors.lastname: Essop
authors.forename: Pinhas
authors.initials: P
authors.lastname: Sareli
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Norton
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood*; D005260:Female; D006439:Hemodynamics; D006801:Humans; D007962:Leukocytes / Q000502:physiology*; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D019808:Losartan