Endotoxin-independent white cell cytokine production in haemodynamically stable patients with idiopathic dilated cardiomyopathy.

Introduction: In heart failure, increased circulating white cell tumour necrosis factor-alpha production could be attributed to elevated plasma endotoxin concentrations or an increase in white cell sensitivity to endotoxin.

Aims: To ascertain whether, in patients with IDC, circulating white cell TNF-alpha production is also mediated through endotoxin-independent mechanisms.

Methods: Whole blood production of TNF-alpha, both with and without the presence of an endotoxin stimulus, was evaluated in 89 controls and in 60 patients with IDC in New York Heart Association functional class I, II or III heart failure and without evidence of oedema, reduced peripheral perfusion or elevated plasma endotoxin concentrations. Circulating concentrations of selected pro and anti-inflammatory factors were also measured.

Results: In patients compared to controls, IgG (p < 0.01) (IgG1 and IgG3), but not IgM concentrations were elevated, and plasma TNF-alpha and TGF-beta concentrations were raised (p < 0.001, p < 0.02 respectively). In addition, endotoxin-free cultured whole blood TNF-alpha production (p < 0.0005) was increased. Against a role for endotoxin-mediated pre-activation of white cells in patients, the sensitivity of white cells to endotoxin, as determined from the excitatory endotoxin concentration producing 50% maximal TNF-alpha production was unchanged. Moreover, in favour of non-endotoxin-mediated white cell activation, the calcineurin inhibitor, cyclosporin-A, which did not alter endotoxin-induced TNF-alpha production, decreased TNF-alpha produced by unstimulated cultured cells in patients to values not significantly greater than those in controls.

Conclusions: We concluded that circulating white cell cytokine over-production can occur through both endotoxin- dependent and -independent mechanisms in IDC.