Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle

Objectives. This study was designed to analyze the effect of iNOS on mitoch ondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF). Background. The molecular mechanisms underlying exerc ise intolerance in CHF are still unclear. Expression of inducible nitric ox ide synthase (iNOS) and reduced phosphocreatine resynthesis have been descr ibed in skeletal muscle of patients with CHF. However, it is unknown whethe r these phenomena are causally related to each other and to exercise tolera nce. Methods. Thirty eight patients with CHF and 8 healthy controls (C) underwen t bicycle ergospirometry and biopsy of the vastus lateralis muscle. Express ion of iNOS was quantified by immunohistochemistry and reverse-transcriptas e polymerase chain reaction, mi-CK by Western-blot. Intracellular presence of NO was confirmed by immunohistochemical quantification of nitrotyrosine (NT). To corroborate clinical findings, L6 rat skeletal myoblasts were incu bated with sodium nitroprusside (SNP). Results. Expression of iNOS was significantly increased in CHF (4.0 +/- 2.8 vs. 0.8 +/- 0.7% iNOS positive tissue area, p < 0.001 vs. C) and inversely correlated to maximal oxygen uptake (r = -0.65, p < 0.001). Intracellular NO-accumulation was confirmed by increased NT levels (13.5 +/- 8.5 vs. 2.0 +/- 1.7% NT-positive tissue area, p < 0.001 vs. C). Mi CK was decreased in CHF (0.84 +/- 0.36 vs, 1.57 +/- 0.60, p < 0.001 vs. C), The inverse correla tion seen between iNOS and mi-CK expression in patients (r = -0.68, p < 0.0 01) was reproduced in incubation experiments with SNP. Conclusions. Increased expression of iNOS in skeletal muscle of patients wi th CHF was inversely correlated with mi-CK expression and exercise capacity . Cell experiments confirmed a causal relationship via NO. These findings e xtend our knowledge of the pathophysiology of exercise intolerance in CHF, (C) 1998 by the American College of Cardiology.