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CLINICAL STUDIES

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

^a Heart Center, Division of Cardiology, University of Leipzig, Leipzig, Germany

Manuscript received May 12, 1998; revised manuscript received August 17, 1998, accepted September 17, 1998.

Address for correspondence: Dr. Rainer Hambrecht, Heart Center, University of Leipzig, Dept. of Cardiology, Russenstr. 19, 04289 Leipzig, Germany
hamr{at}server3.medizin.uni-leipzig.de

Objectives. This study was designed to analyze the effect of iNOS on mitochondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF).

Background. The molecular mechanisms underlying exercise intolerance in CHF are still unclear. Expression of inducible nitric oxide synthase (iNOS) and reduced phosphocreatine resynthesis have been described in skeletal muscle of patients with CHF. However, it is unknown whether these phenomena are causally related to each other and to exercise tolerance.

Methods. Thirty-eight patients with CHF and 8 healthy controls (C) underwent bicycle ergospirometry and biopsy of the vastus lateralis muscle. Expression of iNOS was quantified by immunohistochemistry and reverse-transcriptase 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 incubated 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 correlation seen between iNOS and mi-CK expression in patients (r = –0.68, p < 0.001) was reproduced in incubation experiments with SNP.

Conclusions. Increased expression of iNOS in skeletal muscle of patients with CHF was inversely correlated with mi-CK expression and exercise capacity. Cell experiments confirmed a causal relationship via NO. These findings extend our knowledge of the pathophysiology of exercise intolerance in CHF.

Abbreviations and Acronyms   CMP = cardiomyopathy   CHF = chronic heart failure   CS = citrate synthase   DCM = dilated cardiomyopathy   iNOS = inducible nitric oxide synthase   LVEF = left ventricular ejection fraction   VO2max = maximal oxygen uptake   mi-CK = mitochondrial creatine kinase   NT = nitrotyrosine   RT = reverse transcriptase   SNP = sodium nitroprusside

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