Apoptosis in skeletal muscle of patients with chronic heart failure: Role of inducible nitric oxide synthase, ARC and IL‐1β expression

Abstract

Background: Apoptosis (Ap) of skeletal muscle (SM) myocytes was detected in animal models of chronic heart failure (CHF) and in patients (pts) with CHF. Several in vitro studies demonstrated that inflammatory cytokines and high concentrations of nitric oxide (NO) are potent agents to induce Ap. Recently an apoptosis repressor protein ARC was found to be predominantly expressed in heartand skeletal muscle. It is still unknown which factors induce apoptosis in SM of patients with CHF. Therefore, we analyzed the expression of inflammatory cytokines, ARC and inducible nitric oxide synthase (iNOS) in SM of pts with CHF and correlated these factors with the Occurrence of Ap. Methods: SM biopsies (m. vastus lateralis) of 39 CHF pts (NYHA II-III) and 8 age-matched healthy controls were analyzed by TUNEL for the presence of Ap and by quantitative immunohistochemistry for iNOS, TNF-a, IL-IS and IFN-g. ARC expression was quatified by RT-PCR. Four sections of each biopsy were screened for apoptotic nuclei. A sample with at least 2 positive nuclei per section was classified as positive Maximal oxygen consumption (VOzmax) was determined by ergospirometry. Results: Ap was detected in 15139 (38%) CHF-pts and in none of the controls. Pts with Ap positive SM exhibited a significant lower VOzmax (15.5 f 0.9 vs 19.8 f 0.9 ml/kg min; p = 0.004), a higher iNOS expression (5.6 f 0.8 vs 2.3 rt 0.3% positive tissue area; p < O.OOl), a reduced expression of ARC (0.22 & 0.06 vs 0.40 & 0.06; p = Ol p < 0.02) compared with pts exhibiting Ap negative SM biopsies. No difference was detected between Ap positive and negative SM with respect to local expression of TNF-a and-RN-g. Furthermore a linear correlation between ARC-expression and exercise capacity was detected. Conclusion: For the first time an association between IL18 expression and Ap could be detected in SM of pts with CHF This suggests that IL-l/l and iNOS, as well as a downregulation of ARC, are possibly involved in the regulation of Ap, finally contributing to a reduced exercise capacity.