European Heart Journal Advance Access originally published online on March 12, 2007
European Heart Journal 2007 28(7):821-828; doi:10.1093/eurheartj/ehl541
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Secretory sphingomyelinase is upregulated in chronic heart failure: a second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow
1 Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany
2 Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College, London, UK
3 Department of Anesthesiology and Intensive Care, University of Jena, Germany
4 Department of Cardiology, Charité Medical School, Campus Benjamin Franklin, Berlin, Germany
5 Cardiology Department, Clinical Military Hospital, Wroclaw, Poland
Received 16 April 2006; revised 4 January 2007; accepted 25 January 2007; online publish-ahead-of-print 12 March 2007.
* Corresponding author. Tel: +49 30 450 553507; fax: +49 30 450 553951. E-mail address: wolfram.doehner{at}charite.de
See page 777 for the editorial comment on this article (doi:10.1093/eurheartj/ehm025)
Aims: Sphingomyelinases (SMase) are key regulating enzymes of the intracellular and paracrine ceramide second messenger system that mediates immune response to inflammatory cytokines and oxidative stress. Vascular endothelial cells are a rich and regulatable source of secretory SMase (S-SMase). Chronic heart failure (CHF) is a state of endothelial dysfunction and latent immune activation. The significance of S-SMase has not been studied in CHF in detail. The aim of the present study is to characterize S-SMase activity in patients with CHF in relation to disease severity and to pathophysiological characteristics such as immune activation, vasodilator capacity, and skeletal muscle function and body composition.
Methods and results: S-SMase activity was assessed by a fluorimetric method in 112 patients with CHF (age, 63 ± 11 years; NYHA class I/II/III/IV, 9/48/46/9; LVEF, 30 ± 15%; peak VO2, 18.6 ± 6.7 mL/kg/min) and in two control groups (healthy, n = 13 and hypertensive controls, n = 11). S-SMase activity was similar in both control groups (healthy, 150 ± 121 pmol/mL h; hypertensive, 157 ± 134 pmol/mL h) but was increased by >90% in CHF patients (299 ± 283 pmol/mL h; P = 0.004). S-SMase elevation was not different between ischaemic and non-ischaemic CHF and increased stepwise with NYHA class (I, 206 ± 202; II, 284 ± 242; III, 306 ± 212; IV, 440 ± 665 pmol/mL h; P = 0.003). S-SMase correlated with peak VO2 (R = –0.33, P = 0.0007) and with cytokine activation [tumour necrosis factor-
(TNF-) R = 0.22, P = 0.02; sTNF-R1 R = 0.39, P < 0.0001]. S-SMase further correlated with reduced skeletal (quadriceps) muscle strength (R = –0.46, P < 0.0001) as well as impaired peripheral vasodilator capacity (R = –0.34, P = 0.02). In detailed body composition analysis (DEXA scan), S-SMase activity was highest in patients with cardiac cachexia (405 ± 357 vs. non-cachectic patients: 233 ± 202 pmol/mL h; P = 0.0007) and related to reduced lean tissue parameters but not to fat tissue parameters. In Cox proportional hazard analysis, elevated SMase related to impaired survival, independent of age, NYHA class, and mean BP (hazard ratio 2.92; 95% confidence interval 1.035–8.24; P = 0.04).
Conclusion: S-SMase is upregulated in CHF, independent of aetiology. The association of S-SMase with clinical status, tissue amount, functional capacity of skeletal muscle tissue, and vasodilator capacity suggests that S-SMase-mediated signalling may contribute to regulatory processes of CHF pathophysiology.
Key Words: Chronic heart failure • Inflammation • SMase • Cachexia • TNF-
Co-corresponding author. Tel: +49 3641 9325860; fax: +49 3641 9325862. E-mail address: ralf.claus{at}med.uni-jena.de
These authors contributed equally to this article.
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in EHJ:
- Sphingomyelin metabolism and endothelial cell function
- Arthur C.M. Mulders, Stephan L.M. Peters, and Martin C. Michel
EHJ 2007 28: 777-779.[Extract] [Full Text]