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

Wolfram Doehner, Alexander C. Bunck, Mathias Rauchhaus, Stephan Von Haehling, Frank M. Brunkhorst, Mariantonietta Cicoira, Carsten Tschope, Piotr Ponikowski, Ralf A. Claus, Stefan D. Anker

Research output: Contribution to journalArticle

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Abstract

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-α (TNF-α) 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.

Original languageEnglish
Pages (from-to)821-828
Number of pages8
JournalEuropean Heart Journal
Volume28
Issue number7
DOIs
Publication statusPublished - Apr 2007

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Sphingomyelin Phosphodiesterase
Second Messenger Systems
Body Composition
Heart Failure
Vasodilator Agents
Skeletal Muscle
Cytokines
Control Groups
Cachexia
Ceramides
Quadriceps Muscle
Photon Absorptiometry
Muscle Strength
Oxidative Stress
Endothelial Cells
Tumor Necrosis Factor-alpha
Fats
Confidence Intervals
Muscles
Survival

Keywords

  • Cachexia
  • Chronic heart failure
  • Inflammation
  • SMase
  • TNF-α

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Doehner, Wolfram; Bunck, Alexander C.; Rauchhaus, Mathias; Von Haehling, Stephan; Brunkhorst, Frank M.; Cicoira, Mariantonietta; Tschope, Carsten; Ponikowski, Piotr; Claus, Ralf A.; Anker, Stefan D.

In: European Heart Journal, Vol. 28, No. 7, 04.2007, p. 821-828.

Research output: Contribution to journalArticle

Doehner, Wolfram ; Bunck, Alexander C. ; Rauchhaus, Mathias ; Von Haehling, Stephan ; Brunkhorst, Frank M. ; Cicoira, Mariantonietta ; Tschope, Carsten ; Ponikowski, Piotr ; Claus, Ralf A. ; Anker, Stefan D. / 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. In: European Heart Journal. 2007 ; Vol. 28, No. 7. pp. 821-828.
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abstract = "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-α (TNF-α) 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.",
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TY - JOUR

T1 - Secretory sphingomyelinase is upregulated in chronic heart failure

T2 - A second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow

AU - Doehner, Wolfram

AU - Bunck, Alexander C.

AU - Rauchhaus, Mathias

AU - Von Haehling, Stephan

AU - Brunkhorst, Frank M.

AU - Cicoira, Mariantonietta

AU - Tschope, Carsten

AU - Ponikowski, Piotr

AU - Claus, Ralf A.

AU - Anker, Stefan D.

PY - 2007/4

Y1 - 2007/4

N2 - 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-α (TNF-α) 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.

AB - 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-α (TNF-α) 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.

KW - Cachexia

KW - Chronic heart failure

KW - Inflammation

KW - SMase

KW - TNF-α

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