Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content

Hyacinth M. Empinado, Gergana M. Deevska, Mariana Nikolova-Karakashian, Jeung Ki Yoo, Demetra D. Christou, Leonardo F. Ferreira

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Aims Chronic heart failure (CHF) causes inspiratory (diaphragm) muscle weakness and fatigue that contributes to dyspnoea and limited physical capacity in patients. However, the mechanisms that lead to diaphragm dysfunction in CHF remain poorly understood. Cytokines and angiotensin II are elevated in CHF and stimulate the activity of the enzyme sphingomyelinase (SMase) and accumulation of its reaction product ceramide. In the diaphragm, SMase or ceramide exposure in vitro causes weakness and fatigue. Thus, elevated SMase activity and ceramide content have been proposed as mediators of diaphragm dysfunction in CHF. In the present study, we tested the hypotheses that diaphragm dysfunction was accompanied by increases in diaphragm SMase activity and ceramide content. Methods and results Myocardial infarction was used to induce CHF in rats. We measured diaphragm isometric force, SMase activity by high-performance liquid chromatography, and ceramide subspecies and total ceramide using mass spectrometry. Diaphragm force was depressed and fatigue accelerated by CHF. Diaphragm neutral SMase activity was increased by 20% in CHF, while acid SMase activity was unchanged. We also found that CHF increased the content of C 18-, C20-, and C24-ceramide subspecies and total ceramide. Downstream of ceramide degradation, diaphragm sphingosine was unchanged, and sphingosine-1-phosphate level was increased in CHF. Conclusion Our major novel finding was that diaphragm dysfunction in CHF rats was accompanied by higher diaphragm neutral SMase activity, which is expected to cause the observed increase in diaphragm ceramide content.

Original languageEnglish
Pages (from-to)519-525
Number of pages7
JournalEuropean Journal of Heart Failure
Issue number5
StatePublished - May 2014


  • Dyspnoea
  • Force
  • Myocardial infarction
  • Skeletal muscle
  • Sphingolipids

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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