Altered myocardial force generation in end-stage human heart failure

Z. Papp, Jolanda van der Velden, A. Borbély, I. Édes, Ger J.M. Stienen

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aims: This study aimed to elucidate the molecular background of increased Ca2+ sensitivity of force production in cardiomyocytes of end-stage human heart failure. Methods and results: Ca2+-activated isometric force and the cross-bridge specific rate of force redevelopment (ktr) were determined in Triton-skinned myocytes from end-stage failing and non-failing donor hearts. Measurements (control: pH 7.2, 0 mM inorganic phosphate (Pi)) were performed under test conditions that probed either the Ca2+-regulatory function of the thin filaments (pH 6.5), the kinetics of the actin-myosin cross-bridge cycle (10 mM Pi), or both (pH 6.5, 10 mM Pi). The control maximal Ca2+-activated force (Fo) and ktrmax did not differ between failing and non-failing myocytes. At submaximal [Ca2+], however, both force and ktr were higher in failing than in donor myocytes. The difference in the Ca2+ sensitivities of force production was preserved when the thin filament regulatory function was perturbed by acidosis (pH 6.5) but was abolished by cross-bridge modulation (i.e. by Pi) both at pH 7.2 and at pH 6.5. Pi induced a larger reduction in force but a smaller increase in ktr in the failing myocytes than in the non-failing myocytes at submaximal [Ca2+]. Conclusion: The enhanced Pi sensitivity of the actin-myosin interaction suggests that the Pi release step of the actin-myosin cross-bridge cycle is modified during end-stage human heart failure. This might be of functional importance when Pi accumulates (e.g. during cardiac ischaemia). Moreover, this alteration can influence cardiac energetics and the clinical efficacy of sarcomere targeted agents in human heart failure.

Original languageEnglish
Pages (from-to)160-165
Number of pages6
JournalESC heart failure
Volume1
Issue number2
DOIs
Publication statusPublished - Jan 1 2014

Keywords

  • Actin-myosin cross-bridge cycle
  • Cardiomyocyte
  • Human heart failure
  • Myofilament

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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