Relationship between intracellular calcium and contractile force in stunned myocardium: Direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle

Wei Dong Gao, Dan Atar, Peter H. Backx, Eduardo Marban

Research output: Contribution to journalArticlepeer-review

Abstract

To elucidate the abnormalities of excitation-contraction coupling in stunned myocardium, we measured [Ca2+]i and force in thin fura 2-loaded ventricular trabeculae from control or stunned (20 minutes ischemia followed by 20 minutes reflow at 37°C) rat hearts. At any given [Ca2+]o, force development was significantly lower in the stunned trabeculae than in control trabeculae. In contrast, there was no difference in the amplitude of Ca2+ transients between the two groups. The steady state force-[Ca2+]i relationship, assessed by tetanization in the presence of ryanodine, revealed both a decrease in maximal Ca2+-activated force and an increase in the [Ca2+]i required for 50% activation in stunned trabeculae. Postischemic myocardium also exhibited an accelerated rate of diastolic relaxation that was not due to changes in the rate of Ca2+ transient decay. Destabilization of attached cross-bridges in a quantitative model of cardiac myofibrils accurately reproduced the salient systolic and diastolic features of the stunned phenotype, suggesting an abnormality of the thin filaments. In response to supraphysiological increases in [Ca2+]o, diastolic [Ca2+]i and diastolic tone increased much more in stunned trabeculae than in controls, with the frequent occurrence of aftercontractions. This novel experimental model lends further support to the hypothesis that the primary lesion of excitation-contraction coupling resides at the level of the contractile proteins. The finding of enhanced susceptibility to calcium overload helps to rationalize the functional deterioration of stunned myocardium during intense inotropic stimulation and additionally suggests that stunned myocardium may represent a favorable substrate for triggered arrhythmias.

Original languageEnglish (US)
Pages (from-to)1036-1048
Number of pages13
JournalCirculation research
Volume76
Issue number6
DOIs
StatePublished - Jun 1995

Keywords

  • Aftercontraction
  • Diastolic relaxation
  • Intracellular calcium
  • Myocardial ischemia/reperfusion
  • Myofilament Ca sensitivity

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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