Pathophysiology and Pathogenesis of Contractile Failure in Stunned Myocardium

To investigate excitation-contraction coupling in stunned myocardium, intracellular free calcium concentration ([Ca²⁺]_i) was measured before and after ischemia in perfused hearts using gated ¹⁹F NMR and the Ca²⁺ indicator 5F-BAPTA. Maximal Ca²⁺-activated force was also measured in parallel experiments. Stunned myocardium was created by reperfusion after 15 min global ischemia at 37°C in isolated ferret hearts. In stunned myocardium, peak [Ca²⁺]_i was paradoxically higher than that in control, but maximal Ca²⁺-activated pressure was lower in stunned hearts. These results indicate that contractile failure in stunned myocardium is due to a decrease in the myofilament sensitivity to Ca²⁺ as well as to a decrease in maximal Ca²⁺-activated force; failure of activator Ca²⁺ delivery cannot be implicated. The role of intracellular calcium overload in the pathogenesis of stunned myocardium was also investigated. Time-averaged ¹⁹F NMR measurements directly revealed the increase in [Ca²⁺]_i during ischemia and in the early phase of reperfusion. The strategies to prevent Ca overload during reperfusion with modified reperfusate succeeded in preserving contractile function. Transient Ca overload without ischemia induced by different causes, i.e., high [Ca]₀ perfusion, ventricular fibrillation or treatment with adriamycin, also produced contractile dysfunction that outlasted the interventions themselves. Thus, we propose that transient Ca overload during ischemia and early reperfusion initiates long-lasting contractile dysfunction in stunned myocardium.