Pathophysiology and pathogenesis of stunned myocardium. Depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts.

Contractile dysfunction in stunned myocardium could result from a decrease in the intracellular free Ca2+ transient during each beat, a decrease in maximal Ca2+-activated force, or a shift in myofilament Ca2+ sensitivity. We measured developed pressure (DP) at several Ca0 (0.5-7.5 mM) in isovolumic Langendorff-perfused ferret hearts at 37 degrees C after 15 min of global ischemia (stunned group, n = 13) or in a nonischemic control group (n = 6). At all Ca0, DP was depressed in the stunned group (P less than 0.001). Maximal Ca2+-activated pressure (MCAP), measured from tetani after exposure to ryanodine, was decreased after stunning (P less than 0.05). Normalization of the DP-Ca0 relationship by corresponding MCAP (Ca0 sensitivity) revealed a shift to higher Ca0 in stunned hearts. To test whether cellular Ca overload initiates stunning, we reperfused with low-Ca0 solution (0.1-0.5 mM; n = 8). DP and MCAP in the low-Ca0 group were comparable to control (P greater than 0.05), and higher than in the stunned group (P less than 0.05). Myocardial ATP observed by phosphorus NMR failed to correlate with functional recovery. In conclusion, contractile dysfunction in stunned myocardium is due to a decline in maximal force, and a shift in Ca0 sensitivity (which may reflect either decreased myofilament Ca2+ sensitivity or a decrease in the Ca2+ transient). Our results also indicate that calcium entry upon reperfusion plays a major role in the pathogenesis of myocardial stunning.