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 [Ca]₀ (0.5-7.5 mM) in isovolumic Langendorff-perfused ferret hearts at 37°C after 15 min of global ischemia (stunned group, n = 13) or in a nonischemic control group (n = 6). At all [Ca]₀, DP was depressed in the stunned group (P < 0.001). Maximal Ca²⁺-activated pressure (MCAP), measured from tetani after exposure to ryanodine, was decreased after stunning (P < 0.05). Normalization of the DP-[Ca]₀ relationship by corresponding MCAP (Ca₀ sensitivity) revealed a shift to higher [Ca]₀ in stunned hearts. To test whether cellular Ca overload initiates stunning, we reperfused with low-[Ca]₀ solution (0.1-0.5 mM; n = 8). DP and MCAP in the low-[Ca]₀ group were comparable to control (P > 0.05), and higher than in the stunned group (P < 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.