The aim of the present study was to examine the mechanisms of Ca2+ overload-induced contractile dysfunction in rat hearts independent of ischemia and acidosis. Experiments were performed on 30 excised cross-circulated rat heart preparations. After hearts were exposed to high Ca2+, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O(2) consumption per beat and systolic pressure-volume area (index of a total mechanical energy per beat) in left ventricles from all seven hearts that underwent the protocol. This result suggested a decrease in O(2) consumption for total Ca2+ handling in excitation-contraction coupling. In the hearts that underwent the high Ca2+ protocol and had contractile failure, we found marked proteolysis of a cytoskeleton protein, alpha-fodrin, whereas other proteins were unaffected. A calpain inhibitor suppressed the contractile failure by high Ca2+, the decrease in O(2) consumption for total Ca2+ handling, and membrane alpha-fodrin degradation. We conclude that the exposure to high Ca2+ may induce contractile dysfunction possibly by suppressing total Ca2+ handling in excitation-contraction coupling and degradation of membrane alpha-fodrin via activation of calpain.

Recently, we have consistently observed curved endsystolic pressure-volume relations (ESPVRs) of the left ventricle (LV) in rat blood-perfused [1][2][3] and crystalloid-perfused whole heart preparations [4] and in situ ejecting rat hearts [5,6], like those of the puppy LV [7] and adult canine LV in supernormal contractility [8,9]. These studies suggest more generality of the curvilinear than linear ESPVR in different animal species. Despite this curvilinearity, we have obtained a linear myocardial oxygen consumption per Japanese Journal of Physiology, 49, 513-520, 1999 Key words: excitation-contraction coupling, oxygen consumption, E max (end-systolic pressure-volume ratio), systolic pressure-volume area (PVA). Abstract:We have already reported the linear oxygen consumption per beat (VO 2 )-systolic pressure-volume area (PVA) relation from the curved left ventricular (LV) end-systolic pressure-volume relation (ESPVR) in the cross-circulated rat heart. The VO 2 intercept (PVA-independent VO 2 ) is primarily composed of VO 2 for Ca 2ϩ handling in excitation-contraction (E-C) coupling and basal metabolism. The aim of the present study was to obtain the oxygen cost of LV contractility that indicates VO 2 for Ca 2ϩ handling in E-C coupling per unit LV contractility change in the rat heart. Oxygen cost of LV contractility is obtainable as a slope of a linear relation between PVA-independent VO 2 and LV contractility. We obtained a composite VO 2 -PVA relation line at a mid-range LV volume (mLVV) under gradually enhanced LV contractility by stepwise increased Ca 2ϩ infusion and thus the gradually increased PVA-independent VO 2 values. As a LV contractility index, we could not use E max (ESP-V ratio; ESP/ESV) for the linear ESPVR because of the curved ESPVR in the rat LV. A PVA at a mLVV (PVA mLVV ) has been proposed as a good index for assessing rat LV mechanoenergetics. Since the experimentally obtained PVA mLVV was not triangular due to the curved ESPVR, we propose an equivalent ESP-V ratio at a mLVV, (eESP/ ESV) mLVV , as a LV contractility index. This index was calculated as an ESP-V ratio of the specific virtual triangular PVA mLVV that is energetically equivalent to the real PVA mLVV . The present approach enabled us to obtain a linear relation between PVA-independent VO 2 and (eESP/ ESV) mLVV and the oxygen cost of LV contractility as the slope of this relation.

Background-The long-term outcome of pediatric coronary artery bypass for patients with severe inflammatory coronary sequelae secondary to Kawasaki disease is unknown. Methods and Results-One hundred fourteen children and adolescents ranging in age from 1 to 19 (median, 10) years at operation were followed up for as long as 25 years with a median of 19 years.

We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of alpha-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion (n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo(2)) intercepts (PVA-independent Vo(2); Vo(2) for the total Ca(2+) handling in excitation-contraction coupling and basal metabolism) of Vo(2)-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O(2) costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of alpha-fodrin and the immunostaining of 150-kDa products of alpha-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of alpha-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca(2+) handling by directly inhibiting the proteolysis of alpha-fodrin.

Collaborating with catheter interventions, CABG using the arterial grafts can provide attractive results in patients with obstructive coronary arteries associated with Kawasaki disease.