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Ann Thorac Surg 2003;76:2054-2061
© 2003 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Medical University of South Carolina, and the Ralph H. Johnson Veteran's Association Medical Center, Charleston, South Carolina, USA
Accepted for publication June 5, 2003.
* Address reprint requests to Dr Spinale, Cardiothoracic Research, Strom Thurmond Research Building, 770 MUSC Complex, Suite 625, Medical University of South Carolina, Charleston, SC 29425, USA
e-mail: wilburnm{at}musc.edu
BACKGROUND: Ischemia-reperfusion (IR) injury causes myocardial dysfunction in part through intracellular calcium overload. A recently described pharmacologic compound, MCC-135 (5-methyl-2-[1-piperazinyl] benzenesulfonic acid monohydrate, Mitsubishi Pharma Corporation), alters intracellular calcium levels. This project tested the hypothesis that MCC-135 would influence regional myocardial contractility when administered at reperfusion and after a prolonged period of ischemia.
METHODS: A circumflex snare and sonomicrometry crystals within remote and area-at-risk regions were placed in pigs (n = 18, 32 kg). Coronary occlusion was instituted for 120 minutes followed by 180 minutes of reperfusion. At 105 minutes of ischemia pigs were randomly assigned to IR only (n = 11) or MCC-135 (IR-MCC [300 µg · kg-1 · h-1, n = 7]) administered intravenously. Regional myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (RESPDR [mm Hg/cm]). Myocardial injury was determined by measurement of plasma levels of myocyte-specific enzymes.
RESULTS: At 90 minutes ischemia, mean troponin-I was 35 ± 8 ng/mL with no significant difference between groups. At 180 minutes reperfusion, heart rate was increased by 18% ± 5% in the IR only group (p < 0.05) and was reduced by 11% ± 4% with IR-MCC (p < 0.05). At 90 minutes ischemia RESPDR was reduced from baseline by 51% ± 6% (p < 0.05). By 30 minutes reperfusion, reductions in RESPDR were attenuated with IR-MCC compared with IR only values. The CK-MB levels were increased at 180 minutes reperfusion in the IR only group (52 ± 9 ng/mL) compared with baseline (6 ± 1 ng/mL, p < 0.05) but were attenuated with IR-MCC (24 ± 4 ng/mL, p < 0.05) compared with IR only values.
CONCLUSIONS: Despite similar degrees of injury at 90 minutes ischemia MCC-135 improved regional contractility and reduced the egress of CK-MB. Moreover MCC-135 was associated with decreased heart rate, a determinant of myocardial oxygen demand. Pharmacologic modulation of calcium transport ameliorates myocardial dysfunction in the acute IR period.
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  F. W. Bar, D. Tzivoni, M. T. Dirksen, A. Fernandez-Ortiz, G. R. Heyndrickx, J. Brachmann, J. H.C. Reiber, N. Avasthy, J. Tatsuno, M. Davies, et al. Results of the first clinical study of adjunctive CAldaret (MCC-135) in patients undergoing primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction: the randomized multicentre CASTEMI study Eur. Heart J., November 1, 2006; 27(21): 2516 - 2523. [Abstract] [Full Text] [PDF]
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W. M. Yarbrough and F. G. Spinale MCC-135 Diminishes the Egress of CK-MB but Not of Troponin-I From Cardiomyocytes During Reperfusion: Reply Ann. Thorac. Surg., March 1, 2005; 79(3): 1095 - 1095. [Full Text] [PDF]
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