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J Am Coll Cardiol, 1999; 34:594-602 © 1999 by the American College of Cardiology Foundation |
a Division of Cardiology, Veterans Affairs Medical Center and the University of Minnesota Medical School, Minneapolis, Minnesota, USA
Manuscript received October 28, 1998; revised manuscript received February 28, 1999, accepted April 26, 1999.
Reprint requests and correspondence: Dr. Inder S. Anand, Professor of Medicine, University of Minnesota Medical School, Veterans Affairs Medical Center IIIC, 1 Veterans Drive, Minneapolis, Minnesota 55417
anand001{at}maroon.tc.umn.edu
OBJECTIVES
This study evaluated contractile function in cardiomyocytes isolated from hearts with global left ventricular dysfunction following ischemia-reperfusion.
BACKGROUND
Ischemia followed by reperfusion is associated with transient contractile dysfunction, termed "stunning." It is not clear whether this phenomenon is primarily due to intrinsic cardiomyocyte contractile dysfunction.
METHODS
Global contractile dysfunction was induced in isolated perfused rat hearts (n = 8) using a model of transient global ischemia (20 min) followed by reperfusion (20 min). Hearts perfused uninterrupted for 40 min were used as controls (n = 8). Cardiomyocytes were isolated using enzymatic digestion and were studied under varying degrees of inotropy (using increasing extracellular calcium [Ca2+]o) and loading conditions (varying extracellular perfusate viscosity). Mechanical function was studied with video edge detection and intracellular calcium ([Ca2+]i) kinetics using fura-2 AM.
RESULTS
Global ischemia-reperfusion increased left ventricle (LV) end diastolic pressure (450% vs. 33%, p < 0.01) and reduced LV developed pressure (9% vs. 33%, p < 0.01), LV positive (3% vs. 26%, p < 0.01) and negative (5% vs. 33%, p < 0.01) dP/dt. However, cells isolated from these hearts did not manifest contractile dysfunction. In fact, cell shortening (p < 0.0001) and peak rate of cell shortening (p < 0.05) and increase in [Ca2+]i with each contraction (p < 0.024) were higher in these cells during stimulation with [Ca2+]o of 1 to 10 mmol/liter. The EC50 values for calcium dose response and the slope of the relation between change in [Ca2+]i and change in cell length were no different between the groups. Cell loading (with increasing superfusate viscosity from 1 cp to 300 cp) also did not reveal any abnormalities in cells from the hearts subjected to ischemia-reperfusion.
CONCLUSIONS
Cardiomyocytes isolated from hearts with ischemia-reperfusion-induced LV dysfunction or "stunning" have normal contractile function and normal [Ca2+]i transients, when studied both in the unloaded and loaded state. Our data suggest that nonmyocyte factors such as abnormalities in extracellular matrix or abnormal myocyte-interstitial tissue coupling may be important for the genesis of cardiac contractile failure in the stunned heart.
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