The purpose of this study was to test the hypothesis that abnormal intracellular calcium handling characterizes myocardial stunning. Isolated, isovolumic, buffer-perfused ferret hearts were loaded with the bioluminescent calcium indicator aequorin for simultaneous measurement of After 20 minutes of reperfusion, myocardial stunning occurred, but [Ca2+1L was not significantly different from preischemic levels. Thus, myocardial stunning does not result from decreased levels of activator calcium. The force-pCa relation generated by the stunned hearts was shifted downward compared with that generated by the control hearts, consistent with a decrease in maximum calcium-activated force (Fmax). At steady state during tetanus, the decrease in Fmax was confirmed, but there was no significant difference in the slope of the force-pCa relation of the stunned hearts versus controls. Thus Materials and Methods After the intraperitoneal administration of 1,000 units heparin, male ferrets 10-14 weeks of age were anesthetized with chloroform. Hearts were rapidly excised through a midline sternotomy incision and by guest on
Acute or chronic heart failure may be caused by one or more of a variety of abnormalities including changes in excitation-contraction coupling processes (i.e. decreased availability of activator Ca2+ or a change in myofilament Ca2+ responsiveness), a change in myocardial energetics, or a change in extracellular factors, such as connective tissue content. Most of the animal and human models of acute cardiac failure that we have studied in our laboratory (i.e. negative inotropic responses to drugs, hypoxia, acidosis and ischaemia) appear to involve changes in excitation-contraction coupling as the predominant cause of dysfunction. On the other hand, the models of chronic cardiac dysfunction that we have studied (i.e. chronic right ventricular pressure overload in ferrets, hypertrophic cardiomyopathy in Syrian hamsters, hypertensive cardiomyopathy in rats, hypothyroidism in ferrets, end-stage dilated and hypertrophic cardiomyopathy in man) predominantly appear to reflect a combination of changes involving abnormalities in both excitation-contraction coupling and extracellular factors involving myocyte drop-out and increases in connective tissue content. However. In most of these models of acute and chronic heart failure, abnormal intracellular Ca2+ handling appears to be a major cause of both systolic and diastolic dysfunction.
The purpose of this study was to test the hypothesis that systolic and diastolic dysfunction in left ventricular pressure-overload hypertrophy is caused by abnormal intracellular calcium handling. Experiments were performed with intact, buffer-perfused, isovolumic ferret hearts (n=9 hypertrophied, n=9 control) that were loaded with the bioluminescent indicator aequorin to monitor changes in cytoplasmic calcium. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Compared with their age-matched controls, significant hypertrophy of the left ventricle developed 4 weeks after postvalvular aortic banding; at the time the animals were killed, the left ventricular weight/body weight ratio was increased in the banded animals (5.3x10-3 versus 3.6x1i0-, p<0.001). As indicated by the diastolic pressure-volume relation, left ventricular distensibility was significantly diminished in the hypertrophied hearts. In comparison to the controls, the hypertrophied hearts demonstrated a prolonged duration of isovolumic contraction (time to 90% decline from peak: 278±5.4 versus 247± 10.2 msec,p<0.05), but a marked decrease in peak systolic midwall stress (22.4±5.0 versus 38.6±5.7 g/cm2, p<0.05). The increased duration of isovolumic contraction correlated with a similar prolongation of the calcium transient (time to 90% decline from peak: 245+19.5 versus 127± 13.2 msec,p <0.05), indicating that the rate of sequestration and perhaps release of calcium by the sarcoplasmic reticulum is decreased in hypertrophy. In contrast, control and hypertrophied hearts had similar peak systolic calcium levels (pCa: 6.4±0.2 versus 6.6±0.1, p=NS), indicating that the diminution in peak left ventricular midwall stress developed by the hypertrophied hearts was not due to decreased availability of activator calcium. We conclude that the prolonged time course of left ventricular pressure development, but not the diminished peak isovolumic midwall stress or decreased diastolic distensibility, may be related to alterations in intracellular calcium handling. (Circulation Research 1991;69:1538-1545 V arious models of pressure-overload hypertrophy demonstrate alterations in myocardial structure and function.1-4 Impairment of contractile function, abnormalities in myocardial energetics, and alterations in calcium handling have been documented in papillary muscles and trabecuFrom the Charles A. Dana Research Institute and the Harvard-
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