Relationship of abnormal intracellular calcium mobilisation to myocyte hypertrophy in human ventricular myocardium.

OBJECTIVE: Calcium transients in muscles from patients with end stage heart failure consist of two components (L1 and L2) at physiological extracellular calcium concentrations ([Ca2+]o); the second component (L2) can appear in normal human myocardium at high [Ca2+]o. In muscles from end stage heart failure patients L2 is associated with significant hypertrophy. To expand these observations a group of muscles from control patients with mild hypertrophy but without overt heart disease was studied (n = 8), in which a second calcium transient component was present during high [Ca2+]o. METHODS: Using the ratio of the two components of the calcium transient (L2/L1) seen in trabeculae from heart failure patients as a marker of intracellular calcium mobilisation, the hypothesis was tested that the extent of abnormality in transsarcolemmal calcium flux, and/or sarcoplasmic reticular calcium release and reuptake, correlates with the degree of hypertrophy present. RESULTS: In contrast to non-hypertrophied myocardium, hypertrophied myocardium from patients without heart failure often showed an increase in the L2/L1 ratio at higher [Ca2+]o. Hypertrophied myocardium from patients with failure showed a progressive increase in the L2/L1 ratio, reflecting further impairment of calcium mobilisation. There was a positive correlation between the degree of hypertrophy and calcium mobilisation alterations that was enhanced by raised [Ca2+]o. Altered [Ca2+]i mobilisation may develop early in the course of hypertrophy, before the onset of clinical signs of cardiac dysfunction.

Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion.

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 individual calcium transients and left ventricular pressure. After 15 minutes of global ischemia and 20 minutes of reperfusion, left ventricular developed pressure was significantly reduced (75 +/- 7 versus 93 +/- 6 mm Hg, p < 0.05). During ischemia, [Ca2+]i levels were significantly elevated compared with preischemic levels, both during systole (1.38 +/- 0.31 versus 0.88 +/- 0.2 microM, p < 0.05) and end diastole (0.85 +/- 0.16 versus 0.38 +/- 0.13 microM, p < 0.05). Early during reperfusion, [Ca2+]i was also significantly elevated during systole (1.63 +/- 0.44 versus 0.88 +/- 0.20 microM, p < 0.05) and end diastole (0.75 +/- 0.15 versus 0.38 +/- 0.13 microM, p < 0.05). After 20 minutes of reperfusion, myocardial stunning occurred, but [Ca2+]i 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, we conclude that stunned myocardium is characterized by decreased Fmax without desensitization of the myofilaments to [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular calcium and ventricular function. Effects of nisoldipine on global ischemia in the isovolumic, coronary-perfused heart.

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM, and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

Ventricular function and calcium handling during ischemia.

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([CA2+]i). The present study was designed to determine the effects of the calcium antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with buffer containing 10(-8) M nisoldipine. From the left ventricular developed pressure, the time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i from 0.35 to 0.81 microM and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function (Fig. 1). Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM and in systolic [Ca2+]i to 0.77 microM and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

Altered calcium handling in left ventricular pressure-overload hypertrophy as detected with aequorin in the isolated, perfused ferret heart.

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 (5.3 x 10(-3) versus 3.6 x 10(-3), p less than 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 less than 0.05), but a marked decrease in peak systolic midwall stress (22.4 +/- 5.0 versus 38.6 +/- 5.7 g/cm2, p less than 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 less than 0.05), indicating that the rate of sequestration and perhaps release of calcium by the sarcoplasmic reticulum is decreased in hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Excitation-contraction uncoupling during ischemia in the blood perfused dog heart.

The bioluminescent of Ca(2+)-indicator, aequorin, was loaded into the left ventricular apex of blood-perfused hearts from 13 dogs for simultaneous recording of left ventricular pressure and intracellular calcium levels. During a 2 minute period of ischemia, systolic and diastolic pressures significantly decreased. In contrast, these pressure changes were associated with an increase in both systolic and diastolic calcium reaching a maximum diastolic value of 0.59 microM and a systolic value of 1.11 microM. This apparent dissociation between pressure and [Ca2+]i supports the hypothesis that changes in myofilament Ca2+ responsiveness are of major importance in modulating contractility during ischemia in large mammalian hearts.

Abnormal intracellular calcium handling in acute and chronic heart failure: role in systolic and diastolic dysfunction.

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.