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

Abstract

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 effects of cocaine on intracellular Ca2+ handling and myofilament Ca2+ responsiveness of ferret ventricular myocardium

“…Consequently, in experiments where we wished to minimize catecholamine release to as large an extent as possible threshold stimulation without addition of other agents was employed alone. As shown in Table 1 1989;Perreault et al, 1990a). These results are consistent with the expectation that an increased concentration of intracellular calcium would be reflected at the level of the myofilaments by an enhanced degree of activation.…”

“…We also investigated, in skinned ferret ventricular muscles, the effects of cocaine on myofilament calcium responsiveness, which includes calcium sensitivity, maximal calcium-activated force and the slope of the calcium-force relationship (Perreault et al, 1990a).…”

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

“…Moreover, such contractile changes occur without significant impairment of diastolic function, at variance with other Ca 2+ sensitizers. 16,17 As to the subcellular mechanisms underlying such positive inotropic effects, the contractile state of the muscle can be altered by several mechanisms: 'upstream' mechanisms, (1) altering the amplitude or time course of (3) altering the response of the myofilaments to a given level of occupancy of the calcium binding sites on troponin C. 16,17 Viewed from this perspective, the changes of the Ca 2+ transients observed in our study include a combination of such mechanisms. In fact, the amplitude of the transients was significantly increased compared to baseline.…”

“…16,17 Both components were evaluated in the isolated whole heart by steady-state pressure-Ca 2+ relations obtained by eliciting tetanus with rapid pacing after exposure to ryanodine, according to a previously described technique. 23 ] with repeated and averaged (3-5 tetani) measurements for peak tetanic pressure and light signals at each Ca 2+ level were assessed.…”

Morphological and molecular changes of the myocardium after left ventricular mechanical support

“…Contractile dysfunction during CHF of either aetiology is associated with alterations of Ca 2+ cycling [49]. Downregulated gene expression of sarcoplasmic endoreticular Ca 2+ exchanger have been reported and appear to correlate with contractile dysfunction [50].…”