Ca2+ handling in excitation-contraction coupling requires considerable O2 consumption (Vo 2) in cardiac contraction. We have developed an integrative method to quantify total Ca2+ handling in normal hearts. However, its direct application to failing hearts, where futile Ca2+ cycling via the Ca2+-leaky sarcoplasmic reticulum (SR) required an increased Ca2+handling Vo 2, was not legitimate. To quantify total Ca2+ handling even in such failing hearts, we combined futile Ca2+ cycling with Ca2+ handling Vo 2 and the internal Ca2+ recirculation fraction via the SR. We applied this method to the canine heart mechanoenergetics before and after intracoronary ryanodine at nanomolar concentrations. We found that total Ca2+ handling per beat was halved after the ryanodine treatment from ∼60 μmol/kg left ventricle before ryanodine. We also found that futile Ca2+ cycling via the SR increased to >1 cycle/beat after ryanodine from presumably zero before ryanodine. These results support the applicability of the present method to the failing hearts with futile Ca2+ cycling via the SR.

We conclude that the logistic model better fits LV isovolumic relaxation P(t) than the monoexponential model in the present heart preparation. We therefore propose TL as a better alternative to TE for evaluating LV lusitropism.

We tested our hypothesis that the O2 wasting of Ca2+ handling in the excitation-contraction (E-C) coupling in ryanodine-treated failing hearts could be reflected by a decrease in the internal Ca2+ recirculation fraction (RF). We have reported, using canine excised cross-circulated hearts, that intracoronary ryanodine (40 nmol/l blood) halved left ventricular contractility without decreasing myocardial O2 consumption for the E-C coupling. We previously suspected this mechanoenergetic state to manifest energy wasting of Ca2+ handling due to ryanodine causing leakage of Ca2+ from the sarcoplasmic reticulum. To test this hypothesis, we analyzed all the sporadic spontaneous cases of postextrasystolic potentiation (PESP) obtained during the ryanodine experiments. We calculated RF from the beat constant of the exponential decay component of not only the monotonic type but also the transient alternans type of PESP. Results showed that ryanodine significantly decreased the beat constant in both types of PESP from about 2 to 1.5 beats and hence RF from 0.6 to 0.5 on the average, supporting the hypothesis. This organ-level systems approach to Ca2+ handling using transient alternans PESP as well as monotonic PESP may help obtain better insights into the mechanoenergetics of failing hearts.

In isolated, blood-perfused canine hearts, postextrasystolic potentiation (PESP) decays monotonically after a noncompensatory pause following a spontaneous extrasystole (ES). The monotonic PESP decay yields myocardial internal Ca(2+) recirculation fraction (RF). We have found that after a compensatory pause (CP), PESP decays in alternans, consisting of an exponential and a sinusoidal decay component. We have proposed that this exponential component also yields RF. In the present study, we examined the reliability of this alternative method by widely changing the ES coupling interval (ESI), CP, and heart rate in the canine excised, cross-circulated left ventricle. We found that all PESP decays consisted of the sum of an exponential and a sinusoidal decay component of variable magnitudes whether a CP existed or not. Their decay constants as well as the calculated RF were independent of the ESI and CP. This confirmed the utility of our alternative RF determination method regardless of the ESI, CP, and heart rate. Direct experimental evidence of Ca(2+) dynamics supportive of this alternative method, however, remains to be obtained.

We have recently reported that the postextrasystolic contractile potentiation decays in alternans after a compensatory pause in canine left ventricles even under normal coronary and contractile conditions. The transient alternans appears to consist primarily of a small-magnitude exponential decay and a large-magnitude sinusoidal decay. We, therefore, hypothesized that the contractility (y) of the postextrasystolic alternans beats (beat number x) could be expressed as y = a x exp[-(x-1)/b] + c x exp[-(x-1)/d] x sin[pi(x-0.5)] + yo, where a and c are the normalized magnitudes (relative to the preceding regular beat) of the two exponential terms in the first postextrasystolic beat, b and d are their time constants, and yo is the normalized magnitude of the post-alternans regular beat (approximately 1). The first exponential term represents the monotonic decay. The sine term multiplied by the second exponential term represents the alternating decay. Mathematical curve-fitting indicated: 1) the above equation very closely fitted the alternans data with a squared correlation coefficient of 0.9996 on average, 2) c was 7 times on average greater than a, indicating dominance of the sine component, 3) b and d were 2.5 and 1.0 beats on average, indicating a faster decay of the sine component, and 4) this b was comparable to the time constant of the exponential decay of the postextrasystolic potentiation after no compensatory pause. This study suggests that myocardium has a mechanism to switch the postextrasystolic potentiation between the exponential and alternans decays depending on the first postextrasystolic interval.