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We have reported that the contractility index (E(max)) and the total mechanical energy (PVA) of arrhythmic beats of the left ventricle (LV) distribute normally in canine hearts under electrically induced atrial fibrillation (AF). Here, E(max) is the ventricular elastance as the slope of the end-systolic (ES) pressure-volume (P-V) relation (ESPVR), and PVA is the systolic P-V area as the sum of the external mechanical work within the P-V loop and the elastic potential energy under the ESPVR. To obtain E(max) and PVA, we had to assume the systolic unstressed volume (V(o)) as the V-axis intercept of the ESPVR to be constant despite the varying E(max), since there was no method to obtain V(o) directly in each arrhythmic beat. However, we know that in regular stable beats V(o) decreases by approximately 7 ml/100 g LV with approximately 100 times the increases in E(max) from ~0.2 mmHg/(ml/100 g LV) of almost arresting weak beats to approximately 20 mmHg/(ml/100 g LV) of strong beats with a highly enhanced contractility. In the present study, we investigated whether E(max) and PVA under AF could still distribute normally, despite such E(max)-dependent V(o) changes. The present analyses showed that the E(max) changes were only approximately 3 times at most from the weakest to the strongest arrhythmic beat under AF. These changes were not large enough to affect V(o) enough to distort the frequency distributions of E(max) and PVA from normality. We conclude that one could practically ignore the slight E(max) and PVA changes with the Emax-dependent V(o) changes under AF.

Left ventricular (LV) O2 consumption (V(O2)) per minute is measurable for both regular and arrhythmic beats. LV V(O2) per beat can then be obtained as V(O2) per minute minute divided by heart rate per minute minute for regular beats, but not for arrhythmic beats. We have established that V(O2) of a regular stable beat is predictable by V(O2) = a PVA + b E(max) + c, where PVA is the systolic pressure-volume area as a measure of the total mechanical energy of an individual contraction and E(max) is the end-systolic maximum elastance as an index of ventricular contractility of the contraction. Furthermore, a is the O2 cost of PVA, b is the O2 cost of E(max), and c is the basal metabolic V(O2) per beat. We considered it theoretically reasonable to expect that the same formula could also predict LV V(O2) of individual arrhythmic beats from their respective PVA and E(max) with the same a, b, and c. We therefore applied this formula to the PVA - Emax data of individual arrhythmic beats under electrically induced atrial fibrillation (AF) in six canine in situ hearts. We found that the predicted V(O2) of individual arrhythmic beats highly correlated linearly with either their V(O2) (r = 0.96 +/- 0.01) or E(max) (0.97 +/- 0.03) while both also highly correlated linearly with each other (0.88 +/- 0.04). This suggests that the above formula may be used to predict LV Vo2 of absolute arrhythmic beats from their Emax and PVA under AF.

We have reported that the postextrasystolic (PES) potentiation of left ventricular (LV) contractility usually decays in alternans at heart rates above 80-100 beats/min in the canine excised, cross-circulated heart. We examined whether the PES contractility would also decay in alternans even in the canine in situ heart presumably more physiological than the excised heart. In anesthetized, ventilated, and open-chest mongrel dogs, we measured LV pressure and volume with a micromanometer and a conductance catheter cannulated into the LV and obtained LV end-systolic maximum elastance (E(max)) as the reasonably load-independent contractility index. We inserted an extrasystole followed by a compensatory pause into steady-state regular beats at heart rates above 90 beats/min and analyzed the PES decay pattern of E(max). We found that E(max) potentiated in the first PES beat decayed in alternans within 5-6 PES beats. This indicates that PES contractility also decays in alternans in the normal canine in situ heart.

Mean levels of left ventricular rhythm and contractility averaged over arrhythmic beats would characterize the average cardiac performance during atrial fibrillation (AF). However, no consensus exists on the minimal number of beats for their reliable mean values. We analyzed their basic statistics to find out such a minimal beat number in canine hearts. We produced AF by electrically stimulating the atrium and measured left ventricular arrhythmic beat interval (RR) and peak isovolumic pressure (LVP). From these, we calculated instantaneous heart rate (HR = 60,000/RR), contractility (E(max) = LVP/isovolumic volume above unstressed volume), and beat interval ratio (RR1/RR2). We found that all their frequency distributions during AF were variably nonnormal with skewness and kurtosis. Their means +/- standard deviations alone cannot represent their nonnormal distributions. A 90% reduction of variances of E(max) and RR1/RR2 required a moving average of 15 and 24, respectively, arrhythmic beats on the average, whereas that of RR and HR required 60 beats on the average. These results indicate that a statistical characterization of arrhythmic cardiodynamic variables facilitates better understanding of cardiac performance during AF.

Myocardial Ca(2+) handling in excitation-contraction coupling is the second primary determinant of energy or O(2) demand in a working heart. The intracellular and extracellular routes remove myocardial Ca(2+) that was released into the sarcoplasma with different Ca(2+): ATP stoichiometries. The intracellular route is twice as economical as the extracellular route. Therefore the fraction of total Ca(2+) removed via the sarcoplasmic reticulum, i.e., the recirculation fraction of intracellular Ca(2+) (RF), determines the economy of myocardial Ca(2+) handling. RF has conventionally been estimated as the exponential decay rate of postextrasystolic potentiation (PESP). However, we have found that PESP usually decays in alternans, but not exponentially in the canine left ventricle beating above 100 beats/min. We have succeeded in estimating RF from the exponential decay component of an alternans PESP. We previously found that the Frank-Starling mechanism or varied ventricular preload did not affect the economy of myocardial Ca(2+) handling. Then, to account for this important finding, we hypothesized that the Frank-Starling mechanism would not affect RF at a constant heart rate. We tested this hypothesis and found its supportive evidence in 11 canine left ventricles. We conclude that RF at a constant heart rate would remain constant, independent of the Frank-Starling mechanism.

Neiguan (PC-6) is a traditional acupoint in the bilateral forearms, overlying the median nerve trunk. Neiguan electroacupuncture (EA) has been believed to affect cardiovascular function and used in traditional Chinese medicine to improve or treat a wide range of health conditions and diseases, including angina pectoris, myocardial infarction, hypertension, and hypotension. However, few physiological studies have assessed the beneficial effects of Neiguan EA on the cardiovascular function. In the present study, we investigated its effects on the cardiovascular function in normal open-chest dogs under pentobarbital and fentanyl anesthesia. We also obtained left ventricular (LV) pressure-volume (P-V) data with a micromanometer catheter and a volumetric conductance catheter. Mean arterial pressure, end-diastolic volume, heart rate, stroke volume, cardiac output, and end-systolic pressure gradually decreased by 5 to 10% over 1.5 h without Neiguan EA. Neiguan EA at 40 Hz, however, increased these cardiovascular variables by 10 to 15%, especially end-systolic elastance (Ees) by 40% (p<0.05) over 15 to 60 min. After Neiguan EA was stopped at 1 h, these facilitated cardiovascular variables decreased below the pre-EA level. This beneficial effect of electroacupuncture may contribute to the effectiveness of the acupuncture in Chinese medicine.

In our previous studies, we calculated the internal Ca(2+) recirculation fraction (RF) after obtaining the beat decay constant (tau(e)) of the monoexponential component in the postextrasystolic potentiation (PESP) of the alternans decay by curve fitting. However, this method sometimes suffers from the sensitive variation of tau(e) with small noises in the measured contractilities of the 5th and 6th postextrasystolic (PES) beats in the tail of the exponential component. We now succeeded in preventing this problem by a new method to calculate RF without obtaining tau(e). The equation for the calculation in the new method expresses an alternans decay of PESP as a recurrence formula of PESP. It can calculate RF directly from the contractilities of the 1st through the 4th PES beats without any fitting procedure. To evaluate the reliability of the new method, we calculated RF from the alternans decay of PESP of the left ventricle (LV) of the canine excised cross-circulated heart preparation by both the original fitting and the new method. Although there was no significant difference in the mean value of the obtained RF between these two methods, the variance of RF was smaller with the new method than with the original method. Thus the new method proved useful and more reliable than the original fitting method.

Whether 2,3-butanedione monoxime (BDM, < or = 5mmol/l) suppresses primarily crossbridge cycling or total Ca(2+) handling in the blood-perfused whole heart remains controversial. Although BDM seems to suppress primarily total Ca(2+) handling in canine hearts, more evidence is lacking. We therefore analyzed the cardiac mechanoenergetics, namely, E(max) (contractility), PVA (total mechanical energy), and O(2) consumption of canine BDM-treated hearts by our recently developed integrative method to assess myocardial total Ca(2+) handling. This method additionally required the internal Ca(2+) recirculation fraction. We obtained this from the beat constant of the exponential decay component of the postextrasystolic potentiation. Our analysis indicated significant decreases in both internal Ca(2+) recirculation fraction and total Ca(2+) handling in the BDM-treated heart, but virtually no change in the reactivity of E(max) to total Ca(2+) handling. This result corroborates the view that BDM suppresses primarily total Ca(2+) handling rather than crossbridge cycling in the canine blood-perfused heart.

We have found that a logistic function fits the left ventricular isovolumic relaxation pressure curve in the canine excised, cross-circulated heart more precisely than a monoexponential function. On this basis, we have proposed a logistic time constant (tau(L)) as a better index of ventricular isovolumic lusitropism than the conventional monoexponential time constant (tau(E)). We hypothesize in the present study that this tau(L) would also be a better index of myocardial isometric lusitropism than the conventional tau(E). We tested this hypothesis by analyzing the isometric relaxation force curve of 114 twitches of eight ferret isolated right ventricular papillary muscles. The muscle length was changed between 82 and 100% L(max) and extracellular Ca(2+) concentrations ([Ca(2+)](o)) between 0.2 and 8 mmol/l. We found that the logistic function always fitted the isometric relaxation force curve much more precisely than the monoexponential function at any muscle length and [Ca(2+)](o) level. We also found that tau(L) was independent of the choice of the end of isometric relaxation but tau(E) was considerably dependent on it as in ventricular relaxation. These results validated our present hypothesis. We conclude that tau(L) is a more reliable, though still empirical, index of lusitropism than conventional tau(E) in the myocardium as in the ventricle.

Caffeine causes a considerable O(2) waste for positive inotropism in myocardium by complex pharmacological mechanisms. However, no quantitative study has yet characterized the mechanoenergetics of caffeine, particularly its O(2) cost of contractility in the E(max)-PVA-VO(2) framework. Here, E(max) is an index of ventricular contractility, PVA is a measure of total mechanical energy generated by ventricular contraction, and VO(2) is O(2) consumption of ventricular contraction. The E(max)-PVA-VO(2) framework proved to be powerful in cardiac mechanoenergetics. We therefore studied the effects of intracoronary caffeine at concentrations lower than 1 mmol/l on left ventricular (LV) E(max) and VO(2) for excitation-contraction (E-C) coupling in the excised cross-circulated canine heart. We enhanced LV E(max) by intracoronary infusion of caffeine after beta-blockade with propranolol and compared this effect with that of calcium. We obtained the relation between LV VO(2) and PVA with E(max) as a parameter. We then calculated the VO(2) for the E-C coupling by subtracting VO(2) under KCl arrest from the PVA-independent (or zero-PVA) VO(2) and the O(2) cost of E(max) as the slope of the E-C coupling VO(2)-E(max) relation. We found that this cost was 40% greater on average for caffeine than for calcium. This result, for the first time, characterized integratively cardiac mechanoenergetics of the O(2) wasting effect of the complex inotropic mechanisms of intracoronary caffeine at concentrations lower than 1 mmol/l in a beating whole heart.

We investigated the effects of intracoronary Ca2+ and epinephrine on the intracellular Ca2+ recirculation fraction (RF) and total Ca2+ handling in the left ventricle (LV) of the excised cross-circulated canine heart preparation. We analyzed LV postextrasystolic potentiation (PESP) following a spontaneous extrasystole that occurred sporadically under constant atrial pacing. All PESPs decayed in alternans and none decayed monotonically. We extracted an exponential decay component from the alternans PESP, determined its beat constant (taue), and calculated RF = exp(-1/taue). Increased intracoronary Ca2+ slightly increased taue and RF, but epinephrine did not change them, although both agents enhanced LV contractility 2-3 times. Neither Ca2+ nor epinephrine affected the sinusoidal decay of the alternans PESP. These results indicate that RF via the sarcoplasmic reticulum was slightly augmented by Ca2+, but not by epinephrine. We combined these RF data with LV Ca2+ handling O2 consumption data and obtained 40-110 micromol/kg as the total amount of Ca2+ handled in one cardiac cycle in the control and enhanced contractile states. These results indicate that this new LV-level approach seems to better the understanding of the Ca2+ mass dynamics responsible for the mechanoenergetics enhanced by inotropic interventions.