Junichi Araki

Ventricular contractility in atrial fibrillation is predictable by mechanical restitution and potentiation

We recently found that contractility ( E max) of an individual irregularly arrhythmic beat in electrically induced atrial fibrillation (AF) is reasonably predictable from the ratio of the preceding beat interval (RR1) to the beat interval immediately preceding RR1 (RR2) in the canine left ventricle. Moreover, the monotonically increasing relation between E max and the RR1-to-RR2 ratio (RR1/RR2) passed through or by the mean arrhythmic beat E max as well as the regular beat E max at RR1/RR2 = 1. We hypothesized that this E max-RR1/RR2 relation during irregular arrhythmia could be attributed to the basic characteristics of the mechanical restitution and potentiation. To test this, we adopted a known comprehensive equation describing the force restitution and potentiation as a function of two preceding beat intervals and simulated contractilities of irregular arrhythmic beats with randomized beat intervals on a computer. The simulated E max-RR1/RR2 relation reasonably resembled the one that we recently observed experimentally, supporting our hypothesis. We therefore conclude that the primary mechanism underlying the varying contractilities of irregular beats in AF is mechanical restitution and potentiation.We recently found that contractility (Emax) of an individual irregularly arrhythmic beat in electrically induced atrial fibrillation (AF) is reasonably predictable from the ratio of the preceding beat interval (RR1) to the beat interval immediately preceding RR1 (RR2) in the canine left ventricle. Moreover, the monotonically increasing relation between Emax and the RR1-to-RR2 ratio (RR1/RR2) passed through or by the mean arrhythmic beat Emax as well as the regular beat Emax at RR1/RR2 = 1. We hypothesized that this Emax-RR1/RR2 relation during irregular arrhythmia could be attributed to the basic characteristics of the mechanical restitution and potentiation. To test this, we adopted a known comprehensive equation describing the force restitution and potentiation as a function of two preceding beat intervals and simulated contractilities of irregular arrhythmic beats with randomized beat intervals on a computer. The simulated Emax-RR1/RR2 relation reasonably resembled the one that we recently observed experimentally, supporting our hypothesis. We therefore conclude that the primary mechanism underlying the varying contractilities of irregular beats in AF is mechanical restitution and potentiation.

A new integrative method to quantify total Ca2+ handling and futile Ca2+ cycling in failing hearts

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.

Postextrasystolic transient contractile alternans in canine hearts.

SummaryWe found that postextrasystolic potentiated contractility after a spontaneous extrasystole most frequently decayed as a transient alternans over several beats in excised, cross-circulated, atrially paced canine hearts. This type of heart preparation, which we have been using consistently in mechanoenergetic studies, had normal coronary blood perfusion pressure as well as flow and mechanoenergetic performance. Spontaneous atrial and ventricular extrasystoles occurred occasionally in every heart. Arrhythmic changes in left ventricular (LV) pressure at a fixed volume reflected corresponding changes in contractility. We analyzed nearly 3,600 cases of postextrasystolic potentiation in 68 hearts; 84% decayed as transient alternans, 6% decayed exponentially, and 10% belonged to neither type. We found that a postextrasystolic compensatory pause always preceded the transient alternans after either an atrial or ventricular extrasystole at any constant atrial pacing rate (85–188 beats/min). The decay was either exponential or nonalternating when the pause did not exist after an atrial extrasystole during occasional pacing failure. Therefore, the compensatory pause after either an atrial or ventricular extrasystole seems essential for the postextrasystolic transient alternans of LV contractility in the type of canine heart preparation we have been using.

O2 cost of contractility but not of mechanical energy increases with temperature in canine left ventricle

We investigated the effects of myocardial temperature on left ventricular (LV) mechanoenergetics in the excised, cross-circulated canine heart. We used the framework of the LV contractility ( E max)-pressure-volume area (PVA; a measure of total mechanical energy)-myocardial oxygen consumption (Vo 2) relationship. We have shown this framework to be useful to integrative analysis of the mechanoenergetics of a beating heart. In isovolumic contractions at a constant pacing rate, increasing myocardial temperature from 30 to 40°C depressed E max and increased the oxygen cost of E max, which was enhanced by dobutamine, in a linear manner. However, the slope of the Vo 2-PVA relation (reciprocal of contractile efficiency) and its Vo 2intercept remained constant. Q10values of E max, the oxygen cost of E max, and the oxygen cost of PVA were 0.4, 2.1 and 1.0, respectively, around normothermia. We conclude that the temperature-dependent processes of cross-bridge cycling and Ca2+handling integratively depress E max and augment its oxygen cost without affecting the oxygen cost of PVA as myocardial temperature increases by 10°C around normothermia.We investigated the effects of myocardial temperature on left ventricular (LV) mechanoenergetics in the excised, cross-circulated canine heart. We used the framework of the LV contractility (E(max))-pressure-volume area (PVA; a measure of total mechanical energy)-myocardial oxygen consumption (VO(2)) relationship. We have shown this framework to be useful to integrative analysis of the mechanoenergetics of a beating heart. In isovolumic contractions at a constant pacing rate, increasing myocardial temperature from 30 to 40 degrees C depressed E(max) and increased the oxygen cost of E(max), which was enhanced by dobutamine, in a linear manner. However, the slope of the VO(2)-PVA relation (reciprocal of contractile efficiency) and its VO(2) intercept remained constant. Q(10) values of E(max), the oxygen cost of E(max), and the oxygen cost of PVA were 0.4, 2.1 and 1.0, respectively, around normothermia. We conclude that the temperature-dependent processes of cross-bridge cycling and Ca(2+) handling integratively depress E(max) and augment its oxygen cost without affecting the oxygen cost of PVA as myocardial temperature increases by 10 degrees C around normothermia.

Mechanoenergetics of the negative inotropism of isoflurane in the canine left ventricle : No O2 wasting effect

Background: The mechanisms underlying the negative inotropic effects of isoflurane are incompletely understood. One suggested mechanism is that isoflurane may decrease Ca2+ sensitivity of contractile proteins. If so, more free calcium would be needed to activate contractile proteins to the same degree, which would impose a greater requirement for myocardial oxygen consumption used in the cycling of calcium. In this study, the authors use the excised, cross‐circulated, canine heart model and the volume servopump technique to measure the effects of isoflurane on Emax (a contractile index) and on the relationship between pressure‐volume area (PVA, a measure of total mechanical energy) and myocardial oxygen consumption per beat (VO2). Methods: Effects of intracoronary isoflurane infused via a precoronary oxygenator on myocardial mechanoenergetics were studied during isovolumic contractions. The authors measured left ventricular (LV) pressure, LV volume, coronary flow, and arteriovenous oxygen content difference and computed Emax, VO2 and PVA at 0, 1.0, 1.5, and 2.0% isoflurane. From these data, the authors obtained oxygen costs of PVA and Emax in control subjects and in those receiving 2.0% isoflurane. Results: Emax, PVA, and VO2 dose‐dependently decreased by similar degrees (P < 0.05). Isoflurane did not change the oxygen costs at 1.5% and 2.0% concentration (P < 0.05). Conclusions: These mechanoenergetic findings suggest that the primary method by which isoflurane decreases contractility is not by decreasing Ca sup 2+ sensitivity of contractile proteins but mainly by decreasing Ca2+ handling in the excitation‐contraction coupling without myocardial oxygen wasting effect.

Effects of Intracoronary Fentanyl on Left Ventricular Mechanoenergetics in the Excised Cross-circulated Canine Heart

Background: It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts. Methods: This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross‐circulated canine hearts. The authors used the framework of the Emax (a contractility index)‐PVA (systolic pressure‐volume area, a measure of total mechanical energy)‐VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate Emax, PVA, and VO2. They first obtained the VO2 ‐PVA relationship for varied LV volumes at control Emax. The authors then obtained the VO2 ‐PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2 ‐PVA relationship for varied LV volumes at the final dose of fentanyl. Results: Fentanyl at any concentrations did not significantly change Emax, PVA, and VO2 from the control. The linear end‐systolic pressure‐volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2 ‐PVA relationship remained unchanged by fentanyl. Conclusions: These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

Calcium equally increases the internal calcium recirculation fraction before and after β-blockade in canine left ventricles

SummaryWe studied whether intracoronary Ca administration after β-blockade would increase the internal Ca recirculation fraction (RF) analogously to the Ca administration before β-blockade. This was performed in excised cross-circulated canine hearts. We analyzed the exponential decay component of the postextrasystolic potentiation (PESP) following a spontaneous extrasystole. All the PESPs decayed in alternans with atrial pacing at a constant rate. We obtained the time constant (τe) of the monoexponential decay component of the alternans PESP. An increment of intracoronary Ca by 1.5mmol/1 enhanced the left ventricular contractility indexEmax (end-systolic maximum elastance) by 2.5 times before and after β-blockade with propranolol. The intracoronary Ca after β-blockade slightly but significantly increased τe, and hence increased RF calculated from τe by RF=exp(−1/τe). This was analogous to the slightly increased τc and RF with Ca before β-blockade. We speculate that the myocardial cyclic AMP-dependent phosphorylation level would not significantly alter the effect of intracoronarily administered Ca on myocardial Ca handling, in terms of τe and RF.

Logistic character of myocardial twitch force curve : simulation

SummaryWe found that the isovolumic pressure-time curve of the canine left ventricle closely fitted the difference of two logistic function curves and that the isovolumic relaxation-pressure curve segment was more reliably characterized by a logistic time constant than by the conventional exponential time constant. We therefore hypothesized that the calcium (Ca) transient and the Ca-troponin (Tn) binding and crossbridge (CB) kinetics underlay the logistic character of the ventricular isovolumic pressure curve. We tested this hypothesis with a computer simulation of a simple Ca and CB kinetics model of myocardial isometric twitch force development. We assumed the isometric force curve (F) to be proportional to the instantaneous number of attached CBs that was theoretically given as the difference between the cumulative CB attachment and detachment curves. We radically changed the Ca transient, Ca-Tn binding, and CB kinetic parameters. We always found that both the cumulative CB attachment and detachment curves closely fitted logistic functions. The difference curve of these two best-fit logistic functions closely fitted the theoretical F curve with certain combinations of the Ca transient, the Ca-Tn binding, and the CB kinetic parameters. These results seem to support our hypothesis.

Starling-effect-independent lusitropism index in canine left ventricle: logistic time constant.

The logistic time constant (&tgr;L) has been proposed as a better index of the rate of left ventricular (LV) relaxation or lusitropism than the conventional monoexponential time constant (&tgr;E). However, whether and how the Frank-Starling effect influences &tgr;L remains to be elucidated. We compared the effect of LV volume (LVV) loading on both logistic and monoexponential fittings. The isovolumic LV relaxation pressure curves from the maximum negative time derivative of pressure (-dP/dtmax) were analyzed at 3 different end-points at 4 LVVs of 10, 12, 14, and 16 mL in 8 excised, cross-circulated canine hearts. We found that the logistic fitting was superior to the monoexponential fitting at all LVVs and end-points. LVV loading did not affect &tgr;L but affected &tgr;E slightly. Although the advancing end-point increased both &tgr;L and &tgr;E, the increases were significantly smaller for &tgr;L than for &tgr;E at all LVVs. Moreover, the changes in both the amplitude constants and nonzero asymptotes with the advancing end-point were significantly smaller for the logistic fitting than for the monoexponential fitting. We conclude that &tgr;L served as a more reliable index of lusitropism that is independent of the change in LVV loading or the Frank-Starling effect.

Total Ca handling in canine mild Ca overload failing heart

SummaryWe analyzed total Ca handling of the left ventricle (LV) in the mildly failing heart preparation induced by a temporary intracoronary Ca overloading intervention in eight excised and cross-circulated canine hearts. This Ca intervention consisted of interruption of coronary blood perfusion by Ca-free oxygenated Tyrode perfusion for 10min followed by high-Ca (16 mmol/l) oxygenated Tyrode perfusion for 5 min. This intervention decreased the LV contractility index,Emax (end-systolic maximum elastance), by 40% after restoration of the blood cross-circulation. We expected a Ca overload or paradox failing heart resembling the postischemic stunned heart and being characterized by an increased O2 cost ofEmax. However, LV O2 consumption under mechanically unloading conditions decreased by 30% from control without increasing the O2 cost ofEmax. To obtain a mechanistic view of this failing heart, we investigated cardiac total Ca handling by our integrative analysis method. In this method, we obtained the internal Ca recirculation fraction (RF) from the decay beat constant of the postextrasystolic potentiation following each sporadic spontaneous extrasystole in these failing LVs. We combined the RF with the decreasedEmax and the unchanged O2 cost ofEmax in our recently developed formula of total Ca handling. We found that these failing LVs had a slightly but significantly increased RF accompanied by either a slightly increased futile Ca cycling or a slightly decreased Ca reactivity ofEmax, or both. Any of these three possible changes can account for the unchanged O2 cost ofEmax. This result indicates that the present mildly failing heart has not yet fallen into a typical Ca overload or paradox by the temporary Ca overloading intervention.