Transmural Differences in Mechanical Properties of Isolated Subendocardial and Subepicardial Cardiomyocytes.

We studied the differences in twitch force of subendocardial and subepicardial cardiomyocytes isolated from mouse left ventricular wall at different preloads using an original single cell stretch method recently developed by us. Then, we used our mathematical models of subendocardial and subepicardial cells to predict underlying cellular mechanisms. Transmural differences in the amplitudes of active tension of subendocardial and subepicardial cardiomyocytes were revealed that could be related to the differences in cooperative end-to-end interaction between the neighboring regulatory units of the thin filament.

Effects of bepridil on stretch-activated BKca channels and stretch-induced extrasystoles in isolated chick hearts.

Various types of mechanosensitive ion channels, including cationic stretch-activated channels (SAC(NS)) and stretch-activated BKca (SAKca) channels, modulate heart rhythm. Bepridil has been used as an antiarrhythmic drug with multiple pharmacological effects; however, whether it is effective for mechanically induced arrhythmia has not been well investigated. To test the effects of Bepridil on SAKca channels activity, cultured chick embryonic ventricular myocytes were used for single-channel recordings. Bepridil significantly reduced the open probability of the SAKca channel (P(O)). Next, to test the effects of bepridil on stretch-induced extrasystoles (SIE), we used an isolated 2-week-old Langendorff-perfused chick heart. The left ventricle (LV) volume was rapidly changed, and the probability of SIE was calculated in the presence and absence of bepridil, and the effect of the drug was compared with that of Gadolinium (Gd(3+)). Bepridil decreased the probability of SIE despite its suppressive effects on SAKca channel activity. The effects of Gd(3+), which blocks both SAKca and SAC(NS), on the probability of SIE were the same as those of bepridil. Our results suggest that bepridil blocks not only SAKca channels but possible also blocks SAC(NS), and thus decreases the stretch-induced cation influx (stabilizing membrane potential) to compensate and override the effects of the decrease in outward SAKca current (destabilizing membrane potential).

New calculation of internal Ca(2+) recirculation fraction from alternans decay of postextrasystolic potentiation.

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.

Frank-Starling mechanism retains recirculation fraction of myocardial Ca(2+) in the beating heart.

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.

Mechanoenergetics characterizing oxygen wasting effect of caffeine in canine left 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.

Arterial and left ventricular pressures illude transient alternans of contractility during postextrasystolic potentiation.

We have previously found that the postextrasystolic (PES) potentiation (PESP) of the left ventricular (LV) contractility (Emax) decays typically in transient alternans even in the normally ejecting canine heart. This contradicted the general expectation that arterial pressure (AP) and LV pressure (LVP) usually decay exponentially during PESP. We hypothesized this contradiction to be due to the different cardiodynamic behaviors of AP and LVP from LV Emax during PESP. We tested this hypothesis by measuring AP, LVP, LV volume, Emax, effective arterial elastance (Ea) as an index of afterload, and pulse pressure (PP) during PESP in eight anesthetized open-chest dogs by using the conductance catheter system. We changed Ea by changing the total peripheral resistance (TPR) with methoxamine hydrochloride (iv) and repeated the measurements. Although the Emax alternans patterns during PESP were comparable between the normal and high afterloads, LVP and PP were slightly potentiated and alternated under the normal afterload, whereas LVP and PP were obviously potentiated and alternated under the high afterload. We also simulated the effects of Ea/Emax on the transient alternans of AP and LVP on a computer. Despite the same alternans pattern of Emax, a higher Ea/Emax, which is typical in heart failure, caused a larger PP alternans, whereas a lower Ea/Emax, which is typical in normal hearts, almost eliminated it. These results suggest that a transient alternans of LV contractility during PESP could be overlooked when AP and LVP are monitored in in situ normal hearts.

2,3-Butanedione monoxime suppresses primarily total calcium handling in canine heart.

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.

[Anesthetic management for a patient with mental retardation and unexamined complex congenital heart disease].

An 18-year old female with mental retardation and unexamined complex congenital heart disease received dental care under general anesthesia. Anesthesia was induced and maintained successfully without any significant hemodynamic changes with inhalation of nitrous oxide, oxygen (FIO2 0.25-0.3) and sevoflurane after a heavy premedication (morphine 10 mg, scopolamine 0.3 mg and midazolam 5 mg i.m.). After induction of anesthesia, cardiac anomaly was diagnosed by transesophageal echocardiography as TGA, VSD, PS, and operation was completed without any problem. Two points are considered important in this case; first, to appropriately estimate preoperative cardiac function and second, to adequately manage anesthesia to avoid any hemodynamic fluctuation.

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

Effects of the phosphodiesterase III inhibitors olprinone, milrinone, and amrinone on hepatosplanchnic oxygen metabolism.

OBJECTIVE: To measure the hepatic venous oxygen saturation in patients after cardiac surgery and to compare the effects of olprinone (OLP), a newly synthesized phosphodiesterase III inhibitor, with those of milrinone (MIL) and amrinone (AMR) on hepatosplanchnic oxygen dynamics. Phosphodiesterase III inhibitors are used to improve the hemodynamic state after cardiac surgery. However, the effect of these agents on the hepatosplanchnic circulation has not been investigated thoroughly. DESIGN: Prospective, randomized study. SETTING: University hospital intensive care unit (ICU). PATIENTS: Twenty-nine patients undergoing elective cardiac surgery. MEASUREMENTS AND MAIN RESULTS: In each patient, a 7.5-Fr oximeter catheter was placed in the hepatic vein via the right femoral vein. Catheterization was completed before admission to the ICU, and the study was performed 8 to 24 hrs after surgery, after obtaining stable systemic hemodynamics in the ICU. The patients were assigned randomly to three groups, and they received one of three drugs for 2 hrs (OLP group, 0.3 microg/kg/min of OLP; MIL group, 0.5 microg/kg/min of MIL; AMR group, 10 microg/kg/min of AMR). The authors did not change the patient's hemodynamic interventions, including catecholamines and vasodilators, throughout the study period. Arterial and hepatic venous blood gas data and hemodynamic data (via a pulmonary artery catheter) were obtained before and after drug infusion. Using these data, the authors calculated systemic oxygen delivery and consumption, the systemic oxygen extraction ratio and the hepatosplanchnic oxygen extraction ratio, and the change in hepatosplanchnic blood flow using Fick's equation. Although the increases in cardiac index were not significantly different among the three groups, hepatic venous oxygen saturation increased significantly only in the OLP group (from 47.1% +/-2.6% to 57.0% +/- 1.5% in the OLP group, from 48.4% +/- 2.3% to 50.9% +/- 2.6% in the MIL group, and from 49.8% +/- 3.6% to 50.8% + +/-.7% in the AMR group). The calculated hepatosplanchnic blood flow change was significantly larger in the OLP group than in the other groups (30.1% +/- 5.7% in the OLP group, 9.3% +/- 5.1% in the MIL group, and 2.6% +/- 6.5% in the AMR group). CONCLUSIONS: These results suggest that OLP enhances hepatosplanchnic blood flow and thus may be beneficial in protecting the hepatosplanchnic organs after cardiac surgery.

Effect of prostaglandin E1 and nitroglycerin on portal venous flow during hypothermic extracorporeal circulation: assessment by transesophageal echography.

BACKGROUND: Although several vasodilators are used to control vascular resistance during cardiac surgery, their effects on splanchnic circulation during extracorporeal circulation are unknown. We designed the present noninvasive study to evaluate the effect of prostaglandin E1 and nitroglycerin on portal venous flow during extracorporeal circulation using transesophageal echography. METHODS: We included 26 patients undergoing cardiac surgery with moderate hypothermic extracorporeal circulation in this study. After obtaining hemodynamic stability under extracorporeal circulation, we measured portal venous diameter, mean flow velocity and the velocity time integral using transesophageal echography and calculated portal venous flow. The patients were assigned to two groups where either prostaglandin E1 (N = 13) or nitroglycerin (N = 13) was administered intravenously to maintain perfusion pressure at the level of 70 mmHg. We measured the same parameters 20 and 40 min following administration of the drug. RESULTS: Visualization of the portal vein was obtained by transesophageal echography in anesthetized patients. Calculated portal venous flow significantly increased in the prostaglandin E1 group, while it did not alter in the nitroglycerin group. CONCLUSION: The present results indicate that transesophageal echography may be a feasible tool to assess portal venous flow, and that prostaglandin E1 may improve the blood distribution to the splanchnic area and the liver during hypothermic extracorporeal circulation.

Total Ca2+ handling for E-C coupling in the whole heart: an integrative analysis.

We assessed total Ca2+ handling (transport, flux) in excitation-contraction (E-C) coupling in a beating left ventricle (LV). We developed a new integrative analysis method that utilizes the internal Ca2+ recirculation fraction (RF), O2 consumption (V(O2)) for Ca2+ handling, and O2 cost of Emax (contractility index) of the LV. We obtained the RF from the beat constant of the exponential decay component of the postextrasystolic potentiation, and the O2 cost of Emax from V(O2) measured at different Emax. Our equation calculated the unknown total Ca2+ handling, futile Ca2+ cycling, and Ca2+ reactivity of Emax from the RF and Ca2+ handling V(O2). The calculated total Ca2+ handling fell between 30 and 110 micromol/kg, depending on Emax and pathological conditions. Our method also allowed an assessment of futile Ca2+ cycling and Ca2+ reactivity of Emax in a beating LV. These data are not available using conventional methods. Our method can be used to better understand the pathophysiology of total Ca2+ handling in a beating heart.

Postextrasystolic contractile decay always contains exponential and alternans components in canine heart.

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.

Energy-wasteful total Ca(2+) handling underlies increased O(2) cost of contractility in canine stunned heart.

Postischemic myocardial stunning halved left ventricular contractility [end-systolic maximum elastance (E(max))] and doubled the O(2) cost of E(max) in excised cross-circulated canine heart. We hypothesized that this increased O(2) cost derived from energy-wasteful myocardial Ca(2+) handling consisting of a decreased internal Ca(2+) recirculation, some futile Ca(2+) cycling, and a depressed Ca(2+) reactivity of E(max). We first calculated the internal Ca(2+) recirculation fraction (RF) from the exponential decay component of postextrasystolic potentiation. Stunning significantly accelerated the decay and decreased RF from 0.63 to 0. 43 on average. We then combined the decreased RF with the halved E(max) and its doubled O(2) cost and analyzed total Ca(2+) handling using our recently developed integrative method. We found a decreased total Ca(2+) transport and a considerable shift of the relation between futile Ca(2+) cycling and Ca(2+) reactivity in an energy-wasteful direction in the stunned heart. These changes in total Ca(2+) handling reasonably account for the doubled O(2) cost of E(max) in stunning, supporting the hypothesis.

Total Ca handling in canine mild Ca overload failing heart.

We 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 10 min followed by high-Ca (16mmol/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 of Emax. However, LV O2 consumption under mechanically unloading conditions decreased by 30% from control without increasing the O2 cost of Emax. 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 decreased Emax and the unchanged O2 cost of Emax 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 of Emax, or both. Any of these three possible changes can account for the unchanged O2 cost of Emax. 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.

Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation: simulation.

We have reported that the postextrasystolic potentiation (PESP) decays in alternans or monotonically, respectively, depending on whether the first postextrasystolic beat interval has a compensatory pause or not, in the canine left ventricle. To get better mechanistic insight into the alternans PESP decay, we hypothesized that the myocardial mechanical restitution and potentiation could partly account for both types of PESP decay. To test this hypothesis, we simulated PESP decay on a computer using a documented equation combining myocardial mechanical restitution and potentiation. We changed the first postextrasystolic beat interval after a fixed extrasystolic beat interval without changing regular and other postextrasystolic beat intervals. The simulated PESP decayed in alternans or monotonically as a function only of the first postextrasystolic beat interval. Thus, the myocardial mechanical restitution and potentiation could partly account for both alternans and monotonic decay of PESP. We conclude that myocardial mechanical restitution and potentiation may partly underlie the initial two alternating beats, the first beat being the most potentiated and the second beat being the most depressed, of alternans PESP decay in the canine heart.

Coupling interval from slow to tachycardiac pacing decides sustained alternans pattern.

We discovered that the coupling beat interval from a slow to a tachycardiac pacing period considerably affected the pattern of the beat-to-beat alternation of the tachycardia-induced sustained contractile alternans. We analyzed the relationship between the coupling interval and the pattern and amplitude of the alternans in the isovolumic left ventricle of canine blood-perfused hearts. The alternans pattern and amplitude varied transiently over the first 30-50 beats and became gradually stable over the first minute in all 12 hearts. We discovered that stable alternans, even under the same tachycardiac pacing, had three different strong-weak beat patterns depending on the coupling interval. A relatively short coupling interval produced a representative sustained alternans of the strong and weak beats. A relatively long coupling interval produced a similar sustained alternans but in a reversed order of even- and odd-numbered beats counted from the coupling interval. However, sustained alternans disappeared after 1-3 specific coupling intervals. We conclude that ventricular pacing rate does not solely determine the pattern and amplitude of sustained contractile alternans induced by tachycardia.