Systolic Pressure-volume Area Research Articles

Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes

We have recently reported that exposure of rat hearts to high Ca(2+) produces a Ca(2+) overload-induced contractile failure in rat hearts, which was associated with proteolysis of alpha-fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca(2+) infusion. To test this hypothesis, we investigated left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts, which were subjected to 15 min global ischemia and 60 min reperfusion. Sixty minutes after I/R, mean systolic pressure-volume area (PVA; a total mechanical energy per beat) at midrange LV volume (mLVV) (PVA(mLVV)) was significantly decreased from 5.89 +/- 1.55 to 3.83 +/- 1.16 mmHg.ml.beat(-1).g(-1) (n = 6). Mean myocardial oxygen consumption per beat (Vo(2)) intercept of (Vo(2)-PVA linear relation was significantly decreased from 0.21 +/- 0.05 to 0.15 +/- 0.03 microl O(2).beat(-1).g(-1) without change in its slope. Initial 30-min reperfusion with a Na(+)/Ca(2+) exchanger (NCX) inhibitor KB-R7943 (KBR; 10 micromol/l) significantly reduced the decrease in mean PVA(mLVV) and Vo(2) intercept (n = 6). Although Vo(2) for the Ca(2+) handling was finally decreased, it transiently but significantly increased from the control for 10-15 min after I/R. This increase in Vo(2) for the Ca(2+) handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. alpha-Fodrin proteolysis, which was significantly increased after I/R, was also significantly reduced by KBR. Our study shows that the contractile failure after I/R is similar to that after high Ca(2+) infusion, although the contribution of reverse-mode NCX to the contractile failure is different. An inhibition of reverse-mode NCX during initial reperfusion protects the heart against reperfusion injury.

Normal distribution of ventricular pressure-volume area of arrhythmic beats under atrial fibrillation in canine heart

We previously found the frequency distribution of the left ventricular (LV) effective afterload elastance (E(a)) of arrhythmic beats to be nonnormal or non-Gaussian in contrast to the normal distribution of the LV end-systolic elastance (E(max)) in canine in situ LVs during electrically induced atrial fibrillation (AF). These two mechanical variables determine the total mechanical energy [systolic pressure-volume area (PVA)] generated by LV contraction when the LV end-diastolic volume is given on a per-beat basis. PVA and E(max) are the two key determinants of the LV O(2) consumption per beat. In the present study, we analyzed the frequency distribution of PVA during AF by its chi(2), significance level, skewness, and kurtosis and compared them with those of other major cardiodynamic variables including E(a) and E(max). We assumed the volume intercept (V(0)) of the end-systolic pressure-volume relation needed for E(max) determination to be stable during arrhythmia. We found that PVA distributed much more normally than E(a) and slightly more so than E(max) during AF. We compared the chi(2), significance level, skewness, and kurtosis of all the complex terms of the PVA formula. We found that the complexity of the PVA formula attenuated the effect of the considerably nonnormal distribution of E(a) on the distribution of PVA along the central limit theorem. We conclude that mean (SD) of PVA can reliably characterize the distribution of PVA of arrhythmic beats during AF, at least in canine hearts.

Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics

We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of alpha-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion (n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo(2)) intercepts (PVA-independent Vo(2); Vo(2) for the total Ca(2+) handling in excitation-contraction coupling and basal metabolism) of Vo(2)-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O(2) costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of alpha-fodrin and the immunostaining of 150-kDa products of alpha-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of alpha-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca(2+) handling by directly inhibiting the proteolysis of alpha-fodrin.

A brief regional ischemic-reperfusion enhances propofol-induced depression in left ventricular function of in situ rat hearts.

Propofol is short-acting intravenous general anesthetics that reduces cardiovascular hemodynamics. The effects of propofol on intrinsic myocardial contractility, however, remain debatable. The aim of the current study was to test the hypothesis that inhibitory effects of propofol on left ventricular (LV) contractility and mechanical work capability of in situ ejecting rat hearts are attenuated after a brief regional ischemia and reperfusion. The authors obtained steady-state LV pressure-volume loops and intermittently obtained LV end-systolic pressure-volume relation and evaluated effects of propofol on LV function by end-systolic pressure (ESPmLVV), systolic pressure-volume area (PVAmLVV) at midrange LV volume (mLVV). Propofol (5.2 +/- 0.3 approximately 11.1 +/- 3.7 microg.ml) significantly decreased ESP0.08 to 78 +/- 12% approximately 64 +/- 13% of prepropofol and PVA0.08 to 76 +/- 13%approximately 63 +/- 16% of prepropofol in normal hearts, whereas propofol at a lower concentration (4.1 +/- 1.0 microg/ml) did not. Although brief ischemic-reperfusion per se did not affect LV function, propofol after that, even at a lower concentration (4.1 +/- 1.0 microg/ml), significantly decreased ESP0.08 to 70 +/- 27% of prepropofol and PVA0.08 to 68 +/- 33% of prepropofol. Pretreatment with a protein kinase C (PKC) inhibitor, bisindolylmaleimide reduced the propofol (4.1 +/- 1.0 microg/ml)-induced greater decreases in ESP0.08 and PVA0.08 after brief ischemic-reperfusion to 94 +/- 33% and 92 +/- 39% of prepropofol. In the propofol-infused hearts after brief ischemic-reperfusion, protein kinase C-epsilon translocation to the nucleus-myofibril fraction was found. In contrast to the study hypothesis, brief ischemic-reperfusion enhanced the inhibitory effects of propofol on LV systolic function; this enhancement is attributable to activation of protein kinase C.

Energy utility of failing heart

We investigated left ventricular (LV) mechanoenergetics in acute and chronic failing hearts, induced by high Ca(2+), ischemic-reperfusion injury, diabetes mellitus (DM), and hypothyroidism, using cross-circulated excised rat heart preparations. After high Ca(2+) or ischemic-reperfusion, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O(2) consumption per beat (VO(2)) and systolic pressure-volume area (PVA). This result indicated a decrease in VO(2) for total Ca(2+) handling in E-C coupling. We found proteolysis of a cytoskeletal protein, alpha-fodrin. A calpain inhibitor significantly suppressed contractile failure, decreased VO(2) for total Ca(2+) handling, and membrane alpha-fodrin degradation. In DM, the LV relaxation rate was significantly slower, resulting in the decreased O(2) consumption per min for total Ca(2+) handling in E-C coupling. In hypothyroidism, there were systolic and diastolic failures associated with the decreased O(2) consumption per beat for total Ca(2+) handling in E-C coupling. The protein level of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) was significantly lower in DM and hypothyroidism. We conclude that suppression of O(2) consumption for total Ca(2+) handling, mainly utilized by SERCA2, is a major cause of failing hearts, mediated through degradation of membrane alpha-fodrin via activation of calpain or suppressed expression of SERCA2.

Left Ventricular Mechanoenergetics in Small Animals

Studies on left ventricular mechanical work and energetics in rat and mouse hearts are reviewed. First, left ventricular linear end-systolic pressure-volume relation (ESPVR) and curved end-diastolic pressure-volume relation (EDPVR) in canine hearts and left ventricular curved ESPVR and curved EDPVR in rat hearts are reviewed. Second, as an index for total mechanical energy per beat in rat hearts as in canine hearts, a systolic pressure-volume area (PVA) is proposed. By the use of our original system for measuring continuous oxygen consumption for rat left ventricular mechanical work, the linear left ventricular myocardial oxygen consumption per beat (VO2)-PVA relation is obtained as in canine hearts. The slope of VO2-PVA relation (oxygen cost of PVA) indicates a ratio of chemomechanical energy transduction. VO2 intercept (PVA-independent VO2) indicates the summation of oxygen consumption for Ca2+ handling in excitation-contraction coupling and for basal metabolism. An equivalent maximal elastance (eEmax) is proposed as a new left ventricular contractility index based on PVA at the midrange left ventricular volume. The slope of the linear relation between PVA-independent VO2 and eEmax (oxygen cost of eEmax) indicates changes in oxygen consumption for Ca2+ handling in excitation-contraction coupling per unit changes in left ventricular contractility. The key framework of VO2-PVA-eEmax can give us a better understanding for the biology and mechanisms of physiological and various failing rat heart models in terms of mechanical work and energetics.

Global cardiac function: mechano-energetico-informatics

This review on the global cardiac function covers cardiac mechanics, energetics, and informatics that I have developed with my collaborators over the last 30 years in Japan and USA. We first established E max (end-systolic maximum elastance or pressure/volume ratio) as a new index of ventricular contractility using canine hearts. We then expanded the E max concept to PVA (systolic pressure–volume area consisting of external mechanical work and mechanical potential energy) as an innovative measure of total mechanical energy of ventricular contraction and discovered it to be a reliable determinant of ventricular energetics or O 2 consumption ( V O 2 ). We have discovered that E max shifts the V O 2 –PVA relation and the E max dependency (O 2 cost of E max) varies among different pathophysiological hearts. We also searched for the basis of E max in crossbridge behavior information contained in an X-ray diffraction of papillary muscle. Recently, we established a new integrative analysis to estimate total Ca 2+ recruited for excitation–contraction coupling in a beating heart using the E max–PVA– V O 2 information. These global, mechano-energetico-informatic approaches seem to facilitate better understanding of cardiac function, as required in the present post-genomic era when more physiomic knowledge is required not only in cardiac function but also in all other physiologic functions.

Arterial elastance and heart-arterial coupling in aortic regurgitation are determined by aortic leak severity

Background In aortic valve regurgitation (AR), aortic leak severity modulates left ventricle (LV) arterial system interaction. The aim of this study was to assess (1) how arterial elastance (Ea), calculated as the ratio of LV end-systolic pressure and stroke volume, relates to arterial properties and leak severity and (2) the validity of Ea/Emax (with Emax the slope of the end-systolic pressure-volume relation) as a heart-arterial coupling parameter in AR. Methods and Results Our work is based on human data obtained from a study on vascular adaptation in chronic AR. These data allowed us to assess the parameters of a computer model of heart-arterial interaction. In particular, total peripheral resistance (R) and aortic leak severity—expressed as leak resistance (RL,ao)—were quantified for different patient subgroups (group I/IIa/IIb: Emax = 2.15/0.62/0.47 mm Hg/mL; Ea = 1.24/0.66/0.90 mm Hg/mL; R = 1.9/0.6/0.85 mm Hg·s/mL, RL,ao = 0.35/0.05/0.20 mm Hg·s/mL). A parameter study demonstrated that RL,ao was the main determinant of Ea. With all other parameters constant, valve repair would increase Ea to 2.81, 1.08, and 1.54 mm Hg/mL in groups I, IIa, and IIb, respectively. For a given Ea/Emax, LV pump efficiency (estimated as the ratio of stroke work and LV systolic pressure-volume area) was lower than the theoretical predicted value, except for the simulations with intact aortic valve. Conclusions In AR, Ea is determined by aortic leak severity rather than by arterial system properties. Using Ea/Emax as a coupling parameter in general or as a mechanico-energetic regulatory parameter in particular is questionable. (Am Heart J 2002;144:568-76.)

Rat cardiac contractile dysfunction induced by Ca2+ overload: possible link to the proteolysis of alpha-fodrin.

The aim of the present study was to examine the mechanisms of Ca2+ overload-induced contractile dysfunction in rat hearts independent of ischemia and acidosis. Experiments were performed on 30 excised cross-circulated rat heart preparations. After hearts were exposed to high Ca2+, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O(2) consumption per beat and systolic pressure-volume area (index of a total mechanical energy per beat) in left ventricles from all seven hearts that underwent the protocol. This result suggested a decrease in O(2) consumption for total Ca2+ handling in excitation-contraction coupling. In the hearts that underwent the high Ca2+ protocol and had contractile failure, we found marked proteolysis of a cytoskeleton protein, alpha-fodrin, whereas other proteins were unaffected. A calpain inhibitor suppressed the contractile failure by high Ca2+, the decrease in O(2) consumption for total Ca2+ handling, and membrane alpha-fodrin degradation. We conclude that the exposure to high Ca2+ may induce contractile dysfunction possibly by suppressing total Ca2+ handling in excitation-contraction coupling and degradation of membrane alpha-fodrin via activation of calpain.

No dependency of a new index for oxygen cost of left ventricular contractility on heart rates in the blood-perfused excised rat heart.

We have reported the linear relation of myocardial oxygen consumption per beat (VO(2)) and systolic pressure-volume area (PVA) in the left ventricle of the cross-circulated rat heart. The VO(2) intercept (PVA-independent VO(2)) is primarily composed of VO(2) for Ca(2+) handling in excitation-contraction coupling and basal metabolism. Recently, we proposed a new index for oxygen cost of contractility obtainable as a slope of a linear relation between PVA-independent VO(2) and left ventricular contractility. This index indicates the Ca(2+) handling VO(2) per unit contractility change. However, a dependency of this index on heart rate has not yet been investigated. The aim of the present study was to investigate the dependency of oxygen cost of contractility on heart rate. This is a critical point to compare this cost under different heart rates. At first we found no differences of VO(2)-PVA relations at 240 and 300 beats/min (bpm). Therefore, after control VO(2)-PVA relation at 300 bpm, we gradually enhanced left ventricular contractility by Ca(2+) at a midrange left ventricular volume and obtained the gradually increased PVA-independent VO(2). At each contractility level, the pacing rate was alternately changed at 240 and 300 bpm. We obtained the two composite VO(2)-PVA relation lines and found no significant differences between the slopes of PVA-independent VO(2) and left ventricular contractility relations at 240 and 300 bpm. The present results indicated no dependency of oxygen cost of left ventricular contractility on heart rates within 240--300 bpm. Based on this fact, we concluded that even under the different pacing rates within 240--300 bpm, this oxygen cost is valid for assessing cardiac mechanoenergetics, especially the economy of total Ca(2+) handling in E-C coupling.

Oxygen Wasting for Ca2+ Extrusion Activated by Partial Inhibition of Sarcoplasmic Reticulum Ca2+-ATPase by Cyclopiazonic Acid in Rat Left Ventricles.

In the excised Langendorff-perfused rat whole-heart preparation, a linear relation between left ventricular myocardial oxygen consumption per beat (Vo2) and systolic pressure-volume area (PVA, a total mechanical energy per beat) is obtained from a curved end-systolic pressure-volume relation as in the blood-perfused preparation. The ordinate Vo2 intercept of the Vo2-PVA relation is composed of Vo2 for total Ca2+ handling in the excitation-contraction coupling and basal metabolism. The Vo2 for total Ca2+ handling is mainly consumed by sarcoplasmic reticulum (SR) Ca2+ -ATPase. The aim of the present study was to investigate, in terms of left ventricular mechanoenergetics, how an inhibition of SR Ca2+ -ATPase by cyclopiazonic acid (CPA; 4 micromol/l) affects Ca2+ handling mechanisms in the excised Langendorff-perfused rat whole-heart preparation. The short-term (for 3 to 6 min after onset of the infusion) CPA infusion decreased Vo2 proportionally to the decrease in PVA. The long-term (for 9 to 12 min after the short-term CPA infusion) CPA infusion gradually increased Vo2 almost to the control level with an increase in PVA. The increases in both Vo2 and PVA during this infusion were completely abolished by a Na+/Ca2+ exchanger inhibitor, 3'9,4'9-dichlorobenzamil, indicating the contribution of Na+/Ca2+ exchanger to the increases in Vo2 and PVA. The O2 cost of left ventricular contractility during the long-term CPA infusion was significantly higher than during the short-term CPA infusion. All these results suggest the possibility of the contribution of greater energy-wasting Ca2+ extrusion processes (such as Na+/K+-ATPase coupled to the Na+/Ca2+ exchanger; its stoichiometry is 1 ATP : 1 Ca2+ to the larger oxygen cost of left ventricular contractility.

New index for oxygen cost of contractility from curved end-systolic pressure-volume relations in cross-circulated rat hearts.

We have already reported the linear oxygen consumption per beat (VO(2))-systolic pressure-volume area (PVA) relation from the curved left ventricular (LV) end-systolic pressure-volume relation (ESPVR) in the cross-circulated rat heart. The VO(2) intercept (PVA-independent VO(2)) is primarily composed of VO(2) for Ca(2+) handling in excitation-contraction (E-C) coupling and basal metabolism. The aim of the present study was to obtain the oxygen cost of LV contractility that indicates VO(2) for Ca(2+) handling in E-C coupling per unit LV contractility change in the rat heart. Oxygen cost of LV contractility is obtainable as a slope of a linear relation between PVA-independent VO(2) and LV contractility. We obtained a composite VO(2)-PVA relation line at a mid-range LV volume (mLVV) under gradually enhanced LV contractility by stepwise increased Ca(2+) infusion and thus the gradually increased PVA-independent VO(2) values. As a LV contractility index, we could not use E(max) (ESP-V ratio; ESP/ESV) for the linear ESPVR because of the curved ESPVR in the rat LV. A PVA at a mLVV (PVA(mLVV)) has been proposed as a good index for assessing rat LV mechanoenergetics. Since the experimentally obtained PVA(mLVV) was not triangular due to the curved ESPVR, we propose an equivalent ESP-V ratio at a mLVV, (eESP/ESV)(mLVV), as a LV contractility index. This index was calculated as an ESP-V ratio of the specific virtual triangular PVA(mLVV) that is energetically equivalent to the real PVA(mLVV). The present approach enabled us to obtain a linear relation between PVA-independent VO(2) and (eESP/ESV)(mLVV) and the oxygen cost of LV contractility as the slope of this relation.

Effects of thapsigargin and KCl on the O2 use of the excised blood-perfused rat heart.

We have already reported a curvilinear end-systolic pressure-volume relation and a linear oxygen consumption per beat (Vo2)-systolic pressure-volume area (PVA) relation of the left ventricle in the rat blood-perfused whole heart preparation. Recently, we have proposed that a PVA at an appropriate left-ventricular end-diastolic volume (0.15 ml/g), such as PVA0.15 and the Vo2 intercept (minimally loaded Vo2) of the Vo2-PVA relation, can be good indexes for assessing rat left-ventricular mechanoenergetics. The minimally-loaded Vo2 would mainly consist of Vo2 for Ca 2+ handling in the excitation-contraction (E-C) coupling and basal metabolism. However, the fraction of the Vo2 by the sarcoplasmic reticulum (SR) Ca2+-ATPase in the total Ca2+ handling Vo2 has not yet been examined. To study this for the first time, we investigated the effects of thapsigargin and KCl on left-ventricular mechanoenergetics. Blockade of the SR Ca2+ pump by thapsigargin (2.5 micromol/l) decreased PVA 0. 15 by 65% and decreased the Vo2 intercept by 40% without a change in the slope of the Vo2-PVA relation. We measured the basal metabolic Vo2 by intracoronary KCl and found a 75% decrease in the Vo2 intercept. We conclude that the minimally-loaded Vo2 mainly consists of Vo2 for Ca2+ handling in the E-C coupling (at least 40% is consumed by the SR Ca2+ ATPase) and basal metabolism (25%).

Linear O2 use-pressure-volume area relation from curved end-systolic pressure-volume relation of the blood-perfused rat left ventricle.

We measured rat left ventricular pressure, volume, and oxygen consumption ( = arteriovenous oxygen content differencexcoronary flow) to establish a new evaluation of its mechanoenergetics in the whole heart preparation by using the cross-circulation method. We obtained a curved end-systolic pressure-volume relation in contrast to a linear end-systolic pressure-volume relation in dogs, rabbits, and humans. However, we obtained a linear oxygen consumption per beat (VO2)-systolic pressure-volume area (PVA, a measure of left ventricular total mechanical energy per beat) relation as in other species. Thus PVA can be a good index for assessing rat left ventricular mechanoenergetics. The VO2 intercept and slope of the linear VO2-PVA relation correspond to those in other species. Intracoronary calcium elevated the curved end-systolic pressure-volume relation and significantly increased PVA at 0.15 ml/g of left ventricular end-diastolic volume (PVA0.15) by 50%. Calcium also significantly increased the VO2 intercept of the VO2-PVA relation by 30% without a change in its slope. We conclude that the rat left ventricular end-systolic pressure-volume relation is curved, but the VO2-PVA relation is linear, and that the VO2 intercept is mainly composed of PVA-independent VO2, presumably VO2 for Ca2+ handling in the excitation-contraction coupling and basal metabolism. Therefore we propose PVA at an appropriate left ventricular volume and the VO2 intercept as good rat left ventricular mechanoenergetic indexes despite the nonlinearity of the end-systolic pressure-volume relation.

Ventricular pressure-volume area (PVA) accounts for cardiac energy consumption of work production and absorption.

We briefly review that ventricular systolic pressure-volume area (PVA) can predict changes in myocardial O2 consumption (VO2) associated with cardiac work production (positive work) and absorption (negative work). PVA represents the total mechanical energy of cardiac contraction as it is an integral of mechanical energy generated during systole in the cardiac chamber. We have shown that PVA linearly correlates with VO2 under varied pre- and afterload conditions in the left ventricle of the excised cross-circulated canine heart preparation as well as other heart preparations of different species. PVA is the sum of external mechanical work (EW) and mechanical potential energy (PE) which is almost fully convertible to mechanical work without affecting VO2. To compare the energetic effects of cardiac work production and absorption, we varied the timing of the servo pump motion relative to left ventricular (LV) contraction. When the pump fills the LV during diastole and sucks (allows ejection) during systole, cardiac work is produced by the heart, and hence EW > 0. When the pump fills the LV during systole and sucks during diastole, work is absorbed by the heart, and hence EW < 0. The pressure-volume loop rotates counterclockwise when EW > 0. It rotates clockwise when EW < 0. As the result, PVA (= PE + EW) > PE when EW > 0; PVA < PE when EW < 0. We found that VO2 always linearly correlated with PVA regardless of the polarity of EW. Therefore, PVA is the unique determinant of VO2 in a cardiac chamber in a stable contractility.

Effects of intracoronary caffeine on left ventricular mechanoenergetics in Ca2+ overload failing rat hearts.

How different the effects of caffeine on cardiac mechanoenergetics in failing hearts are from those of normal hearts remains to be fully elucidated. First we successfully instituted a new experimental model of acute mild heart failure in the rat by 0.005 mM Ca2+ Tyrode perfusion. These failing hearts neither decreased left ventricular end-systolic pressure nor increased left ventricular end-diastolic pressure, indicating unchanged left ventricular mechanics. However, their myocardial mitochondrial respiratory function examined by respiratory control index (RCI) and oxygen consumption rate in state III (State III O2) was significantly depressed compared with normal hearts. From these results, we judged that this Ca2+ protocol could make mild Ca2+ overload acute failing hearts and that this model would be appropriate for comparing the effects of caffeine on cardiac mechanoenergetics between normal hearts and these failing hearts. We investigated the effects of caffeine on cardiac mechanoenergetics above a concentration of 0.05 mM that corresponds to the maximum blood concentration after a healthy human subject drinks a cup of coffee or tea. We obtained results indicating that caffeine depressed left ventricular systolic and diastolic functions and decreased a measure of total mechanical energy per beat in terms of systolic pressure-volume area (PVA) more severely in these failing hearts at concentrations (20-fold higher than the concentration in a cup of coffee) lower than those in normal hearts. This result implies that these acute failing hearts are Ca2+ overloaded.

Effects of intracoronary fentanyl on left ventricular mechanoenergetics in the excised cross-circulated canine heart (revised publication).

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. 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. 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. These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

Effects of intracoronary fentanyl on left ventricular mechanoenergetics in the excised cross-circulated canine heart.

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. 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 E(max) (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 E(max), PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control E(max). 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. Fentanyl at any concentrations did not significantly change E(max), 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. These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

Oxygen-Saving Effect of a New Cardiotonic Agent, MCI-154, in Diseased Human Hearts

Objectives. The aim of this study was to examine the left ventricular mechanoenergetic effects of a novel Ca2+sensitizing agent, MCI-154, on diseased human hearts compared with dobutamine.Background. Unlike conventional cardiotonic agents, a Ca2+sensitizer that could produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+could generate force with smaller amounts of Ca2+; thus, it may potentially save energy expenditure.Methods. The left ventricular pressure-volume relation and myocardial oxygen consumption per beat (Vo2) were measured by a conductance (volume) catheter and a Webster catheter. Left ventricular contractility (Emax), systolic pressure-volume area (PVA [index of left ventricular total mechanical energy]) and Vo2were assessed before and after infusion of MCI-154 or dobutamine. The PVA-independent Vo2(Vo2mainly for excitation-contraction coupling) was assessed as the Vo2at zero PVA.Results. Both agents increased Emax comparably (dobutamine: from 3.55 ± 1.10 [mean ± SD] to 5.04 ± 1.16 mm Hg/ml per m2, p < 0.0001; MCI-154: from 3.36 ± 1.26 to 5.37 ± 2.14 mm Hg/ml per m2, p < 0.0001); dobutamine increased total Vo2(from 0.22 ± 0.08 to 0.27 ± 0.09 ml O2, p < 0.05) and PVA-independent Vo2(from 0.019 ± 0.019 to 0.091 ± 0.051 ml O2, p < 0.005); but MCI-154 did not change these variables significantly. Consequently, the oxygen cost of contractility (ΔPVA-independent Vo2/ΔEmax) was less with MCI-154 than with dobutamine (0.14 ± 0.18 vs. 1.10 ± 0.80 J/mm Hg per ml per m2, p < 0.05).Conclusions. These results suggest that the cardiotonic action mediated by MCI-154 could provide an energetic advantage over the conventional cardiotonic action with currently used inotropic agents.(J Am Coll Cardiol 1997;29:613–22)

Effects of milrinone and sulmazole on left ventricular mechanoenergetics in canine hearts

Background: The effect of cardiotonic drugs with calcium-sensitizing effect (Ca 2+ sensitizers) on cardiac mechanoenergetics is not fully understood. Accordingly, the effects of milrinone (a phosphodiesterase inhibitor) and sulmazole (a calcium sensitizer with a phosphodiesterase-inhibiting effect) on left ventricular mechanics and energetics were studied. Methods and Results: In excised, cross-circulated canine hearts, myocardial oxygen consumption (Vo 2), left ventricular contractility index (E max), and systolic pressure-volume area (a measure of ventricular total mechanical energy) were measured before and during administration of either drug. Milrinone significantly increased E max by 108.7 ± 45.9% (mean ± SD), from 6.3 ± 3.5 to 13.1 ± 6.8 mmHg·mL −1·100 g ( P < .05), and sulmazole, by 73.6 ± 54.2%, from 6.3 ± 2.6 to 10.3 ± 2.9 mmHg·mL −1·100 g ( P < .05). Milrinone significantly abbreviated the contraction duration (T max) from 171 ± 19 ms to 153 ± 20 ms ( P < .05), whereas sulmazole did not (164 ± 36 ms to 16131 ms, not significant), suggesting that the inotropic mechanisms of these two drugs differed. However, both drugs significantly increased the V O 2 intercept of the V O 2 /pressure-volume area relation (milrinone: 0.027 ± 0.004 to 0.036 ± 0.003 mL O 2/beat/100 g, P <.05; sulmazole: 0.025 ± 0.005 to 0.032 ± 0.006 mL O 2/beat/100 g, P < .05) without significantly changing the slope (reciprocal of contractile efficiency). This parallel upward shift of the V O 2 /pressure-volume area relation was similar to that observed with epinephrine and ouabain in our previous studies. Conclusions: These results suggest that the two positive inotropic drugs exhibit similar mechanoenergetic effects in the normal canine heart despite the different mechanisms of action.