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The intraparticle diffusion of a fluorescent dye in single microparticles in an aqueous solution was analyzed using fluorescence recovery after photobleaching, with a confocal fluorescence microscope. The fluorescence depth profile of single microparticles, and the fluorescence recovery at the particle center, were measured; further, the intraparticle diffusion coefficient was determined through simulations of three-dimensional diffusion in the respective microparticles. The intraparticle diffusion of coumarin 102 in octadecylsilyl silica gel was limited by the surface diffusion.

An 83-year-old female, who had a history of anterior myocardial infarction, was treated for Alzheimer's disease with donepezil. She suffered from repeated diarrhea and vomiting, and experienced syncope. She was admitted to our hospital and was diagnosed with acute colitis and syncope. On admission, her heart rate was 54beats/min with regular rhythm. Laboratory data showed a low plasma potassium level. Electrocardiogram (ECG) showed poor R progression, ST elevation, negative T in precordial leads, and marked QT prolongation. Transthoracic echocardiogram showed the enlargement of the left atrium and aneurysmal area at the apex. Torsades de Pointes (TdP) with syncope and convulsion were confirmed on ECG monitoring twice after admission. We treated her with potassium chloride and started magnesium sulfate and lidocaine, and then added isoprenaline injection. After these treatments, her heart rate increased and we did not detect TdP again. With the aging population in Japan, prescriptions for donepezil are increasing. We have to be vigilant for syncope in patients taking donepezil, which is possibly related to QT prolongation and TdP.

Background Increased nitric oxide (NO) in the failing heart attenuates the myocardial contractile response to β-adrenergic receptor stimulation. However, the physiological effects of NO on the β-adrenergic post-receptor signaling system are unknown. The objective of the present study was to examine the effects of cardiac NO synthase (NOS) inhibition on left ventricular (LV) hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation in human heart failure. Methods and Results The study group comprised 13 patients with heart failure because of idiopathic cardiomyopathy (IDC). Emax was examined as an index of LV contractility, LV external work (EW), pressure - volume area (PVA), myocardial oxygen consumption (MVO2), and mechanical efficiency (EW/MVO2) with the use of conductance and coronary sinus thermodilution catheters before and during colforsin daropate infusion, and during concurrent infusion of colforsin daropate with the NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA; 200 μmol). Colforsin daropate increased Emax by 53% and EW by 18%, and reduced PVA by 14%, without altering MVO2 or mechanical efficiency. The combination of colforsin daropate with L-NMMA further increased Emax by 26% and reduced PVA by 9%, without altering MVO2 or mechanical efficiency. Conclusions These findings suggest endogenous NO may modulate β-adrenergic post-receptor pathways and preserve myocardial efficiency in patients with IDC. (Circ J 2007; 71: 1268 - 1273)

Serotonin (5HT) can induce coronary artery spasm (CAS) in patients with variant angina (VA). We have previously reported that 5HT(1B) and 5HT(2A) receptors gene were expressed in human coronary arterial smooth muscle cells and that isolated coronary artery from a patient with VA showed the supersensitivity to sumatriptan (SMT), a 5HT(1B/1D) receptor agonist. The aim of the present study was to determine whether SMT can provoke CAS directly or indirectly through platelet aggregation in patients with VA.We evaluated the effects of intracoronary infusion of graded concentrations of SMT on coronary arteries in 9 patients, including 5 documented VA and 4 participants with atypical chest pain as control.SMT provoked CAS in all patients with VA. SMT could not induce CAS in control. SMT (10(-4) M) caused significant contractions (%diameter of baseline; median [interquartile range], 0 [0-18.4]% in VA, as compared with control (proximal segments; 92.6 [77.9-118.9]%, p0.05 vs. VA, distal segments; 92.9 [65.3-158.5]%, p0.01 vs. VA). In control, minor dilation occurred at SMT concentration up to 10(-5) M. SMT could induce in vitro platelet aggregation neither in healthy subjects nor in patients with VA.These findings suggest that activation of 5HT(1B) receptor by SMT can induce CAS directly in patients with VA without platelet activation. This is the first report directly demonstrating the effect of 5HT(1B) receptor activation on human coronary arteries in vivo.

A high prevalence of hepatitis C virus (HCV) infection has been reported among idiopathic dilated cardiomyopathy (DCM) patients. We examined the prevalence of DCM patients with HCV antibody, and the pathophysiological characteristics and responsiveness to neurohormonal antagonism in DCM with HCV. HCV antibodies were determined in 540 patients with cardiac diseases. In 117 DCM patients, clinicopathologic data were evaluated before and 1 year after angiotensin converting enzyme inhibitor and/or beta-blocker (ACE-inhibitor/BB) administration and their prognosis was followed-up for a mean of 72 +/- 41 months. HCV antibodies were found in 12 of 135 DCM patients (8.9%) and in 37 of 405 patients without DCM (9.1%) (P = NS). At baseline, contrary to DCM without HCV, DCM with HCV was associated (P < 0.05) with greater left ventricular (LV) end-diastolic and end-systolic dimension, LV mass, and myocardial diameter in endomyocardial biopsy, and lower % fractional shortening. By multivariate analysis, HCV infection was independently associated with larger LV end-systolic dimension among DCM patients (P = 0.005). The advanced LV dilatation and hypertrophy in DCM with HCV decreased more in response to the ACE-inhibitor/BB therapy compared to DCM without HCV. There were no differences between DCM patients with and without HCV in survival and cardiac event-free rates. In summary, although HCV infection appears not to be the specific cause of DCM, HCV may enhance ventricular remodeling leading to heart failure among DCM patients. Nevertheless, the advanced ventricular remodeling with HCV was adequately reversed by neurohormonal antagonism, and did not lead to an unfavorable outcome.

Background: No-reflow phenomenon is observed in approximately one-third of patients after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), and is associated with poor functional and clinical outcomes. On the other hand, the formation of free radicals in vasculature exerts deleterious effects on coronary microcirculation. Hypothesis: We hypothesized that redox state in coronary circulation may play a crucial role in no-reflow phenomenon in AMI. Methods: Consecutive 26 patients with first AMI who underwent primary PCI

Background Plasma brain natriuretic peptide (BNP) is a sensitive and specific marker of left ventricular (LV) function. In the treatment of heart failure, especially in idiopathic dilated cardiomyopathy (IDC), β-blocker (BB) therapy has been established as a powerful strategy. The purpose of this study was to analyze relationships between changes in BNP level and LV function during BB therapy in patients with IDC. Methods In 30 patients with IDC who had already received conventional therapy, measurement for plasma BNP and norepinephrine levels and echocardiographic indices were evaluated before and 2 and 6 months after carvedilol in 21 patients and at baseline and after 6 months in 9 patients who did not receive carvedilol. Results After 6 months carvedilol treatment significantly improved LV end-diastolic dimension (LVEDD) (65 ± 8 to 61 ± 8 mm) and LV ejection fraction (LVEF) (34% ± 13% to 43% ± 12%) with intergroup differences; it significantly decreased BNP (127 ± 113 to 69 ± 92 pg/mL) with no intergroup difference; however, it did not decrease norepinephrine. BNP correlated strongly with LVEDD, LVEF, and LV mass index in carvedilol-treated patients. The degree of change in BNP correlated with that in LVEDD or LVEF 6 months after carvedilol. All 14 patients with decreased or unchanged BNP levels showed an increase in LVEF, and 4 of 7 with a rise in BNP had decreased or unchanged LVEF. According to receiver operating characteristic analysis, the optimal BNP levels for detecting LVEF Conclusion: Plasma BNP levels may accurately reflect alteration in LV function and structure and can be used as a therapeutic indicator for risk stratification in patients with IDC during BB therapy. (Am Heart J 2001;141:925-32.)

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.

Background —Brief antecedent periods of coronary artery occlusion improve subsequent vessel patency in damaged and stenotic coronary arteries via release of adenosine from ischemic/reperfused myocardium and resultant adenosine receptor stimulation. However, the site of receptor stimulation—circulating blood-borne elements (ie, platelets) versus vessel-wall components of the culprit artery—remains unclear. If platelet adenosine receptors are involved, then the benefits of brief coronary occlusion (1) should be manifested systemically and improve patency at a remote site and (2) should be inhibited by an antagonist of adenosine A 2 receptors, whereas, in contrast, (3) brief vascular occlusion not associated with appreciable adenosine release should be ineffective in improving vessel patency. Methods and Results —In Protocol 1, anesthetized rabbits received 5 minutes of transient coronary occlusion, 5 minutes of transient bilateral carotid occlusion (purported to cause negligible adenosine release from the brain), or no intervention. All rabbits then underwent injury plus stenosis of the left carotid artery, resulting in repeated cyclic variations in carotid blood flow (CFVs). Carotid patency during the initial 2 hours after stenosis (assessed by quantifying the nadir of the CFVs and area of the flow-time profile) was significantly enhanced with antecedent coronary—but not carotid—occlusion versus controls. In Protocol 2, improvement in carotid patency after brief coronary occlusion was corroborated in anesthetized dogs. However, the benefits of brief coronary occlusion were abrogated by the A 2 /A 1 antagonist CGS 15943. Conclusions —Brief antecedent coronary artery occlusion enhanced vessel patency in remote, damaged, and stenotic carotid arteries, largely due to adenosine receptor stimulation on circulating elements.

Although conventional inotropic agents such as catecholamines increase myocardial oxygen consumption, a newly developed inotropic agent, a Ca2+ sensitizer, may be able to increase cardiac output with less myocardial oxygen consumption. By using right-side heart catheterization, we assessed the ratio of the increase in myocardial oxygen consumption per unit increase in cardiac output during beta-adrenergic receptor stimulation (dobutamine, n = 15), phosphodiesterase inhibition (E-1020, n = 10), and Ca2+ sensitization (MCI-154, n = 17) in patients with coronary artery disease. Dobutamine increased cardiac output and myocardial oxygen consumption. E-1020 increased cardiac output but did not change myocardial oxygen consumption. MCI-154 increased cardiac output and decreased myocardial oxygen consumption. The oxygen cost of increasing cardiac output with dobutamine and with E-1020 was different from that with dextran infusion (n = 18); in contrast, the oxygen cost with MCI-154 was significantly smaller. Thus a newly developed Ca2+ sensitizer, MCI-154, may be beneficial for the treatment of heart failure.

The negative inotropism of 2,3-butanedione monoxime (BDM) < or = 5 mmol/l has been attributed primarily to directly suppressed crossbridge force development without much suppressed intracellular Ca2+ handling. However, there is evidence that BDM simultaneously or even primarily suppresses myocardial excitation-contraction (E-C) coupling. We therefore studied the mechanoenergetic effects of intracoronary BDM in the left ventricle (LV) of 11 canine excised cross-circulated hearts. We fully utilized the VO2-PVA-Emax framework that we have developed, where VO2 is myocardial O2 consumption, PVA is the systolic pressure-volume area as a measure of the total mechanical energy, and Emax is a contractility index. We gradually depressed Emax from 5.9 to 3.4 mmHg/(ml/100 g) on average by increasing intracoronary BDM to 2.6 +/- 2.1 mmol/l, and then gradually restored Emax to the pre-BDM level by increasing intracoronary CaCl2. We compared the O2 cost of Emax between BDM and Ca2+. We found that BDM and Ca2+ had a similar O2 cost of Emax. BDM did not affect the concentrations of blood-borne catecholamines. We therefore conclude that the negative inotropism of BDM is primarily due to suppressed E-C coupling in canine blood-perfused hearts.

Mechanical vibration depresses cardiac contractility. We studied the mechanoenergetic effects of this negative inotropism in the left ventricle (LV) of an isolated, cross-circulated dog heart preparation. We took full advantage of the mechanoenergetic relationship among the LV end-systolic elastance (Emax, contractility index), systolic pressure-volume area (PVA), and myocardial oxygen consumption (VO2). PVA is a measure of the total mechanical energy that cardiac contraction generates. PVA correlates closely with VO2. The VO2 intercept of the VO2-PVA relation reflects the VO2 component for excitation-contraction (E-C) coupling plus basal metabolism (PVA-independent VO2). VO2 above the PVA-independent VO2 reflects the VO2 component for mechanical contraction (PVA-dependent VO2). When we applied 70-Hz vibration of 2-mm amplitude to a LV wall region, it instantly decreased Emax and PVA by 20%, followed by a 10% decrease in VO2 at a fixed volume. However, the vibration neither lowered the VO2-PVA relation obtained at different LV volumes, unlike ordinary negative inotropism, nor changed its slope (1.88 +/- 0.23 vs. 1.86 +/- 0.23 x 10(-5) ml O2.mmHg-1.ml-1). The virtually zero delta PVA-independent VO2/delta Emax with vibration indicates a much smaller O2 cost of Emax than that seen with calcium and propranolol inotropism. These mechanoenergetics support the hypothesis that mechanical vibration primarily suppresses cardiac contractility without suppressing E-C coupling.

Left ventricular (LV) contractile dysfunction during acidosis has been reported to be almost reversible in crystalloid-perfused hearts after correction of acidosis. In contrast, we have found that, in blood-perfused hearts, contractile function is paradoxically depressed after correction of acidosis with a transient overshoot of contractility during the recovery of pH. To clarify the mechanism of this phenomenon, we measured the LV contractility index (Emax) and the relation between myocardial oxygen consumption (VO2) and systolic pressure-volume area (PVA, a measure of the LV total mechanical energy) before and after induction and rapid correction of acidosis by CO2 loading (pH 7.00) and unloading in 13 excised cross-circulated canine hearts. During the rapid correction of acidosis in six control hearts, a severe transient overshoot of Emax (404% of acidosis) occurred. However, after correction of acidosis, Emax and PVA were lower than the preacidosis values by 46% (P < .01) and 44% (P < .01) at the same LV volume. When the preacidosis Emax level was restored by Ca2+ infusion, the VO2 intercept (PVA-independent VO2) of the linear VO2-PVA relation exceeded the control value by 18% (P < .05) with an unchanged slope. In addition, the oxygen cost of contractility, defined as the slope of the relation between PVA-independent VO2 and Emax, increased by 83% (P < .01) after correction of acidosis, indicating that postacidosis myocardium requires higher VO2 for nonmechanical activities for a unit increase in Emax. Then, we hypothesized that these mechanoenergetic disorders after rapid correction of acidosis would result from Ca2+ overload via accelerated Na(+)-Ca2+ exchange due to the heavily operating Na(+)-H+ exchange system at the time of rapid pH recovery. To examine this hypothesis, dimethylamiloride, a selective Na(+)-H+ exchange inhibitor, was administered just before the correction of acidosis in the other seven hearts. The administration of dimethylamiloride completely prevented both the mechanical and energetic disorders after correction of acidosis. We conclude that rapid recovery of pH paradoxically depresses myocardial contractility and increases the oxygen cost of contractility through an activation of the Na(+)-H+ exchange system.

The effect of acidosis on left ventricular (LV) mechanoenergetics was assessed in seven excised, cross-circulated dog hearts with the use of the frameworks of the contractility index (Emax) and the relationship between myocardial oxygen consumption (VO2) and pressure-volume area (PVA; a measure of the LV total mechanical energy). Acidosis was stably maintained without hypoxia by appropriately mixing CO2 and air in a membrane oxygenator in the coronary arterial perfusion circuit. Acidosis [pH: 6.98 +/- 0.09 (SD), PCO2: 91 +/- 25 mmHg in the coronary arterial blood] decreased Emax by 45 +/- 12% (P < 0.01) and PVA by 47 +/- 12% (P < 0.01) at a fixed LV volume. When the preacidosis Emax level was restored by Ca2+ infusion during acidosis, unloaded VO2 (the VO2 intercept of the VO2-PVA relation) exceeded the control value by 19 +/- 17% (P < 0.05), indicating that acidosis required higher VO2 for nonmechanical activities at a matched Emax. Moreover, the oxygen cost of enhanced contractility (the incremental ratio of unloaded VO2 to Emax) was 1.53 +/- 0.40 times higher (P < 0.01) during acidosis than preacidosis. We conclude that acidosis results in LV contractile dysfunction accompanied by an increased oxygen cost of contractility. This increased energy cost of the excitation-contraction coupling can be accounted for by a decreased Ca2+ sensitivity of the contractile proteins during acidosis.

Several investigators have found experimentally that the force-time integral varies non-linearly with energy expenditure over the course of a cardiac contraction. Also, recent research findings have indicated that the crossbridge cycle to ATP hydrolysis ratio in muscle fiber systems may not be coupled with a one-to-one ratio. In order to investigate these findings, Huxley's sliding filament crossbridge muscle model coupled with parallel and series elastic components was simulated to examine the behavior of the crossbridge energy utilization and force-time integral vs time. Crossbridge (CB) energy utilization was determined by considering the ATP hydrolysis for the crossbridge cycling, and this CB energy was compared with the force-length energy in a contraction. This CB energy was calculated in both isometric and isotonic contractions as a function of contraction time and compared to the force-time integral. Simulation results demonstrated that the ratio of the force-time integral to CB energy varies strongly throughout the cardiac cycle for both isometric and isotonic cases, as has been observed experimentally. Simulations also showed that using the force-length energy component of energy vs the CB energy gave a better correlation between the total energetic predictions and the force-time integral, agreeing with recent finding that the crossbridge cycle to ATP hydrolysis ratio may not be coupled one-to-one, especially at lower force levels.

To validate the accuracy of human left ventricular (LV) volume measured by the conductance catheter method, conductance volume was compared with LV volume measured by biplane angiography in 19 patients with ischaemic heart disease. Angiographic LV volumes were calculated frame by frame and matched with instantaneous conductance volumes. Calibration was determined by both gain constant, 1/alpha, and parallel conductance, alpha V c. The gain constant, 1/alpha, was the ratio of stroke volume measured by the thermodilution method to that measured by the conductance catheter. The parallel conductance, alpha Vc, was estimated by the saline injection method. There was a good correlation between the corrected conductance volume (Vcc) and the angiographic volume (V angio) such that Vcc = 0.94 V angio + 5.3 ml, r = 0.94, P < 0.001. There were no differences in the correlation coefficients between normal and depressed hearts. Compared with the angiographic data, LV end-diastolic volume, end-systolic volume and ejection fraction were determined accurately by the conductance catheter. We conclude that the conductance catheter method, corrected for gain constant and parallel conductance, can accurately and continuously estimate the LV volume throughout the cardiac cycle in the diseased human heart.

BACKGROUND We hypothesized that the effect of pimobendan (UD-CG 115 BS) to increase calcium sensitivity of contractile protein might result in less myocardial oxygen consumption (VO2) in comparison with dobutamine when they enhance ventricular contractility to the same extent. To examine this hypothesis, we compared the effects of pimobendan and dobutamine on left ventricular contractility and energetics using the frameworks of Emax (contractility index) and the relation between VO2 and PVA (systolic pressure-volume area, a measure of left ventricular total mechanical energy). METHODS AND RESULTS We measured VO2, Emax, PVA, and force-time integral (FTI) in excised, cross-circulated, nonfailing dog hearts. The slope of the VO2-PVA relation reciprocally indicates the efficiency from PVA-dependent VO2 to the total mechanical energy (contractile efficiency). The VO2 intercept of the VO2-PVA relation, i.e., PVA-independent VO2, reflects energy utilization for excitation-contraction coupling. The ratio of FTI to PVA-dependent VO2 can be called contractile economy. Both drugs comparably enhanced Emax. Although the contractile economy was greater by 14 +/- 19% (p less than 0.05) for pimobendan than for dobutamine, the contractile efficiency was similar between the two drugs. Oxygen cost of contractility, defined as the slope of the relation between the PVA-independent VO2 and Emax, was the same between the two drugs. Other mechanoenergetic effects of both drugs were similar except for a greater coronary vasodilating effect of pimobendan. CONCLUSIONS Pimobendan has almost the same mechanoenergetic effects as dobutamine but slightly greater contractile economy and coronary vasodilation. The calcium-sensitizing effect of pimobendan did not save the oxygen cost of contractility.

We compared the oxygen cost of increasing ventricular contractility using Emax (slope of the ventricular end-systolic pressure-volume relation) as the index of ventricular contractility. Contractility was enhanced by calcium and epinephrine in paired experiments on dog left ventricles. Firstly, we obtained left ventricular oxygen consumption (VO2) and systolic pressure-volume area (PVA, a measure of total mechanical energy) of contractions at different volumes in the control contractile state to determine a reference VO2-PVA relation. PVA was obtained as the area in the pressure-volume (P-V) diagram which was bounded by the end-systolic P-V line, end-diastolic P-V curve and systolic P-V trajectory of individual contractions. Secondly, we gradually enhanced Emax with calcium and epinephrine in two consecutive runs at a fixed ventricular volume. Both VO2 and PVA increased with enhanced Emax. From these VO2-PVA data, we calculated the PVA-independent VO2 values at the respective enhanced Emax levels and determined the oxygen cost of Emax as the slope of the relation between the PVA-independent VO2 and Emax. The cost per beat and per 100 g was 0.00158 ml O2/(mmHg/ml) for calcium and 0.00166 ml O2/(mmHg/ml) for epinephrine on average, values not significantly different from each other (P less than 0.05). We conclude that epinephrine and calcium have similar oxygen costs of contractility over a wide range of Emax despite their different pharmacological mechanisms of positive inotropism.

We have recently proposed a mechanical index, equivalent pressure-volume (PV) area (ePVA), as a measure of the total mechanical energy during ventricular fibrillation (VF). ePVA, an analogue of the PV area (PVA) of a beating heart, is the area surrounded by the isobaric line drawn at the VF pressure, the end-systolic and end-diastolic PV relations of the beating state. In the present study, using a closed-air chamber system, we actually produced isobaric contractions, PVAs of which were identical with ePVAs during VF. Myocardial O2 consumption (VO2) during VF was measured and compared with the estimated value from VO2 of isobaric contraction with identical PVA and equivalent heart rate (eHR). eHR, an estimate of the contraction frequency of each myocyte during VF, was determined from unloaded VO2 in beating and fibrillating states. The efficiency of the energy conversion from VO2 for mechanical purposes to the total mechanical energy (contractile efficiency) during VF was calculated as the reciprocal of the slope of the VO2-ePVA relation. The estimated VO2 during VF agreed with measured VO2 (r = 0.96, regression coefficient = 1.13). The slope of the VO2-ePVA relation during VF was not different from that in the beating state in all hearts by analysis of covariance, and mean contractile efficiency during VF (51 +/- 23%) was not significantly different from that in the beating state (40 +/- 12%). We conclude that 1) ePVA is considered to represent the total mechanical energy during VF, and 2) contractile efficiency during VF is comparable to that in the beating state.

We propose new indexes to evaluate the effects of ventricular inotropism and lusitropism on stroke volume. The end-systolic pressure-volume relationship (ESPVR) or its slope (Emax) has been employed to assess ventricular inotropism. The end-diastolic pressure-volume relationship (EDPVR) or compliance has been used to express ventricular diastolic properties or lusitropism. However, their net effect on stroke volume under a given set of preload and afterload pressures has not quantitatively been evaluated. Ejecting volume gain (Ge) was proposed to quantify the inotropic effect on stroke volume by the change in end-systolic volume between the two ESPVR curves obtained before and during an inotropic intervention at a specified ejecting pressure. Ge is a function of afterload pressure. Filling volume gain (Gf) was proposed to quantify the lusitropic effect on stroke volume by the change in end-diastolic volume between the two EDPVR curves before and during a lusitropic intervention at a specified filling pressure. Gf is a function of preload pressure. The net effect of these inotropic and lusitropic effects on stroke volume at these specified preload and afterload pressures can be expressed by the sum of Ge and Gf. We call this sum stroke volume gain (Gsv). Gsv is a function of preload and afterload pressures. Using representative examples, we demonstrate that these new indexes are conceptually useful to quantitatively understand changes in the pumping ability of the heart under simultaneous inotropic and lusitropic effects as a function of ejecting and filling pressures.

We propose equivalent heart rate (eHR) as an estimate of the frequency of contractions of individual myocytes in a fibrillating ventricle by analyzing mechanics and energetics of the ventricle. Using the isolated, cross-circulated dog heart preparation, we determined eHR in two different ways. First, we obtained eHR (eHR1) from myocardial O2 consumption (Vo2)-equivalent pressure-volume area (ePVA) data points during ventricular fibrillation (VF) by utilizing the Vo2-pressure-volume area (PVA) relation in the beating state. PVA is the area surrounded by the end-systolic and end-diastolic pressure-volume relations and the systolic pressure-volume trajectory in the pressure-volume diagram. PVA has been shown to represent the total mechanical energy generated by each contraction. We have recently proposed ePVA as a measure of the total mechanical energy generated by single contractions of all individual asynchronously contracting myocytes in a fibrillating ventricle. ePVA is the area surrounded by the horizontal line at the VF pressure and the end-systolic and end-diastolic pressure-volume relations in the beating state. Second, we measured Vo2 in beating state at various heart rates and Vo2 during VF under a mechanically unloaded condition. By comparing these fibrillating and beating Vo2 values, we determined eHR (eHR2) for the fibrillating state. eHR1 was 216 +/- 27 beats/min and eHR2 was 223 +/- 26 beats/min. These two values were not significantly different. We conclude that the average frequency of contractions of individual myocytes in a fibrillating ventricle is equivalent approximately to 220 beats/min in terms of ventricular energetics.

We carried out a simulation study to obtain insight into the relation between calcium (Ca2+) transients and energy for handling Ca2+ in excitation-contraction (EC) coupling. The simulation incorporated basic Ca2+ kinetics among total released Ca2+ from sarcoplasmic reticulum (SR), myoplasmic free Ca2+ ion concentration, and troponin (Tn)-Ca complex concentration ([TnCa]). The total Ca2+ released from the SR was arbitrarily set as an impulse and three rate constants were used for Ca2+ binding to Tn, Ca2+ dissociation from Tn, and Ca2+ uptake by SR. The results showed that the peak Ca2+ transient varies widely as a reciprocal of the Ca2+ sensitivity of the contractile machinery, despite constant total released Ca2+ and hence, a constant energy for Ca2+ handling. This result suggests a disproportate relationship between the magnitude of Ca2+ transients and the energy for Ca2+ handling when the Ca2+ sensitivity of contractile machinery changes.

SummaryA 53-year-old man, who had been treated for penile origin diffuse large B cell type non-Hodgkin lymphoma (NHL), suffered from right femoral pain and dyspnea. Positron emission tomography (PET) revealed abnormal accumulation in his right femur and cardiac segments. Transthoracic echocardiography revealed massive localized pericardial effusion with the collapse of both ventricles and the mass-like echo in the left atrium. We performed emergent pericardiocentesis and diagnosed this case as a recurrence of NHL with cardiac metastasis. With the use of transesophageal echocardiography (TEE), we confirmed the mass-like echo around the inter-atrial septum, which directly invaded to the aortic ring and the right atrial wall. In order to evaluate the effect of chemotherapy, we performed TEE and observed the precise changes of intra-cardiac tumor size. With the use of TEE monitoring, we could select the appropriate chemotherapeutic regimen, and the tumor became smaller and finally diminished. The femoral accumulation detected by PET also disappeared. We experienced a case of cardiac metastasis of NHL complicated with left ventricular diastolic collapse due to the massive localized pericardial effusion. TEE is a useful tool to evaluate precisely the efficacy of chemotherapy for intra-cardiac tumors.

SummaryA 60-year-old man, suffering from sustained cough and dyspnea on effort, was diagnosed as congestive heart failure. He did not yield the history of having fever or other inflammatory events. His physical examination disclosed a pan-systolic murmur at the apex. Transthoracic color Doppler echocardiography showed moderate to severe mitral regurgitation originated from the linear tear of the anterior mitral leaflet. The tear reached to the mid-portion of the leaflet just within the postero-medial commissure and the regurgitant flow convergence was not hemispheric, but box-like shaped, suggesting that the linear tear was the isolated mitral cleft. Transesophageal echocardiography showed the almost same findings and we found no other anomalies. Surgical treatment was selected to repair the mitral regurgitation. Under operation, we found three consecutive perforations located linearly in the anterior mitral leaflet. The mitral valve replaced with the prosthetic one. The pathological examination of the resected valve showed mucinous degeneration of the chordae tendineae and fibrinoid change without inflammatory cellular infiltration. These findings were compatible with the healed infective endocarditis. Here we experienced a curious case of mitral regurgitation, caused by consecutive three mitral perforations mimicking the isolated anterior mitral cleft.

Infrared and Raman spectra of polyethylene glycol (PEG) complexed with calcium and magnesium chlorides have been measured in aqueous solutions and in isolated complexes. Composition of the calcium complex was obtained as 4.4±0.1 (CH 2 CH 2 O unit):1 (CaCl 2 ):4.5±0.5 (H 2 O) by elementary analysis. From these results, the conformation of PEG in the calcium complex has been proposed to be an alternate conbination of two conformational sequences, (-TGT-TG′T-GTT-TTG-) and (-TGT-TG′T-TGT-GTT-TTG-). For the magnesium complex, the conformation of PEG is supposed to be similar to that of crystalline PEG, with repetition of TGT for the -CH 2 CH 2 O units. The difference in the structure between the calcium and magnesium complexes was explained by the difference in the cation's size.

Although plasma B-type natriuretic peptide (BNP) levels increase with age, the mechanisms responsible for this increase are unknown. We investigated the predictors of elevated BNP in older subjects without cardiac systolic dysfunction and overt renal dysfunction. Furthermore, we analyzed the relations between BNP and its second messenger, cyclic guanosine monophosphate (cGMP), to aging. In 252 subjects (mean age 69 +/- 12 years) with left ventricular ejection fraction/=50% and creatinine levels==1.5 mg/dl, plasma levels of BNP, cGMP, blood urea nitrogen, creatinine, and beta2-microglobulin (an endogenous marker of renal function), estimated glomerular filtration rate, and echocardiographic data were prospectively evaluated. Plasma BNP levels increased with age (r = 0.4, p0.0001). With use of multivariate analysis, predictors of elevated BNP levels were age, use of beta blockers, and serum beta2-microglobulin levels. The molar ratio of cGMP to BNP significantly decreased with aging (r = 0.55, p0.0001). Elevated BNP in older subjects with normal cardiac systolic function may be due in part to renal impairment. With aging, biologic compensation of the cardiac natriuretic peptide system may be attenuated.

Objective— NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22 phox , an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22 phox , the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. Methods and Results— DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22 phox and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22 phox and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22 phox or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. Conclusions— ROS generated by p22 phox -based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.

Heart temperature affects left ventricular (LV) function and myocardial metabolism. However, how and whether increasing heart temperature affects LV mechanoenergetics remain unclear. We designed the present study to investigate effects of increased temperature by 5°C from 36°C on LV contractility and energetics. We analyzed the LV contractility index ( Emax) and the relation between the myocardial oxygen consumption (MV˙o2) and the pressure-volume area (PVA; a measure of LV total mechanical energy) in isovolumically contracting isolated canine hearts during normothermia (NT) and hyperthermia (HT). HT reduced Emaxby 38% ( P < 0.01) and shortened time to Emaxby 20% ( P < 0.05). HT, however, altered neither the slope nor the unloaded MV˙o2of the MV˙o2-PVA relation. HT increased the oxygen cost of contractility (the incremental ratio of unloaded MV˙o2to Emax) by 49%. When Ca2+infusion restored the reduced LV contractility during HT to the NT baseline level, the unloaded MV˙o2in HT exceeded the NT value by 36%. We conclude that HT-induced negative inotropism accompanies an increase in the oxygen cost of contractility.

Background —The results of recent studies suggest that NO synthase may increase in the failing myocardium and that NO modulates the myocardial contractile response to β-adrenergic stimulation. However, there are few data regarding the physiological role of NO in patients with heart failure. The aim of the present study was to address the role of NO in left ventricular (LV) contractile response to β-adrenergic stimulation and corresponding oxygen expenditure in human heart failure. Methods and Results —We studied 15 patients with heart failure due to idiopathic dilated cardiomyopathy (mean ejection fraction 0.33). We examined LV contractility (E max , the slope of end-systolic pressure-volume relation), LV external work (EW), myocardial oxygen consumption (MV̇ o 2 ), and mechanical efficiency (measured as EW/MV̇ o 2 ) with the use of conductance and coronary sinus thermodilution catheters before and during dobutamine (DOB) infusion via a peripheral vein (4.8±0.3 μg · kg −1 · min −1 IV). Heart rate was kept constant with atrial pacing. We carried out a similar protocol during the intracoronary infusion of the NO synthase inhibitor N G -monomethyl- l -arginine (L-NMMA; 200 μmol). DOB increased E max , EW, and MV̇ o 2 (by 77±17%, 39±5%, and 21±5%, respectively), leading to an increase in mechanical efficiency (25.4±3.1% to 29.6±4.1%). L-NMMA alone did not significantly change these variables. Although the concurrent infusion of DOB with L-NMMA increased E max , EW, and MV̇ o 2 (by 140±21%, 64±9%, and 35±5%, respectively) more than DOB alone, mechanical efficiency did not increase further (24.3±3.3% to 29.5±4.5%) because EW and MV̇ o 2 increased in parallel. Conclusions —These data suggest that in patients with idiopathic dilated cardiomyopathy, endogenous NO spares MV̇ o 2 through attenuation of LV contractile response to β-adrenergic stimulation while maintaining LV energy-converting efficiency.

Nitric oxide (NO) is a potent inhibitor of platelet aggregation. However, the benefits of NO-based therapies can be confounded by concomitant hypotension. Monophosphoryl lipid A (MLA) is a nontoxic derivative of endotoxin that purportedly increases nitric oxide synthase (NOS) activity and, presumably, NO production, yet has a hemodynamically benign profile. Thus our aims were to determine whether (a) MLA attenuates in vivo platelet aggregation in damaged and stenotic canine coronary arteries by a NO-mediated mechanism but without reductions in arterial pressure; and (b) the platelet inhibitory effects are manifest in vitro. To address the first aim, anesthetized dogs underwent coronary injury + stenosis, resulting in cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgement of platelet-rich thrombi. In protocol I, dogs received MLA (100 microg/kg + 40 microg/kg/h) or vehicle beginning 15 min before stenosis. Protocol II was identical, except the NOS inhibitor aminoguanidine was coadministered with MLA/vehicle. Coronary patency was assessed throughout the initial 3 h after injury + stenosis. Infusion of MLA did not result in hypotension. However, in protocol I, the median nadir of the CFVs was higher (2.1 vs. 0.8 ml/min; p < 0.05), median duration of total thrombotic occlusion tended to be reduced (0 vs. 10.4 min; p = 0.1), and mean flow-time area, expressed as a percentage of baseline flow, was increased (53 +/- 9% vs. 33 +/- 3%; p < 0.05) in MLA-treated versus vehicle-treated dogs. In contrast, in protocol II, vessel patency was comparable in both groups. Finally, whole blood impedance aggregometry (protocol HI) revealed a significant reduction in the in vitro platelet aggregation in blood samples receiving exogenous MLA, which was blocked by coadministration of exogenous aminoguanidine. Thus MLA attenuates platelet-mediated thrombosis in both damaged and stenotic canine coronary arteries and in vitro, possibly by an NO-mediated mechanism, but without concomitant hypotension.

Some recent trials have shown that angiotensin-converting enzyme (ACE) inhibitors and/or beta blockers can improve left ventricular (LV) function and decrease LV mass in patients with idiopathic dilated cardiomyopathy (IDC). We assessed the prevalence and predictors of patients with IDC that showed marked reverse remodeling (a decrease in LV end-diastolic dimensionor = 5 mm to a final LV end-diastolic dimensionor = 55 mm and an increase in percent LV fractional shorteningor = 5% to a final percent fractional shortening ofor = 25% and a decrease in LV massor = 10%) after 2 years of intensive therapy with ACE inhibitors and/or beta blockers. In 78 patients with IDC (mean age 51 +/- 14 years), the clinical, echocardiographic, hemodynamic, laboratory, and endomyocardial biopsy data were evaluated at diagnosis and serial echocardiography was performed for 2 years. After 2 years of therapy, 20 of 78 patients (26%) showed marked reverse remodeling. Multivariate analysis revealed that higher systolic blood pressure (135 +/- 17 vs 120 +/- 16 mm Hg, p0.001) and lower pulmonary arterial wedge pressure (7 +/- 3 vs 12 +/- 8 mm Hg, p0.01) at diagnosis were independent predictors of reverse remodeling. Then, we further analyzed the prognosis of these patients for a mean of 50 +/- 32 months; 5-year survival (p0.02) and event-free rates (p = 0.001) were better in patients with reverse remodeling than in patients without reverse remodeling.

Brief episodes of ischemia protect or “precondition” the heart and reduce infarct size caused by a subsequent sustained ischemic insult. Despite a decade of intensive investigation, the cellular mechanism(s) responsible for this paradoxical protection remain poorly understood. In this review, we focus on the emerging concept that alterations in intracellular calcium homeostasis may participate in either triggering and/or mediating infarct size reduction with preconditioning.

Background —Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries. Methods and Results —Anesthetized dogs underwent coronary injury+stenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flow=0), and area of the flow-time profile (expressed as percent of baseline flow×180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusion+10 minutes of reflow or a comparable 20-minute control period before injury+stenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54±8% versus 28±9%) in dogs that received antecedent ischemia versus controls ( P 1 /A 2 receptor antagonist PD 115,199 (3 mg/kg IV) before brief antecedent coronary occlusion (protocol 3). Conclusions —Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism.

Background The cellular mechanisms by which brief episodes of ischemia protect or “precondition” the heart and limit infarct size caused by a later period of sustained coronary artery occlusion remain unresolved. We propose that calcium may be an important mediator in eliciting this cardioprotection. Methods and Results To test this hypothesis, anesthetized dogs received a 15-minute intracoronary infusion of 20 mmol/L CaCl 2 or saline before undergoing 1 hour of coronary occlusion and 4 hours of reperfusion (protocol 1). Collateral blood flow during occlusion was measured with radiolabeled microspheres, area at risk of infarction (AR) was delineated by injection of blue dye, and area of necrosis (AN) was determined by tetrazolium staining. AN/AR was reduced from 20±5% in the saline-treated controls to 9±3% in CaCl 2 -treated dogs ( P N , N -dimethyl)-amiloride (an inhibitor of calcium influx via Na + -H + and Na + -Ca 2+ exchange) before the preconditioning stimulus attenuated the protective effect of ischemic preconditioning: AN/AR was 12±1%, larger than the value of 4±1% observed in preconditioned dogs that received saline ( P Conclusions Brief intracoronary infusion of CaCl 2 mimicked, whereas treatment with dimethylamiloride blocked, infarct size reduction with preconditioning, thereby implicating calcium as a mediator of preconditioning in this canine model.

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)

The effect of cardiotonic drugs with calcium-sensitizing effect (Ca2+ 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.In excised, cross-circulated canine hearts, myocardial oxygen consumption (Vo2), left ventricular contractility index (Emax), and systolic pressure-volume area (a measure of ventricular total mechanical energy) were measured before and during administration of either drug. Milrinone significantly increased Emax 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 (Tmax) from 171 +/- 19 ms to 153 +/- 20 ms (P.05), whereas sulmazole did not (164 +/- 36 ms to 161 +/- 31 ms, not significant), suggesting that the inotropic mechanisms of these two drugs differed. However, both drugs significantly increased the Vo2 intercept of the Vo2/pressure-volume area relation (milrinone: 0.027 +/- 0.004 to 0.036 +/- 0.003 mL O2/beat/100 g, P.05; sulmazole: 0.025 +/- 0.005 to 0.032 +/- 0.006 mL O2/beat/100 g, P.05) without significantly changing the slope (reciprocal of contractile efficiency). This parallel upward shift of the Vo2/pressure-volume area relation was similar to that observed with epinephrine and ouabain in our previous studies.These results suggest that the two positive inotropic drugs exhibit similar mechanoenergetic effects in the normal canine heart despite the different mechanisms of action.

Background The negative chronotropic effect of β-blocking agents is likely to provide hemodynamic and energetic advantages. However, the negative chronotropic effect on cardiac energetics observed on the initiation of β-blockade therapy has not been fully elucidated. Methods and Results In 18 patients with heart failure, left ventricular pressure and volume, external work (EW), myocardial oxygen consumption per beat (total V̇ o 2 ), mechanical efficiency (EW/total V̇ o 2 ), and V̇ o 2 for nonmechanical work (total V̇ o 2 −2·EW) were measured with the use of conductance catheter and Webster catheter at the following three states: under control conditions and after β-blockade (0.15±0.07 mg/kg propranolol IV) with and without atrial pacing to keep the heart rate at control levels. Heart rate decreased after atrial pacing was stopped. EW decreased during β-blockade with pacing and returned to the control level after pacing was stopped. Total V̇ o 2 did not change during β-blockade with or without pacing, whereas V̇ o 2 for nonmechanical work increased with pacing and returned to the control level after pacing was stopped. As a result, mechanical efficiency decreased during β-blockade with pacing and returned to the control level after pacing was stopped. Conclusions The negative chronotropic effect of a β-blocking agent may offset the mechanoenergetical deterioration resulting from its negative inotropic effect through a reduction in oxygen expenditure for nonmechanical work. These findings suggest that the negative chronotropic effect is an important aspect of β-blockade therapy.

It has been generally recognized that left ventricular (LV) contractile dysfunction during acidosis is almost reversible after correction of acidosis in crystalloidperfused hearts. In contrast, we have found that LV contractile function is paradoxically depressed after rapid correction of acidosis in blood-perfused hearts. To determine the mechanism of this phenomenon, we measured LV contractility (Emax), total mechanical energy (PVA), and myocardial oxygen consumption (Vo2) before and after correction of hypercapnic acidosis in isolated cross-circulated dog hearts. During acidosis with CO2 loading, Emax decreased significantly. During rapid correction of acidosis by CO2 unloading, a transient overshoot of Emax and concomitant ventricular arrhythmias were followed by a paradoxical decrease in Emax and a significant increase in the oxygen cost of contractility. This result indicates that the postacidotic failing heart requires higher Vo2 for a unit increase in Emax than the normal heart, which energetically resembles postischemic stunned myocardium. When dimethylamiloride, a selective Na+-H+ exchange inhibitor, was administered just before the correction of acidosis, the development of contractile and energetic abnormalities after correction of acidosis was almost completely prevented. Thus rapid correction of acidosis paradoxically depresses myocardial contractility and increases the oxygen cost of contractility through activation of the Na+-H+ exchange system. In addition, the blood-perfused heart behaves differently from the crystalloidperfused heart during the process of recovery from acidosis.

Huxley's sliding filament cross-bridge muscle model coupled with parallel and series elastic components was simulated to examine the conflicting reports on the amount of energy saved by quick release at the peak contraction time. Cross-bridge energy utilization was determined by considering the ATP hydrolysis for the cross-bridge cycling. The quick-release cases were simulated by letting the muscle fiber suddenly shorten to the resting fiber length at peak systole, and then the contraction was allowed to continue at the resting length. Simulation results demonstrated that, using realistic parameter values, typically approximately 15% of the muscle fiber energy is used after peak systole (and approximately 30% of the cross-bridge energy), but this is also a function of the muscle fiber properties characterized by cross-bridge association and dissociation rate constants. Increasing the kinetic rate constants, the series elasticity, the initial fiber length, or the time of peak intracellular calcium will increase the amount of energy left, which may explain some of the discrepancies in the literature. Cardiac muscle hypertrophy will increase the fraction of muscle fiber energy left after peak systole to approximately 30%. The strongest indicator of the percent energy left at peak systole was the time the fiber reached peak systole, and as the fiber reached peak systole faster, the amount of energy saved by quick release increased.

Studies reported in the literature show that the stroke work (SW) versus end-diastolic volume (Ved) relationship, namely, the preload recruitable stroke work relation (PRSW), is experimentally linear in closed-chest dog hearts and its slope reflects left ventricular contractility. We considered the theoretical cardiodynamic conditions necessary for the linearity of the SW-Ved relation by utilizing ventricular end-systolic elastance, Emax (ventricular contractility), and effective arterial elastance, Ea (arterial afterload). We simulated the SW-Ved relation, using four theoretical models of the left ventricle, as follows: Ea is constant and the end-systolic pressure-volume relation (ESPVR) is linear (model 1), or nonlinear (model 2), and Ea is variable and ESPVR is linear (model 3), or nonlinear (model 4). The results show that the SW-Ved relation can be linear in both linear and nonlinear ESPVR models (models 3 and 4) only when Ea is variable. In these models, end-systolic pressure (Pes) and Ea should gradually fall, maintaining the stroke volume (SV) relatively constant with decreases in Ved until the low end of the physiological Ved range. Then, Ea should rise sharply so that Pes does not fall below the critical level. These results suggest that the autoregulation mechanisms of an intact animal operate to adapt the arterial afterload against acute changes in LV preload, maintaining cardiac output and coronary artery pressure. Such mechanisms may thus produce a linear SW-Ved relation over a wide range of conditions.

For the treatment of heart failure, inotropic agents yield short-term hemodynamic improvement. However, inotropic therapy is still an unfilled promise for the treatment of chronic heart failure (1). This may partly result from the fact that inotropic interventions increase myocardial oxygen consumption (VO2). Therefore, the investigation of myocardial energetics in relation to inotropic agents in patients with heart disease has clinical and therapeutic relevance. Recently, the concept of left ventricular (LV) elastance (Emax) and systolic pressure-volume area (PVA) has been proposed by Suga and his colleagues (2,3,4,5). Experimental studies have shown that the relation between VO2 and PVA is linear under a variety of loading conditions. This linear relation has been used to partition VO2 into non-mechanical and mechanical portions. Experimental studies have shown that positive inotropic interventions, which enhance Emax, shift the VO2-PVA relation line upward in a parallel manner. The resultant increase in VO2 intercept of the relation has been considered to be VO2 for non-mechanical work. The relation between Emax and PVA-independent VO2 has been reported to be linear; the slope represents “oxygen cost of contractility” under various inotropic interventions. The aim of this study was to examine the effects of various inotropic agents on human cardiac mechanoenergetics by utilizing the concept of Emax and the VO2-PVA relation. To this end, we compared the effects of the newly developed phosphodiesterase inhibitor E-1020 and a novel Ca++ sensitizing agent, MCI-154, with dobutamine in patients with heart disease.

We examined the effects of a novel water-soluble forskolin derivative, NKH477 (0.5 microgram/kg/min), on arterial-ventricular (A-V) coupling and mechanical energy transduction from heart to circulatory bed in comparison with those of dobutamine (3 micrograms/kg/min) in 8 patients with left ventricular (LV) systolic dysfunction using a conductance catheter method. A-V coupling was assessed as the ratio of the effective arterial elastance (E(a)) to the slope of the end-systolic pressure-volume relation (ESPVR) (E(max), left ventricular contractility index), and the ratio of mechanical energy transduction was obtained as the fraction of PV area (PVA) comprised of stroke work (SW). E(max) (2.59 mm Hg/ml/m2), E(a)/E(max) (1.62), and SW/PVA (0.58) were impaired in control contractile state. NKH477 increased Emax to the same extent as dobutamine. E(a) decreased with NKH477 but not with dobutamine. As a consequence, the decrease in E(a)/E(max) with NKH477 was greater than that with dobutamine (52 vs. 47%, p0.05); the increase in SW/PVA with NKH477 was also greater than that with dobutamine (28 vs. 21%, p0.05). These findings suggest that NKH477 may be a superior alternative to dobutamine in A-V coupling and mechanical energy transduction in patients with LV systolic dysfunction.

Objective: The aim was to characterise the impaired myocardial mechanoenergetics in patients with heart failure due to old myocardial infarction by using the oxygen consumption versus left ventricular pressure – volume area (PVA) relationship. Methods: The ![Graphic][1] o2-PVA relationship was assessed in 15 patients: group N consisted of seven patients with vasospastic angina pectoris whose left ventricular ejection fractions were normal [72(SD 8)%], and group F consisted of eight patients with old myocardial infarction whose left ventricular ejection fractions were reduced [45(11)%]. Left ventricular volume and pressure were measured by the conductance catheter method. ![Graphic][2] o2was measured by thermodilution. Results: Linear ![Graphic][3] o2-PVA relationships with dextran infusions were obtained in both groups (median r = 0.92 v 0.90). There was no difference in the slope between the two groups. There was a positive correlation between Emax and Vo2 at median PVA (Vo2.PVAO.8) in group N. Emax an index of left ventricular contractility, was significantly smaller in group F than in group N, at 5.1(2.1) v 3.2(1.1) mm Hg·ml−1·m2 p

We studied the effects of ejection velocity and resistive properties of the left ventricle (LV) on myocardial oxygen consumption (VO2) in 13 excised cross-circulated dog hearts. Increases in peak ejection velocity (-dV/dt) from 4.0 +/- 1.3 (SD) end-diastolic volume (EDV)/s to 12.7 +/- 5.3 EDV/s with constant EDV and end-systolic volume (velocity run) induced systolic pressure deficit. This decreased pressure-volume area (PVA; a measure of ventricular mechanical energy) and LV end-systolic elastance (Emax) by 47 +/- 14 and 38 +/- 15%, respectively. Unchanged maximum rate of left ventricular pressure rise and time-varying elastance during the isovolumic contraction period at the same EDV indicated that these contractions started with the same contractile state although the quicker ejection caused the greater deactivation. If the PVA deficit due to systolic pressure deficit is attributable to an internal energy-dissipating resistive element, VO2 in the velocity run will not as much decrease in proportion to PVA as in the isovolumic or slowly ejecting control run. However, the decreases in PVA due to increased -dV/dt decreased VO2 to the same extent as in the control run. This result negated the possibility that the pressure and PVA deficits would be caused by a mechanical energy-losing process. The same results were obtained whether or not Emax was decreased by quick ejection. We conclude that the pressure and PVA deficits and the proportionally decreased VO2 during quick ejection are mainly attributable to suppression of a ventricular mechanical energy generation process, but not of mechanical energy-losing process, by ejecting deactivation.