Pressure-volume Area Research Articles

Effect of ouabain on the relation between left ventricular oxygen consumption and systolic pressure-volume area (PVA) in dog heart

We studied the effect of ouabain (digitalis) on the relation between left ventricular (LV) O2 consumption (VO2) and pressure-volume (P-V) area (PVA) in 7 excised cross-circulated canine heart preparations. PVA is a measure of the total mechanical energy generated by LV contraction and was obtained as the specific area in the P-V diagram circumscribed by the end-systolic P-V line, end-diastolic P-V curve, and the systolic P-V trajectory. Ouabain (0.11 mg, intracoronary-arterially) increased Emax (LV contractility index) by 58 +/- 44% (mean +/- SD) from 7.8 +/- 3.4 to 12.0 +/- 4.8 mmHg/(ml/100 g LV). PVA correlated linearly with LV VO2 per beat in either the control (r greater than 0.97) or the ouabain run (r greater than 0.96) in individual hearts. Ouabain increased the VO2-axis intercept of the regression line of VO2 on PVA from 0.029 +/- 0.004 in the control run to 0.036 +/- 0.009 ml O2/beat/100 g LV without significantly changing the slope [(1.53 +/- 0.24).10(-5) ml O2/(mmHg/ml)] of the regression line. This slope is equivalent to the contractile efficiency value of 44 +/- 6% from the excess VO2 above unloaded VO2 to PVA. The parallel elevation of the VO2-PVA relation with ouabain was similar to the results produced by epinephrine and Ca2+ in our previous studies. Ouabain, like epinephrine and Ca2+, did not change the contractile efficiency from the PVA-dependent fraction of VO2 to PVA.

Right ventricular mechanical and energetic properties.

To formulate right ventricular (RV) mechanical and energetic properties in terms of the time-varying elastance model, Emax and the systolic pressure-volume area (PVA) of RV were measured in the excised cross-circulated heart preparation, while the left ventricle was beating unloaded. Emax of RV was constant, and independent of the RV volume, the stroke volume, the ejection velocity, and the pre-ejection period in the control contractile state. Enhancement of the contractile state with calcium increased Emax, and reduction of the contractile state with propranolol decreased Emax. The whole heart oxygen consumption (Vo2) was linearly regressed on PVA of RV, in both the control and the calcium-enhanced contractile state. Calcium elevated the regression line in a parallel manner. The slope of the regression line was (1.85 +/- 0.19) x 10(-5) ml O2/mmHg ml in the control state, and (1.57 +/- 0.44) in the calcium state. These slope values were similar to those in left ventricle (LV). We therefore conclude that mechanical and energetic properties of RV are similar to those of LV.

Progressive hypoxemia limits left ventricular oxygen consumption and contractility.

To study the cardiac effects of progressive hypoxemia, we measured the left ventricular end-systolic pressure-volume relation (ESPVR), myocardial oxygen consumption (MVO2), and myocardial oxygen delivery (MQO2) in eight thoracotomized dogs anesthetized with fentanyl and droperidol. We specifically looked for evidence of oxygen supply limitation of MVO2 and depressed contractility (altered ESPVR) during stepwise decreases in inspired oxygen fraction. We hypothesized that the reported relation between MVO2 and left ventricular pressure-volume area (PVA) may hold when inadequate MQO2 determines MVO2, which then may limit PVA, manifested partly as a change in the ESPVR. Initially, as arterial oxygen saturation was decreased from 95 +/- 3% to 64 +/- 14%, coronary blood flow increased so that MQO2 was maintained with no change in myocardial extraction ratio (ERm = MVO2/MQO2). During this first phase, lactate utilization, PVA, and ESPVR did not change. When oxygen saturation was further reduced, coronary blood flow rose no higher and ERm increased, but not enough to maintain MVO2. Lactate consumption decreased and ST segments rose, signaling a change from aerobic metabolism. MVO2 decrease was associated with a fall in PVA, which was due to a fall in blood pressure and a significant depression of the ESPVR. Specifically, the volume intercept of the ESPVR increased in all dogs (6.5-20.1 ml, p less than 0.0001), accounting for two thirds of the increase in end-systolic volume. The slope of the ESPVR decreased during hypoxia (13.3-6.1 mm Hg/ml, p less than 0.02), accounting for only one third of the observed increase in end-systolic volume. We believe that the evidence of anaerobic metabolism, the decrease in PVA, and the depression of the ESPVR demonstrates onset of oxygen supply limitation of MVO2. Our data are consistent with the hypothesis that limited MVO2 may limit PVA. The hypoxic volume intercept alteration of the ESPVR is different from changes in the slope of ESPVR seen with other interventions. This may be analogous to recent observations in isolated muscle that show hypoxic depression in contractility to be different from other interventions.

Cardiac cooling increases Emax without affecting relation between O2 consumption and systolic pressure-volume area in dog left ventricle.

We studied the effects of cardiac cooling by 7 +/- 2 degrees C (SD) from 36 degrees C on both contractility index (Emax) and the relation between O2 consumption per beat (VO2) and systolic pressure-volume area (PVA) of the left ventricle in the excised cross-circulated dog heart preparation. PVA represents the total mechanical energy generated by a contraction. The VO2-PVA relation divides measured VO2 into unloaded VO2 and excess VO2. The slope of the VO2-PVA relation represents inversely the efficiency of the contractile machinery to convert chemical energy from the excess VO2 to total mechanical energy. Cooling is known to decrease myosin ATPase activity (Q10 of 2-3), which in turn is expected to increase the chemomechanical efficiency of cross bridges. Therefore, we expected an increase in the efficiency and hence a decreased slope of the VO2-PVA relation with cooling. The cooling increased Emax by 46 +/- 13% and the time to Emax by 45 +/- 27%. Pacing rate was constant or had to be slightly decreased to avoid arrhythmias with cooling. We found that neither the slope of the VO2-PVA relation nor unloaded VO2 significantly (p greater than 0.05) changed with the cooling. This result contradicts the expected increase in the efficiency with cooling. We conclude that cardiac cooling by 7 degrees C from 36 degrees C does not increase the efficiency of the contractile machinery in excised cross-circulated dog left ventricle.

Paired pulse pacing increases cardiac O2 consumption for activation without changing efficiency of contractile machinery in canine left ventricle.

The relation between cardiac O2 consumption (VO2) and the total mechanical energy (TME) generated by contraction was studied under paired-pulse (PP) pacing and compared with that under single-pulse pacing at the same basic rate as PP pacing and at the double-pacing rate in ten excised cross-circulated canine left ventricles (LV). TME was assessed by the systolic pressure-volume (P-V) area (PVA) defined as the area bounded by the end-systolic and end-diastolic P-V curves and the systolic P-V trajectory. The VO2-PVA relation was linear under PP pacing as well as at control and double heart rates. PP pacing increased LV contractility index Emax from 6.3 +/- 3.3 (SD) to 18.0 +/- 8.6 mmHg/(ml/100 g) and elevated markedly the VO2-PVA relation by increasing the VO2-axis intercept (or PVA-independent VO2) from 0.62 +/- 0.11 to 1.13 +/- 0.35 J.beat-1.100 g-1. However, PP pacing did not change the slope of the VO2-PVA relation at 2.24 +/- 0.53 (dimensionless). The efficiency from PVA-dependent VO2 (total VO2-PVA-independent VO2) to PVA (=TME), calculated as the reciprocal of the slope of the VO2-PVA relation, was also constant at 47 +/- 11% regardless of PP pacing. These results are similar to previous results obtained by positive inotropic interventions with catecholamines and Ca2+. We conclude that PP pacing augments the PVA-independent VO2 for activation without affecting the efficiency of the contractile machinery to generate TME from the PVA-dependent VO2.

Optimal contractility and minimal oxygen consumption for constant external work of heart.

We theoretically considered the relation between left ventricular O2 consumption (MVO2) and a contractility index (Emax), searching for an optimal Emax that minimizes MVO2 for a given external mechanical work. We used one equation relating Emax with ventricular pressure and volume and another equation relating MVO2 with pressure-volume area (PVA). PVA is theoretically and experimentally a good predictor of MVO2 with Emax as a parameter. Then we could theoretically show the existence of the optimal Emax. For example, MVO2 was minimized to 8.9 ml O2.min-1.100 g-1 at an Emax of 6.3 mmHg.ml-1.100 g when cardiac output was 1.2 l/min, afterload pressure was 100 mmHg, and heart rate was 150 beats/min. These values can be observed experimentally in a 10- to 15-kg dog. Optimal Emax values for a wide range of external work fall in the middle of the normal working range of Emax. Thus our MVO2-PVA-Emax relationship supports the contemporary concept of the optimal contractility that MVO2 for a given cardiac external work is minimum at a middle level of ventricular contractility.

O2 consumption of dog heart under decreased coronary perfusion and propranolol.

We compared the effects of decreased coronary perfusion pressure (CP) and propranolol on the relation between left ventricular O2 consumption (VO2) and systolic pressure-volume area (PVA). PVA represents total mechanical energy generated by contraction and is the area under the end-systolic pressure-volume (PV) line and systolic PV trajectory. In excised cross-circulated dog hearts, a decrease in CP from 82 (mean) to 51 mmHg decreased ventricular contractility index Emax (slope of end-systolic PV relation) by 17% (P less than 0.05) and slightly (P less than 0.05 in 3 of 11 hearts) lowered the VO2-PVA relation in a parallel fashion. A further decrease in CP to 32 mmHg decreased Emax by 56% (P less than 0.05) and considerably (P less than 0.05) lowered the VO2-PVA relation by decreasing both the VO2-axis intercept by 26% (P less than 0.05) and the slope by 24% (P less than 0.05) from control. Propranolol decreased Emax by 48% (P less than 0.05) and the VO2-axis intercept by 25% (P less than 0.05) without changing the slope (P greater than 0.05). We attributed the different response of the VO2-PVA relation to the difference of the coronary O2 supply-demand balance between decreased CP and propranolol.

Efficiencies from consumed O2 and pressure-volume area to work of in situ dog heart.

We studied the efficiencies from oxygen consumption (VO2) to external mechanical work (EW), from VO2 to the systolic pressure-volume area (PVA), and from PVA to EW, and the effects of cardiac output and contractility index (Emax) on these efficiencies in the left ventricle of open-chest, right-heart-bypassed dogs. PVA is an intermediate form of energy between VO2 and EW. PVA, EW, and Emax were determined by an abrupt occlusion of the ascending aorta. The right-heart bypass allowed us to collect all coronary venous return for VO2 measurement. The EW/VO2 efficiency ranged between 4 and 21%, the PVA/VO2 efficiency ranged between 5 and 27%, and the EW/PVA efficiency ranged between 60 and 95%. At a given Emax, EW/PVA efficiency was independent of cardiac output, but PVA/VO2 and EW/VO2 efficiencies increased with cardiac output. An increase in Emax by dobutamine increased EW/PVA efficiency, but decreased PVA/VO2 and EW/VO2 efficiencies. We could theoretically account for these changes in EW/PVA, PVA/VO2, and EW/VO2 efficiencies of the in situ heart by the VO2-PVA relation and its dependence on Emax that we had observed.

Crossbridge model compatible with the linear relation between left ventricular oxygen consumption and pressure-volume area.

Ventricular pressure-volume area (PVA) is a specific area in the pressure-volume diagram, which represents the total mechanical energy generated by each contraction, consisting of stroke work and mechanical potential energy at end-systole. Animal experiments have shown that PVA is correlated linearly with the ventricular oxygen consumption (Vo2) per beat under a variety of loading conditions in a stable contractile state. The slope of the Vo2-PVA line has been shown to remain constant in different contractile states, implying a constant stoichiometry between Vo2 and PVA. As a first step to understand the nature of this Vo2-PVA relation, we devised a new crossbridge (CB) model to theoretically relate PVA with the total enthalpy change associated with the ATP hydrolysis for all CB cycles. One of the most important assumptions on which this model analysis depended was that the time-varying elasticity model could simulate the instantaneous pressure-volume relation. The result of this analysis implied that the empirical linear Vo2-PVA relation could be attributed to the energy balance between energy input and output of the chemomechanical transduction associated with CB cycles during a ventricular contraction.

Oxygen-saving effect of negative work in dog left ventricle.

We compared left ventricular oxygen consumptions (VO2) of contractions performing negative external work (EW less than 0) and positive external work (EW greater than 0) that developed comparable peak systolic pressures in the excised cross-circulated dog hearts. We changed the polarity of ventricular work with volume servo-pump and measured both left ventricular VO2 and systolic pressure-volume area (PVA). PVA represents the total mechanical energy generated by contraction and is equal to the area circumscribed by the end-systolic and end-diastolic pressure-volume (PV) relation curves and the systolic PV trajectory. For comparable peak systolic pressures of approximately 90 mmHg, contractions performing negative EW of -834 +/- 327 mmHg.ml.100 g left ventricle-1 had 27 +/- 11% smaller VO2 and 62 +/- 12% smaller PVA than those performing positive EW of 851 +/- 329 mmHg.ml.100 g-1. The smaller VO2 for negative EW could be accounted for by the linear VO2-PVA relation regardless of the polarity and magnitude of work. The results indicate that negative work can save VO2 of contractions to develop a given peak systolic pressure.

Ventricular systolic pressure-volume area (PVA) and contractile state (Emax) determine myocardial oxygen demand.

We have briefly reviewed the recent advances in the understanding of primary determinants of cardiac oxygen consumption (Vo2). We focused on our own experimental findings that Vo2 is a function of left ventricular systolic pressure-volume area (PVA), as a measure of total mechanical energy generated by contraction, and the left ventricular contractility index (Emax). We conclude that the cardiac oxygen demand of the ongoing contractions is equivalent to Vo2 and is a precise function of PVA and Emax whether coronary oxygen supply is normal or mildly limited in the excised, cross-circulated dog left ventricle. However, when the coronary oxygen supply is severely limited, Vo2 may not always be equivalent to the oxygen demand capability shown by the heart when its coronary oxygen supply is restored.

Left ventricular O2 consumption and pressure-volume area in puppies.

We studied the relation between O2 consumption (VO2) and systolic pressure-volume (PV) area (PVA) in the left ventricles of eight puppies (2-4 mo old). PVA is the area circumscribed by the end-systolic and end-diastolic PV curves and systolic PV trajectory. We assumed PVA to represent the total mechanical energy generated by ventricular contraction. We produced isovolumic contractions at different volumes in the left ventricles isolated and cross-circulated with adult dogs. VO2 closely correlated with PVA in each of control contractile state, an enhanced contractile state with epinephrine, and a depressed contractile state with propranolol in each heart. The slope of the regression line of VO2 on PVA was not significantly affected by epinephrine and propranolol. The regression line shifted upward with epinephrine and downward with propranolol. These characteristics of the puppy's VO2-PVA relation were comparable to those of the adult dog. These results suggest that similar relations hold between myocardial mechanics and energetics in both the puppy and adult dog despite the differences in the heart size and contractile properties.

Relation between oxygen consumption and pressure-volume area of in situ dog heart.

We studied the relation between O2 consumption (VO2) and the systolic pressure-volume area (PVA) in the left ventricle of open-chest dogs. PVA and the slope (Emax) of the end-systolic pressure-volume line were determined by an abrupt occlusion of the ascending aorta. VO2 linearly correlated with PVA in control contractile state, where Emax was 15.8 +/- 4.4 (SD) mmHg/ml with intact reflexes and 11.5 +/- 1.2 mmHg/ml with blocked reflexes. Emax and the VO2 axis intercept of the VO2-PVA line were greater in the in situ heart than in the excised cross-circulated dog heart in our previous study. Enhancement of contractile state by dobutamine increased Emax by 60-80% and shifted the VO2-PVA line upward, increasing the VO2 axis intercept by 38% with intact reflexes and by 79% with blocked reflexes. The slope had a tendency to increase with dobutamine, but the increase was statistically insignificant. We conclude that PVA and Emax obtained by the aortic-occlusion method can account for changes in VO2 with changes in loading conditions and contractility in an in situ dog heart.

Relation between oxygen consumption and pressure-volume area of in situ dog heart

Page H31: T. Nozawa, Y. Yasumura, S. Futaki, N. Tanaka, Y. Igarashi, Y. Goto, and H. Suga. “Relation between oxygen consumption and pressure-volume area of in situ dog heart.” Page H37: Fig. 6: Although the last sentence of the legend states “Solid lines are linear regression lines, and inner and outer pairs of dashed curves around them are 95% confidence limits of regression lines and data points, respectively,” these dashed lines show one standard deviation of both the slope of the regression line and the sampled data from the regression line. The authors forgot to multiply these standard deviation values by t value (2.069 for degrees of freedom = 23) for P le 0.05 in the computer software to obtain the 95% confidence limits. The other statistical results in Fig. 6 are correct.

Prospective prediction of O2 consumption from pressure-volume area in dog hearts.

Systolic pressure-volume area (PVA) is the area circumscribed by the end-systolic pressure-volume (PV) line, the end-diastolic PV curve, and the systolic PV trajectory of the ventricle. PVA represents the total mechanical energy generated by ventricular contraction. Myocardial O2 consumption (VO2) linearly correlates with PVA under different pre- and afterloads in the dog left ventricle. The linear VO2-PVA relation parallel shifts with changes in contractility index Emax. We have retrospectively obtained VO2 = A X PVA + B . Emax + C, where A, B, and C are regression coefficients. We used this equation to prospectively predict VO2 from measured PVA and Emax in a new group of dog left ventricles. Coefficient of determination (CD) of measured VO2 from predicted VO2 was 0.86 +/- 0.09 (SD) in individual hearts, but decreased to 0.72 when data of the five hearts were pooled. These prospective CDs in individual hearts and all hearts were smaller than retrospective CDs in the individual hearts (0.90 +/- 0.06). Inter-individual variations of A,B, and C caused the lower prospective predictability.

Force-time integral decreases with ejection despite constant oxygen consumption and pressure-volume area in dog left ventricle.

We have shown that systolic pressure-volume area (PVA), which is equivalent to the total mechanical energy generated by ventricular contraction, correlates linearly with myocardial oxygen consumption, VO2, in canine left ventricle. Systolic force-time integral, FTI, also correlates with VO2. In this study, stroke volume was increased from 0 (isovolumic) in isolated cross-circulated canine left ventricle in a stable contractile state while keeping PVA constant with a servo pump. Ventricular total force was calculated from ventricular pressure and volume by the force-equilibrium equation and was integrated from the end of diastole to the end of systole as identified with the time of Emax to yield FTI. Under the conditions of constant PVA, FTI significantly (p less than 0.001) decreased by 10 +/- 7% and 25 +/- 8% with increases in stroke volume from 0 to 8 +/- 4 ml and 17 +/- 3 ml and in ejection fraction from 0 to 0.24 +/- 0.10 and 0.61 +/- 0.05, respectively, while VO2 and Emax remained constant. Therefore, we conclude that in a stable contractile state, it is possible to keep PVA constant even when stroke volume and ejection fraction are varied and that under such conditions, FTI no longer predicts VO2. PVA remains a reliable predictor of VO2 regardless of ventricular loading conditions.

Influence of ventricular contractility on non-work-related myocardial oxygen consumption.

The relationship between myocardial oxygen consumption (MVO2) and the total pressure-volume area (PVA), which represents the total mechanical work performed during a cardiac cycle, has been shown to be linear and independent of loading conditions: MVO2 = aPVA + b. When inotropic state is enhanced, the MVO2-PVA relation shifts upward (increase in b), and when inotropic state is depressed the relation shifts downward (decrease in b). However, the quantitative relationship between contractility and b (the non-work-related myocardial oxygen consumption) determined over a wide range of contractilities is not known. In seven isolated blood perfused canine hearts, left ventricular (LV) contractility was increased by dobutamine and decreased with nifedipine or reduction of coronary blood flow. At each level of contractility, the end-systolic pressure-volume relationship (ESPVR) and the MVO2-PVA relation were determined. For each heart, the resulting values of b (ml O2/beat) were plotted as a function of Emax (mmHg/ml), an index of contractility defined as the slope of the ESPVR. There was a linear relation between Emax and b over a wide range of contractilities; on average, b (ml O2/beat) = 0.0036 Emax (mmHg/ml) + 0.0101 [r = 0.929-0.978 (95% confidence interval)], when Emax was varied over an average range of 2.8-9.6 mmHg/ml. These results suggest a common underlying determinant of contractility and non-work-related oxygen consumption.

Cardiac energetics and the Fenn effect.

The energy output of a cardiac contraction can be divided into several phenomenologically measured components, although it must be emphasized that such subdivisions are often thermodynamically misleading. There is an activation term that relates to Ca++ release and retrieval, a work term and a stress or load-dependent heat term. The work and load-dependent energy terms presumably have their origin in the actin-activated myosin ATPase. It can be shown that the enthalpy: load relationship has a similar format across both mammalian and amphibian hearts: the scaling of both the energy and load axes is however altered by changes in contractility. The fact that enthalpy production is so clearly load-dependent indicates that there is a Fenn effect in cardiac muscle, although the discovery that energy output is greatest in an isometric contraction clearly contradicts one of the two central findings of Fenn's skeletal muscle investigations. Cardiac oxygen consumption per beat can be linearly correlated with ventricular systolic pressure--volume area (PVA) which is defined in terms of stroke work and potential energy components. If the basal and activation components are subtracted out cardiac muscle can be shown to operate at a constant PVA efficiency. The existing myothermic and polarographic data can be reconciled with the PVA concept.

Dissociation of pressure-rate product from myocardial oxygen consumption in dog.

Although the pressure-rate product (double product; DP) is generally recognized as a good index of myocardial oxygen consumption (VO2), catecholamines are reported to change the VO2-DP relationship. However, the separate influences of chronotropism and inotropism on the VO2-DP relation have not been studied. Therefore, we examined these influences in anesthetized open-chest dogs by cardiac pacing and dobutamine infusion. We observed two different VO2-DP lines under the separate chronotropic and inotropic changes. We interpreted such VO2-DP relations by the concept of the pressure-volume area (PVA). PVA is a measure of total mechanical energy for ventricular contraction and is a specific area in the ventricular pressure-volume (P-V) diagram circumscribed by the end-systolic and end-diastolic P-V relation curves and the systolic segment of the P-V trajectory. The empirical VO2-PVA relation that had been obtained in our previous studies reasonably simulated the dissociation of DP from VO2 under separate changes in chronotropism and inotropism.

Ventricular efficiency predicted by an analytical model.

Based on the recent data from the literature, we derived analytic expressions for ventricular stroke work (SW), ventricular O2 consumption, and the ratio of the former to the latter, defined as ventricular efficiency, in terms of ventricular contractile properties and arterial afterloading properties. The ventricular properties were quantified by Ees and V0, the slope and volume axis intercept, respectively, of the linear end-systolic pressure-volume relationship. Ventricular afterload was represented by the effective arterial elastance (Ea), a parameter that is dependent on aortic input impedance parameters. O2 consumption was assessed by estimating ventricular pressure-volume area, which has been shown to be linearly related to O2 consumption. Model analysis indicated that SW is maximum when Ea = Ees, the afterload that results in the greatest efficiency is always less than that which provides the maximum SW, the SW and efficiency of a weak heart are more sensitive to changes in afterload than in a strong heart, and there is a sigmoidal relation between ventricular efficiency and end-diastolic volume that reaches its maximum at volumes outside the upper limit of the physiological range. Further analysis of the model indicated that under physiological conditions ventricular and arterial properties may be adjusted more toward optimization of efficiency than SW.