Toshiyuki Takasago

Epinephrine and calcium have similar oxygen costs of contractility

SummaryWe 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 100g was 0.00158ml O2/ (mmHg/ml) for calcium and 0.00166 ml O2/(mmHg/ml) for epinephrine on average, values not significantly different from each other (P < 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.

Coupling between regional myocardial oxygen consumption and contraction under altered preload and afterload

OBJECTIVES This study was designed to assess the relation between left ventricular regional myocardial oxygen consumption (VO2) and variables of regional myocardial contractile function under various loading conditions. BACKGROUND Although the relation between global VO2 and global ventricular function has been extensively studied, the relation between regional VO2 and regional myocardial contraction is not fully understood. METHODS Myocardial shortening (regional area shrinkage), regional work, regional total mechanical energy index and regional VO2 were measured under variously altered loading conditions in the isolated, blood-perfused dog left ventricle. Regional total mechanical energy per beat was quantified by wall tension-regional area area (TAA) by the analogy of left ventricular pressure-volume area. Left ventricular loading conditions were altered by changing end-diastolic volume and stroke volume with a servo pump as follows: 1) increased preload (increased end-diastolic volume and stroke volume at a constant ejection fraction), 2) decreased afterload (increased stroke volume at a constant end-diastolic volume), 3) increased preload and afterload (increased end-diastolic volume at a constant stroke volume), and 4) altered mode of contraction (ejecting vs. isovolumetric contractions). RESULTS During increased preload, all three variables correlated positively with regional VO2 (r = 0.78 to 1.00). During decreased afterload, the correlation was negative for area shrinkage (r = -0.65 to -0.91) and variable for regional work (r = -0.55 to 0.98) but positive and highly linear for TAA (r = 0.80 to 0.99). During increased preload and afterload, the correlation was again negative for area shrinkage (r = -0.77 to -0.97) but positive for regional work (r = 0.83 to 0.93) and TAA (r = 0.95 to 0.99). During altered mode of contraction, the correlation was insignificant for area shrinkage (r = 0.24 to 0.57) and moderate for regional work (r = 0.50 to 0.79), whereas again highly linear for TAA (r = 0.95 to 0.98). Thus, only TAA correlated closely with regional VO2 under any loading conditions. Furthermore, the slope and regional VO2 intercept of the regional VO2-TAA relation was remarkably consistent among the different hearts and loading conditions. CONCLUSIONS We conclude that there is a tight coupling between regional VO2 and regional total mechanical energy represented by TAA regardless of left ventricular afterload and preload conditions.

Comparison of the cardiac force-time integral with energetics using a cardiac muscle model

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, Huxleys 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.

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

BACKGROUND 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. METHODS AND RESULTS 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. 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.

Ejecting volume, filling volume and stroke volume gains: New indexes of inotropism and lusitropism

SummaryWe 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 sumstroke 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.