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999 Decreased Contractile Efficiency and Increased Nonmechanical Energy Cost in Hyperthyroid Rabbit Heart Relation Between Consumption and Systolic Pressure-Volume Area or Force-Time Integral 02 Yoichi Goto, Bryan K. Slinker, and Martin M. LeWinter Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Both systolic pressure-volume area (PVA) and force-time integral (FM1) have been used as measures of oxygen consumption per beat (Vo2) in the isolated left ventricle. The reciprocal of the slope of the Vo2-PVA relation has been considered to reflect the chemomechanical energy transduction efficiency of the contractile machinery (contractile efficiency), whereas its Vo2 intercept consists of energy cost of excitation-contraction coupling and basal metabolism. To examine whether the increase in myosin isoform V1/V3 ratio in hyperthyroid rabbits decreases contractile efficiency and to determine overall mechanisms of higher oxygen consumption in hyperthyroid hearts, the Vo2-PVA and Vo2-FTI relations as well as the end-systolic pressurevolume relation were assessed in cross-circulated, isovolumically beating hearts isolated from normal, hyperthyroid, and hypothyroid rabbits. Normalized initial slopes of the rising limb of the curvilinearly fitted end-systolic pressure-volume relation (E'm., ventricular contractility index) were similar for normal and hyperthyroid groups. However, the slopes and Vo2 intercepts of the Vo2-PVA and Vo2-Fll relations were greater in hyperthyroid hearts than in normal hearts. Accordingly, in the hyperthyroid hearts, the contractile efficiency (27±6%) was lower and left ventricular Vo2 for excitation-contraction coupling (0.028±0.004 ml 02Jbeat/100 g) was higher than in normal hearts (40±4% and 0.021±0.005 ml 02/beat/100 g, respectively). This decreased contractile efficiency in the hyperthyroid hearts was attributable to myosin isoform alteration rather than to increased (-adrenoceptors because isoproterenol did not affect the slope of the Vo2-PVA relation in all groups. In contrast, the slope of the Vo2-FTI relation was significantly increased by isoproterenol in all groups. Neither the Vo2-PVA nor the Vo2-FH relations in hypothyroid hearts were different from those in normal hearts except for significantly lower Vo2 for basal metabolism. We conclude that in hyperthyroid rabbits, the left ventricle has decreased contractile efficiency and increased energy cost of excitation-contraction coupling and that the decreased contractile efficiency in hyperthyroid hearts is probably due to the increased V1NV3 ratio of the myosin isoform component. In addition, this study demonstrates that the Vo2-PVA and Vo2-FTI relations dissociate depending on the intervention, even in the same isovolumic contraction mode. (Circulation Research 1990:66:999-1011) From the Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vermont. Supported in part by National Institutes of Health Biomedical Research Support Grant S0705429 and by Grant-in-Aid 63770619 for Scientific Research from the Ministry of Education, Science, and Culture of Japan. Address for correspondence: Yoichi Goto, MD, Department of Cardiovascular Dynamics, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Saita, Osaka 565, Japan. Address for reprints: Martin M. LeWinter, MD, Cardiology Unit, Department of Medicine, University of Vermont, Burlington, VT 05405. Received April 12, 1989; accepted November 2, 1989. It has been shown that hyperthyroid hearts consume more oxygen than euthyroid hearts both in situl,2 and in papillary muscle preparations.3'4 Studies in papillary muscles isolated from hyperthyroid animals have shown that this higher oxygen consumption is attributable to increased contractility assessed by the force-velocity relation and increased basal oxygen consumption.3'4 However, mechanisms of higher oxygen consumption in hyperthyroid hearts have not been fully elucidated in terms of whole ventricular mechanics coupled with energetics. 1000 Circulation Research Vol 66, No 4, April 1990 Electromagnetic \Ele eReservr Heating Flow tt Roller Pump ~~~~~~~Ju9pular4 Vein Support Rabit Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 FIGURE 1. Schematic illustration of cross-circulated rabbit heart preparation. LV left ventricle; ECG, arteriovenous oxygen content difference analyzer. Recent studies have shown that left ventricular oxygen consumption per beat (Vo2) linearly correlates with systolic pressure-volume area (PVA) in the isolated, cross-circulated heart of the normal dog5-7 and rabbit.8 PVA is the area circumscribed by the end-systolic and end-diastolic pressure-volume relations (ESPVR and EDPVR, respectively) and the systolic pressure-volume trajectory.5 The reciprocal of the slope of the linear Vo2-PVA relation has been considered to reflect the chemomechanical energy transduction efficiency of the contractile machinery6 9 (hereafter referred to as contractile efficiency), whereas its Vo2 intercept reflects the oxygen cost of excitation-contraction (E-C) coupling and basal metabolism.5 However, no specific intervention has been reported to change the slope of the Vo2-PVA relation (i.e., the contractile efficiency appears to be constant and independent of heart rate, preload, afterload, mode of contraction [isovolumic versus ejecting], and acute changes in contractility).5'6 Even an acute change in myosin-ATPase activity produced by cooling does not affect the contractile efficiency.7 However, the effect of chronic changes in myosinATPase activity or VJV3 isoform ratio on contractile efficiency has not been studied. Thyrotoxic stress in the rabbit is known to alter the myosin isoform component from predominantly V3 to predominantly V110,'1 and to increase myosinATPase activity.10-12 Thus, the first purpose was to examine the influence of thyroid state on the relation between Vo2 and PVA (i.e., to examine whether an alteration of myosin isoform VJV3 ratio changes contractile efficiency) in the rabbit left ventricle and, hence, to determine overall mechanisms of higher oxygen consumption in hyperthyroid hearts. In addi- ]1,arotid Artery electrocardiogram;AVOX, tion, because force-time or tension-time integral has also been used as a measure of myocardial energy consumption,13-17 the second purpose was to assess the relation between Vo2 and force-time integral (FTI) in the hyperthyroid ventricle and to compare it with the Vo2-PVA relation. Materials and Methods Animal Models Forty-three New Zealand White rabbits weighing 2.4-4.5 kg were divided into three groups (10 normal, 25 hyperthyroid, and eight hypothyroid rabbits). Hyperthyroidism was produced by 14 daily intramuscular injections of 0.2 mg/kg body wt 1-thyroxine. Animals were weighed daily, and the dose of 1thyroxine was reduced to 0.1 mg/kg if body weight fell below 80% of the original value. Both the protocol and the source of animals were the same as those of Alpert et al'2 and Litten et all" and have been shown to induce a major shift of myosin isoform component from V3 to V," and almost double myosin-ATPase activity in the rabbit ventricle.1""2 Hypothyroidism was produced by adding 0.8 mg/ml propylthiouracil (PTU) to the drinking water during a period of 3 weeks.16 Heart Preparation Experiments were performed on the isolated, cross-circulated (blood-perfused) rabbit heart supported by anesthetized intact rabbits (Figure 1). The details of the surgical procedure have been described elsewhere.8 In brief, four rabbits (one heart donor, one blood donor, and two supporters) were premedicated with fentanyl (0.044 mg/kg i.m.) and droperi- Goto et al Thyroid Status and Contractile Efficiency Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 dol (2.2 mg/kg i.m.), anesthetized with ketamine (20 mg/kg i.m.) and xylazine (1 mg/kg i.m.), tracheotomized, and artificially ventilated. Thereafter, anesthesia was maintained with supplemental intramuscular doses of ketamine and xylazine. Rectal temperature of the heart donor rabbit was measured. The heart donor rabbit was then thoracotomized, and the innominate artery was cannulated and connected to the perfusion circuit. Heparinized (1,500 units/kg) arterial blood from the carotid arteries of the two support rabbits flowed to an arterial reservoir, from which the blood was transported to the coronary system of the donor heart by a perfusion pump (Masterflex, Cole-Parmer, Chicago, Illinois). Coronary venous blood draining from the right ventricle of the donor heart was returned to the external jugular veins of the support rabbits. The supported beating heart was excised from the chest cavity after cross-circulation was started, so there was no interruption of the coronary circulation during surgery. Mean coronary perfusion pressure was monitored and kept constant between 80 and 110 mm Hg throughout each experiment. To measure left ventricular pressure and volume, a thin latex balloon (unstretched volume, 4 ml) mounted on a Y-shaped connector was placed in the left ventricle and secured with a purse-string suture around the mitral valve ring. Coronary blood flow was monitored with an electromagnetic flowmeter and measured accurately with a graduated cylinder by timed collection. Coronary arteriovenous oxygen content difference was measured continuously with an AVOX analyzer (A-VOX Systems, San Antonio, Texas).18 The AVOX analyzer was calibrated with a Lex-O2-Con oxygen content analyzer (Lexington, Waltham, Massachusetts) that was calibrated with distilled water saturated with 100% oxygen at 00 C in each experiment. The temperature of the excised heart was maintained at 36-37° C. To maintain arterial pH, Po2, and Pco2 of the support rabbit within physiological ranges, supplemental oxygen was given or respiratory rate was changed if necessary. In addition, indomethacin (1 mg/kg i.v.) was given to the support rabbits to maintain their mean arterial pressure at more than 60 mm Hg. This dose of indomethacin was effective in improving the support rabbits' arterial pressures, which gradually fell after the initiation of cross-circulation. No direct effect of indomethacin was observed on the Vo2-PVA relation of the excised heart. Also, previous studies have shown that indomethacin does not affect coronary vascular responsiveness.19 Our preliminary study in seven other normal rabbit hearts without any inotropic intervention showed that left ventricular peak isovolumic pressure at a constant ventricular volume at 90 and 120 minutes after an initial measurement (+0.4+10.0% and -6.2±15.4%, respectively) did not significantly differ from the initial value of 98+13 mm Hg. This indicates stability of our cross-circulated heart preparation compared with crystalloid-perfused hearts.20 1001 Experimental Protocol Fourteen hyperthyroid rabbits died during the 2-week period of 1-thyroxine administration, and two normal, three hyperthyroid, and one hypothyroid hearts were unavailable due to technical failures during the surgical preparation. Experiments were therefore performed on eight normal, eight hyperthyroid, and seven hypothyroid hearts. With baseline contractile conditions, coronary perfusion pressure, electrocardiogram, left ventricular pressure, coronary blood flow, and coronary arteriovenous oxygen content difference were measured during steadystate isovolumic contractions. Then, left ventricular volume was varied within a range between V0 (at which peak isovolumic pressure was zero) and an arbitrary maximal volume at which peak systolic pressure exceeded coronary perfusion pressure or end-diastolic pressure reached approximately 13 mm Hg. Persistent contact of the ventricular balloon with the endocardium, even at a ventricular volume near V0, was indicated by the findings that peak isovolumic pressure declined monotonously to zero in proportion to a gradual decrease in ventricular volume to V0 and that reproducibility of the V0 value between multiple measurements was excellent (difference between measurements, <0.02 ml). Measurements were repeated when ventricular pressure and arteriovenous oxygen content difference stabilized at each new ventricular volume.8 This set of measurements with a constant, baseline contractile state was termed the first control run. In five normal, three hyperthyroid, and four hypothyroid hearts, isoproterenol (0.02 ,ug/min) was infused into the coronary perfusion tubing with an infusion pump (Harvard Apparatus, South Natick, Massachusetts), and measurements were repeated in a similar manner as the first control. After isoproterenol was discontinued and baseline steady state was reached again, 20% KCI solution was infused into the perfusion tubing at a rate of 0.02-0.05 ml/min to produce cardiac arrest. Ten minutes after the initiation of cardiac arrest, coronary blood flow and arteriovenous oxygen content difference were measured at the V0 volume to determine oxygen consumption for basal metabolism. Measurements during cardiac arrest were not made in two of the five normal hearts because a stable baseline condition could not be obtained after discontinuation of isoproterenol. In three normal, five hyperthyroid, and three hypothyroid hearts, potassium chloride arrest measurements were made after the first control run, and second control and isoproterenol runs were conducted thereafter. Heart rate was kept constant by left atrial pacing during the control run in all but two hyperthyroid hearts. It was also kept constant during the isoproterenol run in three normal and three hyperthyroid hearts but not in the remaining hearts. Data Analysis End-systolic pressure-volume relation. Data were recorded on a pen recorder and stored on computer Circulation Research Vol 66, No 4, April 1990 1002 Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 disk at a sampling interval of 5 msec for off-line data analysis with a DEC PDP 11/73 computer. Left ventricular end-diastolic and end-systolic pressures were determined as the minimal and peak pressures of the isovolumic contractions, respectively. Tm., the time to end systole, was determined as the time from the onset of the Q wave of electrocardiogram to peak left ventricular pressure. Left ventricular volume was determined as the sum of the volume of saline within the left ventricular balloon and the volume of the balloon walls and connector within the left ventricle. This intraventricular balloon method for volume measurement of the rabbit left ventricle has been validated.21 The ESPVR data were fitted by a parabolic equation: (1) Pes=aVes2+bVes+c where PeS and Ves are end-systolic pressure and volume and a, b, and c are parameters.8,22 The significance of departure from linearity of each ESPVR was tested by analysis of variance (ANOVA).23 Although an insignificant departure from linearity was present in some hearts, the parabolic ESPVR data analysis was continued in these hearts because if the ESPVR is linear, the parameter a will have a value of zero. Left ventricular contractile state was assessed by the initial slope of the rising limb of the parabolic ESPVR, E'ml,822 which was calculated from the derivative of Equation 1 at Pes of 0 mm Hg as E'm =(b2-4ac)112 (2) If the ESPVR is linear (i.e., if the parameter a is zero), E'max is equal to b, which is precisely the same as the slope of the linear ESPVR, Ema,,.24 The volume axis intercept of the curvilinear ESPVR, V0, was determined as V0=[-b+(b2-4ac)1/2]/2a (3) E'm: and V0 were normalized for left ventricular weight. In addition, E'ma) was normalized for left ventricular chamber size as E'max.V0.8'25 Left ventricular oxygen consumption. Left ventricular Vo2 was calculated as follows. First, the total Vo2 per minute (ml 02/min) was calculated as the product of coronary blood flow (ml/min) and coronary arteriovenous oxygen content difference (vol%) and divided by heart rate to yield total Vo2 per beat (ml 02/beat). Left ventricular Thebesian flow was neglected because it is only 1-4% of the total coronary blood flow in this preparation.8 Then, left ventricular Vo2 was obtained by subtracting right ventricular Vo2 from the total Vo2. Because the right ventricle was kept mechanically unloaded and collapsed by continuous hydrostatic drainage, right ventricular Vo2 was considered to be minimal, constant, and independent of left ventricular loading conditions.67 This right ventricular-unloaded Vo2 was calculated as biventricular-unloaded Vo2 times right ventricular weight divided by biventricular weight. Because biventricular- PVA= S1 + S2 + S3 I E 'IEnd-systole E (D 1- J3 W End-dlastole -. VO k--S 3 Left Ventricular Volume (ml) FIGURE 2. Calculation of systolic pressure-volume area (PVA) based on the curvilinear ESPVR analysis. PVA was deternined as the sum of the three areas on the pressurevolume diagram, S1, S2, and S3. (See text for details.) unloaded Vo2 varies with changes in ventricular contractile state,5 unloaded right ventricular Vo2 was determined during both control and isoproterenol runs. Left ventricular Vo2 was normalized for 100 g left ventricular weight (ml 02beat/100 g). Left ventricular Vo2 during potassium chloride arrest was expressed in milliliters of oxygen per minute per 100 g. Because unloaded Vo2 is mainly used for E-C coupling and basal metabolism,5 Vo2 for E-C coupling (ml OJbeat/100 g) is estimated as unloaded Vo2 per minute minus Vo2 for basal metabolism divided by heart rate. Pressure-volume area. Left ventricular systolic PVA is the area that is bounded by the ESPVR and EDPVR and the systolic pressure-volume trajectory in the pressure-volume diagram.5,6 It consists of both external mechanical work and elastic potential energy in ejecting contractions or of potential energy only in isovolumic contractions in which external work is zero. Using the curvilinear ESPVR analysis, PVA was calculated as the sum of three areas shown in Figure 2: a triangular area formed by the three straight lines connecting the end-systolic, enddiastolic, and V0 points (S1); a small upper area between the straight line connecting V0 and the end-systolic point and the curvilinear ESPVR (S2); and a small lower area between the straight line connecting V0 and the end-diastolic point and the curvilinear EDPVR (S3). S, was calculated as (Pes-Ped) x(V-VO)/2 where Pe, and Ped are endsystolic and end-diastolic pressures and V is ventricular volume. S2 was calculated as a/6 x (V-VO)3 where a is a parameter in Equation 1. S3 was calculated as PedX(V-Vo)/4 because the EDPVR is reasonably approximated by a third power of (V-V0).5 The small area below the volume axis was not included in the calculated PVA.5,8 PVA was normalized for left ventricular weight (mm Hg.ml/beat/100 g). Vo2-PVA relation. The relation between left ventricular Vo2 and PVA was obtained in each run. Linear regression analysis was used to determine the slope (ml OJmm Hg/ml) and the Vo2 intercept (ml OJbeat/100 g) of each Vo2-PVA relation. Goto et al Thyroid Status and Contractile Efficiency 1003 TABLE 1. Group Characteristics Original body weight (kg) Final body weight (kg) LV weight (g) RV weight (g) LV/original body weight ratio (xlO -3) LV/final body weight ratio (X10-3) Rectal temperature (0 C) LV, left ventricle; RV, right ventricle. *p<0.05 compared with hypothyroid group. tp<0.01 compared with normal group. :p<0.01 compared with hypothyroid group. §p<0.05 compared with normal group. Normal (n=8) 3.5+±0.5 3.5±0.5 4.9±0.5 1.6±0.2 1.4+0.2 1.4±0.2 39.7±0.4 Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Theoretically, PVA is an expression of total mechanical energy.5-7 The dimensionless ratio of PVA (in joules per beat per 100 g) to excess Vo2 above the unloaded Vo2 (in joules per beat per 100 g) has therefore been considered the ratio of total mechanical energy output to energy input that is used exclusively for mechanical contraction, which reflects the chemomechanical energy transduction efficiency of the contractile machinery9 or contractile efficiency. This contractile efficiency differs from mechanical efficiency, which is given by the ratio of external mechanical work to total Vo2 or Vo2 minus basal metabolism.6 The contractile efficiency was estimated as the reciprocal of the slope of the linear Vo2-PVA relation8 according to Suga et al.5-7 Force-time integral. FTI is the time integral of total ventricular wall force through one cardiac cycle. Total ventricular wall force (F) (g) was calculated as 1.36 (g/cm2/mm Hg) multiplied by the product of ventricular pressure (P) (mm Hg) and lumen cross-sectional area (A) (cm2) based on the force-equilibrium equation for a sphere.15,26 Because isovolumic contractions were used, lumen area A was considered to be constant throughout one cardiac cycle. Thus, F=1.36.P *A= 1.64PV2/3. To obtain FTI, this total wall force was integrated through one cardiac cycle according to the methods of Gibbs and Gibson13 and Holubarsch et al.16 The relation between Vo2 and FTI per beat was assessed by linear regression analysis. Statistics Comparisons of variables among the groups were made by one-way ANOVA.23 When the F test indicated a statistically significant difference among the groups, Student's t test with Bonferroni's correction for multiple comparisons was used to determine the significance of difference between groups.23 The same method was used to compare the slopes and intercepts of the ESPVR, Vo2-PVA relation, and Vo2-FTI relation among the groups on the assumption that the slope and intercept values of individual regression lines reliably represented their true values because the correlation coefficients were close to unity in every heart.5-7 The slopes of the Vo2-PVA Hyperthyroid (n=8) 3.1+0.4* 2.3±0.3tt 4.6±0.7 1.6±0.3 1.5±0.2* 2.0±0.2tt 41.9±0.8tt Hypothyroid (n=7) 3.7±0.4 3.6±0.4 4.5±0.6 1.5±0.1 1.2±0.1 1.2±0.1 39.0±0.5§ relation were also compared between groups by applying analysis of covariance (ANCOVA) to the relation between excess Vo2 above unloaded Vo2 and PVA for pooled data. Comparisons of paired variables before and during isoproterenol infusion were performed by paired t test. The slopes and intercepts of the ESPVR, Vo2PVA relation, and Vo2-FTI relation before and during isoproterenol infusion also were compared by paired t test, with the same assumption. A value of p <0.05 was considered statistically significant. Data are presented as mean+SD unless otherwise indicated. Results Group Characteristics Body weight, ventricular weight, and body temperature of the three groups are summarized in Table 1. Original body weight and the ratio of left ventricular weight to original body weight in the hyperthyroid group were lower than those in the hypothyroid group but did not differ significantly from those in the normal group. Both left and right ventricular weights were similar among the three groups. Because the hyperthyroid group lost 23.3+±7.1% (p<0.01) of original body weight during the course of i-thyroxine treatment, the ratio of left ventricular to final body weight was significantly higher in the hyperthyroid group than the other two groups (bothp<0.01). Body weight of the hypothyroid group did not change from the original value. Rectal temperature was higher in the hyperthyroid group and lower in the hypothyroid group than the normal group, which is consistent with the systemic effects of hyperthyroidism and hypothyroidism, respectively. Cardiac Mechanics Variables Figure 3 shows representative recordings obtained from normal, hyperthyroid, and hypothyroid hearts. It is of note that in the hyperthyroid heart, the duration of contraction is markedly shorter and coronary blood flow is higher than in the other two hearts despite the similar heart rates and peak systolic pressures. Table 2 summarizes cardiac mechanics variables in the three 1004 Circulation Research Vol 66, No 4, April 1990 HYPOTHYROID HYPERTHYROID NORMAL 11'- ECG 100 LV Pressure (mmHg) 0[ \_---1 12 rA-V 02 Difference (vol %) LVV 1.1 mI CBF 5.1ml/min LVV CBF 0.9 92 ml mI/mn LVV 1.0 ml CBF 3.3mlin Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 O.5sec FIGURE 3. Representative recordings of electrocardiogram (ECG), left ventricular (LV) pressure, and arteriovenous (A-V) 02 difference obtained from normal, hyperthyroid, and hypothyroid hearts at similar heart rate and peak isovolumic pressure. Left ventricular volume (LVV) and coronary blood flow (CBF) are also indicated by numerals in the bottom of each panel. In the hyperthyroid heart, the duration of contraction is markedly shorter and coronary blood flow is higher than other two hearts. Paced heart rate was slightly higher in the hyperthyroid group, although the difference among the three groups did not reach statistical significance (p=0.06). Maximal measured left ventricular volume, end-diastolic pressure at maximal volume, and peak systolic pressure at maximal volume were similar among the groups, indicating that measurements were made under comparable mechanical loading conditions. Maximal rate of left ventricular pressure rise groups. (dP/dt) was significantly higher and Tm shorter in the hyperthyroid group than in the other two groups. In the hypothyroid group, maximal left ventricular dP/dt was significantly lower than in the normal group, whereas Tma was similar. End-Systolic Pressure-Volume Relation Two normal and four hyperthyroid hearts showed significant nonlinear ESPVRs by ANOVA23 (p<0.01) TABLE 2. Cardiac Mechanics and the End-Systolic Pressure-Volume Relation Normal 204±21 1.23±0.23 Hyperthyroid (n=8) 215+21 1.03±0.10 Hypothyroid (n=7) 188± 16 1.21±+0.13 7.0±3.0 5.5+2.3 7.7±3.1 103±12 98±11 93±13 1,367±208 147± 10 1,900-262*t 109±13*t 1,086+ 160t 157±+12 0.987 279.2±119.2 13.6±5.7 0.56±0.04 11.5±1.2 153.6±61.9 0.992 265.6±+138.1 11.9+5.5 0.43±0.03* 9.5±1.2t 114.7±62.9 0.996 163.6+64.2 7.1±2.5t 0.46±0.03* 10.4+±1.6 (n=8) Heart rate (beats/min) Maximal measured LV volume (ml) LV end-diastolic pressure at maximal LV volume (mm Hg) LV peak pressure at maximal LV volume (mm Hg) LV max dP/dt at maximal LV volume (mm Hg/sec) TmaX at maximal LV volume (msec) End-systolic pressure-volume relation Correlation coefficient (median) E'ma, (mm Hg/mi) Normalized E'm,,a (mm Hg/[ml/100 g]) V0 (ml) Normalized V0 (ml/100 g) E'ma,,Vo (mm Hg) 75.3±30.4* LV, left ventricle; max dP/dt, maximal rate of left ventricular pressure rise; Tma,, time to end systole; Em.., initial slope of the rising limb of the end-systolic pressure-volume relation (ESPVR); VO, volume axis intercept of the ESPVR. The ESPVR was obtained by a parabolic curve fitting. *p<0.01 compared with normal group. tp<O.O1 compared with hypothyroid group. tp<O.05 compared with normal group. Goto et al Thyroid Status and Contractile Efficiency A 1007 -3i Y = AWX^2 + B*X + C E A = 2 0 a. B A.X'^2 + B*X Y = 0) -17. 5 B 1-32 1 0 a 9997 Y= AX + + FIGURE 4. Plots of represenend-systolic (ESPVR, o) and end-diastolic (x) pressurevolume relation obtained in a C tative = B =42.6 C -154.6 R =0.999 Y = *X + B A 156.9 B= -68.3 R 0.990 1005 7s5 c -66.9 R A 09 50. B =194.5 BR hyperthyroid (panel A) -45. 5 RGY and hypo- thyroid (panel B) heart. Solid and dotted lines indicate linear and a- parabolic regression lines, 25- cI 0 9.i _ 7.Q --L3 X 9. 6 x --Z .9 XX i _ .9 a i; 2 J,$ x x Left Ventricular Volume it. a @.4 X f.2 1: 6 respec- tively, for the ESPVR Analysis of variance indicated a significant nonlinearity of the ESPVR in panel A but not panel B. x Left (ml) Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 with concavity toward the volume axis, as shown in Figure 4A. On the other hand, ESPVRs from six normal, four hyperthyroid, and all hypothyroid hearts showed insignificant departure from linearity, as shown in Figure 4B. Table 2 summarizes the parabolic regression data of the ESPVR in all hearts. The correlation coefficient was close to unity in each heart. Although the estimated V0 from Equation 3 (0.48+0.07 ml) was less than the directly measured V0 (0.50+0.08 ml, p<0.01), the difference (3.5+2.9%) was practically negligible. Both E'm,, normalized for left ventricular weight and E'ma,,V0 (E'ma normalized for left ventricular chamber size), which are indices of ventricular contractile state,8,25 were significantly lower in the hypothyroid than in the normal group. However, neither index was significantly different between the normal and hyperthyroid and between the hyperthyroid and hypothyroid groups. Thus, the average baseline contractile states in the normal and hyperthyroid hearts were not significantly different. Ventricular Volume (ml) Vo2-PVA Relation Table 3 summarizes variables of cardiac energetics in the three groups. Coronary perfusion pressure and maximal measured PVA were similar among the groups. However, average coronary blood flow, Vo2 measured at the maximal PVA, and mechanically unloaded Vo2 were significantly higher in the hyperthyroid than in the normal and hypothyroid groups. Figure SA shows representative Vo2-PVA relations obtained in one normal, one hyperthyroid, and one hypothyroid heart, and Figure 5B depicts the linear regression lines of the Vo2-PVA relations of all 23 hearts. The correlation was highly linear in each heart; the median correlation coefficient was 0.971 in the normal, 0.982 in the hyperthyroid, and 0.971 in the hypothyroid groups. The slope, Vo2 intercept, and contractile efficiency are summarized in Figures 6A-6C. The slope was significantly greater in the hyperthyroid group (2.58x10-5+0.45x10-5 ml OJ mm Hg/ml) than the normal (1.70x 10-5±0.21 x 10-5 TABLE 3. Variables of Cardiac Energetics Normal (n=8) Hyperthyroid (n=8) 91±+ 12 8.5±1.9*t Hypothyroid (n=7) 97±+10 CPP (mm Hg) 90+9 5.3±2.7 5.8±0.9 Average CBF (ml/min) Maximal measured PVA 809±+184 686±253 761±283 (mm Hg.ml/beat/100 g) LV Vo2 at maximal PVA 0.044±0.008 (ml O2/beat/100 g) 0.057±0.011tt 0.041±0.010 Unloaded LV Vo2 0.030+0.006 (ml O2/beat/100 g) 0.038+0.005t§ 0.026±0.007 LV Vo2 during KCl arrest 1.66+0.42 (ml O2/min/100 g) 2.04±0.40§ 1.03+0.39: LV Vo2 for E-C coupling 0.020±0.007 0.021±+0.005 (ml OJbeat/100 g) 0.028±0.004t* CPP, coronary perfusion pressure; average CBF, averaged value of mean coronary blood flow under various ventricular loading conditions in baseline contractile state in a given heart; PVA, pressure-volume area obtained from parabolic curve fitting to the end-systolic pressure-volume relation; LV Vo2, left ventricular oxygen consumption; E-C coupling, excitation-contraction coupling. *p<0.01 compared with normal group. tp<0.05 compared with hypothyroid group. tp<0.05 compared with normal group. §p<0.01 compared with hypothyroid group. 1006 Circulation Research Vol 66, No 4, April 1990 e..T A 9.98 *8 A.X + 9 HYPERTHYROID (x) Y a a* 90.999935 R 0 0 _~NORMA 0. A 041 9_.9 9 'I HYPOTHYROIDC+) N a 11 Aa 0 .999152 W152 R * 0.951 0.o 0. 02- 9.96 e.996 CL(a) 9.9817 e. cJ °00 0A2 61 _J 0 1_ _ , 3 6 12t PVA (mrnHgmbeatl100 g) 9 e d--:t= 3e9 PVA 129t= (mnHg-mVlbeat/100 g) FIGURE 5. Panel A: Plot of representative Vo2-PVA relation obtained in a normal (o), hyperthyroid (x), and hypothyroid (+) heart. The correlation is highly linear in each heart. Panel B: Linear regression lines of the 17o2-PVA relation in all 23 hearts. Regression lines of hyperthyroid hearts (dashed lines) have apparently steeper slope and higher Vo2 intercept values than those of normal (thick solid lines) and hypothyroid (thin solid lines) hearts. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 ml 02/mm Hg/ml) and hypothyroid (1.89x10` ±0.28x10` ml OJmmHg/ml) groups. As a result, the contractile efficiency (Figure 6C) was significantly lower in the hyperthyroid (26.6±5.5%) than the normal (39.6±4.3%) and hypothyroid (36.0±5.2%) groups. The Vo2 intercept (Figure 6B) was significantly greater in the hyperthyroid group (0.038±0.005 ml O2/beat/100 g) than in the normal (0.030±0.006 ml O2/beat/100 g) and hypothyroid (0.027±0.007 ml beat/100 g) groups, although there was noticeable interindividual variability, as seen in Figure 5B. The Vo2 intercept values obtained from linear regression analysis were almost the same as the directly measured unloaded Vo2 in all three groups (Table 3). Comparisons of the slope of the Vo2-PVA relation between groups was also made by ANCOVA for pooled data. To eliminate interindividual variability in unloaded Vo2, unloaded Vo2 was subtracted from total Vo2 for each data point. The obtained correlation between excess Vo2 and PVA was linear in each group (r=0.946 in normal, 0.960 in hyperthyroid, and 0.942 in hypothyroid groups). ANCOVA indicated a significantly higher slope value (p <0.01) in the hyperthyroid group (2.69x 10-5 ml OJmm Hg/ml) than in the normal (1.82 x 10-5 ml OJmm Hg/ml) and hypothyroid (1.75 x 10-5 ml Omm Hg/ml) groups. Also, the Vo2-PVA relation was assessed using the conventional linear ESPVR analysis in the same manner as in the previous study.8 Both the slope and Vo2 intercept of the Vo2-PVA relation were significantly higher in the hyperthyroid group (slope, 3.02x10-5+0.43x10-5 ml O2/mm Hg/ml; Vo2 intercept, 0.038+0.005 ml O2/beat/100 g) than in the normal (2.17x 10-5 ml O2/mm Hg/ml and 0.030± 0.006 ml O2/beat/100 g; both p<0.05) and hypothyroid (2.09x10-5 ml O2/mm Hg/ml and 0.027±0.007 ml O2/beat/100 g; bothp<0.01) groups. These results were similar to the results obtained from the nonlinear ESPVR analysis and again indicate lower contractile efficiency and higher nonmechanical energy cost in hyperthyroid hearts. Left ventricular Vo2 for basal metabolism was measured during potassium chloride arrest in six normal, eight hyperthyroid, and seven hypothyroid hearts (Table 3). It was slightly greater in the hyperthyroid than in the normal hearts (p=0.11) but significantly lower in the hypothyroid group than in the other two groups. As a result, estimated Vo2 for E-C coupling was significantly higher in the hyperthyroid group than in the other two groups (Table 3). Both Vo2 for E-C coupling and basal metabolism were significantly correlated with the Vo2 intercept in all 21 hearts in which Vo2 for basal metabolism was measured (r=0.953 and 0.751, respectively), indicating that the interindividual variability of the intercept was attributable to both Vo2 for E-C Vo2 cou- pling and basal metabolism. Vo2-FTI Relation The Vo2-FTI relation was also highly linear in each heart; the median correlation coefficient was 0.976 in the normal, 0.982 in the hyperthyroid, and 0.970 in the hypothyroid groups. Similar to the Vo2-PVA relation, the slope of the Vo2-FTI relation (Figure 6D) was significantly greater in the hyperthyroid group (9.82x 10-4+2.95x 10-4 ml O2/g/sec/100 g) than in the normal (4.84x10 4±1.82x10-4 ml OJ g/sec/100 g) and hypothyroid (4.98x10-40.84x10 ml OJg/sec/100 g) groups. Also, similar to the Vo2PVA relation, the Vo2 intercept of the Vo2-FTI relation (Figure 6E) was higher in the hyperthyroid group (0.037+0.005 ml O2/beat/100 g) than in the normal (0.029±0.007 ml O2/beat/100 g) and hypothyroid (0.026±0.007 ml O2/beat/100 g) groups. Effect of Isoproterenol The effects of isoproterenol were assessed in seven normal, seven hyperthyroid, and four hypothyroid hearts. Normalized E'max increased significantly in all three groups (normal, 12.4±5.4 to 16.4±5.8 mm Hg/ [ml/100 g]; hyperthyroid, 10.0±3.4 to 24.1±14.1 mm Hg/[ml/100 g]; hypothyroid, 7.2±3.7 to 13.5 ±3.8 Goto et al Thyroid Status and Contractile Efficiency V02-PVA Relation 1007 V02-PVA Relation s0 NB rNornl -EHyper-~~~~~~~~~~~~~ 0~ 0 MS c 25 NB -9 1 V02-FTI Relation 59. -' C*C 1025 *2s re0 130 NormW Hype H~p W. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 0 25 V02-FTI Relation -59 1 Norma 12 D N 50.05ENE , H H N H H FIGURE 6. Bar graphs showing comparisons of parameters ilo2-PVA relation (panels A-C) and the V~o2-FTI relation (panels D and E) among the groups. The slope (panel A) and the lV°2 intercept (intcpt) of the ilo2PVA relation (panel B) are greater and the energy conversion efficiency of the contractile machinery (panel C) is lower in the hyperthyroid group than in the other two groups. Also, the slope (panel D) and the iV,o2 intercept of the iVo'2-FTI relation (panel E) are greater in the hyperthyroid group than in other groups. *p<0.05, **p<0.01, and NS=insignificant difference by analyzsis of variance and Student's t test with Bonferroni's correction. Mean + SEM is indicated. Hyper Hypo FIGURE 7. Bargraphs showing effects of isoproterenol on the Vo2-PVA and Vo2-FTI relations. Percent changes from control values are shown. The slope of the Vo2-PVA relation (panel A) was not affected by isoproterenol, whereas the V02 intercept (intcpt) of the Vo2-PVA relation (panel B), the slope (panel C), and the Vo2 intercept of the VorFTI relation (panel D) significantly increased during isoproterenol administration. *p<0.05, **p<0.01, and NS=insignificant changes from control by paired t test. Mean ±SEM is indicated. of the g]; all p<0.05), whereas VO remained unchanged in the normal (1 1.4+.1.0 to 11.2+--1.3 mlllO00 g) and hypothyroid groups (9.3+1.3 to 9.7+t2.0 mlV100 g) and decreased in the hyperthyroid group (9.3+-t1.0 to 8.5 +-1.5 mlllO0 g; p <0.05). This indicates that ventricular contractile state increased with isoproterenol in all mm H9/[m1V100 groups. The Vo2-PVA relation was linear in each heart both before and during isoproterenol administration as indicated by the high correlation coefficient; the median was 0.968 (control) and 0.938 (isoproterenol) in the normal, 0.982 and 0.973 in the hyperthyroid, and 0.977 and 0.917 in the hypothyroid groups. Figures 7A and 7B show percen.t changes in the slope and 'V02 intercept of the V02-PVA relation compared with the respective control values. During isoproterenol, the slope of the Vo2-PVA relation did not change significantly from control in any of the three groups (Figure 7A). In contrast, the Vo2 intercept of the Vo2-PVA relation increased significantly from control in all groups (Figure 7B). Thus, adrenergic stimulation alone did not change the contractile efficiency, whereas it increased the nonmechanical oxygen cost.5 The Vo2-FTI relation was also linear in each heart under each condition; the median correlation coefficient was 0.981 (control) and 0.963 (isoproterenol) in the normal, 0.986 and 0.963 in the hyperthyroid, and 0.983 and 0.940 in the hypothyroid groups. In contrast to the results of the Vo2-PVA relation, the slope of the Vo2-FTI relation during isoproterenol increased significantly from control in all three groups (Figure 7C). The Vo2 intercept of the Vo2-FTI relation also increased significantly from control in all groups (Figure 7D). Thus, ,B-adrenergic stimulation increased both the slope and Vo2 intercept of the Vo2-F1I relation. Discussion This was the first study of the effect of a chronic alteration of myosin V1V3 ratio on the slope of the Vo2-PVA relation (i.e., on the contractile efficiency) of the left ventricle. The major new findings are that (3- 1008 Circulation Research Vol 66, No 4, April 1990 1) the hyperthyroid rabbit left ventricle has a steeper slope and a higher Vo2 intercept of the Vo2-PVA relation (i.e., a decreased contractile efficiency and increased energy cost of E-C coupling) compared with normal and hypothyroid left ventricles and 2) the decreased contractile efficiency in the hyperthyroid hearts probably is due to an increased V1!N3 ratio of myosin isoforms rather than an alteration in ,f-adrenoceptors. These findings suggest that there are two mechanisms for higher oxygen consumption in the hyperthyroid heart: lower efficiency of chemomechanical energy transduction and higher cost for calcium handling. Also, the present study demonstrates that depending on the imposed intervention, the Vo2-PVA and Vo2-FTI relations can show either directionally similar or dissociated responses, even in the same isovolumic contraction mode. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Ventricular Contractility and Thyroid State In the present study, neither E'max nor E'mxVO differed between the normal and hyperthyroid groups, although both the higher maximal dP/dt and shorter Tmax suggest a higher crossbridge cycling rate in the hyperthyroid heart. This could occur because Em. or E'max is related to force generation and dP/dt and Tmax are related to the velocity of contraction. In general, force-related contractility indices are more directly related to pump performance of the ventricle, although the physiological significance of velocity-related contractility indices could increase in a situation such as hyperthyroidism with a high heart rate. This discrepancy of force-related (Emax) and velocity-related (dP/dt) indices of contractility is in accordance with the previous studies by Buccino et a127 and Taylor et al.28 Both studies reported a significant increase in the velocity of shortening assessed by the force-velocity relation and either no or only a slight increase in maximum isometric tension in isolated papillary muscles27 or the whole ventricle28 of hyperthyroid animals. These findings suggest that in hyperthyroidism, a VJV3 change affects only one of the two major components of "contractility" (i.e., it accelerates the time course of force generation but does not alter force-generating capacity of the heart muscle). The decreased E'max in the hypothyroid hearts is compatible with previous studies showing a decreased peak isometric tension and a left and downward shift of the force-velocity relation in hypothyroid animals.27,28 However, if the above speculation that a VJV3 change does not alter forcegenerating capacity of heart muscle is true, the decrease in Emmax cannot be ascribed to an additional increase in the myosin V3 isoform in the hypothyroid hearts. One possible explanation is a decreased number of 8-adrenoceptors in the hypothyroid animals.29 Efficiency of the Contractile Machinery The most important finding of the present study is that the contractile efficiency is significantly lower in the hyperthyroid hearts than in the normal and hypothyroid hearts. This is the first time an intervention has been shown to affect contractile efficiency assessed from the slope of the Vo2-PVA relation. Although myosin isoform composition was not determined in the hearts used in the present study, a shift of myosin isoform from predominantly V3 to predominantly V1 has been demonstrated in previous studies using the same source of animal supply and the same protocol to produce hyperthyroidism.11,12 There are several possible explanations for the increased slope of the Vo2-PVA relation in the hyperthyroid hearts. The first possibility is that Vo2 for E-C coupling and basal metabolism increases with an increase in PVA in the hyperthyroid hearts, because energy use for E-C coupling30 and basal metabolism31 have been reported to increase with an increase in muscle length. If so, the higher slope value of the Vu2-PVA relation could be due to a PVA-dependent (or volume-dependent) increase in nonmechanical Vo2 rather than decreased contractile efficiency in the hyperthyroid hearts. However, studies in normal, isolated, blood-perfused dog hearts have shown that the Vo2 of ejecting contractions from a high preload against nearly zero afterload with a small PVA is virtually equal to the Vo2 for unloaded contractions32 and that Vo2 during potassium chloride arrest does not increase with an increase in ventricular volume.33,34 Because it seems very unlikely that this volume independence of nonmechanical Vo2 would be different between normal and hyperthyroid hearts, it is assumed that nonmechanical Vo2 is independent of changes in ventricular volume or PVA in both normal and hyperthyroid hearts. The second possible explanation is that increased ,/-adrenergic activity in the hyperthyroid hearts might be responsible for the higher Vo2-PVA slope value. Although studies examining changes in norepinephrine content of the hyperthyroid ventricle have not been conclusive,27,35 recent reports indicate that the number of /8-adrenoceptors increases in the hyperthyroid rat heart29 and that /8-adrenergic stimulation increases both myosin-ATPase activity36 and crossbridge cycling rate37 in the normal rat heart. However, ,B-adrenergic stimulation did not change the slope of the Vo2-PVA relation in either the normal or the hypothyroid hearts in the present study, as was reported in a previous study in the normal dog.5 Therefore, the increased slope of the Vo2-PVA relation in the hyperthyroid hearts in the present study cannot be ascribed to increased /-adrenergic stimulation in the hyperthyroid hearts. Thus, the third and most likely explanation for the increased slope of the Vo2-PVA relation in the hyperthyroid hearts is a decreased contractile efficiency due to a shift of myosin isoforms from predominantly V3 to predominantly V1. Because contractile efficiency may reflect both the efficiency of conversion of Vo2 to ATP (the efficiency of oxidative phosphorylation in synthesizing ATP) and of ATP to PVA (the efficiency of the contractile machinery to generate total mechanical energy by hydrolyzing ATP),69 this decreased contractile efficiency could Goto et al Thyroid Status and Contractile Efficiency Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 be caused by either a decreased Vo2-to-ATP efficiency or a decreased ATP-to-PVA efficiency. However, because normal oxidative phosphorylation efficiency has been reported in hyperthyroid dog' and cat4 hearts, the decreased contractile efficiency is most likely due to decreased efficiency of ATPto-PVA conversion in the hyperthyroid heart. However, the underlying mechanism of this decrease in contractile efficiency or ATP-to-PVA efficiency is unclear. Does it result directly from increased myosin-ATPase activity and its associated increased crossbridge cycling rate? Although recent studies have shown that catecholamines increase both myosinATPase activity36 and crossbridge cycling rate,37 they did not change the slope of the Vo2-PVA relation in either the present study or a previous study.5 Further, cardiac cooling, which is believed to decrease the crossbridge cycling rate, also does not alter the slope of the Vo2-PVA relation.7 Thus, changes in crossbridge cycling rate are not always accompanied by changes in contractile efficiency. One explanation is that the magnitude of a change in myosin-ATPase activity or crossbridge cycling rate caused by these acute interventions might be much smaller than that induced, by hyperthyroidism -so small that the slope of the Vo2-PVA relation is not sensitive enough to detect such a change. In support of this, recent studies have indicated that crossbridge cycling rate increases by only 26% with adrenaline,37 whereas it increases by 120% with hyperthyroidism.38 Another explanation is that there might be regulatory mechanisms of contractile efficiency other than a simple change in crossbridge cycling rate (e.g., numbers of crossbridges or on and off time12). Further studies will be needed to elucidate the relation between contractile efficiency and crossbridge kinetics under various conditions. In the present study, the slope of the Vo2-PVA relation was similar between the normal and hypothyroid groups. Because cardiac myosin of normal adult rabbits is composed mainly of the V3 form," administration of PTU may not have induced a major additional alteration in myosin isoform composition. This may account for the similar slope of the Vo2-PVA relation and, hence, the similar contractile efficiency between the normal and hypothyroid groups. Unloaded Vo2 The higher left ventricular Vo2 for E-C coupling in the hyperthyroid hearts is in accordance with the study of Skelton et al,3 which showed increases in Vo2 for isotonic contractions against any level of afterload in hyperthyroid cats. Although this increase in Vo, for E-C coupling might be explained in part by a change in fl-adrenoceptors in the hyperthyroid hearts,29 it was not accompanied by an increase in E'ma, in the present study. This dissociation between increases in Emax and Vo2 for E-C coupling contrasts with the results obtained in the isolated dog heart,5,39 which demonstrate proportional increases in Em. and the Vo2 for E-C coupling with catecholamines or calcium. Also, 1009 this result is opposite in direction to cardiac cooling, which induces an increase in Emax without an increase in the Vo2 intercept of the Vo2-PVA relation.7 The mechanism of this dissociation is not known. It has been demonstrated in skinned rabbit ventricular muscle that the thyroid state does not influence the force-[Ca2,] relation.40 However, in hyperthyroid hearts, the rate of calcium transport by sarcoplasmic reticulum is higher than in normal hearts,41-43 although the peak level of free myoplasmic calcium during contraction assessed by aequorin signals does not differ from normal for a similar peak isometric tension development.43 These results, together with the present findings, suggest the possibility that the energy cost of a unit of calcium handling is higher (i.e., the efficiency of E-C coupling is lower) in the hyperthyroid than in the normal hearts, accounting for an increased Vo2 without a change in Ema.. Another possible mechanism for the higher Vo2 intercept is an uncoupling of mitochondrial oxidative phosphorylation, which has been reported to be caused by large doses of thyroxine.44 However, as mentioned previously, normal oxidative phosphorylation efficiency has been reported in hyperthyroid dog' and cat4 hearts. The interindividual variability of the Vo2 intercept (Figure 5B) was similar to those observed in previous studies.5845 Although the true mechanism for this interindividual variability remains unclear,45 the present study has indicated that both Vo2 for E-C coupling and basal metabolism are responsible for this variability. In addition, a preliminary study suggests that baseline plasma catecholamine level of the support animal may be responsible in part for this variability.46 Vo2-PVA and Vo2-FTI Relations Other intriguing findings in the present study are the similarities and dissimilarities between Vo2-PVA and Vo2-FTI relations. Suga et a126 have shown that PVA and FTI dissociate only when stroke volume and ejection fraction are varied greatly. In contrast, it was demonstrated in the present study that Vo2-PVA and Vo2-FTI relations dissociate in response to isoproterenol, even in the same isovolumic contraction mode. Recently, it has been shown that V02 decreases despite having the same PVA under a specific condition in which ventricular volume is reduced rapidly at end systole.47 This indicates that PVA may be imperfect as an expression of total mechanical energy under this unusual condition. However, the fact that PVA is so closely correlated with Vo2 under most conditions in many studies5-8'26'39'45 lends strong support to the idea that it is a reliable index of total mechanical energy produced by crossbridge cycling5'6 and that the reciprocal of the slope of the Vo2-PVA relation reflects contractile efficiency9 under most conditions, including those in the present study. On the other hand, the reciprocal of the slope of the Vo2-FTI relation is analogous to thermomechanical economy (the ratio of tension-time integral to tension-dependent heat) as measured by myothermal 1010 Circulation Research Vol 66, No 4, April 1990 studies.1314,16,17 This index of economy differs from contractile efficiency because the Vo2-FTI relation includes the time domain; the dimensions of the Vo2-FTI economy are given in joules per gram per second or centimeters per second (i.e., the unit of velocity). The exact mechanism of directionally similar responses to hyperthyroidism and dissociated responses to isoproterenol between contractile efficiency and Vo2-FTI economy are not known. One possibility is that, as suggested earlier, the two indexes simply have differing sensitivities to changes in crossbridge cycling rate, such that when crossbridge cycling rate is increased enough with hyperthyroidism, directionally similar, significant changes are seen with both approaches. Another possibility is that the two approaches reflect different (i.e., time-invariant and time-variant) aspects of crossbridge energetics. Further study will be needed to resolve this issue. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Acknowledgments We thank Stephen Bell and David Robbins for their excellent technical assistance. We also thank Dr. Hiroyuki Suga, National Cardiovascular Center, Japan, for his helpful comments in preparation of this manuscript. References 1. Piatnek-Leunissen D, Olson RE: Cardiac failure in the dog as a consequence of exogenous hyperthyroidism. Circ Res 1967; 20:242-252 2. Talafih K, Briden KL, Weiss HR: Thyroxine-induced hypertrophy of the rabbit heart: Effect on regional oxygen extraction, flow, and oxygen consumption. Circ Res 1983;52:272-279 3. Skelton CL, Coleman HN, Wildenthal K, Braunwald E: Augmentation of myocardial oxygen consumption in hyperthyroid cats. Circ Res 1970;27:301-309 4. Gunning JF, Harrison CE Jr, Coleman HN: Myocardial contractility and energetics following treatment with d-thyroxine. Am J Physiol 1974;226:1166-1171 5. Suga H, Hisano R, Goto Y, Yamada 0, Igarashi Y: Effect of positive inotropic agents on the relation between oxygen consumption and systolic pressure volume area in canine left ventricle. Circ Res 1983;53:306-318 6. Suga H, Igarashi Y, Yamada 0, Goto Y: Cardiac oxygen consumption and systolic pressure volume area. Basic Res Cardiol 1986;81(suppl 1):39-50 7. Suga H, Goto Y, Igarashi Y, Yasumura Y, Nozawa T, Futaki S, Tanaka N: Cardiac cooling increases E without affecting relation between 02 consumption and systolic pressurevolume area in dog left ventricle. Circ Res 1988;63:61-71 8. Goto Y, Slinker BK, LeWinter MM: Similar normalized Emax and 02 consumption-pressure-volume area relation in rabbit and dog. Am J Physiol 1988;255:H366-H374 9. Gibbs CL, Chapman JB: Cardiac mechanics and energetics: Chemomechanical transduction in cardiac muscle. Am J Physiol 1985;249:H199-H206 10. Martin AF, Pagani ED, Solaro RJ: Thyroxine-induced redistribution of isoenzymes of rabbit ventricular myosin. Circ Res 1982;50:117-124 11. Litten RZ III, Martin BJ, Low RB, Alpert NR: Altered myosin isozyme patterns from pressure-overloaded and thyrotoxic hypertrophied rabbit hearts. Circ Res 1982;50:856-864 12. Alpert NR, Mulieri LA, Litten RZ: Functional significance of altered myosin adenosine triphosphatase activity in enlarged hearts. Am J Cardiol 1979;44:947-953 13. Gibbs CL, Gibson WR: Energy production in cardiac isotonic contractions. J Gen Physiol 1970;56:732-750 14. Gibbs CL, Gibson WR: Isoprenaline, propranolol, and the energy output of rabbit cardiac muscle. Cardiovasc Res 1972; 6:508-515 15. Weber KT, Janicki JS: Myocardial oxygen consumption: The role of wall force and shortening. Am J Physiol 1977; 233:H421-H430 16. Holubarsch Ch, Goulette RP, Litten RZ, Martin BJ, Mulieri LA, Alpert NR: The economy of isometric force development, myosin isoenzyme pattern and myofibrillar ATPase activity in normal and hypothyroid rat myocardium. Circ Res 1985; 56:78-86 17. Holubarsch Ch, Hasenfuss G, Blanchard E, Alpert NR, Mulieri LA, Just H: Myothermal economy of rat myocardium, chronic adaptation versus acute inotropism. Basic Res Cardiol 1986;81(suppl 1):95-102 18. Shepherd AP, Burger CG: A solid-state arteriovenous oxygen difference analyzer for flowing whole blood. Am J Physiol 1977;232:H437-H440 19. Hintze TH, Kaley G: Prostaglandins and the control of blood flow in the canine myocardium. Circ Res 1977;40:313-320 20. Parrish MD, Ayres NA, Kendrick BT, Fixler DE: Maturational differences in the isolated isovolumic rabbit heart. Am J Physiol 1986;251:H1143-H1148 21. Goto Y, Slinker BK, LeWinter MM: Accuracy of volume measurement of rabbit left ventricle by balloon method. Am J Physiol 1988;255:H394-H396 22. 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Taylor RR, Covell JW, Ross J Jr: Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. J Clin Invest 1969;48:775-784 29. Limas C, Limas CJ: Influence of thyroid status on intracellular distribution of cardiac adrenoceptors. Circ Res 1987; 61:824-828 30. Allen DG, Kurihara S: The effects of muscle length on intracellular calcium transients in mammalian cardiac muscle. J Physiol 1982;327:79-94 31. Whalen WJ: Some factors influencing 02 consumption of isolated heart muscle. Am J Physiol 1960;198:1153-1156 32. Yasumura Y, Nozawa T, Futaki S, Tanaka N, Suga H: Minor-preload dependence of 02 consumption of unloaded contraction in dog heart. Am J Physiol 1989;256:H1289-H1294 33. Monroe RG, French G: Ventricular pressure-volume relationships and oxygen consumption in fibrillation and arrest. Circ Res 1960;8:260-266 34. Nozawa T, Yasumura Y, Futaki S, Tanaka N, Suga H: No significant increase in 02 consumption of KCl-arrested dog heart with filling and dobutamine. Am J Physiol 1988; 255:H807-H812 35. Kurland GS, Hammond RP, Freedberg AS: Relation of thyroid state to myocardial catecholamine concentration. Am J Physiol 1963;205:1270-1274 36. Winegrad S, Weisberg A, Lin LE, McClellan G: Adrenergic regulation of myosin adenosine triphosphatase activity. Circ Res 1986;58:83-95 37. Hoh JFY, Rossmanith GH, Kwan LJ, Hamilton AM: Adrenaline increases the rate of cycling of crossbridges in rat cardiac Goto et al Thyroid Status and Contractile Efficiency 38. 39. 40. 41. 42. 43. muscle as measured by pseudo-random binary noisemodulated perturbation analysis. Circ Res 1988;62:452-461 Shibata T, Hunter WC, Sagawa K: Dynamic stiffness of barium-contractured cardiac muscles with different speeds of contraction. 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Physiol Rev 1962;42:605-673 Suga H, Yamada 0, Goto Y, Igarashi Y, Yasumura Y, Nozawa T, Futaki S: Left ventricular 02 consumption and pressurevolume area in puppies. Am J Physiol 1987;253:H770-H776 Ohgoshi Y, Futaki S, Yaku H, Goto Y, Suga H: Effects of blood-born catecholamines on left ventricular Em,,x and oxygen consumption in the excised cross-circulated dog heart (abstract). Jpn Circ J 1989;53:587 Yasumura Y, Nozawa T, Futaki S, Tanaka N, Suga H: Time-invariant oxygen cost of mechanical energy in dog left ventricle: Consistency and inconsistency of time-varying elastance model with myocardial energetics. Circ Res 1989; 64:764-778 KEY WORDS * thyroxine * isoproterenol * crossbridge cycling * myosin isozyme * pressure-volume relation Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Decreased contractile efficiency and increased nonmechanical energy cost in hyperthyroid rabbit heart. Relation between O2 consumption and systolic pressure-volume area or force-time integral. Y Goto, B K Slinker and M M LeWinter Circ Res. 1990;66:999-1011 doi: 10.1161/01.RES.66.4.999 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/66/4/999 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. 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