hysiological Reviews Published and Copyright by The American Physiological Society

Vol. 70, No. 2, April 1990

Ventricular HIROYUKI

Energetics SUGA

Department of Cardiovascular Dynamics, National Cardiovascular Center ResearchInstitute, Osaka,Japan

I. Introduction .............................................................................. II. Total Mechanical Energy of Ventricular Contraction ........................................ A. Time-varying elastance model .......................................................... B. Difference from stretched elastic body model ............................................ III. Cardiac Oxygen Consumption and Pressure-Volume Area .................................... A. Assumptions .......................................................................... B. Loadingconditions ..................................................................... C. Heartrate ............................................................................. D. Inotropicstates ........................................................................ E. Unloaded contraction and arrest ........................................................ F. Coronary perfusion .................................................................... G. Rightventricle ........................................................................ H. Heart size ............................................................................. I. Hypertrophy .......................................................................... J. Hyperthyroidism ...................................................................... K. Insituheart ........................................................................... L. Mammalian species other than dogs ..................................................... M. Force-length area ...................................................................... IV. Oxygen-Wasting Effect .................................................................... V. FennEffect ............................................................................... VI. Efficiency ................................................................................. A. Efficiency from oxygen consumption to pressure-volume area ............................. ............................................. B. Efficiency from oxygen consumption to ATP C. Efficiency from ATP to pressure-volume area ............................................ D. Efficiency from oxygen consumption to external work .................................... ................................................... E. Efficiency from ATP to external work VII. RemainingProblems ...................................................................... VIII. Conclusion.. ..............................................................................

I. INTRODUCTION

The subject of myocardial energetics was extensively reviewed by Gibbs (62) for Physiological Reviews in 1978 and by Gibbs and Chapman (68) for Handbook of PhysioZogy in 1979. These reviews emphasized studies of the mechanoenergetic coupling of myocardium based on heat (or enthalpy) measurement. Over the last decade, three major lines of research on cardiac energetics have been preeminent. One major line is the study of the heat-load relation by Gibbs and colleagues (62-70, 72, 73,76,77). Another major line is the work of Alpert and colleagues on the economy of force generation of the myocardium (7-11, 89, 100, 102, 144). The third major line is ventricular energetics based on a new measure of the total mechanical energy generation of the ventricle 0031-9333/90

$1.50 Copyright

0 1990 the American

Physiological

Society

247 248 248 249 250 250 251 254 254 257 259 260 260 261 261 261 262 262 262 262 264 264 265 267 268 268 269 270

by myself and my colleagues (126,164-166,212,213,217, 218,220-233,242,244,246-248,250). One of the major advantages of this new measure of the total mechanical energy of the ventricle is that it allows myocardial contractile efficiency to be determined directly (233,242), which is not possible with the heat-load relation (62,68,70) or economy of force (7-10) methods. Another major advantage of this total mechanical energy concept is that it can be quantified by a specific area in the pressure-volume (P-V) diagram that is bounded by the end-systolic and end-diastolic P-V relations and the systolic P-V trajectory. The P-V diagram has many advantages over other methods of analyzing cardiac performance

that use such myocardial

contractile parameters as force and shortening velocity (119, 122, 186). The new measure of total mechanical energy extends the utility of the P-V diagram beyond 247

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248

HIROYUKI

cardiac mechanics and dynamics to include also cardiac energetics and mechanoenergetic coupling under a variety of loading and contractile conditions (186,233,242). However, the correlation of total mechanical energy with O2 consumption (vo2) has two major shortcomings compared with* the correlation of myocardial load and heat. One shortcoming is that the fraction of vo2 for activation cannot be clearly distinguished from that for contractile events except in the case of mechanically unloaded contractions (?29, 288). The other shortcoming is that the fraction of VO, corresponding to the initial heat cannot be separated from that corresponding to the recovery heat (70,233). Although many details have been revealed of the energetics of skeletal muscle (103, 132, 173, 281), much yet remains unknown in cardiac energetics, not only on molecular and cellular levels but also on organ or system levels. This discrepancy was recognized anew at the Third International Conference on Muscle Energetics (168a). The purpose of this review is 1) to summarize ventricular energetics understood in the light of relationships between the new measure of ventricular total mechanical energy generation and VO,, which was experimentally determined in the excised, cross-circulated dog heart preparation; and 2) to correlate cardiac energetics seen in this light with cardiac energetics studied in terms of the heat-load relation and the economy of force. The new and most important concept offered within the present scope is the load- and contractility-independent constant contractile efficiency (or stoichiometry) of the myocardium, a measure of which has not yet been attained within the framework of either the heat-load relation or the economy of force. II. TOTAL

MECHANICAL

OF VENTRICULAR

SUGA

Volume

70

sents the total mechanical energy generated by the contraction. The total area consists of two smaller areas: one is the area for external work (EW), surrounded by the P-V loop, and the other is the area for mechanical or elastic potential energy (PE) between the end-systolic and end-diastolic P-V relation curves on the origin side of the P-V loop (212). Thus PVA = EW + PE. The shapes of the instantaneous as well as the end-systolic and end-diastolic P-V curves do not affect the definition and determination of total mechanical energy and PVA (212,243). Although the amount of EW is independent of the model used, the nature and amount of PE depend on the mechanical model of the heart. In fact, in the Hill model of myocardium, consisting of a contractile element (CE) and a series elastic element (SE), elastic PE is generated in the SE (43,213). This PE, called “internal work” of the CE, is only about one-third of the end-systolic elastic PE (215). Moreover, actually extractable external work from the relaxing ventricle exceeds the internal work (214, 215). For these reasons, we adopted PE instead of internal work (212,213). Although PVA has been determined exclusively on the basis of the ideal time-varying elastance model, more complex time-varying elastance models may be needed to simulate P-V relations under a variety of loading and contractile conditions (239,287). An output resistance may be needed to simulate the flow dependence of the elastance (107, 146, 199, 239, 269). This

B

ENERGY CONTRACTION

Unloaded 0

A. Time- Varying Elastance

Model

The new measure of total mechanical energy of ventricular contraction was proposed by me (212) and is based on the time-varying elastance model of the ventricle (184-187, 235, 236, 240). The simplest version of the time-varying elastance model consists only of an ideal elastance that increases and decreases as a function of time during each contraction (186, 199, 236, 240,256). The energy consequences of time-varying elastance provide the theoretical basis for measurement of total mechanical energy. This energy can be quantified as a specific area, the systolic P-V area (PVA), in a P-V diagram, as shown in Figure 1A (66,67,70,126,171,212, 218,220,225,226,229,233,242,248). Mechanical energy is generated with an increase in the time-varying elastance and the counterclockwise rotation of the instantaneous P-V relation curve (171,212, 229). The total area swept by the instantaneous P-V curve on the origin side of the working P-V point during a contraction repre-

0

Vo,

PVA

A

PVA

PVA

FIG. 1. A: schematic of pressure-volume trajectory loop (P-V loop) of ejecting contraction, ESPVR line, end-diastolic pressure-volume relation (EDPVR) curve, EW, PE, and systolic PVA in P-V diagram. PVA is area circumscribed by heavy curves and is sum of EW and PE. V0 is volume-axis intercept of ESPVR. B: schematic of voz vs. PVA relation (diagonal line). VO, under Vo2-axis intercept of vo2PVA relation is called unloaded VO,. VO, above unloaded voz is called excess VO,. C schematic of VO,-PVA relation. It is elevated in a parallel manner by positive inotropism as indicated by arrow. Isoefficiency lines (lo-100%) from (total) 00~ to PVA are superimposed (dotted lines). D: schematic of excess VO,-PVA relation. It falls on or near 40% isoefficiency line. [Adapted from Suga et al. (ZZO).]

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April

1990

VENTRICULAR

series resistance consumes energy when ejection flow exists so that EW would be underestimated by the energy loss (212, 287). Furthermore, the existence of the series resistance requires a second elastance to simulate transient pressure changes (190, 239, 269). The series resistance combined with the second elastance would produce less ventricular pressure both transiently and steadily than that predicted from the ideal (i.e., nonviscous) time-varying elastance. Because PVA is determined from measured left ventricular (LV) pressure, the actually determined PVA may slightly but variably underestimate the true total mechanical energy generated in the time-varying elastance (212,287). The underestimation of PVA by the ideal time-varying elastance model would be ~10% in ordinary ejecting contractions (212). Other possible refinements of the time-varying elastance model, which might make it more realistic, include the elastance and resistance that depend on the history of LV pressure, volume, and velocity (52, 85,86, 96,107,110,133,166,167,169,199,200,239,251,274,286). Also, in addition to the ejecting (or shortening) deactivation (107, 199, 200, 234, 239), a newly perceived and intriguing but complicating factor is the ejecting (or shortening) activation, which refers to the end-systolic pressure surplus after a relatively small stroke volume over the peak isovolumic pressure at the same end-systolic volume (110,166,167,251,286). Despite these possible complications of the time-varying elastance model, PVA has been determined in practice as the area under the end-systolic P-V relation (ESPVR) curve (usually linear) and the actually obtained systolic P-V trajectory, as shown in Figure 1A. Both LV end-systolic and end-diastolic P-V curves dive into the negative pressure range after their intercepts with the volume axis at two different points (208, 219, 249). The area below the volume axis has an inverted triangular shape of -8 ml/100 g LV in base width and ~10 mmHg in depth (249). The PVA below the volume axis is ~40 mmHg ml (249), negligibly small compared with the normal range of PVA (500-3,000 mmHg ml) (218, 221, 233, 242). Despite its insignificance in the PVA of ordinarily loaded contractions, the small PVA below the volume axis still represents the mechanical energy generated by contraction. Part of this energy is available to be released as EW to suck blood into the LV during relaxation despite zero or a slightly negative filling pressure (249). The PVA may appear somewhat similar to the work capacity, defined as the area bounded by the endsystolic and end-diastolic P-V curves and the actual or hypothetical isovolumic P-V line at a given end-diastolic volume (EDV) (112, 113). The work capacity has been proposed as a measure of potential ventricular work of contractions at a given EDV (112, 113). However, the work capacity is fundamentally different from PVA in that the former refers to the maximal potential work from any specified EDV, whereas the latter refers to the actual EW plus PE of any contraction. The work capacity at a given EDV is equal to the PVA of the isovolumic contraction at this EDV. The PVA of an l

l

249

ENERGETICS

ejecting contraction from a given EDV is variably smaller than the work capacity at this EDV. The work capacity is not referred to again. B. D$erence

From

Stretched

Elastic

Body Model

The time-varying elastance model is different in energetics from the classic stretched elastic body or viscoelastic model that was discarded for skeletal muscle half a century ago (50a, 52, 58, 67, 70, 166, 186, 243). However, the two models have often been confused with each other (50a, 51,52). The difference is substantial in terms of their energetics (50a, 70,166,186,230). Force generation of skeletal muscle was first simulated by a stretched elastic body, the elastance of which increases instantly like a cocked spring at the onset of contraction (95). Decreases in force with increases in shortening velocity were simulated by the viscosity of the model (95). The energy consequence of the viscoelastic model is that the total amount of energy stored in a contracting muscle that can be released from it is given in terms of elastic PE at the onset of contraction and is constant regardless of the subsequent course of contraction (186,243). The energetics of the viscoelastic model have proven inconsistent with skeletal muscle energetics in that a contracting muscle generates more energy (shortening heat plus work) under shortening than in isometric contractions (Fenn effect) (50a, 58, 176, 281). Thus the viscoelastic model has been completely discarded in skeletal muscle physiology (50a, 51, 66, 67, 70, 95, 166, 186, 243, 281). However, the Fenn effect of cardiac muscle is different from the Fenn effect originally described in skeletal muscle, and even the Fenn effect of skeletal muscle at high temperatures is different from the Fenn effect as it was originally stated (58, 176). The time-varying elastance model can simulate, although phenomenologically, the cardiac version of the Fenn effect (70, 77, 166,186). Therefore the Fenn effect of cardiac muscle is reconcilable with the energy consequence of the timevarying elastance model of the ventricle (66, 67, 70, 212,243). The essential difference in the energetics of the ventricular time-varying elastance model from that of the cocked spring model is that the elastance of the former increases gradually during systole and shortening, whereas the elastance of the latter increases instantly at the beginning of contraction and before any shortening (243). Moreover, modern models of muscle contraction contain a spring in each cross bridge as the major element to store elastic PE, and the total number of stretched springs of the cross bridges is assumed to increase with force and hence elastic PE (108, 109,173, 281). Therefore the concept of a time-varying elastance seems basically compatible with cardiac muscle in both mechanics and energetics (70). Although attempts have recently been begun to explain mechanistically the time-varving elastic properties of the ventricle and the

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250

HIROYUKI

consequent concept of PVA on the basis of cross-bridge models (29,290), much yet remains unsolved. III.

CARDIAC

OXYGEN

PRESSURE-VOLUME

CONSUMPTION

AND

AREA

A. Assumptions

In a series of experimental studies in my as well as in other laboratories over the last decade, many pieces of evidence have been accumulating that indicate that LV vo2 correlates with PVA in a characteristic manner under a variety of loading and contractile conditions (26, 126, 186, 218, 225,233, 242). Before reviewing these experimental studies, major assumptions used in our studies on PVA and its relation to vo2 are reviewed first. Our studies have used exclusively the LV of the excised, cross-circulated dog heart preparation, which is similar to that used in our cardiac mechanics studies (186, 234, 236-239, 252-255). The major advantages of this heart preparation for cardiac energetics and mechanics are that 1) there is no interruption of coronary circulation during preparation, 2) direct measurement of intraventricular volume is possible, 3) coronary perfusion pressure can be kept separate from intraventricular pressures, 4) there is no sympathetic and vagal neural control, 5) direct pharmacological intervention is possible through the coronary circulation, and 6) direct measurements can be made of coronary flow and coronary arteriovenous O2 content difference, and hence cardiac TO, can be determined directly and accurately. Major disadvantages are 1) surgical invasion; 2) dependence on blood-borne humoral factors, including catecholamines; 3) disruption of the lymphatic system; 4) gradual weakening over 4-6 h during the experiment; and 5) severed chordae tendineae, necessary for a better fitting of the intraventricular volumetric balloon. Cardiac 00, per minute has been determined as the product of coronary flow measured by an electromagnetic flowmeter and arteriovenous O2 content difference obtained by various methods in different studies over 10 years (218, 225, 229, 231, 233, 242). An A-VOX system (flowing whole blood O2 content difference meter) (197) has been most preferred in recent studies in my laboratory (220). It is reliable despite changes in hematocrit over 10-80s (210). The A-VOX system was calibrated against a Lex Oa-Con O2 content meter or an IL 282 CO-oximeter in each experiment (220). The LV thebesian flow is l-2% of total coronary flow and was practically negligible (219). The total 00, of the heart preparation with right ventricle (RV) and both atria collapsed is assumed to be the sum of vo2 for LV mechanical contraction and 00, for both basal metabolism and excitation-contraction (EC) coupling of both LV and RV (218,233). Atria1 00~ is neglected, because both atria are collapsed. Either basal metabolism or energy utilization for EC coupling per unit muscle mass is assumed to be ecyual between RV and LV (218. 233). Left

SUGA

Volume

70

ventricle 00, is obtained by subtracting vo2 of the unloaded beating RV, which is assessed by partitioning the total VO, of unloaded RV and LV by their weights, although RV vo2 was neglected in earlier studies (225, 229,231). The 00~ of mechanically unloaded contraction is discussed further in section IIIE. The myocardium, unlike skeletal muscle, has negligible O2 and oxidative reserves, indicating no significant O2 debt (88). Although a steady-state rate of VO, was reached within l-2 min after the onset of regular stimulation because of diffusion across the diameter of an isolated superfused myocardium preparation (157), the delay between the mitochondrial vo2 and O2 uptake from the capillary is much smaller in capillary-perfused myocardium, because the diffusion time shortens inversely with the square of radius (62). Therefore steady-state VO, is considered to be equivalent in practice to the total energy utilization with an equivalence of 1 ml O2 k 20 J (41, 49, 62, 225, 229, 233). For more details on this equivalence, see section VIBI. In earlier studies, PVA was determined by manual planimetry (126, 225, 228). However, since the development of computer software to calculate PVA from the pressure and volume signals, PVA has been determined as the area swept by a line segment connecting the end-systolic unstressed volume (V,) and a working P-V point drawing the systolic segment of a P-V trajectory (186, 228, 231, 233, 243). The empirical relation between 60, and PVA is schematically shown in Figure 1B. IIere Voz consists of the unloaded Vo2, primarily for both basal metabolism and EC coupling, and the excess voz above the unloaded 60,. (For a more detailed discussion of unloaded vo2, see section 11071.) Because voz and PVA, on a per beat basis, can be considered to be the total energy input and output of each contraction of the ventricle, respectively, the slope of the line connecting the origin and the working VO,-PVA point is dimensionless and indicates reciprocally the efficiency from the total voe to the total mechanical energy in terms of PVA, as shown in Figure 1C (229,232). This efficiency varies widely depending on the loading and contractile conditions (229, 232). It decreases as PVA decreases because of the considerable amount of unloaded 00, for both basal metabolism and EC coupling (229). The excess vo2 above the unloaded VO, (see Fig. 1B; see sect. IIIJ!Z) can be considered the effective energy input for generating the total mechanical energy (229, 232). The fraction of PVA in the excess 00, above the unloaded VO, can be called “contractile efficiency.” Figure 1D shows schematically the relationship between the excess VO, and PVA. The reciprocal of the slope of the excess Vo,-PVA relation is the contractile efficiency. When the VO,-PVA relations with different elevations are parallel to each other, they fall on the same excess VO,-PVA relation, and therefore their contractile efficiencies are the same, as shown in Figure 1D. The contractile efficiency becomes dimensionless or can be expressed as a percentage after both 00, and PVA are expressed in the same unit of energy, e.g., joules. For more details on these efficiencies. see section VI.

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April 1990

VENTRICULAR

Although there are many indexes of ventricular contractility (120), the slope (E,,, or E,,) of the ESPVR line has been used in most studies on the Vo2-PVA relation, because this contractility index is closely coupled with PVA in the P-V diagram (186,229). Either Emax or & was proposed as the maximal or end-systolic value of the time-varying elastance [E(t)] of LV (184-187,240). It has dimensions of millimeters mercury per milliliter or millimeters mercury per (milliliters per 100 g LV) when normalized for 100 g LV. This unit is that of volume elastance (186). The advantages of &.,ax as a global index of ventricular contractility have been well recognized (119, 120, 184-187). This index represents the magnitude of maximal or end-systolic compression of the LV normalized for its volume. The index has been shown to be relatively independent of preload and afterload within their normal ranges in the excised, cross-circulated dog heart (120, 184-187, 236, 240), although there are exceptions to this load independence (25,52,106,110,184-187,251). The index increases with positive inotropic interventions and decreases with negative inotropic interventions in general (184-187, 236, 240). The relationships of Emax to other contractility indexes, such as ejection fraction, maximum velocity (vmax), and change in pressure over time (dP/dt), have been derived theoretically and examined empirically (120, 145, 146, 235). When an ESPVR is curvilinear (25, 82, 186, 217, 245), PVA is obtained as the area under the nonlinear ESPVR curve (82, 217, 247). Obtaining PVA under the straight line connecting V0 and the end-systolic P-V point variably underestimates the total mechanical energy of the contraction. B . Loading Conditions 1. dEjecting and isuvolumic contractions

The hypothesis proposed by Suga (212), that PVA as a measure of the total mechanical energy correlates closely with VO,, was validated first by reanalyzing other investigators’ data in the literature (212) and then by experiments in the LV of excised, cross-circulated dog hearts (126). In this study, LV pressure and volume loads were widely varied in both isovolumic and ejecting contractions with a servo-pump system (237), and coronary arteriovenous O2 content difference was determined by sampling coronary arterial and venous bloods in the steady state, determining their O2 contents with an IL 182 CO-oximeter, and multiplying the O2 content difference by coronary flow to yield vo2. A high and linear correlation was found between Vo2 and PVA, both on a per beat basis, in every LV (126) in a manner schematically shown in Figure 1B. The correlation coefficient (r) was always high (m-0.92), and regression analysis yielded an empirical equation: VO, (ml 02/beat) = A X PVA (mmHg . ml beat-l) + B, where A (slope) = 1.53 X 10s5 ml O2 mmHg-l ml-‘) and B (vo2axis intercept) = 0.019 ml O/beat on average (126). l

l

l

251

ENERGETICS

When both vo2 and PVA are expressed in joules, this equation becomes vo2 (J/beat) = 2.30 X PVA (J/beat) + 0.39, where the slope coefficient 2.30 is dimensionless (Table 1, study I). The reciprocal of this slope value is 0.44. This value means that the contractile efficiency from the excess To2 to PVA is 44% on average (Table 1, study 1). This efficiency is represented by the inverse slope of the excess Vo,-PVA relation, as schematically shown in’ Figure 1D. Study 2 of Table 1 found the Vo2-PVA relations obtained in separate sets of isovolumic and ejecting contractions in individual dog hearts to be comparable to each other in both slope and Vo2-axis intercept (225). When both isovolumic and ejecting contractions were pooled, they yielded Vo, (ml O,/beat) = 1.64 X 10e5 X PVA (mmHg ml. beat-‘) + 0.015 (ml 02/beat) with r > 0.95 (225). The slope value yielded the contractile efficiency of 45% on average (Table 1, study 2). The square of r is the coefficient of determination. An average r of 0.95 between VO, and PVA yields If! of 0.925, indicating that 93% of the variance of 00, is attributable to the variance of PVA (225). The remaining percentage that should be attributed to other factors is ~7% on average (225). This small fraction may be attributable in part to the variance of the force-time integral (216). The unique VOW-PVA relation was further confirmed by experimental evidence that the VO,-PVA relation is not significantly affected by the course of the systolic P-V trajectory (244). Moreover, as long as PVA is zero or nearly zero, vo2 remains near the VoZ-axis intercept of the VO,-PVA relation obtained in the same contractile state, whether the contraction is isovolumitally unloaded at V0 or first preloaded and then quickly released (288). The same load independence of the Vo2-PVA relation holds in a stably enhanced or depressed contractile state induced by various inotropic interventions (60, 166,217,220,224,229,250,286; Table 1). All these results indicate that VO, correlates closely and linearly with PVA regardless of ventricular loading conditions in a given stable contractile state. The load independence of the Vo,-PVA relation contrasts with the heat-load relation (62,65-70,77) and the economy of force (9, 10, 100, 102) as follows: the heat-load relation is a linear or curvilinear relation between total or active heat (enthalpy), on the ordinate, and load (stress or force), on the abscissa. The heat-load relation of isometric contractions is always lower than that of isotonically shortening contractions (62,68,70). This reflects the Fenn effect of myocardium that energy utilization (either heat or Vo2) for a given peak pressure (force) is greater for ejecting (shortening) contractions than for isovolumic (isometric) contractions (27,34, 66, 67,77,166,177,271). Existence of the Fenn effect means a limitation of pressure, force, or stress alone as a unique correlate of myocardial energy utilization when shortening conditions vary (34, 62, 177, 221, 228, 271). The economy of force generation, defined as the ratio of the time integral of force to the activity-related heat, has a thermodynamic basis and has been used in l

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252 TABLE

HIROYUKI

1. Summary

contractile

eficiency

Study

of slope and l&-axis intercept of Tie,-PVA as reciprocal of slope of Tie,-PVA relation

Animal

3 4 5 6 7 8 9 10 11 12

Dog

l-4

PUPPY

15

Dog

16

Dw

17

Dog

18 19

Rabbit Rabbit

20 21 22

Rabbit Ferret Human

Conditions

2.30 2.49 2.43 2.47 2.88 2.24 2.61 2.70 2.79 2.91 2.63 3.06 2.27 2.32 2.43 2.58 2.35 2.25 2.61 2.47 2.64 2.47 2.50 2.39 1.89 2.78 2.36 2.21 2.13 1.74 2.58 2.39 2.41 2.49 2.10 4.36 5.29 3.81 2.86 2.56 3.88 2.83

Ik 0.22 k 0.63 k 0.63 + 0.23 +_ 0.77 t 0.75 k 0.66 k 1.01 + 0.48 +_ 0.72 k 0.38 k 0.66 k 0.41 k 0.33 k 0.34 k 0.38 k 0.58 t 0.59 + 0.49 + 0.42 f 0.86 t 0.80 + 0.36 k 0.36 k 0.42” t 0.29 + 0.66 k 0.60 k 0.77 AI 0.49 k 0.35 k 0.82 t 0.42 Ik 0.53 k 0.55 t 1.28 2 1.56 2 0.39 _+ 0.66 f. 0.32 + 0.68 + 0.42

2.60 + 0.20

patients

Values are *means + SD. Conditions, experimental intercept, same VO,-PVA relation; contractile efficiency, isovolumic and ejecting contractions, pooled; isovolumic, data not normalized for 100 g LV. bEfficiency value because of ventricular overload under severe underperfusion. lar septum. “Unloaded right ventricular VO, was zero. calculated from mean slope value.

relation

Slope (di mensionless)

Isovolumic + ejecting Isovolumic Ejecting Isovolumic + ejecting Control Quick release Low heart rate High heart rate Control Calcium Control Epinephrine Control Ouabain Control OPC 8212 Control Paired pulse Control Cooling Control Propranolol 80 mmHg 50 mmHg 30 mmHg Right ventricle Calcium Control Epinephrine Propranolol Control Hypertrophy Hyperthyroid Dobutamine Propranolol In situ Dobutamine Propranolol Control Control Hyperthyroid Hypothyroid Papillary muscle Myocardium

1 2

13

SUGA

Volume

TO

and vo,-Axis Intkcept, J beat-’ 100 g-’ l

l

0.39 0.33 0.33 0.34 0.64 0.63 0.42 0.42 0.45 0.67 0.35 0.62 0.58 0.72 0.46 0.62 0.62 1.18 0.57 0.64 0.54 0.38 0.56 0.50 0.42 0.80 1.16 0.47 0.58 0.29 0.94 0.94 0.54 0.64 0.44 0.57 0.99 0.66 0.60 0.61 0.77 0.52

k 0.06’ t 0.17 t ‘0.18 t 0.18 _+ 0.19 _+ 0.14 t 0.22 + 0.22 + 0.24 t 0.26 + 0.16 k 0.28 AZ 0.08 rf: 0.18 t 0.13 + 0.18 + 0.11 k 0.32 AI 0.11 k 0.15 zk 0.26 z!I 0.14 + 0.10 z!I 0.08 t 0.06 + 0.14d _+ 0.20d AI 0.22 k 0.22 2 0.10 k 0.15 k 0.13 + 0.06 k 0.10 k 0.07 * 0.28” t 0.16” t 0.23” t 0.18 k 0.13 k 0.10 t 0.14

0.77 k 0.11

Contractile Efficiency, % 43.6b 42.5 44.9 44.7 37.0 50.1 40.6 42.3 37.3 36.0 38.1 33.9 44.7 43.3 41.8 39.6 43.5 44.9 38.2 43.1 41.7 44.3 40.8 42.5 55.1 36.5 45.6 46.2 50.1 56.0 38.7b 41.8b 42.6 41.4 50.2 24.8 20.2 26.4 37.0 39.6 26.6 36.0 42, 38.5g 35

t t t t t t k k t_ t k t k * k t k + k z!I t k t k t t t k k

11.0 9.8 10.9 9.9 19.3 10.2 14.2 7.3 9.7 5.2 6.5 7.1 5.5 5.8 6.3 10.0 13.0 8.8 10.3 14.0 13.7 6.4 6.5 11.9” 3.6 15.6 13.3 19.4 19.1

Reference 126 225

287 231 229 229 282 60 217 220 224 224

283 247

161 t 8.8 k 9.6 t 11.2 2 5.9 t 5.7 If: 2.6 t 10.3 t 4.3 k 5.5 k 5.2 -45

241

164

81 82f

67,66 14

conditions; slope, slope of VO,-PVA relation in a given contractile state; V02-axis calculated as reciprocal of slope of VO,-PVA relation. Isovolumic + ejecting, both isovolumic contractions only; ejecting, ejecting contractions only. ‘Raw intercept determined from mean slope. “Slope and efficiency values were underestimated dNormalized value for weight of right ventricular free wall and interventricu‘Detailed values were obtained by personal communication. “Efficiency was

muscle physiology for a long time (8, 281). Although it shows how economically that muscle can generate force and maintain it, it does not explicitly show how economically the muscle can generate mechanical power and work. The economy of force seems to reflect the slope of the heat versus the force-time integral curve (62,68-70). The economy of force must be determined in shortening contractions if its relation to mechanical efficiency is of interest (82). For further differences and relations be-

tween the VO,-PVA relation and the economy of force or the heat-load relation, see section VI. 2. Uniqueness of pressure-volume area as a correlate of oxygen consumption

Isovolumic and ejecting contractions with comparable PVA have virtually the same 00, despite the sig-

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nificantly greater peak pressure, peak force, and time integrals of pressure and force in isovolumic contractions (221,228). The systolic time integral of force (271), known as a primary determinant of oo2, decreases with increases in ejection fraction from zero despite constant PVA and VO, (221). This seems a manifestation of the Fenn effect in that an ejecting or shortening contraction has a greater vo2 than the isometric contraction with a given force-time integral (62) or peak force (34, 271). For more details on this subject, see section V. The Vo2 of the pressure-loaded contraction is considerably greater than that of the volume-loaded contraction performing comparable EW (188, 230). A greater VoZ of the former is accompanied by a greater PVA, and the VqZ-PVA data of both contractions fall on the isovolumic VO,-PVA relation in the same contractile state (230). Oxygen cost per unit EW and per unit PE of PVA have been compared by statistical methods and proved to be equal to each other (226,227). The O2 costs of EW and PE are the same as the slope of the regression equation of 00, on PVA (226,227). Changes of the P-V trajectory during relaxation, which changes the relative sizes of EW and PE in the same PVA, do not significantly affect the systolic P-V trajectory, PVA, E,,,, and the Vo2-PVA relation (222). All these results indicate the uniqueness of PVA as a correlate of vo2 in the dog LV (186). 3. Negative

work

When the LV receives mechanical work from outside, it is said to perform negative work by the sign convention (223). For comparable systolic pressures, qontractions performing negative work have smaller VO, than those performing (positive) work of the same absolute value, and both vo2 data points fall on the same Vo2-PVA relation (223). The smaller energy utilization for negative work is consistent with a similar effect in skeletal muscle, which can normally perform negative work when stretched (44). Negative work probably decreases the rate of ATP hydrolysis in skeletal muscle but is unlikely to synthesize ATP (281). Although myosin adenosinetriphosphatase (ATPase) is capable of reversible operation, its extent is practically negligible (281). Instead, most negative work in skeletal muscle seems to be converted to PE in various series and parallel elastic structures, including cross bridges, to develop force without consuming energy (267). Because negative work performed during systole is extracted as external work during the following relaxation of the LV, the negative work seems to. be used to increase PE during systole, saving ATP and VO, for a given developed pressure (223). Although the LV does not normally perform net negative work, regions of the LV wall (79, 80, 255) and papillary muscle (194) often perform negative work. Because a weak muscle is stretched by a strong muscle (275), the smaller VO, for negative work may be benefi-

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253

cial to the stretched region (13,79,80,189), particularly when this region is hypoxic or ischemic (118). 4. Quick release

Although PVA is not affected by changes in the P-V trajectory during relaxation (222, 223), the Vo,PVA relation of contractions, the load of which is initially isovolumic and then quickly released at various timings, is less steep by lo-30% than the Vo2-PVA relation of entirely isovolumic contractions in the same contractile state (287; Table 1, study 3). Moreover, the slope of the VO,-PVA relation of the quick release contractions decreases with increases in the release speed (287). Quick-release contractions at end systole save 10% 00, on average relative to 00, of entirely isovolumic contractions, although their PVAs are the same (287). This 00, savings is close to the 10% of Monroe (160), greater than the ~0% of Elzinga et al. (51) and Duwel and Westerhof (48), and smaller than the 36% of Cooper (37) and Hisano and Cooper (96). The reason for this variation remains to be solved (96,287). The considerable decrease in 00, by quick release cannot be accounted for by the significant dependence of vo2 on myocardial length (37). The reduction of the slope of the VO,-PVA relation by quick release cannot simply be explained by the concept of PVA (96,264,287). However, the linear VOW-PVA relation of quick-release contractions indicates that 00, for generating a unit amount of mechanical energy is constant throughout systole (287), supporting the concept of PVA (287). The VO, per unit systolic force-time integral is greater at the beginning of contraction and decreases gradually with contraction (37, 264). This result indicates that generation and maintenance of active tension are energy dependent at all phases of isometric contraction, including the relaxation phase (37,264). However, this time-dependent To2 per unit systolic force-time integral proves to be equivalent to the time-invariant vo2 per unit mechanical energy generation during systole because of the nonlinear relation between the increments in force-time integral and PVA with time (287). Therefore both the time dependence of O2 cost of force development (37, 264) and the time independence of O2 cost of mechanical energy generation (287) seem to be two different expressions of the same energetic properties of LV (287). The degree of vo2 savings by quick release depends on the mode of contraction in papillary muscle: both quick-released isometric contraction at any systolic timing and quick-released isotonic contraction before shortening decreases vo2, but quick-released isotonic contraction during shortening does not decrease VO, unless there is a large afterload (38). Saturation of EC coupling with high Ca2+ and caffeine at a low temperature lessen the percent decrease in 90~ by quick release from 36 to only 7% (38). Furthermore, not only quick release but also instantaneous load and length changes

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regulate vo2 during the normal isotonic contraction (38). These aspects remain to be studied with PVA. The decreases in 00, by quick release may appear to indicate a limitation of PVA as a correlate of vo2 (96, 287). Introduction of some internal energy loss in the time-varying elastance model may partially solve this problem (216,290). Quick release is unlikely to decrease vo2 by decreasing the vo2 for EC coupling, because entirely quick released contractions from different EDVs with zero PVA have the same 00, as the totally unloaded contraction at V0 (288). C. Heart

Rate

Study 4 of Table 1 found that the VO,-PVA relations on a per beat basis in the dog LV paced atrially at two different rates (between 80 and 220 beats/min) were virtually the same (231). The VO,-PVA relation has the same slope value and the same dimensions, whether VO, and PVA are expressed either per beat or per minute. The heart rate independence of the VO~-PVA- relation involves heart rate-independent slope and Vo2-axis intercept per beat (231). The Voz-axis intercept, which is virtually the same as unloaded VO,, consists primarily of basal metabolic VO, and 00, for EC coupling (218, 229, 233). Because basal metabolic rate per minute is considered to be independent of heart rate (62, 68, 75), basal metabolic vo2 per beat decreases reciprocally with increases in heart rate (231). The unchanged vo2axis intercept per beat then suggests gradual increases in 00, for EC coupling per beat with increases in heart rate (231). In fact, j!Zmax increases by -10% with increases in heart rate from 80 to 220 beats/min (231, 240), suggesting an increase in vo2 for Ca2’ handling with increases in heart rate (277). The heat-load relationship of rabbit papillary muscle is independent of stimulus rate, although the relation between heat and the tension-time integral becomes steeper with stimulus rate (16, 62). The steeper heat versus tension-time integral relation means a decreased economy of muscular contraction. The heataxis intercept or the tension-independent heat per stimulus only slightly increases with stimulus rate (62), consistent with the heart rate-independent Vo2-PVA relation on a per beat basis (231).

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was virtually the same as the unloaded vo2, increased 1.5 times from 0.023 ml O2 beat-’ 100 g-l on average, whereas the slope remained virtually unchanged at 1.9 X 10e5 ml O2 mmHg-l ml-’ (229). The excess VO,-PVA relations before administration of Ca2+ and under Ca2+ were almost superimposed in a manner similar to Figure 1D. The contractile efficiency from excess VO, to PVA was unchanged at 36% on average (Table 1, study 5). Because the administered Ca2+ did not significantly increase basal metabolic f702 of KCl-arrested LV, the elevated Vo2-PVA relation was considered to reflect primarily an increase in vo2 for augmented EC coupling (229). For more details of this aspect, see section IIIE. The parallel shift of the Vo2-PVA relation looks similar to the parallel shift of the heat-load relation with Ca2+ observed in papillary muscles (62). The parallel elevation of the heat-load relation was ascribed to an increased activation energy for an augmented EC coupling (62), as suggested by an increased Ca2+ transient (135). l

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D. Isotropic

States

1. Calcium

The effect of increased extracellular Ca2+ on the VO,-PVA relation is dramatic in excised, cross-circulated dog LVs paced at a fixed rate (166,229). In study 5 of Table 1, when Emax was increased 1.7 times on average, the linear VO,-PVA relation rose significantly in a parallel manner in most hearts (166,229), as schematically shown in Figure IC. The Vo2-axis intercept, which

2. Catecholamines

The effect of catecholamines on the Vo2-PVA relation is also dramatic, even with a constant paced heart rate. In one study, when Emax was increased 1.8 times on average by epinephrine given intravenously or intracoronary arterially, the VO,-PVA relation was elevated in a parallel manner along the TO, axis in the same way as with Ca2+ (229; Table l., study 6), as schematically shown in Figure 1C. The Vo2-axis intercept increased 1.7 times from 0.018 ml O2 beat-l 100 g-l on average, whereas the slope did not change at 1.9 X 10e5 ml O2 mmHg-’ ml-l on average. The excess VO,-PVA relations before administration of epinephrine and under epinephrine were almost superimposed, similar to Figure 1D. The contractile efficiency from the excess 00, to PVA was unchanged at 36% on average (Table 1, study 6). Similar responses of Emax and the VO,-PVA relation have been observed with dobutamine (26, 164,166, 287; Table 1) and isoproterenol (unpublished observations). The increase in the elevation of the Vo2-PVA relation (1.67 times on average in Vo2-axis intercept) by epinephrine was comparable to that (1.56 times) by Ca2+ when both positive inotropic agents increased Emax to the same extent (1.84 and 1.68 times, respectively) in two groups of dogs (229). The change in Vo2-axis intercept divided by the change in Emax showed no significant difference between epinephrine and Ca2’ (229, 233). When epinephrine and Ca2+ were given one after the other to increase Emax to comparable extents in the same heart, the VO,-PVA relation was elevated by similar increments (229, 233). Because catecholamines similar to Ca2+ did not significantly increase basal metabolic TO, of the KCl-arrested heart, the elevated Vo2-PVA relation was considered to reflect primarily an increased VO, for augmented EC coupling (165, 229, 287). In addition, mechanically unloaded contractions that are variably preloaded but quick released to prol

l

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duce zero PVA and unloaded contractions at V0 with zero PVA have virtually the same 00, (288). This result indicates the preload independence of the unloaded VO,. Basal metabolic vo2 is also preload independent (165). Therefore it has been suggested that the To2 fraction for EC coupling is virtually independent of PVA (288). Under this assumption, it is legitimate to ascribe the changes in the elevation of the VO,-PVA relation to changes in contractile state, even though the To2 fraction for basal metabolism and EC coupling cannot be clearly distinguished from the To2 of a contraction generating a finite PVA (229, 233). It is intriguing that the effect of catecholamines on the Vo,-PVA relation was similar to that of Ca2+ despite their different pharmacological mechanisms of positive inotropism (229), i.e., involvement of both padrenergic receptor and adenosine 3’,5’-cyclic monophosphate (CAMP) system by catecholamines (53, 136, 155, 211, 259). The step responsible for the VO, for EC coupling is mainly the Ca2+ uptake, primarily by sarcoplasmic reticulum (SR) and secondarily by sarcolemmal Ca2+ pump, both consuming ATP by Ca2+-dependent ATPase (259-261). If comparable amounts of Ca2+ were involved to increase Emax to the same extent by administration of extracellular Ca2’ and catecholamines, the comparable 00, for EC coupling and hence comparable elevation of the VO,-PVA relation would be reasonable (229). For more details on this aspect, see section III~B. The parallel shift of the VO,-PVA relation appears similar to the parallel shift of the heat-load relation with catecholamines observed in papillary muscles (62). The parallel elevation of the heat-load relation has been ascribed to an increased activation energy for an augmented EC coupling (62), and this mechanism was later confirmed by the finding of an increased Ca2+ transient (3, 53, 135). The relationship of heat to the force-time integral increases in slope with catecholamines (16,62), consistent with a decreased economy of force (89). This is mainly due to a shortened duration of contraction (62, 89). For more details on this aspect, refer to section VIC. Phenylephrine, an cw-agonist with weak ,&agonist activity, given intracoronary arterially at a rate of 0.1-0.2 mg/min was found to increase Emax by 1.3 times and to elevate the Vo2-PVA relation with a 1.3 times increase in the Vo2-axis intercept but without a change in the slope in the dog LV (Y. Yasumura and H. Suga, unpublished observations). Methoxamine, a pure a-agonist, given intravenously at a high bolus dose of 4 mg did not increase E,,,, heart rate, and Vo2 in the same LV preparation (Yasumura and Suga, unpublished observations). These results indicate that the VO,-PVA relation and Emax are not affected by an a-agonist in the excised, cross-circulated dog LV. However, cu-adrenergic receptors have been found in membranes isolated from fetal, neonatal, and adult dog ventricular myocardium (ZZ), and they increase in number and in sensitivity with ischemia in the dog as well as in the cat and the guinea pig (17,92). Unlike the response of dog hearts, in rabbit (53), bovine (Zl), and human hearts (ZO), a-agonist can normally enhance contractility. The effect of

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a!-agonists studied.

on the VO,-PVA

relation

remains

to be

3. Digitalis

In study 7 of Table 1, a pretoxic dose of ouabain increased Emax gradually over 30 min by 1.6 times on average at a fixed heart rate and elevated the Vo,-PVA relation in a parallel manner (282), similar to Figure 1C. The excess Vo2-PVA relations before administration of digitalis and under digitalis were almost superimposed, similar to Figure 1D. The contractile efficiency from excess i702 to PVA was unchanged at 44% on average. The Vo2-axis intercept or unloaded VO, was elevated 1.3 times. The Vo,-PVA relation rose by a slightly smaller increment, when normalized for the increase in E,,,, with ouabain than with catecholamines and Ca2+ (282). The primary action of digitalis is the inhibition of the sarcolemmal Na+ pump (1). This inhibition in turn inhibits Na+ efflux, and the resulting gain in the intracellular Na+ concentration ([Na’]i) increases Ca2+ influx or decreases Ca2+ efflux or both through a Na+-Ca2+ exchange mechanism. Therefore it remains unknown why Ca2’ elevates the Vo2-PVA relation with greater sensitivity on average than ouabain. In one study, the heat-load relation was slightly (20%) elevated in an almost parallel manner, and the heat versus force-time integral relation was also shifted upward, with slope unchanged, by ouabain (62). 4. New cardiotonic

agents

The effects of some new cardiotonic agents on the Vo2-PVA relation and Emax were studied in excised, cross-circulated dog LVs (60). The drug OPC 8212 increased EmaX and elevated the VO,-PVA relation in a parallel manner (60). The slope of the Vo2-PVA relation remained virtually unchanged from control (Table 1, study 8). The sensitivity of the elevation of the 002PVA relation to Emax was comparable to those of catecholamines and Ca2’ (60). Milrinone and sulmazole produced similar results (61) consistent with the parallel elevation of the heat-load relation by amrinone (76). The shortened contraction by amrinone (76) decreased the economy of force. The drug DPI 201-106 also elevated the VO,-PVA relation to the same extent as epinephrine (61a). New cardiotonic agents differ from both cardiac glycosides and ,&adrenergic agonists in that they do not affect the Na+-K+ pump, nor does their action appear to depend on adrenergic receptors (179). Their action is largely due to phosphodiesterase inhibition, although other mechanisms may also contribute (6, 35). These other mechanisms include the Ca2+-sensitizing effect on contractile proteins that shifts the force-pCa curve to the left, similar to the effect of sulmazole, UD-CG 115, and DPI 201-106 (93, 207, 266). As long as CAMP is increased by a cardiotonic agent, it elevates the Vo2-PVA relation and increases E,,,, because more Ca2’ must be

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handled in the EC coupling (53,76). In one study, when the duration of contraction was shortened less by UD-CG 115 than by isoproterenol in rat hearts, the economy of force also decreased less with UD-CG 115 than with isoproterenol (89). 5. Postextrasystolic potentiation

In study 9 of Table 1, the VO,-PVA relation was elevated in a parallel manner, i.e., without a change in the slope, when paired pulse pacing increased Emax 2.7 times (217). Because each paired pulse pacing produced EC couplings twice, the number of EC couplings per minute under paired pulse pacing was twice the heart rate. The Vo2 of EC coupling per beat was estimated, assuming a constant basal vo2 per minute. The 00, of a paired pulse contraction per EC coupling was then found to be more than twice that of a single pulse contraction (217). This finding suggests that the elevated VO,-PVA relation under paired pulse pacing is largely because of the augmented EC coupling (217), as evidenced by the augmented Ca2+ transient in variably potentiated contractions (295). However, unless the prematurity was very high, so that the premature contraction was fused with the relaxation phase of the preceding postextrasystolic contraction, the Vo2-PVA relation on a per minute basis remained unchanged (T. Nozawa and H. Suga, unpublished observations). 6. Pacing site

When the pacing site is varied from the atrium to the ventricle and within the ventricles, peak isovolumic pressure, E,,,, and PVA at a fixed EDV have been found to decrease maximally by 25% with increases in the duration (activation time) of the QRS complex by ventricular pacing (23). However, 00, decreases only slightly along the same VO,-PVA relation, without skipping to a lower VO,-PVA relation as expected from the decreased Emax (23). This mechanoenergetic dissociation was ascribed to a decrease in the effective mass of myocardium that actively participated in chamber contraction (23). A similar dissociation was observed when the duration of QRS of the LV surface ECG widened suddenly by spontaneous intraventricular block (unpublished observations). 7. Cooling

In study 10 of Table 1, when the dog LV was paced at a constant rate, cooling by 7°C from 36OC doubled E lllaX and increased 1.5 times the time to Emax (220), which was expected from the positive inotropic effect of myocardial cooling (147). The Vo2-PVA relation was linear and load independent at both temperatures. Study IO showed two surprising findings, however. 1) Unlike the - responses with catecholamines and Ca2+ (229), the VO,-PVA relation was not significantly ele-

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vated with the cooling inotropy (220). 2) The slope of the VO,-PVA relation was, on average, 1.73 X 10m5 ml 02. mmHg-l . ml-l at normal temperature and 1.66 X 10s5 ml O2 mmHg-l . ml-l under cooling, that is, not significantly different under the two conditions (220). This constancy of the slope indicates that the contractile efficiency from the excess 00, to PVA was also constant (40% on average) despite cooling. The temperature-independent contractile efficiency is intriguing in the light of a presumably decreased myosin ATPase and cross-bridge cycling rate (Q = 2-3) (220). The unchanged slope of the VO,-PVA rel.%ion is consistent with the unchanged slope of the heat-load relation at different temperatures (16, 62, 147). The decrease in the slope of the heat versus forcetime integral relation (16) because of the prolonged duration of contraction under cooling indicates an increased economy of force. The discrepancy between the unchanged contractile efficiency and the increased economy of force under cooling may be accounted for by the different natures of efficiency and economy of force (ZZO), as discussed in detail in section VIE& Nevertheless, it remains possible that there is a change in the contractile efficiency that was too small to be detected by the Vo2-PVA relation. The cooling inotropy seems to result from the slowed rates of various physical and chemical processes, such as decreased cross-bridge cycling (183, 198), decreased rate of Na+ and Ca2+ transport and exchanges (55, 196), decreased rate of reaction of Ca2+ with contractile proteins or increased Ca2+ sensitivity of myofilament (55), and decreased compliance of series elasticity (293). The unchanged Vo2-axis intercept suggests that an increased i70, for EC coupling under cooling was offset by a lower basal metabolic vo2. A low Q10 (= 1.3) of basal metabolism (150) suggests that the basal metabolic Vo2 decreases by 20%, and hence the VO, for EC coupling increases only a little in the 7OC cooling experiment (220). A study with ryanodine, which eliminates Ca2+ release from SR (196), suggests that a change in SR function is not the principal mediator of the large increase in force associated with cooling of mammalian myocardium from 37 to 25OC. This lack of connection accounts reasonably for the absence of significant elevation of the Vo2-PVA relation with cooling inotropy (220). In other experiments, the heat-load relation of rabbit, cat, and rat papillary muscles was elevated in a parallel manner by cooling from 30 to ZO”C, with a 75-100s increase in the force-independent heat (16,62, 147). However, this increase in the force-independent heat was much smaller than with isoproterenol (16). The reason why there is no significant change in the Vo2-axis intercept in the dog heart, in contrast to these increases in the force-independent heat in smaller animal hearts, remains unknown (220). l

8. Negative inotropic agents

In study 11 (224) of Table 1 as well as in other studies (166,247,286), a @-blocker propranolol caused a

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considerable decrease in the Vo2-axis intercept without changing the slope of the VOW-PVA relation when EmaX was halved. The slope of the VO,-PVA relation was constant at 1.70 X 10m5 ml 0, mmHg-l . ml-‘, and the contractile efficiency from the excess TO, to PVA was 42% on average before and after administration of propran0101. Effects of cholinergic agents on the VO,-PVA relation remain to be studied. Acetylcholine and carbachol are related to the regulation of intracellular CAMP and GMP and can directly decrease the force of contraction (63). They have been shown to decrease VO, of the nonworking heart (78). This result could be interpreted to show that acetylcholine decreased the force-independent energy, i.e., the opposite of the effect of positive inotropism (63). Verapamil and nifedipine, Ca2’ antagonists that inhibit transsarcolemmal Ca2+ influx, have been shown to lower the VO,-PVA relation (26, 286). The reduced Ca2+ influx probably decreases the intracellular Ca2+ involved in each contraction and hence decreases VO, by decreasing the force-independent energy. l

E. Unloaded Contraction and Arrest 1. Unloaded oxygen consumption

The unloaded i702 means the 00, of a mechanically unloaded contraction with zero PVA. It has been measured directly in isovolumic contractions at V0 in a given contractile state (229,288). The unloaded VO, corresponds to the load-independent heat in myothermic studies (62). Unloaded To2 was found to increase with enhancement of contractile state by catecholamines, Ca2’, ouabain, and some new cardiotonic agents (26,60, 166, 229, 291), although not with cooling (ZZO), as reviewed in section III D. The load-i ndepen .dent he at always increases wi th any posi tive in otropic agents, ineluding cooling, in myocardium preparations (63). A statistically significant positive correlation (r 1 0.6) was found between unloaded 00, and Emaxenhanced by either epinephrine or Ca2+ (232) between different dog hearts (220). The low r was attributable to the interindividual variations of both unloaded vo2 in the control contractile state and its sensitivity to Emax (232). The interindividual variation of the unloaded VO, in the control contractile state was largely accounted for (? = 0.70) by that of blood-borne endogenous catecholamines (Y. Ohgoshi and H. Suga, unpublished observations). Directly determined unloaded Vq2 is virtually the same as the Vo,-axis intercept of the VO,-PVA relation (60,166,291). Therefore unloaded 00, is close to D in the regression equation of vo2 = A X PVA + D (229, 232). However, there is a tendency for the unloaded 00~ to decrease gradually by one- ‘fourth ov er lo-30 min when unloaded contractions are maintain ed (Yasumura and Suga, unpublished observations). . The unloaded (nonwork related) vo2 changes lin-

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and deearly with E,,,, increasing with dobutamine creasing with nifedipine and ischemia in the isolated blood perfused dog LV (r > 0.93) (26). This result yielded an empirical equation: unloaded vo2 = B X Emax + C, where B = 0.0036 ml 02. mmHg-’ . ml and C = 0.010 ml 02/beat on average over a wide range of EmaX.This result suggests a common underlying determinant of contractility and unloaded VO, and the existence of a single linear relation between unloaded vo2 and E,,,, regardless of inotropic interventions in each given heart, although both B and C varied between different hearts (26). The average B value in this study (26) was close to that in the previous study with epinephrine and Ca2+ (232). Even the unloaded ventricle contracting with zero PVA changes its shape. The shape change suggests existence of myocardial shortening against internal load and residual mechanical energy generation. However, VO, of unloaded contractions did not decrease any further when the beating LV was collapsed by negative pressure (249). This result suggests that the unloaded contraction at V0 has only a negligible residual energy generation relative to the unloaded VO,. The vo2 values of contractions that are mechanically unloaded throughout systole by quick release from a large EDV are close to the Vo2 of unloaded contractions at V0 (288). These i70, data may be called PVA independent, because PVA is zero or almost zero in any of these contractions. Therefore the vo2 attributable to the length-dependent activation is negligible in the dog LV (288), unlike in papillary muscle (37). This result also indicates that the iTo2 for unloaded myocardial shortening is negligible (288) despite residual crossbridge cycling for shortening, unlike the shortening heat of skeletal muscle (62, 66, 67, 281). However, the result seems consistent with the unexpectedly large sliding distance of actin filament induced by a myosin cross bridge during one ATP hydrolysis cycle under a totally unloaded condition in an in vitro actomyosin system (284). It remains unknown whether the PVA-independent Vq2 is always constant regardless of PVA, because this VO, component cannot be clearly separated from the PVA-dependent vo2 in contractions with positive PVA. 2. Energy for excitation-contraction

coupling

The unloaded To2 consists predominantly of the vo2 for EC coupling and the basal metabolic vo2 (229). The 60, for EC coupling corresponds to the activation heat or force-independent component of the active heat in excess of basal metabolic heat (62). The VO, for electrical excitation seems negligibly small (62,130). As for the residual mechanical energy generation remaining even in the unloaded contraction, see section IIIEI. The vo2 for EC coupling is used for lowering sarcoplasmic Ca2+ from 10-5-10-6 to lOA eq/l by active transport, mainly by SR, to relax contraction (55, 259, 261). Changes in contractility by catecholamines and Ca2+ are accompa nied by propo lrtional changes in th .e amount

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of Ca2+ involved in the EC coupling (3, 53, 295). Such Ca2+ changes would then change the energy required for sequestration of Ca2+ I) primarily by SR; 2) auxiliarily by the sarcolemma, where the Na+-K+-ATPase and Ca2+-ATPase as well as the electrogenic Na+-K+ and Ca2+-Na+ exchanges are important; and 3) trivially by mitochondria (123). A tight coupling exists between two moles of Ca2+ transported and one mole of ATP hydrolyzed in myocardial SR as in skeletal muscle (70, 90a, 132, 259, 261). This tight Ca:ATP stoichiometry suggests that Vo2 for EC coupling is proportional to the amount of Ca2+ involved in the EC coupling regardless of the Ca2’ release and uptake speeds (70,229). However, there is evidence of the futile cycling of Ca2+ in SR, i.e., an intracellularly localized spontaneous release of Ca2+ from SR in resting mammalian myocardium (28). If there is reuptake of such released Ca2+ by SR, extra energy would be required for this futile cycling. However, energy expenditure for reuptaking such leaked Ca2+ in the resting muscle has been estimated to be -0.13 cal g-l min-’ or -7% of the resting muscle metabolism (90a). The Ca:ATP stoichiometry also decreases when the passive permeability of SR to Ca2+ is increased by experimental detergents (261), elevated pH (90a), or higher temperature (90a). The disturbed stoichiometry can be normalized by ryanodine (116,192). Both Ca2+ uptake and the Ca2+-dependent ATPase of cardiac SR are nearly tripled by the phosphorylation of phospholamban in the membrane of SR (143, 259-261). The stoichiometric Ca:ATP coupling was maintained under this condition (260, 261). Catecholamines and CAMP augment both the initial rate of Ca2+ release into the cytoplasm during the early phase of contraction and the rate of reduction of Ca2+ during relaxation (2). An increased rate of release and an increased amount of Ca2+ stored in SR may add to the amount of Ca2+ available for delivery to the contractile proteins in subsequent contractions (258). A greater Ca2+ transient is needed for a comparable contractility under catecholamines than an increased level of extracellular Ca2+ (53), primarily because the Ca2+ sensitivity of troponin C decreases with the CAMP-dependent phosphorylation of troponin I (205). This difference makes one expect that with catecholamines there will be a greater increase in EC coupling and hence unloaded VO, for a comparable increase in Emax than with Ca2+. However, the elevations of the Vo2-PVA relation for comparable increases in Emax by catecholamines and Ca2+ were found, unexpectedly, to be comparable (186, 229). The amount of Ca2+ in SR reached during physiological contraction appears to be much lower than 50-100 nmol/g wet muscle necessary for full activation (54). The 20 and 70% maximum force developments have been thought to require 17 and 26 nmol/g wet muscle to be delivered to myofibrils in dog heart (206); on the other hand, the 50% maximum myofibrillar activation is known to require a total Ca2+ release well above 100 nmol/g wet wt in the intact cardiac cell (172). One activation-relaxation cycle requires release and l

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reuptake of ~200 nmol/g wet muscle (90a). The SR seems capable of removing as much as 250 nmol/g wet muscle during relaxation (261), which is significantly greater than the amount of Ca2+ that must be removed from the fully activated contractile system to effect complete relaxation. The activation (or EC coupling) energy of 0.4 J/100 g observed experimentally in a control contractile state corresponds to -100 nmol Ca2+/g tissue or more to be released per beat on the basis of a Ca2+ pump stoichiometry of 2 Ca2+/ATP (66). Then vo2 for EC coupling of ~0.3-0.4 Jo beat-l 100 g-l in the excised, cross-circulated dog heart (229) suggests the involvement of 60-100 nmol Ca2+/g tissue (68,172). The muscle spends -1 meal/g (0.4 J/100 g) for Ca2+ transport in a single twich (90a), which is consistent with the above value. The parallel shifts of the Vo2-PVA relation under varied levels of contractility (E,,,) (28,229) are consistent with the contemporary concept that the primary cellular change accompanying changes in contractility is the amount of Ca2+ released to the myofilaments per beat. The close relation between unloaded vo2 and Emax is consistent with the linearity of the relation noted between Ca2+ transients and contractility (277). This close relation also seems consistent with a fixed and linear stoichiometry between Ca2+ uptake and ATP consumption by SR independent of the contractile state (70,261). Certain types of inotropic interventions should cause deviations from the simple relation between unloaded i702 and EmaX. For example, if an agent exerts its inotropic action by changing the sensitivity of the myofilaments to Ca2+ rather than by altering the amount of Ca2+ provided to the myofilaments, then deviations from the ordinary unloaded VO,-E,,, relation could be anticipated. Such agents include some new cardiotonic agents (such as sulmazole, OPC 8212, UD-CG 115, DPI 201-106) that affect the Ca2+ sensitivity of troponin (262). However, in the on-going studies in my laboratory, the effects of OPC 8212 (60, 61), sulmazole (61), milrinone (61), and DPI 201-106 (61a) on the VO,-PVA relation were similar to the effects of catecholamines and Ca2+ in that the Vo2-PVA relation was elevated in a parallel manner to a similar extent with each agent. Evidence exists for a length-dependent activation in cardiac muscle (3, 42). One mechanism is an increased amount of Ca2’ involved in the EC coupling (276), and the other mechanism is an increased Ca2+ sensitivity of troponin C (94). If easier binding of Ca2+ to troponin is associated with its less easy release from troponin, the activation energy at a longer muscle length might be expected to be greater than at a shorter muscle length (42). In fact, 00, of a quickly released contraction at maximum length (L,,,) was found to be 1.75 times greater than 00, of contraction at slack length (37). However, at a higher Ca2+ medium with caffeine, and at a lower temperature, there was no significant length dependence of unloaded VO, in myocardium (39). In contrast to this length-dependent EC coupling and its energetics in saline-perfused rabbit or l

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259

ENERGETICS

ferret myocardium, unloaded vo2 did not significantly depend on EDV in cross-circulated dog hearts (288). The ejecting activation is most intriguing. Ejection activation means an increased Emax of the ejecting contraction with a relatively small stroke volume relative to the isovolumic Emax at the same end-systolic volume (106,110,166,167,251,286). The VO,-PVA point of such a contraction with ejecting activation was found to fall on the VO,-PVA relation of isovolumic contractions despite the greater Emax of the ejecting contractions (166, 286). This suggests that the PVA-independent vo2 components of these ejecting and isovolumic contractions are identical with each other despite the different Emax values. This phenomenon can be accounted for by the finding that shortening of myocardium increased the Ca2’ sensitivity of myofilament but not the amount of Ca2’ for the EC coupling (105, 138).

metabolic 00, at zero Emax of a beating LV, which is a new method to assess basal metabolic vo2 in a beating heart (26, 291). This intercept value was found to be ~0.01 ml 02. beat-l 100 g-l at a heart rate of loo-130 beat/min (26, 291). Basal metabolic 00, is considered to consist mainly of energy utilization for maintenance of the intracellular ionic environment and cellular structures and secondarily of the energy loss in the futile cycles (168). The Na+-K+ pump contributes to only 5-20% of the basal metabolism (63). During a repetitive electrical activity, a considerable Na+ entry occurs that increases the Na+ pump activity to maintain the ionic environment. The fraction of energy for protein synthesis in basal metabolic i702 seems very small, because 00, of unloaded arrested heart is unchanged despite ~30% increase in protein synthesis under a doubled aortic pressure (127).

3. Energy for electrical activation

F. Coronary Perfusion

When complete electromechanical dissociation was effected. by removing Ca2+ in a beating dog heart, unloaded VO, decreased by 0.0004 ml O2 100 g-l stimulation (130). This small 00, is considered 00, for electrical excitation. It is 0.94 existed between force-length area (FLA) and 00, in a stable contractile state (96). The FLA correlated better with VO, than did peak force and force-time integral (96). The slope of the VO,-FLA line was 0.013 -t 0.001 nl beat-l. erg-‘, which is convertible to 2.6 t 0.2 (dimensionless) (Table 1, study 21). The contractile efficiency from excess vo2 to FLA as the reciprocal of the slope was -39% (96), falling within a normal range (30-50s) observed in dog and rabbit hearts (Table 1). This result seems reasonable, because ferret myocardium is normally V3 dominant (154). The Vo2-axis intercept was -0.04 ml O2 beat-l 100 g-l (96), which is comparable to that of rabbit LV (81) but 1.5-2 times greater than that of dog LV in a control contractile state (Table 1). The difference might be related to the differences of species (151), temperature (147), or heart rate. When heat was measured instead of VO,, rabbit papillary muscle also showed a linear correlation between heat and FLA (66, 67). The slope yielded a contractile efficiency of 42-45s (Table 1, study 20). However, FLA was found to be greater than the heat liberated during relaxation, and this liberated heat l

l

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70

was proportional to peak force rather than FLA in rabbit papillary muscle (51). This result was presented as evidence against the validity of FLA as the total mechanical energy generation (51). This aspect must be further studied in detail. IV.

OXYGEN-WASTING

EFFECT

This effect refers to an increased vo2 associated with an enhanced contractile state despite artificially maintained systolic force or pressure or their time integrals (84,175,177,229,285,291). The magnitude of the 02-wasting effect is proportional to indexes of contractility, such as maximum dP/dt and vmax, regardless of such factors as catecholamines, Ca2+, and paired pulse stimulation (84). For this reason, contractility has been considered to be a major determinant of Vo2 (19). The parallel shift of the VO,-PVA relation with a change in contractile state seems to match the concept of the 02-wasting effect of positive inotropism (19, 84, 131, 175). The parallel shift of the heat-load relation with a change in contractile state (62) also matches this effect. When PVA is kept zero in unloaded contraction, 00, increases by positive inotropic interventions (26,60, 164,229,291). This increased VO, seems the basis of the 02-wasting effect: the increased unloaded VO, in an enhanced contractile state is due to an increased VO, for an enhanced EC coupling, because the basal metabolic TO, remains unchanged by positive inotropism (165). The parallel elevation of the VO,-PVA relation by positive inotropism seems to be due to an increased VO, for EC coupling regardless of PVA (229). The sensitivity of the 02-wasting effect to a change in Emax is reflected by coefficient B in the empirical equation of VO, = A X PVA + B X Emax + C (232). It is high for catecholamines and Ca2+ (229), smaller for digitalis (282), and minimal for cooling (220). The q2-wasting effect became implicit when a new index of VO,, called the pressure-work index, was correlated with VO, under changes in contractility (177). The 02-wasting effect also becomes implicit when the maximal active mechanical efficiencies of LV (or myocardium) in different contractile states are close to each other (62, 291). The mechanism of the apparent disappearance of the 02-wasting effect involves proportional increases in VO, for both PVA and EC coupling with changes in contractile state (291).

l

V. FENN

EFFECT

The Fenn effect is a phenomenon described originally in frog sartorius muscle, namely, that a tetanized and shortening skeletal muscle releases more energy than an isometric contraction (58, 159, 176, 281). This effect has been confirmed by different investigators, but the relative magnitude of the extra energy differs greatly depending on the experimental methods and materials (66, 67, 159, 176, 281). The Fenn effect has

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been understood as a manifestation of increased ATP splitting during working contractions relative to isometric contractions (281). When the energetics of a shortening contraction are compared with those of an isometric contraction, where the final and initial lengths are different but the active tension is the same, the Fenn effect can be duly evaluated (159). The Fenn effect exists in cardiac muscle but in a different way (27, 34, 67, 166). A shortening or ejecting contraction has a greater vo2 than an isometric or isovolumic contraction at a comparable systolic wall stress or pressure (27, 34, 67, 166). The increment in 00, is proportional to the EW (27, 34, 67,166). The concept of PVA and the VO,-PVA relation are reconcilable with the Fenn effect both theoretically and experimentally (67,70,166,186,230). Figure 2, A and B, shows theoretically that PVA, as a function of afterload pressure, changes in a different manner in ejecting and isovolumic contractions: the PVA of an ejecting contraction with a rectangular P-V loop trajectory is greater by EW than the PVA of an isovolumic contraction at the same end-systolic (afterload) pressure and volume as those of the ejecting contraction. Figure 2C shows that when the PVA versus afterload pressure curve is converted to the voz versus afterload pressure curve by the empirical equation vo2 = A X PVA + D, the 00, versus afterload pressure curve of ejecting contractions is greater than that of isovolumic contractions by the sum of EW and EW-related heat loss. This theoretical prediction was supported experimentally (166) as follows. C

A

U

Volume

Afterload

Pressure

3t

EC Coupling Basa 1 Afterload Pressure

FIG. 2. A: schematic of EW, PE, PVA, ESPVR (slope of which is E,,, and volume-axis intercept is V,) in P-V diagram. Solid line rectangle is a P-V trajectory of an ejecting contraction, and dashed line rectangle is a P-V trajectory of another ejecting contraction with a higher afterload pressure. B: theoretical curves of PVA of ejecting and isovolumic contractions as a function of afterload pressure. EW corresponds to height difference between ejecting and isovolumic curves. PE corresponds to height of isovolumic curve. C: theoretical curves of predicted VO, of ejecting and isovolumic contractions as a function of afterload pressure. HeatEw, heat energy loss associated with production of EW; heat PE, heat energy loss associated with generation of PE; EW plus heat EW, height difference between ejecting and isovolumic curves; PE plus heatpE, height of isovolumic curve. Ratio of EW or PE to heat is considered to be always 4:6 according to constant efficiency of 40% from excess VO, to mechanical energy. 60, fraction labeled EC coupling indicates VO, for excitation-contraction coupling. Basal, VO, for basal metabolism.

ENERGETICS

263

When vo2 is plotted against afterload pressure of isobarically afterloaded contractions from a preset EDV and isovolumic contractions at+different volumes less than or equal to this EDV, there are two Vo2-afterload pressure curves (Fig. 2B): the higher one is convex upward, and the lower one is convex downward. The difference in the height between the two curves corresponds to the extra (not excess) 00, associated with the ejection #and stroke work (166). The contractile efficiency from extra 00, because of the Fenn effect to external work has been found to be constant at 47% on average, comparable to the contractile efficiency from excess VO, to PVA in the same hearts (166). A similar Fenn effect has been observed in the heat-load curve of myocardium (62, 67, 70, 176). Therefore the PVA concept, as well as the linear Vo2-PVA relation, is consistent with the Fenn effect not only qualitatively but also quantitatively (67, 70, 166). In this respect, the PVA concept and the linear VO,-PVA relation involve the autoregulatory mechanism of the contractile machinery to adjust its mechanical output energy to the load. The autoregulatory mechanism suggested by the Fenn effect and the VO,-PVA relation is such that an extra VO, is coupled to a certain EW regardless of afterload and shortening (70, 166). The same EW can be produced either by a greater shortening against a smaller load or by a smaller shortening against a larger afterload, both requiring the same extra VO, and probably the same extra ATP consumption. This means that the extra ATP consumption is proportional to EW but not to the amount of shortening per se. Shortening against zero afterload is not accompanied by extra VO, (244, 288). The cardiac Fenn effect seems to contradict the energetics of the contemporary sliding filament model in which the number of cross-bridge steps and hence the amount of shortening is assumed to be proportional to the number of ATP molecules split (108, 109). The cardiac Fenn effect seems consistent with the unusually long travel of cross bridges per ATP split under unloading conditions in an in vitro actomyosin system (284). The cardiac Fenn effect supports the energy consequence of the time-varying elastance model of the LV (166, 186, 213), whereas the skeletal Fenn effect does not (51, 52, 186, 243). Intriguingly, both vo2 and PVA of an ejecting contraction with a relatively small stroke volume or ejection fraction sometime exceed slightly those of an isovolumic contraction at a preset EDV (166, 286, 289). Therefore the downward parabolic Voz-afterload curve sometimes has a small hump immediately below the isovolumic end. Such a contraction, having VO, and PVA values slightly greater than their isovolumic values at the fixed EDV, corresponds to a contraction with a shortening activation effect of unknown cause (106, 110, 251, 286). The Emax of this slightly activated contraction is slightly greater than that of an isovolumic contraction at a fixed EDV. Despite the greater E max, PVA, and OO,, the Vo,-PVA data point of this contraction was found to fall on the same VO,-PVA relation in the same run with a stable inotropic background (166, 286). When a comparable increment in

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Emax was produced by dobutamine, the ~o~-PVA data point deviated upward (286). Therefore the ejecting-activated contraction is unlikely to be caused by an increased Ca2+. The relation to the skeletal Fenn effect (176) of the hump of the Vo,-afterload relation caused by this ejecting activation (166) remains unknown. A similar hump has been observed occasionally in the heat-load relation of isotonic contractions of myocardium (74, 76). More detailed studies are warranted to reveal the mechanism of the hump and its relation to the Fenn effect. VI.

EFFICIENCY

Efficiency of a system means the fraction of effective energy (or power = energy/time) output from the system in the total energy (or power) input to the system and is given by a dimensionless value or percentage. Because both voq and PVA represent the energy input and output, the VO,-PVA relation contains information on efficiency in a physically sound manner (67, 70, 212, 218, 220, 229, 232, 233, 242, 246). The slope of the line connecting the origin and a working total or excess Vo2-PVA point, after both coordinates are expressed in the same unit of energy, e.g., joules, indicates reciprocally the efficiency of energy conversion from total vo2 (Fig. 1C’) or excess VO, (Fig. 1D) to the total mechanical energy measured by PVA (218, 229, 233, 242). Of these two efficiencies, only the efficiency from the excess vo2 to PVA is called “contractile efficiency.” This feature of PVA is not shared by other indexes of 00, or myocardial energetics, such as peak pressure, peak force, and their time integrals (10, 62, 271). For this reason, the VO,-PVA relation allows us to analyze cardiac energetics and mechanoenergetic coupling in a manner not posible with the heatload relation (62) or the economy of force (7-10, 100, 102). Figure 3 shows the energy flow diagram from vo2 to EW that is reviewed in the next section. Note that the contractile efficiency determined from the slope of the VO,-PVA relation is different from the conventional mechanical efficiency of the heart, which is the ratio of EW in VO, (see sect. v1D1).

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contractility-dependent increase in the PVA-independent vo2, which is considered to be a manifestation of the 02-wasting effect of positive inotropism (229) (see sect. Iv). 2. From excess oxygen consumption pressure-volume area

to

The slope of the VO,-PVA relation is largely independent of loading conditions in a given contractile state (229,233,242,246,250; Table 1). It is also independent of inotropic interventions (26, 186, 229, 242, 246, 250; Table 1). Under the assumption that the unloaded iTo2 (PVA-independent 00,) for both basal metabolism and EC coupling is constant regardless of PVA in a given contractile state (sect. IIIE), the excess VO, (PVA-dependent 00,) above the unloaded i70, is considered as the effective energy input for mechanical contraction. Under the assumption that PVA is the total mechanical energy output from the contractile machinery, the reciprocal of the slope of the Vo2-PVA relation gives the contractile efficiency of energy conversion from the excess Vo2 to PVA (218,229,246,250), as schematically shown in Figures 1D and 3. This load-independent contractile efficiency was -40% on average (range: 30-50s) in many studies on adult dog LVs (26,229) as well as puppy LVs (247), dog RVs (283), rabbit LVs (81), ferret papillary muscles (96), and human LVs (14) in the control contractile state despite the diversity of species and heart sizes (Table 1). The load-independent contractile efficiency from the excess vo2 to total mechanical energy remains unchanged despite acute positive and negative inotropic

Mechanical 30-50%

A. Eficiency Franz Oxygen Consumption to Pressure- Volume Area 1. From total oxygen consumption pressure-volume area

to

The efficiency from the total i702 to PVA varies with PVA in a given contractile state, because the total VO, consists of a sizable constant PVA-independent (unloaded) i70, and a variable PVA-dependent (excess) VO,, as shown in Figure 1C (229). This efficiency is zero at zero PVA. It increases with increases in PVA in any given contractile state (229). It is smaller for a given PVA in a higher contractile state (229). This is due to a

FIG. 3. Energy flow diagram from O2 consumption to EW via ATP and then PVA. Horizontal line divides O2 and ATP into two components: top component is related to mechanical activity, and bottom component is related to nonmechanical activity of myocardium. Efficiency from O2 to enthalpy of ATP split is 6070%. Efficiency from O2 consumption used for mechanical activity to total mechanical energy in terms of PVA was found to be ~40%. Efficiency from enthalpy of ATP split for mechanical activity to PVA was then calculated to be 60-70%. Efficiency from PVA to EW depends on loading conditions. Nonmechanical fraction of O2 is converted to heat, called recovery heat (heat,). ATP used for excitation-contraction coupling (EC) and basal metabolism (BM) is converted into heat called initial heat (heati). Potential energy part of PVA is also converted to heat called initial heat (heat;).

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interventions in individual dog hearts (27, 60, 166, 229, 291; Table 1). In study 10 of Table 1, the contractile efficiency intriguingly remained unchanged under 7°C cardiac cooling in the dog LV despite a cross-bridge cycling rate presumably decreased by cooling (220). In study 15, the contractile efficiency remained unchanged despite pressure-overloaded hypertrophy in the dog LV (161). Three- to five-week hyperthyroidism does not affect the efficiency in adult dog LVs (241; Table 1, study 16). These two chronic results could be accounted for by the dominant &-type myosin isozyme that persists despite hypertrophy and hyperthyroidism in dog hearts (178, 241, 257). The unchanged contractile efficiency under cooling is particularly intriguing in the light of the presumably decreased cross-bridge cycling rate (Q10 = 2-3) (87,147, 183, 198) and the slowed contraction (141). The crossbridge cycling rate probably decreases by 3550% under 7OC cooling, consistent with the increased duration of systole by 45% (220). The slowed cross-bridge cycling probably increased the economy of force (7,lO). Despite the expectation, there was no change in the slope of the VO,-PVA relation (220). This intriguing fact suggests a possibility that the contractile efficiency is not necessarily proportional to the economy of force (241). A similar discussion may hold for the unchanged contractile efficiency with catecholamines (229) despite an increased cross-bridge cycling rate (99,279) and a significantly decreased economy of force by catecholamines and CAMP (89, 101). For a further discussion, see section VIE. The constant contractile efficiency is also intriguing in the light of the variation in speed or duration of contraction among different animal species, although this variation suggests different cross-bridge cycling rates and hence different economy of force and slope of the heat-load relation (8, 151). The constancy of the contractile efficiency despite the probably changed cross-bridge cycling rate and economy of force are further discussed in section VIE. The contractile efficiency from the excess Vo, to PVA is the product of two efficiencies: one is the efficiency from VO, to ATP synthesis, and the other is the efficiency from ATP hydrolysis to the generation of total mechanical energy, as shown in Figure 3. The former is the efficiency of the oxidative phosphorylation, and the latter is the efficiency of the cross-bridge cycling (115). Therefore there are two ways of interpretation of the constant contractile efficiency. One interpretation is that both efficiencies are unchanged, and the other interpretation is that both efficiencies are changed reciprocally to keep their product constant. This problem is common to analyses of cardiac energetics by vo2, because OO,, unlike heat measurement, is equivalent to the energy utilization for both initial events (both activation and contraction) hydrolyzing ATP and recovery events (oxidative phosphorylation) synthesizing ATP (10, 62).

265

ENERGETICS

B. E$iciency

1. Energy

From

equivalent

Oxygen Consumption

to ATP

of oxygen

The energy needed for cardiac contraction derives from the breakdown of metabolic substrates, mostly aerobically, i.e., by consuming O2 (62). Different substrates have different calorie values (or enthalpy) when burnt with OZ: 327 kcal/mol lactate, 670 kcal/mol glucose, and 2,385 kcal/mol palmitate. However, their energy equivalents of vo2 are comparable: 20.33,20.84, and 19.36 J/ml 02, respectively (41,49). The maximal possible difference in these caloric equivalents is ~4% (41, 49). This variation is practically negligible in the calculation of the energy equivalent of VO,. Conventionally, 20 J/ml O2 (= 448 kJ/mol O2 = 107 kcal/mol 02) is assumed as a representative value for the energy equivalent of VO, for both glucose substrate in artificial saline perfusate and a mixture of substrates in whole blood (32, 62, 229). Although free fatty acids have long been considered to be the preferred substrate of the heart (162a), lactate was the preferred substrate (87% of total substrate) for myocardial energy production when lactate (>4.5 mmol/l blood), glucose, and free fatty acid were abundant (46a). Because lactate was 7-11 mmol/l blood in the excised, cross-circulated dog heart preparation (224), lactate was probably the dominant substrate when the VOW-PVA relationship was studied in my laboratory (233, 242). The entire enthalpy of the substrates, however, is not recovered in ATP, and the rest is dissipated as recovery heat (30,31,47,62,68,70). The ratio of the energy recovered in ATP to the energy equivalent of VO, is the efficiency of the oxidative phosphorylation (see sect. vIB3). 2. Phosphate-to-oxygen

ratio

The efficiency of oxidative phosphorylation is primarily determined by the phosphate-to-oxygen (P:O) ratio, i.e., the number of moles of ATP produced divided by the number of moles of O2 atoms consumed in aerobic metabolism (31,62). This ratio is relatively constant at -3 regardless of the substrate (31, 62, 68, 69). For example, the complete oxidation of 1 mole of lactate yields 36 moles of ATP, consuming 6 moles of 02, and the P:O ratio is 3.0. The complete oxidation of 1 mole of glucose, including glycolysis, yields 38 moles of ATP, consuming 6 moles of 02, with a P:O ratio of 3.2. The complete oxidation of 1 mole of palmitic acid (a free fatty acid) produces a total of 129 moles of ATP, consuming 23 moles of 02, with a P:O ratio of 2.8. Thus the P:O ratio falls within t7% around a value of 3.0 (31,202). However, the P:O could be smaller by 5-30% when the intracellular futile cycles are activated (168, 203, 268). The contribution of the futile cycles to the VO,PVA relation remains unknown. Decreases in the P:O ratio from 3.0 mean decreases in the efficiency of the

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oxidative phosphorylation. When the contractile efficiency remains unchanged, a smaller P:O ratio means a greater efficiency of the cross-bridge cycling. The P:O ratio has not been determined in the excised, cross-circulated dog heart, and the ratio has been assumed to be 3.0 in the previous analyses (218,233). 3. Enthalpy

of ATP

The molar enthalpy (AH) of ATP hydrolysis is -48 kJ/mol (70, 103, 104), where the minus sign is the sign convention in thermodynamics (68). The AH per six moles of ATP is -288 kJ, and one mole of O2 is consumed with AH of -448 kJ. The metabolic efficiency of ATP synthesis by oxidative phosphorylation then becomes 65% theoretically. The substrate-dependent variation of the P:O ratio by t7% from 3.0 makes the efficiency fall between 60 and 70%) as shown in Figure 3. A metabolic efficiency of 59% has often been assumed in myocardium on the basis of the initial and recovery heat measurement (30,31,70). A metabolic efficiency of 65% was assumed in skeletal muscle (115). Smaller metabolic efficiency values (36-55%) have been obtained in rabbit myocardium from the initial and recovery heat measurement with a higher time resolution thermopile (8, 9, 89). However, clear temporal separation of the initial heat and the recovery heat is difficult in myocardium, unlike in skeletal muscle at O°C (30, 31, 62). Therefore the early fast phase of the heat generation cannot be ascribed solely to the initial heat (30). If it is true that metabolic efficiency is smaller in myocardium, it may be owing to a smaller P:O ratio, because the enthalpy of ATP is constant (30,68). In the excised, cross-circulated dog heart, the metabolic efficiency of the oxidative phosphorylation remains to be determined. 4. Free energy change of ATP hydrolysis Free energy change (AG) of ATP hydrolysis is equal to the maximum mechanical work that could be extracted from contracting muscle operating at, ideally, 100% thermodynamic efficiency (62). A modern estimate of AG of ATP split in cardiac muscle is -60 kJ/ mol(70,117), where the minus is the sign convention in thermodynamics. The relation between AH and AG is given by AG = AH - TAS, where T is absolute temperature and AS is the molar entropy (not enthalpy) change; TAS means a certain fraction of AH that is bound to the material involved in the reaction is not available, or not free, to do work (62, 68). The value of T is always positive, and therefore when AS is positive, as in the ATP hydrolysis, AG is greater in absolute value than AH (62, 68). Theoretically, -AG, which is often called affinity (A) of the hydrolysis of ATP, is equal to -AG, + RZln([ATP]/[ADP] [Pi]), where AG, is the standard free energy change under standard conditions of, for example, PH and Dw+1, and R is the gas constant (64, 117). The

Volume

TO

term [ATP]/[ADP] [Pi] is the cytoplasmic phosphorylation potential (64), falling between 10,000 and 30,000 for rat skeletal muscle (90a). Under normal aerobic conditions in the heart, A is 58-60 kJ/mol(64,90a) but could fall to 30-50 kJ/mol during hypoxia (4, 64, 202). The value of 40 kJ/mol is a level at which the Ca2+ pump would no longer be able to pump Ca2+ into SR (90). It has been suggested that the decrease in A is directly responsible for the fall in force production (117). Mechanical performance could be affected by a reduced A in two ways: 1) by a direct effect on the contractile machinery or Z) by an effect on Ca2+ sequestrated by SR and hence on Ca2+ release. Increases in Pi correlated closely with decreased maximal Ca2+-activated force of tetanized myocardium (137). Values for AH of -48 kJ/mol and AG of -58 kJ/mol of ATP hydrolysis yield a AG:AH ratio of 1.2 in cardiac muscle (65). Therefore the efficiency from 00, to AG of ATP split is 20% higher than that to AH of ATP split. When the efficiency from AH of VO, to ATP split is 60%, the efficiency from AH of VO, to AG of ATP split will be 72% (70). However, the efficiency from AH of 00, to AG of ATP could vary between 37 and 75%, depending on experimental conditions, and the normal values of this efficiency of in vivo cardiac muscle would range between 45 and 65% (202). The AG of ATP hydrolysis has not been determined in the excised, cross-circulated dog heart. If it varies according to the loading and contractile conditions of the heart, the efficiency of cross-bridge cycling from AG of ATP split would change reciprocally despite the load- and contractility-independent contractile efficiency from the excess VO, to PVA. 5. Use of ATP Primarily, ATP is hydrolyzed by I) myosin ATPase in the contractile machinery, Z) Ca2+-ATPase in SR, 3) Na+-K+-ATPase in sarcolemma, and 4) various protein phosphorylations (30, 77). The first usage is related to the mechanical activity of contractions (Fig. 3) from which the mechanical energy is generated. For the details of this process, see References 132,173,281 and the next section. The three other modes of ATP hydrolysis are related to the nonmechanical activities of contraction (Fig. 3). Of the ATP used for nonmechanical activities, the two major fractions are thought to be used for activation, or EC coupling, and basal metabolism (30; Fig. 3). The basal metabolic fraction includes ATP usage for maintenance of ionic environment by Na+-K+ pump, synthetic purposes (glycogen, triglyceride, and protein synthesis), and some futile metabolic cycles (168). The futile cycles may use ATP while apparently cycling in two directions without net change in the direction of the pathway, including constant turnover of glycogen and triglyceride and constant uptake and release of Ca2+ by mitochondria (168). However, this fraction of ATP is ill defined and seems small (168). This futile fraction may increase under the existence of

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excess free fatty acids and catecholamines (168). Some small amount of ATP is used to phosphorylate proteins in response to CAMP (77). C Eflciency

From

A TP to Pressure-

1. Eficiency

of contractile machinery

Volume Area

The load- and contractility-independent contractile efficiency from the excess vo2 to PVA is ~40% (Table 1). It is the reciprocal of the slope of the linear VO,-PVA relation and is the product of two efficiencies (70, 220, 229, 233, 246; see sect. VI&‘). One is the metabolic efficiency of the oxidative phosphorylation (60-70%), and the other is the chemomechanical efficiency of crossbridge cycling in the contractile machinery converting energy from AH of ATP split to total mechanical energy in terms of PVA, as shown in Figure 3. If the 40% is divided by the first 60-70%, the efficiency from AH of ATP split to PVA is calculated to be also 60-70% (66,67, 70,186, 233), as shown in Figure 3. Because AG of ATP split is 20% higher under the best aerobic conditions than AH of ATP split (30, 70; see sect. vrB4), the efficiency from 00, to AG of ATP split is 70-80%, and the efficiency of PVA generation from AG of ATP would be reduced to 50-60% in cardiac muscle (70,233). An important question is whether the load- and contractility-independent contractile efficiency (Table 1) means the constancy of the efficiency of the contractile machinery independent of loading and contractile conditions. The answer is affirmative if 1) the excess VO, is entirely PVA dependent and 2) the metabolic efficiency is constant. The first assumption seems probable, as reviewed in section IIIE. The second assumption may not always hold, as mentioned in section VIBZ. The load-independent contractile efficiency in a given contractile state probably implies the load-independent efficiency of cross-bridge cycling, because changes in ventricular loading conditions are unlikely to change the metabolic efficiency of oxidative phosphorylation unless myocardial ischemia occurs by overload or metabolic substrates are changed (4, 64, 168, 202). However, inotropic agents may alter contributions of free fatty acids as a metabolic substrate and vo2- and ATP-wasting futile cycles to myocardial energetics (168,268). Then the metabolic efficiency is changed and the efficiency of the contractile machinery is changed reciprocally even when the contractile efficiency remains unchanged. Therefore the relatively constant contractile efficiency that has been observed under different contractile states in the excised, cross-circulated dog heart, as reviewed in section III, D, F, and J, does not always indicate a constant efficiency of the contractile machinery. The efficiency of the contractile machinery ~100% may be attributable to the inefficiency of the attachment and detachment of cross bridges to generate mechanical energy (70, 290). This efficiency is lower than that of the chemiosmotic ATPase that has an almost

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100% efficiency, because the membrane potential across which ion transport occurs is equal to the magnitude of AG of ATP (32,91). Because PVA is theoretically a maximal limitation of external mechanical work from a given EDV and under a given afterload, the efficiency value of 50-60% from AG of ATP to PVA mentioned may indicate the maximal thermodynamic efficiency. In one study, the thermodynamic efficiency in isotonic contraction reached 38% in papillary muscle, which is considered to be a quite high value for the chemomechanical transduction process (30). This thermodynamic efficiency is two-thirds to four-fifths of the maximal thermodynamic efficiency @O-60%) estimated above. The rest may be degraded into heat. The thermodynamic efficiency may increase toward the theoretical maximum of 50-60% by allowing external work production even during relaxation (214, 215). Quick-release experiments have yielded a less steep VOW-PVA relation and hence a 1.1-1.3 times higher efficiency from excess VO, to total mechanical energy than ordinary ejecting and isovolumic contractions (287; section 111B4).This result will increase the efficiency from AH of ATP to PVA to 70-90% and the efficiency from AG of ATP to PVA to 60-80%. The higher efficiency of the contractile machinery in quick-release contractions is considered to be the result of the shortened duration of force maintenance after the quick release and hence decreased number of cross-bridge cyclings (37,287,290). Z. Myosin adenosinetriphosphatase activity contractile eficiency

and

The efficiency of the contractile machinery may be expected to change with myosin ATPase activity in the same way as the economy of force does (7-10, 70, 147, 153, 241). However, against this expectation, the slope of the VO,-PVA relation remains relatively constant in different species (dog, puppy, rabbit, ferret, human), and the efficiency of the contractile machinery as the reciprocal of the slope remains largely unchanged at 30-50% (14,81,96,229,233,246; Table 1). Even myocardial cooling does not affect the slope of the VOW-PVA relation, despite presumably decreased myosin ATPase activity at &lo of 2-3 (220). Therefore the mechanical efficiency of the contractile machinery seems largely independent of myosin ATPase or cross-bridge cycling rate under the assumption of unchanged metabolic efficiency (see sect. VIB). An intriguing observation has been made that the slope of even the heat-load relation does not change with cooling in rabbit and rat papillary muscles, although the heat versus force-time integral relation may be less steep at a lower temperature (71, 147). Although catecholamines increase v,,, in myocardium, no corresponding increase in myosin ATPase activity was observed in dog hearts in earlier studies (121, 191). However, cross-bridge cycling rate was recently shown to increase with catecholamines or CAMP in rat myocardium (99, 278, 279). P-Adrenergic stimulation

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seems to modify V1 myosin more sensitively than V3 myosin (278). The economy of force was shown to decrease with catecholamines in rat (89) and human (101) hearts. However, there is no evidence that the slope of the Vo2-PVA relation is influenced by inotropic agents in dog hearts (220,229,241). An increase in the economy of force has been observed in pressure-overloaded rat and rabbit hypertrophied hearts accompanied by the decreased myosin ATPase activity caused by the isomyosin shift from V1 to V3 or from cy-to ,&type (7-12,180,182,257). However, there is no evidence that the shift from V1- to &-type myosin can increase the contractile efficiency from the excess VoZ to PVA. A decrease in the economy of force has been observed in the hyperthyroid heart because of the increased myosin ATPase activity caused by the isomyosin shift of V3 to V1 in rabbit (7, 9-11, 180, 257). The unchanged VOW-PVA relation in hyperthyroid dog LV is no evidence against this expectation, because &-type myosin does not appear despite a 3- to 5-wk administration of L-thyroxine (0.3 mg/kg daily) (241). However, recently the VOW-PVA relation was found to become significantly steeper in hyperthyroid rabbit LVs than in normal and hypothyroid rabbit LVs, and the contractile efficiency from the excess 00, to PVA decreased from control and hypothyroid values of 36-40s to 27% on average (82). Simultaneously, the relation between 00, and wall force-time integral was significantly steeper in the hyperthyroid rabbit LVs than in control and hypothyroid rabbit LVs, indicating a decreased economy of force (82). This is the first evidence that the slope of the VO,-PVA relation and the contractile efficiency to PVA could change with the economy of force under the influence of changes in myosin ATPase activity. Further confirmation may be needed.

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efficiency is not contradicted by the load-dependent mechanical efficiency of EW, because EW is a variable fraction of PVA (232). External work is zero, and hence the mechanical efficiency is zero in either isovolumic contractions or completely unloaded contractions from a given preload (59, 62, 232). External work and the mechanical efficiency are maximal in the middle of the afterload range (50,59). Quantitatively, at a given set of EeS and EDV, the mechanical efficiency is maximized when arterial-equivalent elastance (E8) is lower than 0.5E,, (24). The term E, was proposed as the inverse slope of the diagonal line connecting the end-systolic and end-diastolic P-V points (253, 255). When E, is equal to EeS, EW becomes maximal in contractions from a fixed EDV (253, 255). When ventricular afterload pressure and cardiac output are fixed, the mechanical efficiency calculated by a predictive equation (232, 248) can theoretically be minimized at Emax (optimal contractility) in the middle of its working range (263). Existence of such an optimal contractility remains to be studied experimentally. 2. Active

mechanical

eflciency

Active mechanical efficiency is the efficiency after basal metabolism is subtracted from the denominator of the conventional mechanical efficiency (62, 65, 291). It is the ratio of EW to the sum of EW and active energy utilization (62). The active efficiency is variably but slightly higher than the conventional efficiency. The maximal active efficiency (10-30s ) usually remains unchanged despite changes in contractile state, except in the failing state (62,65,291). The 02-wasting effect of positive inotropic agents disappears in the maximal active mechanical efficiency (62,291). This result suggests a parallelism between changes in PVA-independent and PVA-dependent vo2 components (291).

D. Eficiency From Oxygen Consumption to External Work

E. E$iciency

1. Mechanical e$icienc y

1. Myosin adenosinetyiphosphatase

From

ATP to External

Work

mechanical eflciency

The mechanical efficiency of the heart is conventionally defined as EW divided by total 00, or EW divided by the sum of EW, active heat, and resting heat (62). This efficiency has a downward parabolic relation to the load and has a peak near or slightly below the middle of the load range, not only in myocardium but also in skeletal muscle in general (50,59,62,63,166,232, 281, 291). This efficiency increases from 0% in isovolumic or isometric contraction to 10-30s in ejecting or shortening contraction, with decreases in afterload, and then decreases to 0% when ejection or shortening occurs against zero load (62, 166, 232). This efficiency varies as a function not only of loading but also of inotropic conditions in a manner predictable as a function of PVA and Emax(232). The load-independent constancy of the contractile

The active efficiency still contains the activation energy for the Ca2+ pump. The efficiency called myosin ATPase mechanical efficiency can be calculated by subtracting the activation energy from the total enthalpy input and further subtracting the recovery heat (30). It peaks at 45% (30). When this efficiency is considered from AG of ATP split to EW, it decreases to 38% (30). This efficiency has been called myosin ATPase thermodynamic efficiency (30). It is two-thirds to three-fourths of the contractile efficiency from AG of ATP to PVA (50-60s) (sect. VIC). This fraction probably depends mainly on the fraction of EW in PVA (24, 232, 255). The contractile efficiency from AG of ATP to PVA seems the maximum limitation of the myosin ATPase thermodynamic efficiency, and the contractile

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ApmL! 1990

VENTRICULAR

efficiency from AH of ATP to PVA seems the maximum limitation of the myosin ATPase mechanical efficiency. 2. Mechanical eflciency and economy

The efficiency from ATP to EW seems to remain largely unchanged despite considerable changes in the economy of force (40, 62, 70, 151). The economy decreases from hypothyroidism to euthyroidism and further to hyperthyroidism in rabbit heart with increases in myosin ATPase activity associated with isomyosin shift from V3 to VZ to V1 (7-U). The difference in economy of force exists generally among muscles of different intrinsic speeds of shortening (8, 15, 151). Myosin ATPase activity or cross-bridge cycling rate or energy cost of tension also varied acutely with catecholamines (99,279). Despite a change of myosin ATPase activity by two to three orders of magnitude between muscles in different animals, the range of mechanical efficiency was relatively small (15, 281). The small size of the changes in the mechanical efficiency despite considerable changes in the economy of force in response to changes in myosin ATPase activity seems to be accounted for as follows. First, myosin ATPase activity is proportional to the speed of shortening and inversely proportional to the contraction time of muscle in general (15, 87). Namely, the higher the ATPase activity (130- to ZOO-fold), the greater the intrinsic speed (240-fold) and the shorter the contraction time (15,87). However, the ratio of the speed of shortening to ATPase activity varies only threefold (15). This ratio also falls in the same range when myosin ATPase, shortening speed, and contraction time are changed over a temperature range of 5-35OC (15,87). This result suggests that the mechanical efficiency of muscle does not sensitively change with myosin ATPase activity. Second, the relative insensitivity of the mechanical efficiency of muscle to velocity of shortening has been shown (280). Skeletal muscle contraction is characterized by Hill’s characteristic equation (281): (F + a)(v + b) = b(FO + a) = constant, where F is the isotonic force, F, is the isometric force, v is the shortening velocity, a is the heat constant, and b is the energy liberation rate constant. The curvature of the F-v relation is proportional to the ratio FJa. The term F,/a has been related to the thermodynamic efficiency of the muscle (280,281). After this, thermomechanical (or heat) economy of isometric contraction was defined as isometric tension (F,) or the tension-time integral (JFdt) divided by the heat (H) associated with the isometric response (7, 8). This ratio (F,/H or JFdt/H) was found to be proportional to F,/a (8). Thus a slower muscle generates force more economically than a faster muscle (8). Although Hill’s equation was originally believed to hold generally in muscles, it is now clear that it does not hold universally, even in skeletal muscle (281). The generality of Hill’s equation is much weaker in myocardium (163). However, on the basis of Hill’s equation, the product of F and v is the mechanical power of contraction, which is smaller for a greater curvature or FJa. The

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ENERGETICS

curvature and F,/a increase with decreases in vmax in myocardium as well as in skeletal muscle (8). With the use of Hill’s equation, the myosin ATPase mechanical efficiency (30) for isotonic contraction can be given by the ratio of Fv to (F + a)v, where Fv is the mechanical power output and (F + a)v is the rate of energy utilization by the contraction in excess of basal metabolism and activation energy or the sum of mechanical power and shortening heat. The term Fv/(F + a)v is reduced to l/(1 + a/F), which is l/(1 + Za/F,) at F = 0.5F,. For example, a/F, is 0.25 in frog skeletal muscle and 0.072 in tortoise muscle (280, 281), 0.33 for adult rat fast muscle and 0.17 for adult rat slow muscle (8,281), and 0.26 for thyrotoxic rabbit heart muscle and 0.17 for pressure-overloaded hypertrophied rabbit heart (8). Then l/(1 + Za/F,) is calculated to be 60-67s for the faster muscles and 75-87s for the slower muscles, the difference being a factor of only 1.1 (heart), 1.2 (fast vs. slow muscle), and 1.3 (frog vs. tortoise). The small sensitivity of this efficiency seems related to the constant VoZ-PVA relation, assuming that external work at F = 0.5F, is a constant fraction of PVA. These efficiency values are decreased when activation energy (E) is included in the denominator of the myosin ATPase mechanical efficiency so that active mechanical efficiency (with recovery heat excluded) is expressed as Fv/[(F + a)v + EJ In fact, Fv/[(F + a)v + E] was 45% in frog skeletal muscle and 77% in tortoise skeletal muscle (280). These values decreased to 20 and 35%) respectively, when recovery heat was included (280). Thus a 3.4 times difference of F,/a was reduced to only a 0.6 times difference in the mechanical efficiency. Simultaneously, the ratios of vmax, myosin ATPase activity, and economy of isometric force were 5.7, 15, and 42, respectively, for frog versus tortoise (281); 2.5, 2.3, and 6.4, respectively, for rat fast versus slow muscle (281); and 2.0, 2.5, and 2.0, respectively, for thyrotoxic versus pressure-overloaded heart (8, 144), the values of which are much greater than those for mechanical efficiency. This theoretical consideration also indicates the insensitivity of the mechanical efficiency of muscle to wide changes in myosin ATPase activity and other related parameters. Because PVA represents the maximum limit of mechanical work, the contractile efficiency to mechanical energy would reasonably have a similar insensitivity to myosin ATPase activity. The actin-activated myosin ATPase activity of V1 type and V3 type differ only twofold (7, 10, 174). Therefore even this full change may only slightly affect the mechanical efficiency of the heart according to the above considerations. VII.

REMAINING

PROBLEMS

Major interesting problems remain to be solved. First, the concept of PVA as a measure of total mechanical energy derives from the ideal time-varying elastance model (212). Although the concept of PVA (or total mechanical energy) may be somewhat modified with complexity of the ventricular mechanical model,

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the load- and contractility-independent slope of the Vo,-PVA relationship is almost an empirical fact. The generality of this fact and the mechanism underlying this factual relation must be pursued by more extensive experiments using different heart and myocardium preparations under a variety of experimental conditions, as well as by theoretical studies (29, 290). Second, the slope of the VOW-PVA relation, intriguingly, has some interindividual scatter around the mean (225, 229). The underlying mechanism of this scatter has been searched for in vain: no significant correlation has been found between the slope and LV weight, heart rate, or Emax (225, 229). In each LV, the slope did not change even with cooling, which presumably decreases myosin ATPase activity and cross-bridge cycling rate and increases the economy of force (220). It remains unknown whether or not the interindividual variation of the slope reflects the interindividual difference in efficiency of either the oxidative phosphorylation or the contractile machinery or both (see sect. VI@. Much remains to be studied in this area. Finally, the smaller slope of the VO,-PVA relation of preloaded and then quickly released contractions contradicts the straightforward induction of the timevarying elastance model (96, 287). Elucidation of the mechanism behind this phenomenon will promote a better understanding of myocardial energetics as well as the nature of PVA. VIII.

CONCLUSION

The correlation of voz (myocardial O2 consumption) with the new measure of total mechanical energy of ventricular contraction in terms of PVA (systolic P-V area) has enabled us to study cardiac mechanoenergetic coupling through a new window that was first opened by the concept of PVA about 10 years ago. The most important finding attributable to PVA and its tight coupling with 00, is the load- and contractility-independent stoichiometry of energy conversion from the excess VO, above unloaded vo2 to the generation of total mechanical energy quantified by PVA. This finding could indicate the load- and contractility-independent stoichiometry of energy conversion of the cross-bridge cycling under the assumption of a constant metabolic efficiency of the oxidative phosphorylation. Despite the advantageous feature of PVA, problems remain to be solved empirically and theoretically. Although PVA is theoretically a quantity of energy and correlates empirically with TO,, the nature of PVA and its linear counterpart FLA, particularly their potential energy part, remains to be identified by using more realistic cross-bridge kinetics. For this identification, more details not only of energy transduction steps in the cross-bridge cycling in general (132, 173, 281) but also of their intricate load-dependent autoregulatory control in myocardium (8,66,67,70) remain to be elucidated. For the reader who is interested in a wider scope of cardiac and myocardial energetics and related aspects

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of muscle energetics in general, References 47, 57, 91, 103, 104, 112, 132, 142, 156, 168, 170, 173, 181, 186, 195, 201,257,265,273,281,294 are recommended. I thank the late Dr. Kiichi Sagawa for allowing me to start cardiac energetics research while I was in his group in the USA and for encouraging me even after I came back to Japan and Dr. Ishio Ninomiya for providing generous support in the form of finance; space, and manpower for me to continue cardiac energetics research while I was in his group.

REFERENCES 1. AKERA, T., AND T. M. BRODY. The role of Na+, K+-ATPase in the inotropic action of digitalis. PharmacoZ. Rev. 29: 187-220, 1978. 2. ALLEN, D. G., AND J. R. BLINKS. Calcium transients in aequorin-injected frog cardiac muscle. Nature Lond. 273: 509-513, 1978. 3. ALLEN, D. G., AND S. KURIHARA. Calcium transients in mammalian ventricular muscle. Eur. Heart J. 1, SuppZ. A: 5-15, 1980. 4. ALLEN, D. G., P. G. MORRIS, C. H. ORCHARD, AND J. S. PIROLO. A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis. J. Physiol. Lond. 361: 185-204, 1985. 5. ALLEN, D. G., AND C. H. ORCHARD. Intracellular calcium concentration during hypoxia and metabolic inhibition in mammalian ventricular muscle. J. Physiol. Lond. 339: 107-122, 1983. 6. ALLOUSI, A. A., AND A. E. FARAH. Amrinone: a new oral and parenteral cardiotonic agent. Trends Pharmucol. Sci. 1: 143-146, 1980. 7. ALPERT, N. R., AND L. A. MULIERI. Increased myothermal economy of isometric force generation in compensated cardiac hypertrophy induced by pulmonary artery constriction in the rabbit. Circ. Res. 50: 491-500, 1982. N. R., AND L. A. MULIERI. Myocardial adaptation to 8. ALPERT, stress from the viewpoint of evolution and development. In: Basic Biology of Muscle: A Comparative Approach, edited by B. M. Twarog, R. J. C. Levine, and M. M. Dewey. New York: Raven, 1982, p. 173-188. N. R., AND L. A. MULIERI. Heat, mechanics, and 9. ALPERT, myosin ATPase in normal and hypertrophied heart muscle. Federation Proc. 41: 192-198,1982. 10. ALPERT, N. R., AND L. A. MULIERI. Determinants of energy utilization in the activated myocardium. Federation Proc. 45: 2597-2600,1986. 11. ALPERT, N. R., L. A. MULIERI, R. Z. LITTEN, AND C. HOLUBARSCH. A myothermal analysis of the myosin crossbridge cycling rate during isometric tetanus in normal and hypertrophied rat hearts. Eur. Heart J. 5, Suppl. F: 3-11,1984. 12 APSTEIN, C. S., Y. LECARPENTIER, J. J. MERCADIER, J. L. MARTIN, F. PONTET, C. WISNEWSKY, K. SCHWARTS, AND B. SWYNGHEDAUW. Changes in LV papillary muscle performance and myosin composition with aortic insufficiency in rats. Am. J. Physiol. 253 (Heart Circ. Physiol. 22): H1005-HlOll, 1987. 13. APSTEIN, C. S., AND J. D. OGILBY. Effects of “paradoxical” systolic fiber stretch on ischemic myocardial contracture, compliance, and contractility in the rabbit. Circ. Res. 46: 745-754, 1980. 14. ASANOI, H., T. KAMEYAMA, S. ISHIZUKA, M. FUJITA, AND S. SASAYAMA. Influence of inotropic state on energy conversion efficiency of human left ventricle (Abstract). Circulation 78, Suppl. II: 11-6, 1988. 15. BARANY, M. ATPase activity of myosin correlated with speed of muscle shortening. J. Gen. Physioh 50: 197-216, 1967. 16. BARCLAY, J. K., C. L. GIBBS, AND D. S. LOISELLE. Stress as an index of metabolic cost in papillary muscle of the cat. Basic Res. Cardiol. 74: 594-603, 1979. 17. BENFEY, B. G., M. S. ELFELLAH, R. I. OGILVIE, AND D. A. VARMA. Antiarrhythmic effects of prazosin and propranolol

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19. 20.

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Ventricular energetics.

hysiological Reviews Published and Copyright by The American Physiological Society Vol. 70, No. 2, April 1990 Ventricular HIROYUKI Energetics SUGA...
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