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