Hypertension. 1998;31:949-960
(Hypertension. 1998;31:949-960.)
© 1998 American Heart Association, Inc.
Myocardial Contractile Efficiency and Oxygen Cost of Contractility Are Preserved During Transition From Compensated Hypertrophy to Failure in Rats With Salt-Sensitive Hypertension
Isao Morii;
Yasuki Kihara;
Moriaki Inoko;
; Shigetake Sasayama
From the Department of Cardiovascular Medicine (Internal Medicine III),
Kyoto University Graduate School of Medicine, Kyoto, Japan.
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Abstract
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Abstract—In Dahl-Iwai rats,
salt-sensitive hypertension causes concentric left
ventricular hypertrophy (LVH) at the age of 11
weeks, which is followed by LV dilatation with global hypokinesis and
pulmonary congestion, ie, LV failure (LVF), at 16 to 18 weeks
of age. To address the question of whether the cardiac remodeling from
LVH to LVF is associated with modulations of mechanoenergetic
properties, we serially measured the LV pressure-volume area (PVA) and
myocardial oxygen consumption (M
O2) in
isolated, isovolumically contracting hearts from this animal model. The
end-systolic pressure-volume relationships obtained by stepwise
changes of the LV volume were fit into a binominal regression model,
which provided a value of LV contractility
(Ees) and a volume intercept (V0). A slope (the
reciprocal of the LV contractile efficiency) and a PVA-independent
MO2 were determined by a regression
analysis of the MO2-PVA
relation. The procedure was repeated at different Ca2+
concentrations in perfusate to estimate the oxygen cost of
contractility
(dMO2/dEes).
The MO2 was further evaluated during
K+-induced cardiac arrest to delineate the basal
metabolism, which was independent of the E-C coupling.
During the transition from LVH to LVF, the Ees was
decreased by 50% (from 681 to 338 mm Hg · g ·
mL-1, P<.001), which was associated with a
substantial increase in V0 (from 0.002 to 0.07 mL,
P<.01). These alterations in both the inotropic state
and the ventricular shape were associated with a 45%
decrease in the PVA-independent MO2
(from 800 to 440 mL O2 · beat-1
· g-1, P<.01). Despite these marked
changes between the two stages, both the LV contractile efficiency and
the oxygen cost of contractility remained unchanged.
The MO2 during cardiac arrest also
showed an equal level among the groups; hence, from LVH to LVF, the
nonmechanical O2 consumption by the E-C coupling decreased
in a manner parallel to the basal contractile state. We conclude that
(1) in this animal model, the heart failure transition is associated
with a marked decrease in myocardial contractility and
with ventricular remodeling; (2) despite these changes, the
efficiency of the chemomechanical conversion is highly preserved; and
consequently, (3) the total energy consumption per unit of failing
myocardium is diminished along with its reduced
nonmechanical energy expenditure for E-C coupling. These
mechanoenergetic properties might constitute an adaptive mechanism in
the energy-starved condition of chronically diseased myocardium.
Key Words: heart failure • contractility • ventricular function • rats, Dahl
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Introduction
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In states of chronic
heart failure, the biochemical composition of the
ventricular wall, the orientation of the cardiac muscle
fibers, and the geometry of the ventricular chamber are all
altered. LV remodeling is the term used to describe these facets of
cardiac adaptation in disease.1 Some aspects of
the remodeling process may be beneficial to overall cardiac
function2 3 4 ; however, most of the other aspects
are maladaptive in the long term.5 On the basis
of a number of recent clinical trials,6 7 8 9 10 which
consistently reached the conclusions that (1)
ventricular remodeling is progressive in nature, (2) the
patients show limited survival, and (3) unloading therapies are
beneficial for restoring the life expectancy of these patients, it is
generally assumed that the ventricle with remodeling not only decreases
the myocardial contractility but also wastes excessive
energy by producing a unit force resulting in an energy-starved
condition.11 12 Despite the presence of several
established animal models of heart failure, this important issue has
been investigated in a very limited number of
studies,13 14 15 and the results obtained are
inconsistent. The reasons for the inconsistency may
be a lack of suitable reference animals, difficulties in documenting
the condition before the heart failure transition, or massive fibrosis
that makes the accurate normalization of the energy utilization per
tissue erroneous.
Recent studies in our laboratory16 17 have shown
that when the proper timing of the initiation of high salt diet is
selected, DS rats show LV concentric hypertrophy with
normal midwall stress and neurohumoral activities. These findings are
soon followed by the dilatation and global hypokinesis of LV with
elevated midwall stress, augmented hormonal activities, and
pulmonary congestion. The alterations of chamber and myocardial
contractility have been demonstrated during the
transition from compensatory LVH to LVF in both in
vivo16 17 and in vitro16
studies. Hence, this animal model might provide an opportunity to
investigate the changes in myocardial energetics during the mechanical
transition/remodeling process. The concepts of systolic LV
elastance (Emax) and PVA proposed by Suga and
others18 19 20 have facilitated research on
myocardial mechanoenergetics in isolated animal
hearts,21 22 23 as well as in in vivo human
hemodynamics.24 In the
present study, using the PVA versus myocardial
MO2 framework in hearts
isolated from DS rats at different stages, we quantitatively delineated
the alteration of myocardial energetics that occurred during the heart
failure transition/ventricular remodeling process.
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Methods
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Dahl Rat Heart Failure Model
Male inbred DS and DR rats that were obtained from Brookhaven
National Laboratories (Upton, NY) were bred and supplied by Eisai Co
(Tokyo, Japan).16 The rats were fed a 0.3% NaCl
(low salt) diet after weaning until the age of 6 weeks, after which
they were fed an 8% NaCl (high salt) diet. The special diet and tap
water were given ad libitum throughout the experiment. As we reported
previously,16 17 under this protocol, DS rats
develop concentric LVH at the age of 11 weeks (LVH-DS) followed by
marked LV dilatation at the age of 16 to 20 weeks (LVF-DS). During the
latter stage, DS rats show the labored respiration with LV global
hypokinesis and enlargement that is characteristic of congestive heart
failure. After the onset of respiratory distress, these rats die within
1 week of pulmonary congestion. For the present study, we
used LVH-DS (n=12), LVF-DS (n=11), and age-matched DR (11-week-old and
18-week-old; n=11 and 10, respectively) strains of animals. The details
of the time course of transition to LVF, changes in neurohumoral
factors, and pathological findings are described
elsewhere.16 17
To ascertain the LV functional status between the two stages (LVH and
LVF), transthoracic echocardiography
and tail-cuff blood pressure measurement were performed on the day
before the animals were killed for the isolated heart
experiments.16 M-mode echocardiograms at the
papillary muscle level were guided by the two-dimensional long-axis
image (model HP77010, Hewlett-Packard Co, with a 7.5-MHz sector scan
probe) and recorded under mild anesthesia
(pentobarbital 15 mg/kg IM). We determined the LV
end-diastolic diameter (EDD) as the widest and the LV
end-systolic diameter (ESD) as the narrowest dimension in the
M-mode recordings. The LV posterior wall thickness (PWT) was
measured at the time of the EDD measurement. For each measurement, data
from five repeated records were averaged. From these measurements,
the LV fractional shortening (FS) and LV end-systolic
meridional wall stress
(
m)25 were calculated
according to the following formulas:
 | (1) |
 | (2) |
The peak systolic blood pressure (SBP) in Equation 2
was
obtained noninvasively from the tail-cuff pressure
measurement.16
Isolated Heart Preparation
In each experiment, a rat was heparinized (2000 U/kg IP) and
then anesthetized with sodium pentobarbital (100 mg/kg IP). A
midline sternotomy was performed, and the inferior and
superior venae cavae were ligated near their insertions into the right
atrium. The heart was rapidly excised and submerged into
oxygenated perfusate (37°C, composition provided
below). The severed end of the ascending aorta was immediately fed over
a 16-gauge needle (covered with silicone tubing) that was connected to
a Langendorff coronary perfusion
system.26 The perfusate flow was
initially adjusted to provide a mean CPP of 100 to 120 mm Hg. The
CPP was readjusted to 140 mm Hg at the end of preparation. The
coronary flow rate was kept constant during the experiment.
This relatively high CPP was used because of the systemic hypertension
in DS rats. In preliminary experiments, hearts isolated from DR rats
showed the typical Gregg's phenomenon27 in the
range of 80 to 150 mm Hg and were stable in this perfusion
range.
The LV apex was punctured with a thin piece of Tygon tubing to
discharge the Thebesian drainage.26 Another piece
of soft silicone tubing with a fenestrated tip was advanced into the
right ventricle via the main pulmonary artery and then held in
place by suturing it securely at its base. The opposite end of this
tube was placed 5 cm below the position of the heart, and the collected
fluid (all perfusate through the coronary sinus and the
right ventricular Thebesian veins) was passed down the tube
by siphoning.
The left atrial appendage was opened, and a thin latex balloon
that was attached to the end of a 10-cm piece of stiff polyethylene
tubing was inserted into the LV cavity through the mitral valves. The
balloon was held in place by a purse-string suture around the mitral
annulus, ensuring that the circumflex coronary artery was not
damaged. The balloon and tubing were filled with water and connected to
a pressure transducer (Hewlett-Packard 1280A) for measurement of the
isovolumic LV pressure. The balloon volume was controlled using a
calibrated 0.5-mL gas-tight Hamilton syringe.28
To prevent contamination of the latex balloon elastance in the LV
pressure measurement, the balloon was tested before each experiment and
used only when it did not generate any pressure until the intraballoon
volume exceeded 0.5 mL. The volume of the balloon plus the tip of the
tubing within the balloon (range, 0.12 to 0.18 mL) was measured by
water displacement after all fluid was withdrawn from inside the
balloon; this value was added to the volume infused inside the balloon
to obtain the total LV volume.
A bipolar pacing catheter was inserted into the right ventricle through
the right atrium and then connected to an electronic stimulator
(SEN-3201, Nihon-Kohden) that was paced at 10% above the threshold at
3.33 Hz (200 bpm).26
The heart was submerged into the heat-jacketed organ bath at 37°C.
The flow rate of the coronary perfusion was kept constant by an
adjustable-speed rotary pump (Masterflex model 7523-10, Cole-Parmer
Instruments Co), and the CPP was continuously monitored from the
sidearm of the perfusion line that was attached to another pressure
transducer. The perfusate was composed of (in mmol/L) NaCl
135.0, KCl 5.0, Na2HPO4
0.33, MgCl2 1.0, CaCl2 0.7,
dextrose 10.0, and HEPES 5.0.26 28 The pH was
adjusted to 7.40 with NaOH at 37°C, and the solution was continuously
bubbled with 100% O2 to yield a maximal oxygen
tension. The heart was allowed to stabilize for at least 30 minutes,
during which time the LVP, CPP, and the O2
tension of the coronary effluent (vide infra) were
monitored.
MO2 Measurement
The O2 contents of the
coronary perfusate and the effluent were continuously
monitored with a pair of O2 electrodes (Clark
type, Unique Medial Co), one of which was inserted to the perfusion
line at the level of the ascending aorta and the other of which was
positioned inside the pulmonary arterial drain
tubing.28 Sodium dithionate was used to determine
the baseline of the electrodes at the beginning of each experiment. The
gains of the electrodes were calibrated against the perfusate
solution, which had been equilibrated with 100%
O2. The O2 content was
referred to a Lex-O2-CON blood gas
analyzer. The MO2 was
determined as the difference of O2 contents
between the two electrodes (A-VDO2) times the
coronary flow (CF) rate. The CF rate was measured by the timed
collection of the pulmonary effluent in a calibrated
cylinder.
Experimental Protocols
In all preparations, the LV mechanical performance and
MO2 were studied while the
workloads were varied by stepwise increments of the LV volume. The
pacing rate (3.33 Hz) and the CF rate (adjusted to 140 mm Hg at
the end of preparation) were kept unchanged. The measurements were
repeated when the LVP and A-VDO2 reached a steady
state at each LV volume. One series of the volume run was usually
completed within 30 minutes. The reproducibility of the maneuver was
checked by observing that the values of the ESPVR (vide infra) were
always within 95% confidence limits in the DR strain (n=6) after
multiple volume runs. On the basis of this observation, we set a
criterion that the data would be discarded when the LVP after a run had
not returned to a level >90% of the control LV volume.
After the initial volume run (Ca2+ 0.7
mmol/L), the Ca2+ concentration in the
perfusate was increased to 1.0 mmol/L and then to 2.0
mmol/L. At each Ca2+ level, the volume run was
repeated using the same incremental protocol. Recordings at the
Ca2+ concentration of 1.0 mmol/L were taken
as the standard. Along with the exclusion criterion, the results of the
following animals were not included in the data analysis
because of their incomplete recovery after each of three serial volume
runs: 6 of the 12 LVH-DS rats, 5 of the 11 DR rats at 11 weeks, 5 of
the 11 LVF-DS rats, and 4 of the 10 DR rats at 18 weeks. Subsequently,
6 animals from each group were subjected to the data analysis
(vide infra). The stability of the preparations and the reproducibility
of responses to the workloads appeared not to differ among these
groups.
At the end of the study, the heart was arrested by replacing the
perfusate with that containing 30 mmol/L KCl (NaCl was
reduced to 110 mmol/L).13 23 The LV balloon
volume was gradually reduced until zero pressure was attained, and the
LV volume at that time was recorded as the reference chamber volume
(Vref).4 13 After the
measurement of the Vref was repeated three times,
the heart was removed from the Langendorff system and the weights of
the LV and right ventricular free wall were measured.
Data Analysis
In each volume run, the LV end-diastolic
(Ped) and end-systolic
(Pes) pressures were plotted against the LV
volume (V) to construct the pressure-volume diagram. To assess the
contractile state of the LV, the ESPVRs were fit into a nonlinear
regression analysis13 23 28 29 :
 | (3) |
where V0 is the volume
axis-intercept of the ESPVR and Ees is the slope
of the extrapolated ESPVR at the volume of V0.
is the index of the degree of ESPVR curvilinearity. The
significance of that represented the curvilinearity of
ESPVR was determined by Student's t test.
The EDPVRs were fit to a monoexponential
equation4 13 :
 | (4) |
where Ved is the end-diastolic
volume, P0 is the pressure at
Ved=0, and ß and 
are nonlinear fit
parameters. Diastolic chamber stiffness
(dPed/dVed)
was calculated from the first derivative of Equation 4.
The pressure-volume relationships have limitations in the
assessment of the contractile state of the unit myocardium
because of their dependence on chamber size and ventricular
mass. To further quantify the myocardial contractile state, a
stress-strain analysis with a thick-walled spherical
ventricular model was used (see Appendix
for details). The
end-systolic circumferential wall stress-strain relation was
fit by the following equation:
 | (5) |
where es is the end-systolic
stress, 
es is the end-systolic strain,
and A and B are fit parameters.
The total energy liberated by the ventricle under the isovolumic
conditions was quantified by the PVA. The PVA was defined as the area
circumscribed by the ESPVR, EDPVR, and the systolic portion of
the pressure-volume trajectory.18 19 21 The value
of PVA was normalized by the LV mass to 1 g. The value of
MO2 was reported as
milliliters of O2 per beat per gram LV after the
estimated right ventricular
MO2 was subtracted. The
MO2 by an unloaded right
ventricle might consist of a small part of the measured
MO2; hence, it was
approximated by multiplying the
MO2 value at unloaded
contractions (the intercept of
MO2 axis at estimated zero
PVA) by the ratio of the right ventricular mass to the
total heart mass.21 28 30 To assess the
contractile efficiency, a linear regression analysis was then
performed to quantify the slope (C) and intercept (D)
parameters of the
relationship:18 19 21 23 28 30
 | (6) |
The enhancement of Ees by increasing
the Ca2+ concentration in the perfusate
shifted the MO2-PVA
relationship in a parallel manner (increases in the intercept D,
whereas the slope C was unaffected). Therefore, the relationship
between Ees and the corresponding PVA-independent
MO2 (intercept D) was plotted
to the following equation:
 | (7) |
where the slope of this regression line, E, represents
the oxygen cost of
contractility.13 20 29 31
Statistics
Data are presented as mean±SEM unless indicated
otherwise. Comparisons of variables among the groups were made by
one-way ANOVA. When the F test indicated a significant difference among
the groups, the difference in mean values was tested by Fisher's
protected least-significant difference method. Comparisons of the
MO2-PVA regression lines and
comparisons of the regression lines of PVA-independent
MO2 on
Ees among the groups were performed by ANCOVA.
Significant differences were determined by F test. Values of
P<.05 were considered significant.
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Results
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Transition from LVH to LVF in Dahl Rats
Table 1 summarizes the
hemodynamic and pathological profiles of the Dahl rats
enrolled in the data analysis. The LVH-DS and LVF-DS groups
showed systemic hypertension to the same extent. Despite the excessive
afterload, the systolic wall stress of the LVH-DS remained
within the normal range because of a 53% increase in the wall
thickness.16 17 In contrast, in the LVF-DS, the
wall stress increased to a level four times greater than that in the
age-matched controls. This was associated with a marked increase in the
chamber diameter and a decrease in the fractional
shortening.16 17 The unstressed LV volume
(Vref) in the LVF-DS rats also showed a 58%
increase. This set of changes seen in DS rats during a short period
provides a paradigm of the transition from LV compensatory
hypertrophy to decompensated failure with the typical
features of LV remodeling. The control animals, DR rats fed the same
high salt diet, did not develop systemic hypertension and maintained a
normal hemodynamic profile with no increase in the LV
to body weight ratio.
Changes of Systolic Ventricular Mechanics
During Transition to Heart Failure
Fig 1 presents the
pressure-volume relationships plotted from the
representative hearts. During each volume run, five to
eight points at end systole and at end diastole were
plotted. We observed that both the ESPVR and the EDPVR in the LVH-DS
group were consistently shifted to the left (upward) of those
in the 11-week-DR group. In contrast, both the ESPVR and EDPVR in the
LVF-DS rats were located to the right (downward) of those in the
18-week-DR group.
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Figure 1. ESPVR and EDPVR in representative
experiments: left, LVH-DS vs 11-week-DR; right, LVF-DS vs 18-week-DR.
LVV and LVP represent left ventricular volume and
pressure, respectively. The Ca2+ concentration in the
perfusate was 1.0 mmol/L. Symbols show the individual
data, and the superimposed lines show the curve fitting for each
group.
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Because inspections of the ESPVRs suggested that their curvilinearity
could alter depending on the stage or the ventricular
size,29 32 we used a parabolic (binominal) curve
fitting (Equation 3) for the analysis, which provided reliable
fits in preparations from all four groups (the r values are
presented in Table 2). The
coefficient of the second term () was significantly different from
the nil value in the LVH-DS and DR groups, indicating their nonlinear
relationships. By contrast, in the failing hearts of the LVF-DS, the
relationship typically showed a linear fitting, and the value for this
group was not significantly different from zero. The result supported
the idea that for the comparative analysis of the ESPVR among
hearts of different sizes or from different stages such as those
examined in this study, the binominal nonlinear fitting might be more
suitable than the standard linear regression method.
Table 2 summarizes the data of the ESPVR of the four groups. The
LVH-DS group showed a significant increase in
Ees, whereas the V0 was
equivalent to that of the age-matched DR rats. In contrast, in the
LVF-DS rats, the Ees was markedly reduced to 50%
of that of the LVH-DS rats and to 78% of that of the age-matched DR
rats, which was associated with a significant increase in
V0. This change in V0 was
consistent with the twofold increase in
Vref measured in the
K+-arrested condition (Table 1).
Changes of Myocardial Contractility
The contractile states of the unit myocardium in
the isolated hearts were estimated independently of the chamber
geometry and mass by a stress-strain relationship. In Fig 2, the end-systolic stress-strain
relations from all experiments were plotted, and the fitted lines for
each group were superimposed on the individual data. The regression
line of the LVH-DS group was significantly different from the lines of
the other three groups in its shift toward the left. By contrast, the
line of the LVF-DS group was located to the right of the others. The
relations between the 11-week-DR and the 18-week-DR were
superimposable. Hence, the hypercontractile state of the
unit myocardium caused the increased
Ees in the LVH-DS rats, whereas it
showed a marked decrease during the transition and resulted in the LV
hypocontraction in the LVF-DS rats.
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Figure 2. End-systolic stress-strain relationships
in the LVH-DS (left) and LVF-DS (right) rats compared with those of the
age-matched DR rats (n=6 in each group). The Ca2+
concentration in the perfusate was 1.0 mmol/L. Symbols
(closed symbols for the DS rats and open symbols for the age-matched DR
rats) show individual data, and the superimposed lines show the curve
fitting for each group.
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Diastolic Ventricular Mechanics
As noted above, the EDPVR in the LVH-DS group was located to
the left side of the control, whereas the EDPVR in the LVF-DS group
shifted to the right and downward. Despite these alterations, the
diastolic chamber stiffness, , as estimated from the
monoexponential fitting, was not significantly
different among the groups (Table 2). We further examined the slope of
the EDPVR at a common end-diastolic pressure of 15
mm Hg.13 The values were also similar among the
groups (112 and 110 mm Hg/mL in 11-week-DR and 18-week-DR,
127 mm Hg/mL in LVH-DS, and 136 mm Hg/mL in LVF-DS; no
significance between any two groups). In crystalloid-perfused
preparations, the diastolic chamber characteristics might
be affected by the tissue water content.24 33 34
The myocardial flow rates (CF/LV mass), however, were not different
among the groups (25 mL/g in both 11-week- and 18-week-DR, 25 mL/g in
LVH-DS, and 23 mL/g in LVF-DS; no significant difference between any
two groups).
Effects of Inotropic Intervention and Myocardial
Energetics
The myocardial contractility was varied by
changing the Ca2+ concentration in the
perfusate
([Ca2+]o) from 0.7
mmol/L to 1 mmol/L and then to 2 mmol/L. As shown in Fig 3A, the end-systolic points at
any [Ca2+]o level were
fit equally well by the binominal regression. The increase in
[Ca2+]o did not affect
the value of V0. In contrast, the levels of
Ees were significantly augmented in both the
LVH-DS and LVF-DS groups (Fig 3B). It is noteworthy that although the
baseline levels of Ees were different by
approximately twofold between the two stages, their percentages of
augmentation by this increase in
[Ca2+]o were similar
(53% in LVH-DS, 57% in LVF-DS).
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Figure 3. A, Changes in ESPVRs during inotropic intervention
in the LVH-DS (left) and LVF-DS (right) rats in
representative experiments. LVV and LVP
represent left ventricular volume and pressure,
respectively. The inotropic states were varied by changing the
Ca2+ concentration in the coronary
perfusate from 0.7 mmol/L to 1.0 mmol/L, and then to
2.0 mmol/L. Symbols show the individual data, and the superimposed
lines show the curve fitting for each group. Note that the regression
lines appear curvilinear for the LVH-DS group, whereas those for the
LVF-DS group are much more linear. B, Grouped data of a value of LV
contractility (Ees) during the inotropic
intervention with [Ca2+]o (0.7 to 2.0
mmol/L) in the LVH-DS (open bars, n=6) and the LVF-DS (solid bars, n=6)
groups.
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Fig 4 shows the grouped data of the
MO2-PVA relationships from the
LVH-DS and 11-week-DR rats (left) and LVF-DS and 18-week-DR rats
(right). The MO2-PVA relations
were highly linear in the range examined in all groups, and their lines
were essentially in parallel. Hence, the slope C was unchanged among
the groups. Interestingly, the line of the LVH-DS group was located in
a position superior to that of the age-matched controls, whereas
the line of the LVF-DS group was located inferior to that
of the 18-week-DR rats. This resulted in a 45% reduction of the
intercept D during the transition from LVH-DS to LVF-DS. In contrast,
between the 11-week-DR and 18-week-DR groups, the intercepts were
equal, resulting in their superimposable
MO2-PVA relations.
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Figure 4. PVA-MO2
relationships in the LVH-DS (left) and LVF-DS (right) rats compared
with those of the age-matched DR rats. Each point (closed symbols for
the DS rats and open symbols for the age-matched DR rats) was obtained
during a stepwise change of the LV volume. Grouped data from 6 animals
in each group are presented. Lines show the linear regressions.
The Ca2+ concentration in the perfusate was
1.0 mmol/L; the ventricular pacing was set at 3.33
Hz.
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The inotropic run by changing
[Ca2+]o
consistently affected the levels of intercept D in all stages.
However, the [Ca2+]o
level did not modulate the slope C in any group (Table 3). The changes of intercept D by
[Ca2+]o were plotted
against the concomitant increases in Ees in Fig 5, and the slopes are presented
as E (Equation 7) in Table 3. This value, an index of the oxygen cost
of contractility, did not differ significantly among
the groups.
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Table 3. Analysis of
MO2 and PVA Relations and
Ees and PVA-Independent MO2
Relations: Summary of Linear Regression Analysis
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Figure 5. Ees versus PVA-independent
MO2 relationships (oxygen cost of
contractility) during inotropic intervention in the
LVH-DS (n=6), LVF-DS (n=6), and their age-matched DR groups (n=6,
respectively). The inotropic states were varied by changing the
Ca2+ concentration in the perfusate from 0.7
mmol/L to 1.0 mmol/L, and then to 2.0 mmol/L. The individual
data are plotted. The lines show results of the linear regressions.
These four lines are essentially superimposable.
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To further elucidate what aspect of the cellular oxygen consumption was
reduced in the failing myocardium, we measured the
MO2 in the
K+-arrested hearts. The remaining
MO2 in this condition should
be derived from subcellular activities that were independent of the E-C
coupling.13 23 35 Despite substantial differences
in the PVA-independent MO2,
the K+-arrested myocardium from any
stage consumed the same amount of oxygen (36±5 mL
O2 · g LV-1
· min-1 in LVH-DS, 37±5 mL
O2 · g LV-1
· min-1 in LVF-DS, NS, n=6, respectively; Fig 6). This result indicates that the
substantial reduction of myocardial oxygen consumption in heart failure
transition is primarily due to the diminished subcellular activity
regarding the E-C coupling.
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Discussion
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Heart Failure Transition and Ventricular Remodeling in
Dahl Rats
DS rats were developed in 1962 from the Sprague-Dawley strain by
Dahl and Iwai.36 37 When fed a high salt diet
after weaning (5 to 8 weeks), these rats develop marked systemic
hypertension and have a limited lifespan; they die by the early stage
of their maturity.38 39 It was generally assumed
that uremia due to hypertensive nephrosclerosis was the
cause of the early death.38 However, in our
previous study,16 17 we found that when the high
salt regimen was started when these rats were 6 weeks old, they died at
18 weeks of age from typical LV dysfunction with pulmonary
congestion. This condition was associated with marked increases in LV
systolic wall stress, atrial natriuretic peptide,
and plasma catecholamines but with only a modest impairment
of renal function.16 In contrast to this terminal
stage of LV failure, the same animals at 11 weeks of age showed normal
to hyperdynamic LV function, normal LV wall stress, and normal
neurohumoral conditions despite the presence of the similar afterload
stress (compensatory concentric LVH). On the basis of these
observations, we have proposed this strain as a new model of heart
failure in which investigations could be focused on key factors to
initiate the transition toward heart failure. There are several types
of animal models of LV failure, including senile spontaneous
hypertensive rats,40 rats with chronic aortic
banding41 or coronary-ligated
infarction,42 cardiomyopathic
hamsters,43 and dogs with chronic
tachycardia–induced heart failure.44
Because each animal model, including ours, has both advantages and
disadvantages, investigators should select the most appropriate model
on the basis of their research needs and purposes. In this regard, the
DS rat model provides an opportunity to address questions concerning
the pathophysiological changes that occur during
heart failure transition.
In the present study, using coronary-perfused hearts
isolated from Dahl rats, we confirmed that the marked alteration of
chamber contractility in association with changes in
the LV mass and geometry occurred during a short period of transition
from LVH to LVF. The stress-strain analysis precluded the
possible role of the chamber geometry as a major cause of the LV
contractile dysfunction and further suggested that a substantial change
of the contractile performance of unit myocardium
played the critical role in the chamber dysfunction. We demonstrated
previously that this transition process to LVF was not associated with
the significant loss of contractile elements (in LVF-DS, the
fibrosis/cross-sectional area remained <2.0%, and this tissue
fibrosis occurred mainly around the epicardial coronary
arteries and not in the subendocardial layers).16
The present data further indicate that the E-C coupling process in
each myocardial cell is responsible for this mechanical deterioration.
We also demonstrated here for the first time that the failing
myocardium utilized 45% less oxygen for its basal
activities (PVA-independent O2 cost) when
compared with the preceding compensatory myocardium. At the
same time, both the contractile efficiency and the oxygen cost of
contractility remained unchanged. Thus, we confirmed
that the efficiency of chemomechanical conversion is highly preserved
despite the chronically diseased condition with contractile failure.
Consequently, the total oxygen consumption per unit of failing
myocardium was diminished along with its reduced activity
in the E-C coupling process.
Mechanoenergetics in the Failing Rat Heart
The mechanical characteristics of isolated rat hearts under
crystalloid coronary perfusion were extensively evaluated by
Wannenburg et al.28 They reported that the
preparations were stable over a period of 60 minutes and that the
general characteristics of the ESPVR were similar to those reported for
isolated blood-perfused dog21 and
rabbit30 hearts. They also showed that the ESPVRs
were equally well fit to both linear and nonlinear curves and that the
presented Ees values were comparable to
those in standard blood-perfused hearts. Our nonlinear regression
analysis of ESPVR in the DR and LVH-DS hearts showed that the
curvilinearity index was significantly different from nil. This
indicates that the nonlinear regression is more suitable for this
analysis than is the linear regression for such minuscule
hearts. However, the dilated hearts of the LVF-DS rats
presented a linear ESPVR. This stage-dependent difference is
not surprising, since as discussed
elsewhere,29 32 the ESPVR unfolded into a sigmoid
shape when the relationship was plotted on a wide range of pressure.
The smaller the heart, the closer to the upper corner of the sigmoid
configuration the relationship locates and vice versa, as is known for
the hearts from larger animals. Hence, along with the progression of
remodeling, the apparent relationship might become more linear by
shifting the operating range toward the middle portion of the sigmoid
curve. The values of Ees estimated in our control
animals (435 to 451 mm Hg · g ·
mL-1) were lower than those reported by
Wannenburg et al28 (645 mm Hg ·
g · mL-1). However, this is not
discordant when our relatively lower Ca2+
concentration in the control perfusate is taken into account
(1.5 mmol/L in the Wannenburg et al28 study
versus 1.0 mmol/L in our study). Taken together, the results
obtained from our experimental settings were qualitatively and
quantitatively consistent with those observed by Wannenburg et
al, and they further validated the efficacy of the PVA analysis
in such small hearts.
There are few experimental studies regarding the quantitative
analysis of mechanoenergetics in the failing heart, and the
observations that have been obtained are controversial. Goto et
al14 demonstrated the downward and parallel
displacement of the PVA-MO2
relationship in isolated hearts from pacing-induced failing dogs. Using
the same rapid-pacing dog hearts, however, Wolff et
al13 reported that the slope became steeper in
the failing heart while the PVA-independent
MO2 (intercept) remained
unchanged. The causes of these differences have not been elucidated.
One major shortcoming of these two studies is that neither of them
showed the sequential changes in these relationships before and after
the heart failure transition. Using isolated hearts from senile
spontaneously hypertensive rats, Brooks et al15
showed that the systolic stress generation at a given oxygen
consumption was depressed in both failing and nonfailing
myocardium. They interpreted this result as indicating that
the energy utilization of the hypertrophic and failing hearts was less
economical. However, the
stress-MO2 relationship
described may lack a conceptual background in chemomechanical theory.
In addition, a significant loss of myocardial cells and their
replacement with massive fibrosis45 may
complicate the normalization of oxygen consumption per unit of
myocardium. In our study, these issues were obviated by a
set of serial observations in genetically uniform animal
strains46 and by the established pressure-volume
framework. Our results indicated that the parallel and downward shift
of the PVA-MO2 relation is
essential during the heart failure transition, which was
consistent with the study in dogs by Goto et
al.14 In a patient group in which the
Ees levels were widely scattered in a range from
0.8 to 8.8 mm Hg/mL, Kameyama et al47
showed a constancy of the slope of
PVA-MO2 relation (2.46±0.33),
whereas their oxygen axis intercepts decreased along with the reduction
in Ees. Another clinical study by Takaoka et
al24 also presented a similar
distribution of the PVA-MO2
diagram among patients with different levels of LV
contractility. Taken together, these observations
suggest that despite the significant differences in species, heart
size, and etiology of the disease, failing hearts in the decompensated
state might share the common mechanoenergetic characteristics in that
they feature a reduction in the oxygen consumption for the basal
metabolism with no remarkable change in contractile
efficiency.
Subcellular Mechanisms of Mechanoenergetic Changes in the
Failing Heart
The K+-arrested heart showed a
significant reduction in the PVA-independent
MO2 (by 55% to 76%).
Surprisingly, although the MO2
intercept in the beating hearts was different depending on the diseased
condition, the levels were equalized after flaccid cardiac arrest (Fig 6). This novel finding clearly indicates that the stage-dependent
change in the MO2 intercept
relates to the activities of subcellular systems that halt when the
contraction stops. The energy expenditure for the basal
metabolism, in contrast, is independent of the disease
conditions.
The contraction-related process, namely the E-C coupling, includes
energy-dependent components such as actomyosin ATPase,
Ca2+- and Mg2+-dependent
ATPase in the sarcoplasmic reticulum, and sarcolemmal ATPases for the
Ca2+ pump and Na+
pump.48 These ATPase activities are tightly
coupled with the amount of activator
Ca2+ released to the cytosolic space during
membrane depolarization. The ATP consumption increases along with the
increase in the activator Ca2+, which
is expressed as increases in the
MO2 intercept on the
PVA-MO2 framework. This type
of change in energy utilization was well characterized during acute
inotropic interventions by several inotropic
agents.21 Therefore, the mechano-energetic
character of the failing heart appears to be similar with acute
interventions with negative inotropic agents. Actually, the reduced
MO2 intercept in the failing
heart was augmented to a level equal to that of the age-matched DR rats
when the extracellular Ca2+ concentration was
increased to 2.0 mmol/L. Such chronic conditions may occur in two
ways: one is the reduction of the amount of activator
Ca2+ due to the loss or inactivation of ATPases
in the presence of enough ATP/phosphocreatine; the other is the
reduction of cytosolic ATP/phosphocreatine which limits the activities
of these enzymes, resulting in a decrease in
Ca2+. In the present study, we could not
dissect these two mechanisms. However, in another series of experiments
using the same Dahl rat strains, we demonstrated that the
Ca2+ uptake was reduced by 41% in the presence
of a constant ATP concentration in isolated sarcoplasmic reticular
vesicles from the failing DS myocardium. In contrast, these
values in the LVH-DS rats were equal to those of control strains
(unpublished observations, Kihara et al, 1997). Furthermore, in studies
using the same animals, the cytosolic Ca2+
transients from the failing DS rats showed a significant reduction in
amplitude compared with that in the LVH-DS
rats.49 These independent observations strongly
suggest that in this heart failure model, the reduction in the number
of ATP-dependent enzymes and the subsequent decrease in the amount of
mobilized Ca2+ might contribute to the decrease
of energy expenditure for the E-C coupling. These subcellular changes
may not be specific to these rat strains because the downregulation of
sarcoplasmic reticular ATPase was demonstrated in several experimental
models, as well as in explanted human myocardium, in both
protein and mRNA levels.50 A decrease in
actomyosin ATPase was also reported in human failing
myocardium.51
Chemomechanical Conversion Efficiency
We observed that despite a decrease in the energy expenditure for
E-C coupling, neither the contractile efficiency nor the oxygen cost of
contractility were affected during the transition to
heart failure. There was a slight tendency toward a decreased slope of
the PVA-MO2 relationship
between the LVH-DS and LVF-DS groups
(2.35±0.05x10-5 mL
O2 ·
mm Hg-1 · mL-1
versus 2.16±0.07x10-5 mL
O2 ·
mm Hg-1 · mL-1);
however, these values were not significantly different
(P=.20). In addition, they did not show any significance
against the age-matched DR groups. Thus, we concluded that changes in
the chemomechanical conversion efficiency were not the essential factor
in the heart failure transition.
In hypothyroid animals, the isozyme shift of the myosin heavy chain was
associated with increases in contractile efficiency at the expense of
decreased contraction velocity.28 52 A similar
isozyme shift may occur in the rat heart with chronic pressure
overload.53 54 Our preliminary study showed a
30% increase in the expression of ß-myosin heavy chain mRNA in the
LVH-DS (in comparison with the age-matched DR), but the increase was by
only 24% in the LVF-DS rats (unpublished observations, Kihara et al,
1997). These data suggest that the myosin isozyme shift was in progress
in our preparations in both the LVH-DS and the LVF-DS groups. However,
these changes appeared not to be sufficient to modulate the slope of
the contractile efficiency on the
PVA-MO2 diagram. The
cross-bridge cycling rate may also change in the failing
heart.51 However, it was noted that the coupling
rate between ATP hydrolysis and cross-bridge cycling is not fixed in a
one-to-one relation; rather it varies depending on the loading
condition up to 1:6 or more.55 56 Hence, these
changes may not strictly affect the contractile efficiency.
In the present study, the chemomechanical efficiency was quite
constant in a narrow range from 44% to 48% despite different disease
conditions. In excised dog hearts, the efficiency was reported to be
limited to the same range at all loading conditions, heart rates, and
inotropic interventions.21 57 58 In in vivo human
LV in various contractile states, Kameyama et
al47 and Takaoka et al24
also reported these values to be approximately 41% to 45%. The
chemomechanical efficiency represents a product of the
chemical conversion rate during mitochondrial respiration and the
mechanical conversion rate during ATP consumption for the E-C coupling.
The consistency of this surprisingly high efficiency may
indicate that these chemomechanical processes are preserved at the
optimal level regardless of the contractile state or of the presence of
chronic disease conditions.
Remodeling and Diastolic Chamber Compliance
Despite the progress of LV chamber remodeling during the heart
failure transition, our analysis of passive chamber elastance
in the EDPVR did not show significant changes. Our analysis
could be biased by the narrow pressure range we measured or by the
coronary perfusion with a crystalline solution, in which the
tissue water content increased by sixfold to
eightfold.59 However, the values of (a
nonlinear parameter of chamber stiffness) were comparable
to those reported in blood-perfused isolated
hearts.13 60 In the isolated heart from dogs with
pacing-induced heart failure, Wolff et al13 did
not observe changes in the chamber compliance, whereas the chamber
showed significant remodeling. This finding is consistent with
ours. These observations suggest that the remodeling process is not
necessarily associated with the increase in myocardial stiffness unless
significant tissue fibrosis occurs during the course, as has been
demonstrated in senile spontaneously hypertensive
rats.45 Because diastolic
abnormalities repeatedly have been reported as a primary manifestation
of heart failure in experimental as well as clinical
settings,61 our data support the hypothesis that
the diastolic dysfunction in failing myocardium
is critically determined not by the passive tissue architecture but by
more dynamic factors such as intracellular Ca2+
handling or cross-bridge cycling.34 62
Hypercontractile State in LVH-DS Rats
The present study showed that the LV in the compensatory
hypertrophic state in the LVH-DS rats had an increased chamber
contractility, above that in the age-matched DR rats.
The end-systolic stress-strain relationship indicated that this
was not due to the chamber geometry or its loading conditions. At the
same time, the level of the PVA-independent
MO2 showed a significant
increase above control. This independent measure further supported the
presence of the supercontractile state in the hypertrophic
myocardium. Therefore, the hypercontractile state preceded
the subsequent heart failure transition, which in turn resulted in a
marked change to the hypocontractile state below the control level.
Accordingly, our previous studies16 17 showed
that the in vivo measurements of ESPVR in the LVH-DS rats were located
to the left side of those in the age-matched DR. Because the hormonal
factors such as catecholamines were not elevated in the
LVH-DS rats,16 17 these factors were not likely
the direct cause of the hypercontractile state. Furthermore, in the
present study with isolated hearts, we examined the effects of an
intrinsic release of tissue catecholamines by adding
3x10-7 mol/L propranolol to the
perfusate in two preparations from the LVH-DS rats. However,
the developed pressure was decreased only modestly, and the contractile
state remained elevated. Recent studies in hypertrophic myocytes
isolated from spontaneously hypertensive rats support our
observation.63 64 65 Brooksby et
al65 suggested that the increased contractile
state was caused by an increase in the Ca2+
influx during the prolonged action potential because it disappeared
under a membrane voltage clamp. Taken together, these observations
suggest that our finding of a hypercontractile state in the LVH-DS rats
was not an artificial observation nor was it due to an inappropriate
selection of control animals. Rather, such a level of
contractility might be required to normalize the wall
stress in the presence of excessive afterload. The excessive energy
expenditure in this "compensatory" state may provide a detrimental
access to the heart failure transition.
Conclusion
In conclusion, decreases in myocardial
contractility and ventricular remodeling
occurred during the transition from LVH to LVF. Despite the marked
change in myocardial contractility, both the
contractile efficiency and the oxygen cost of
contractility of the LV myocardium in these
two stages remained unchanged. Thus, the efficiency of chemomechanical
conversion was highly preserved even in the chronically diseased
myocardium. Consequently, the total energy consumption per
unit of failing myocardium showed a decrease in a manner
parallel to its contractile state by reflecting the reduced E-C
coupling activity. This observation is consistent with our
recent findings that the intracellular Ca2+
transients and the sarcoplasmic reticular activities of the LV
myocardium were decreased (resulting in diminished basal
contractility) at the time of heart failure
transition.49
|
Selected Abbreviations and Acronyms
|
|---|
| CPP |
= |
coronary perfusion pressure |
| DR |
= |
Dahl salt-resistant (rats) |
| DS |
= |
Dahl salt-sensitive (rats) |
| EDPVR |
= |
end-diastolic pressure-volume relationship |
| ESPVR |
= |
end-systolic pressure-volume relationship |
| LV |
= |
left ventricular, left ventricle |
| LVF |
= |
left ventricular failure |
| LVH |
= |
left ventricular hypertrophy |
| MO2 |
= |
myocardial oxygen consumption |
| PVA |
= |
pressure-volume area |
|
|
Appendix 1
|
|---|
In the balloon-fixed isovolumic heart preparation, instantaneous
natural strain () at the cross-sectional area of the
ventricular wall in the equatorial plane was assumed
as
 | (8) |
where Vball is the latex balloon volume,
Vwall is the ventricular wall volume
(1.05 mL/g LV mass), and Vref is the
K+-arrested LV volume (reference volume).
The end-systolic circumferential wall stress
(es) was calculated by a balanced-force
equation for a thick-walled spherical
geometry66 :
 | (9) |
where Pes is the end-systolic LV
pressure, Ri is the internal radius of the LV
cavity
([3Vball/4
]1/3), and h
is the LV wall thickness, which was calculated as follows:
 | (10) |
|
Acknowledgments
|
|---|
We thank Yoichi Goto, MD, PhD, and Samir K. Saha, MBBS, MPhil,
PhD, for their helpful suggestions and critical reading of the
manuscript. The study was supported in part by grants-in-aid from the
Ministry of Education, Science, and Culture (A0-1, 06454291, and
07557343), and Research Grants from the Ministry of Health and Welfare
(5A-2, 7A-2, and 7A-4), Japan.
|
Footnotes
|
|---|
Reprint requests to Yasuki Kihara, MD, PhD, Department of Cardiovascular Medicine (Internal Medicine III), Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo, Kyoto 606, Japan.
Received October 14, 1997;
first decision November 11, 1997;
accepted November 24, 1997.
|
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Abstract
Introduction
P<.05 compared with the LVH-DS rats.