(Circulation. 1995;92:1011-1019.)
© 1995 American Heart Association, Inc.
Articles |
Bioenergetic Consequences of Left Ventricular Remodeling
From the Cardiovascular Division, Department of Medicine, and the Center for Magnetic Resonance Research, University of Minnesota Medical School, Minneapolis.
Correspondence to Jianyi Zhang, MD, PhD, Cardiovascular Division, University of Minnesota Medical School, Box 508 UMHC, Minneapolis, MN 55455.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Left ventricular (LV) remodeling is associated with LV dysfunction and decrease of coronary flow reserve. The underlying mechanisms responsible for these alterations are unclear. Changes in myocardial high-energy phosphate levels may be associated with these alterations.
Methods and Results Twelve dogs with LV remodeling secondary to
discrete necrosis produced by transmyocardial DC shock were compared
with 8 normal dogs. LV mass and end-diastolic volume were
measured by magnetic resonance imaging 7 days before and 12.9±1.3
months after DC shock. Transmurally localized 31P nuclear
magnetic resonance spectra from five layers across the LV wall were
obtained simultaneously with transmural blood flow measurements
(microspheres) under basal conditions and during pacing at 200 and 240
beats per minute. LV mass and end-diastolic volume were
significantly increased after DC shock (33% and 26%, respectively,
each P<.01). Under basal conditions, the subendocardial
creatine phosphate (CP)/ATP ratio was significantly lower in remodeled
LV compared with the control group (1.71±0.09 versus 2.04±0.09,
P<.05). The subendocardial CP/ATP ratio was inversely
correlated with both the increase in LV mass and LV
end-diastolic volume (r=-.77 and
r=-.70, P<.01 and P<.05,
respectively). In remodeled myocardium, pacing induced a significant
increase in LV end-diastolic pressure (from 8±1 to 20±3
mm Hg, P<.05), which was accompanied by a significant
decrease of subendocardial/subepicardial (Endo/Epi) blood flow ratio
(from 1.01±0.10 to 0.63±0.11, P<.05) and a
significant
decrease in subendocardial CP/ATP ratio (from 1.78±0.07 to
1.61±0.10,
P<.05) and increase of 
Pi/ATP ratio
(from 0 to 0.24±0.05, P<.01). The decrease in
subendocardial CP/ATP ratio was correlated with the decrease in
Endo/Epi blood flow ratio (r=.79, P<.05).
Conclusions These results demonstrate that alterations in myocardial high-energy phosphate levels are correlated with the extent of LV remodeling. In remodeled hearts, pacing-induced tachycardia produces further changes of myocardial high-energy phosphate levels in the subendocardium that appear to be related to ventricular dysfunction and redistribution of blood flow away from the subendocardium.
Key Words: ventricles • hypertrophy • phosphates • myocardium • ischemia • spectroscopy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Extensive experimental and clinical literature has demonstrated that ventricular remodeling occurs after myocardial damage.1 2 Moreover, remodeling appears to have a negative impact on prognosis in this setting.3 4 The mechanisms underlying this deleterious impact on outcome remain poorly understood. It was proposed that remodeled myocardium may experience an imbalance between energy supply and demand that could impede contractile function.5 Observations supporting this hypothesis include the increase in left ventricular (LV) wall stress that develops as a result of progressive LV chamber enlargement, the decrease of coronary blood flow reserve,6 7 the relative deficiency in the growth of capillaries in remodeled myocardium,8 and at a cellular level, the excessive growth of the myofibrillar component of cardiac myocytes compared with mitochondrial growth.5 Moreover, data from our laboratory have demonstrated the existence of alterations in oxidative phosphorylation regulation under basal conditions in remodeled canine myocardium distant from a transmural scar.9 These alterations may be related to each other, and they became more prominent during cardiac stress, contributing to the deleterious effects of LV remodeling.
In the heart, oxidative ATP synthesis is kinetically regulated by the levels of its primary substrates, ADP, Pi, mitochondrial NADH, and O2 and the level of activation of ATP synthesis. Recent developments have established NMR spectroscopy as a powerful technique for investigation of myocardial bioenergetics. By 31P nuclear magnetic resonance (NMR) spectroscopy, the myocardial high-energy phosphate (HEP) compounds ATP and creatine phosphate (CP) and the hydrolysis product inorganic phosphate (Pi) are detected nondestructively and repetitively. In addition, cytosolic "free" ADP content can be calculated from the CP/ATP ratio and myocardial creatine content. As a consequence of the central role of these compounds in myocardial bioenergetics, 31P-NMR spectroscopy can provide new and unique insights into myocardial bioenergetics. Myocardial steady-state HEP levels do not correlate with HEP turnover rate. In the myocardium, the steady-state ATP turnover rate (ie, the steady-state rates of oxidative ATP synthesis and hydrolysis are in equilibrium) is determined by the performance requirements of the heart. The mechanism that controls the set point of steady-state ATP level in normal myocardium is not known. The purpose of this study was to examine the bioenergetic consequences of remodeled myocardium under basal conditions and during pacing-induced tachycardia. In particular, the relations between abnormalities in high-energy phosphate (HEP) levels, ventricular function, regional myocardial blood flow, and extent of ventricular remodeling were examined.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Studies were performed on 12 dogs in which LV remodeling occurred subsequent to discrete necrosis produced by transmyocardial DC shock. Results were compared with those from 8 normal dogs. All experimental procedures were approved by the University of Minnesota Animal Resources Committee. The investigation conformed with the "Guide for the Care and Use of Laboratory Animals" published by the US National Institutes of Health (NIH publication 85-23, revised 1985).
Production of LV Damage by DC Shock
LV damage was produced by
DC shock as previously
described.10 11 Briefly, animals were anesthetized
with
sodium pentobarbital and intubated. A small area of the left side of
the chest over the maximal precordial impulse was shaved. Arterial
catheterization was performed at the femoral artery. A pigtail catheter
was advanced retrogradely across the aortic valve. A premeasured soft
metallic guide wire was then passed through the catheter, with 5 mm of
wire extending beyond the catheter tip into the LV cavity. One
electrode paddle was placed on the left chest at the point of maximal
cardiac impulse. The second electrode was connected to the proximal end
of the guide wire at its site of entry into the femoral artery. One
shock of 80 J/kg body wt was administered at 20- to 60-second
intervals. Heart rhythm was monitored throughout the procedure.
Cardioversion was occasionally needed to treat a hemodynamically
significant run of ventricular tachycardia. In these instances, this
cardioversion was counted as one of the individual shocks for that
animal. Temporary bradycardia occurred on some occasions after DC
shock, but this rarely persisted or required therapeutic intervention.
After DC shock, the guide wire, pigtail catheter, and arterial sheath
were removed. Dogs were then transferred to a postoperative care area,
where they were observed for a period of 24 hours. Animals were then
followed for a period of 12.9±1.3 months (mean±SEM) to allow for
the
development of remodeling.
Estimation of LV Mass and End-Diastolic Volume by Magnetic
Resonance Imaging
The magnetic resonance imaging studies were
performed on a
Siemens Medical System 1.5-T magnet equipped with standard hardware. To
increase the signal-to-noise ratio, an 18-cm Helmholtz coil was used.
All of the imaging sequences were synchronized to the ECG signal
obtained from the leads placed on the shaved skin surface of the dog.
Scout images were taken in the axial plane with an ultrafast
gradient-echo sequence (Turboflash).12 The parameters for
this sequence were repetition time/echo time (TR/TE) angle of 6 ms/3 ms
and 8°, respectively, and a matrix of 128x256 within a field
of view of 250 mm. The delay after the inversion pulse was kept to a
minimum of 15 ms, resulting in a bright blood signal and a hypointense
myocardium. From the axial scout images, a long-axis image was
obtained. The short-axis orientation was aligned perpendicular to the
long axis of the left ventricle. After completion of the Turboflash
sequence, a gradient-echo (fast imaging with steady-state precision
[FISP]) cine sequence was performed to provide images from which the
calculations of ventricular mass and volume were obtained. The
parameters for the FISP sequences were TR/TE angle of 30 ms/10
ms/60°, respectively, with a matrix of 128x256 within a field of
view of 250 mm. A section thickness of 10 mm with no interslice gap was
used with short-axis images obtained from apex to base.
LV mass and end-diastolic volume were calculated from the end-diastolic image. Epicardial and endocardial borders were outlined with a light pen. Areas were calculated with computer-assisted planimetry and a commercially available software package (Siemens). LV mass measurement in each slice was calculated by subtracting the total area enclosed by the endocardium from that enclosed by the subepicardium. The resultant area was multiplied by the slice depth of 1 cm to obtain the volume of each slice and then by 1.05 (specific gravity of myocardium) to calculate the mass. The total LV mass was obtained by adding together the masses of all slices. The LV end-diastolic volume of each slice was represented by the area enclosed by the endocardium. The total LV volume was computed by adding the volumes of all slices. Imaging studies were performed 1 week before the shock procedure (control) and within 7 days of the 31P NMR study.
Experimental Preparation
Twelve animals with documented LV
remodeling and 8 healthy
animals serving as a control group were anesthetized with sodium
pentobarbital (30 mg/kg IV), intubated, and ventilated with a
respirator with supplemental oxygen. Arterial blood gases were
maintained within the physiological range by adjustment of the
respiratory settings and oxygen flow. A heparin-filled polyvinyl
chloride catheter, 3.0-mm OD, was introduced into the right femoral
artery and advanced into the ascending aorta. A left thoracotomy was
performed in the fourth intercostal space, and the heart was suspended
in a pericardial cradle. A second heparin-filled catheter was
introduced into the left ventricle through the apical dimple and
secured with a purse-string suture. A similar catheter was placed into
the left atrium through the atrial appendage. A bipolar epicardial
pacing electrode was sutured to the right atrial appendage. A
28-mm-diameter NMR surface coil was sutured onto the LV wall. In the
remodeled left ventricle, this coil was sutured onto the LV free wall
away from the apical scar. The pericardial cradle was then released and
the heart allowed to assume its normal position. The surface coil leads
were connected to a balance-tuned circuit external and perpendicular to
the thoracotomy incision. The animals were then placed in a Lucite
cradle and positioned within the magnet.
Myocardial Blood Flow
Myocardial blood flow was measured with
microspheres, 15 µm in
diameter, labeled with 141Ce, 51Cr,
95Nb, 85Sr, or 46Sc (NEN Corp).
Microspheres were agitated in an ultrasonic mixer for 15 minutes before
injection. For each measurement, approximately
3x106 microspheres were administered into the left
atrial catheter and flushed with 5 mL of normal saline. A reference
sample of arterial blood was drawn from the aortic catheter at a rate
of 15 mL/min beginning 5 seconds before microsphere injection and
continuing for 120 seconds. Radioactivity in the myocardial and blood
reference specimens was determined with a gamma spectrometer with
multichannel analyzer (model 5912, Packard Instrument Co) at window
settings chosen for the combination of radioisotopes used during the
study.13 Activity in each energy window, background
activity, and sample weight were entered into a digital computer
programmed to correct for contaminant activity from the associated
isotopes, as well as for background activity, and to compute the
corrected counts per minute per gram of myocardium. With the rate of
withdrawal of the reference blood specimen (Qr) and the
radioactivity of the reference specimen (Cr) known,
myocardial radioactivity (Cm) was used to compute
myocardial blood flow (Qm) as
Qm=Qrx(Cm/Cr).
Blood flow was expressed as milliliters per minute per gram
myocardium.
Spatially Localized 31P NMR Spectroscopic
Technique
Measurements were performed in a 40-cm-bore 4.7-T magnet
interfaced with a SISCO (Spectroscopy Imaging Systems
Corp) console. The LV pressure signal was used to gate NMR data
acquisition to the cardiac cycle, while respiratory gating was achieved
by triggering the ventilator to the cardiac cycle between data
acquisitions.14 31P and 1H NMR
frequencies were 81 and 200.1 MHz, respectively. Spectra were recorded
in late diastole with a pulse repetition time of 6 to 7 seconds. This
repetition time allowed full relaxation for ATP and Pi
resonances and approximately 90% relaxation for the CP resonance. CP
resonance intensities were corrected for this minor saturation; the
correction factor was determined for each heart from two spectra
recorded consecutively without transmural differentiation, one with
15-second repetition time to allow full relaxation and the other with
the 6- to 7-second repetition time used in all the other
measurements.
Radiofrequency transmission and signal detection were performed with a 28-mm-diameter surface coil. The coil was cemented to a sheet of silicone rubber 0.7 mm thick and approximately 50% larger in diameter then the coil itself. A capillary containing 15 µL of 3 mol/L phosphonoacetic acid was placed at the coil center to serve as a reference. The proton signal from water detected with the surface coil was used to homogenize the magnetic field and to adjust the position of the animal in the magnet so that the coil was at or near the magnet and gradient isocenters. This was done with a spin-echo experiment and a readout gradient. The information gathered in this step was also used to determine the spatial coordinates for spectroscopic localization.14 Chemical shifts were measured relative to CP, which was assigned a chemical shift of -2.55 ppm relative to 85% phosphoric acid at 0 ppm.
Spatial localization across the LV wall was performed with the method of rotating frame experiment using adiabatic plane-rotation pulses for phase modulation–image-selected in vivo spectroscopy/Fourier series window (RAPP-ISIS/FSW).15 Detailed data with regard to voxel profiles, voxel volume, and extensive documentation of the accuracy of the spatial localization obtained in phantom studies and in vivo have been published elsewhere.14 15 16 17 Briefly, signal origin was restricted by use of B0 gradients and adiabatic inversion pulses to a column coaxial with the surface coil perpendicular to the LV wall. The column dimensions were 17x17 mm. Within this column, the signal was further localized by use of the B1 gradient to five voxels centered about 45°, 60°, 90°, 120°, and 135° spin rotation increments.14 15 16 17 FSW localization used a nine-term Fourier series expansion. The Fourier coefficients, the number of free induction decays acquired for each term in the Fourier expansion, and the multiplication factors used to construct the voxels were reported previously.14 15 18 The position of the voxels relative to the coil was set by use of the B1 magnitude at the coil center, which was experimentally determined in each case by measuring the 90° pulse length for the phosphonoacetic acid reference located in the coil center. Each set of spatially localized transmural spectra was acquired in 10 minutes. A total of 96 scans were accumulated within each 10-minute block.
Resonance intensities were quantified by integration routines provided
by the SISCO software. ATP
resonance was
used for ATP determination. Since data were acquired with the
transmitter frequency positioned between the ATP and CP
resonances, off-resonance effects on these peaks were virtually
nonexistent. However, ATPß is subject to the
off-resonance phenomenon, and this effect varies with proximity to the
surface coil because of the inhomogeneity of the magnetic field
generated by the surface coil.14 16 Consequently,
ATPß is not suitable for evaluating the relative ATP
contents or the CP/ATP ratio. The numerical values for CP and ATP in
each voxel were expressed as CP/ATP. Pi levels were
measured as changes from baseline values (Pi) with
integrals obtained in the region covering the Pi
resonance.
Experimental Protocol
Aortic and LV pressures were measured
with Spectramed pressure
transducers positioned at midchest level and recorded on an
eight-channel direct writing recorder (Coulbourne Instrument Co). LV
pressure was recorded at normal and high gain for measurement of
end-diastolic pressure. Hemodynamic measurements and
31P NMR spectra were first obtained during control
conditions. Midway through the 10-minute acquisition period, a
microsphere injection was performed for determination of myocardial
blood flow.
After completion of the baseline measurements, atrial pacing was begun at a rate of 200 beats per minute with a physiological stimulator delivering rectangular pulses 3 ms in duration at 2.5 times threshold voltage (model S-88, Grass Instruments). Arterial and LV pressures were recorded continuously to ensure that steady-state hemodynamic conditions had been achieved. After 3 minutes of pacing, 31P NMR spectra were obtained over the ensuing 10-minute period. Pacing was then discontinued, and the animal was allowed to recover for 15 to 20 minutes. Atrial pacing was then begun at a rate of 240 beats per minute, and 31P NMR spectra were again obtained as described above over the ensuing 10-minute period. Microspheres were injected for measurement of myocardial blood flow midway through the data acquisition period of each pacing rate. The pacing protocol was complete in 8 of 12 dogs with ventricular remodeling. Two of the 12 dogs studied died of ventricular fibrillation at the end of pacing at 240 beats per minute intervention, and 2 had technical difficulties during the pacing protocol.
Tissue Preparation
After completion of the study, an
epicardial biopsy and LV wall
specimen were taken and frozen in liquid nitrogen for subsequent
analysis of ATP and total creatine contents by use of a
high-performance liquid chromatography technique.19 The
heart was then fixed in 10% buffered formalin. The atria, right
ventricle, aorta, and large epicardial vessels were dissected from the
left ventricle. The left ventricle was then sectioned into four
transverse rings of approximately equal thickness parallel to the
mitral valve ring so that a myocardial ring approximately 2.0 cm thick
contained the region of myocardium located directly beneath the surface
coil. The region of myocardium directly beneath the surface coil was
removed and sectioned into three transmural layers from epicardium to
endocardium, weighed on an analytical balance, and placed into vials
for counting. Similar myocardial specimens were obtained from the
lateral and posterior LV wall to ensure that the measurements from
regions of myocardium corresponding to the surface coil were typical
for the entire left ventricle.
Data Analysis
Hemodynamic data were measured directly from
the chart
recordings. For evaluation of the cardiac interval duration, the upward
and downward spikes of dP/dt were taken as the onset and termination of
LV systole. The integral numerical values for CP, ATP, and
Pi during each experimental condition are expressed as
CP/ATP and Pi/ATP ratios. All the integrals were
performed by an observer unaware of magnetic resonance imaging results
demonstrating the extent of remodeling and were obtained with the
SISCO software. 31P spectra from the first,
third, and fifth voxels were taken to represent subepicardium,
midmyocardium, and subendocardium, respectively.
Paired Student's t test was used for comparing subepicardial versus subendocardial values. Unpaired t test was used for the data between the groups, and one-way ANOVA with replications was used for the data during different experimental conditions in the same group. A value of P<.05 was required for significance. When significance was found, individual comparisons were made by Scheffé's method. All values are expressed as mean±SEM.
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Results |
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Characteristics of LV Remodeling in Canine DC Shock Model
Twelve adult mongrel dogs (mean body weight, 21.5±0.9 kg) developed LV remodeling secondary to localized transmural necrosis produced by DC shock. The mean period from DC shock to 31P NMR study was 12.9±1.3 months. During this time period, LV mass increased from 85.6±2.7 to 113.9±3.3 g (P<.01) and LV end-diastolic volume increased from 66.5±2.3 to 83.9±2.8 mL (P<.01). These changes are typical of the natural history of ventricular remodeling in this model.11 The ratio of LV weight to body weight in remodeled hearts was 5.46±0.23 g/kg, which was significantly greater than the value of 4.33±0.10 g/kg in 8 healthy dogs (P<.01).
Hemodynamic Data
Hemodynamic measurements during the
31P NMR
spectroscopic study are shown in Table 1
. During sinus
rhythm, there was no significant difference in heart rate between
normal dogs and dogs with ventricular remodeling.
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Mean aortic pressure and LV systolic pressure were significantly lower in animals with ventricular remodeling at baseline conditions as well as during rapid pacing compared with the control group. Neither parameter changed significantly in either group as heart rate increased.
LV end-diastolic pressure (LVEDP) was not different
between groups at baseline. In response to pacing, however, LVEDP
increased progressively in hearts with LV remodeling but not in normal
hearts (P<.05, Table 1
).
The product of
heart rate times LV systolic pressure (rate-pressure
product) was not different between the two groups of animals during
sinus rhythm. However, the rate-pressure product was significantly
lower in animals with remodeled ventricles during pacing at 240 beats
per minute (P<.05, Table 1).
The cardiac
interval duration, evaluated by measurement of the time
interval between the upward and downward spikes of dP/dt, was not
significantly different between the groups during sinus rhythm. During
rapid pacing, the duration of systole was significantly longer and
diastole significantly shorter in remodeled hearts compared with normal
hearts (P<.01, Table 1).
Myocardial Blood Flow
In this model, the DC shock produced
transmural damage that later
resulted in a transmural scar. The blood flow rate in the scar area
(data not shown) was not significantly different from that of the
remote area, indicating that this model represents a form of
"open artery necrosis." Regional myocardial blood flow data are
displayed in Table 2. Under basal conditions, myocardial
blood flow (milliliters per minute per gram wet weight) was not
significantly different between the two groups. In the normal hearts,
pacing produced graded increases in myocardial blood flow as heart rate
increased (P<.01, Table 2), while transmural blood
flow
distribution remained unchanged. In remodeled ventricles, however,
pacing resulted in a redistribution of blood flow away from
subendocardium (P<.05, Table 2), which produced a
progressive decrease in the ratio of subendocardial to subepicardial
blood flow (Endo/Epi) (P<.01, Table 2). A
correlation was
observed between the Endo/Epi ratio and the increase in LVEDP during
tachycardia (Fig 1, r=-.64,
P<.09).
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HEP Levels Under Basal Conditions and During Tachycardia
Examples of transmural spectra sets acquired from a normal heart
under basal conditions and during pacing at 240 beats per minute are
shown in Fig 2A and 2B. Spectra obtained from a
heart
with LV remodeling under the basal conditions and during pacing at 240
beats per minute are shown in Fig 3A and 3B.
Voxels were
positioned such that a voxel labeled as Epi was over the outer edge of
the LV wall, while the voxel most distant from the coil, labeled as
Endo, was positioned over the subendocardium with little penetration
into the LV cavity. The voxel labeled as Mid lies over the midwall.
These three voxels labeled as Epi, Mid, and Endo have virtually no
overlap; there is, however, partial overlap between adjacent voxels in
the five-voxel set. The details and the accuracy of this spatial
localization 31P NMR spectroscopic technique has been
previously examined on phantoms and on in vivo
hearts.14 15 16 Spectra at baseline in
the normal hearts were
characterized by high CP and ATP levels, while Pi was too
low to be detected at the signal-to-noise ratio of the spectra. Spectra
from the remodeled ventricle demonstrate a decrease of CP/ATP ratio
across the LV wall (Fig 3A) compared with the spectra from a
normal LV
(Fig 2).
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The group data for the transmural CP/ATP ratio
at baseline are
summarized in Table 3. The CP/ATP ratio was
significantly lower in the subendocardium of remodeled hearts (Table
3,
P<.05) compared with normal hearts. The subendocardial
CP/ATP ratio was plotted against the documented increase in ventricular
mass (Fig 4A) and volume (Fig 4B) to determine
whether a
relation exists between the extent of remodeling and bioenergetic
abnormalities. The data indicate that the decrease of subendocardial
CP/ATP ratio is correlated with the severity of the LV remodeling (Fig
4; r=-.77 and
r=-.70, P<.01 and
P<.05, respectively).
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A comparison of the effect of pacing
on transmural HEP and
Pi levels between normal and remodeled ventricle is shown
in Figs 2 and 3 and Table 4. The
changes of CP/ATP and
Pi/ATP ratios are summarized in Table 4. Pacing
resulted in no significant change in CP/ATP and
Pi/CP ratios in normal hearts (Fig 2 and Table
4). In remodeled ventricles, in contrast, pacing resulted in a
significant decrease of CP/ATP ratio and increase of
Pi/CP ratio, which was most marked in the
subendocardium (Fig 3 and Table 4).
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A
correlation was observed between the changes in CP/ATP ratio,
Pi/CP ratio in the subendocardium during pacing
at 240 beats per minute, and subendocardial underperfusion (Fig
5A and 5B, r=.79 and
r=.69;
P<.05 and P<.06, respectively).
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Biopsy Data
ATP levels obtained from subepicardial biopsies
were
significantly lower in remodeled ventricles than in normal
ventricles (Table 5). Myocardial total creatine levels
were not significantly different between groups (Table 5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The major findings of the present study are that (1) the decrease in subendocardial CP/ATP ratio in remodeled myocardium is correlated with the extent of LV mass increase and chamber dilatation; (2) myocardial ATP levels are significantly decreased in remodeled ventricles; (3) in remodeled ventricles, pacing-induced tachycardia results in a decrease of CP/ATP ratio and an increase of
Pi/CP ratio that are most prominent in the
subendocardial layers; (4) in remodeled myocardium, the changes of HEP
levels during tachycardia are associated with a redistribution of blood
flow away from the subendocardium; and (5) the blood flow
redistribution away from the subendocardium during tachycardia observed
in remodeled hearts correlates with the pacing-induced increase in
LVEDP.
Characteristics of Experimental Model
Ventricular damage in
the present study was produced by
transmyocardial DC shock. This insult produces a moderate degree of
transmural necrosis involving the anteroapical wall of the left
ventricle.10 11 Subsequent to this damage, the left
ventricle demonstrates a remodeling process characterized by an
increase in ventricular mass and chamber dilatation accompanied by
humoral and hemodynamic changes.11 In the present
study, hearts were excised 13 months after the DC shock damage. The
thinning of the scar and increased mass of the remote myocardium during
this period of time make the postmortem evaluation of percentage of
myocardial damage invalid, although a transmural scar was unmistakably
observed in each heart. However, the severity of myocardial damage by
the DC shock has been evaluated previously at 17.6% of the LV
myocardium.10
Transmural Blood Flow Distribution Under Basal Conditions and
During Rapid Pacing
At baseline, there was no significant difference
in myocardial
regional blood flow between normal and remodeled ventricles. During
rapid pacing, a graded increase in myocardial blood flow was observed
in normal hearts. In remodeled hearts, in contrast, rapid pacing was
accompanied by a redistribution of blood flow away from the
subendocardium that resulted in a progressive decrease of Endo/Epi
ratio with no significant increase of mean myocardial blood flow. The
Endo/Epi ratio was correlated with the increase in LVEDP (Fig
1). These
data indicate that abnormalities in myocardial regional blood flow
exist in remodeled myocardium. While these abnormalities are modest at
rest, a significant deterioration occurs during stress, resulting in
marked subendocardial hypoperfusion. These changes may be caused, in
part, by the pacing-induced increases in LVEDP, which compromise
subendocardial perfusion through the effect of increase in
extravascular compressive force. Moreover, the documented relative
prolongation of systole compared with diastole during rapid pacing
would further compromise blood flow. Finally, it is possible that
remodeled myocardium displays capillary rarefaction, as has been
documented in the rat infarct model.8 If so, this also
could restrict flow reserve.
HEP Levels Under Basal Conditions
The biopsy data in the
present study indicate that
subepicardial ATP is significantly decreased in remodeled compared with
normal myocardium. Previous studies have shown that the myocardial ATP
level is normal in hearts with moderately severe LV
hypertrophy20 and decreased in hearts with severe
hypertrophy.21 It is possible that decreased ATP levels
are related to the severity of mass increase or the development of
congestive heart failure. The reasons for the depressed level of ATP in
remodeled hearts are complex and speculative. Although repetitive
subendocardial ischemia could result in the loss of ATP
precursor, the results of the present study indicate that the
subepicardial ATP level could not be ascribed to intermittent
ischemia, since blood flow to this layer was not affected
during tachycardia stress. Therefore, it is not likely that the
decreased ATP level was caused by lost ATP precursor during chronically
repetitive ischemia. In the myocyte, the steady-state rate of
ATP turnover is determined by the work state of the heart. However, the
mechanism that controls the set point of normal steady-state ATP level
in the myocardium is unclear. The decreased ATP level observed in the
remodeled myocardium may also reflect alterations in
Ca2+ dynamics,22 23 cellular enzymes
such as Ca2+ ATPase,24 25 or other
cellular characteristics. These are beyond the scope of this
discussion.
In the normal heart under basal conditions, a transmural
gradient of
CP/ATP ratio with lower values in the subendocardial layers was found
previously either by biopsy26 or by spatially localized
31P-NMR
spectroscopy.14 16 20 27 A
lower
CP/ATP ratio in the endocardium results from a uniform distribution of
ATP across the wall and a lower CP in the
endocardium.14 16 26 This gradient is
thought to be
secondary to a greater systolic force generation in the endocardium
compared with the epicardium,28 whereas the endocardial
blood flow is selectively impeded during systole. Therefore, it was
proposed that subendocardial O2 delivery in normal heart
under resting conditions is at the brink of "oxygen limitation"
with respect to ATP synthesis requirements, since an increase of blood
flow or decrease of oxygen demand results in an increase of endocardial
CP/ATP ratio.27 This oxygen limitation does not limit
mechanical function, however, since increase of oxygen delivery by
maximum coronary artery dilation does not increase myocardial oxygen
consumption or contractile function.27 29 In the
present study, the subendocardial CP/ATP ratio was significantly
lower in remodeled hearts than in normal hearts under basal conditions
(P<.01, Table 3). These results are in agreement
with our
previous study using the same model9 and the study of
Neubauer et al30 in which the LV remodeling was produced
by left anterior descending coronary artery ligation in the rat heart.
The bioenergetic abnormality may be explained by an imbalance between
oxygen supply and demand. Problems with the supply aspect of this
equation have already been demonstrated through analysis of
regional blood flow at rest and during stress.6 It is
likely that while oxygen supply may be reduced, demand may be increased
as a result of increased wall stress due to chamber dilation. Moreover,
the greater increase in myofibril content within the myocyte compared
with mitochondrial growth may also increase oxygen
demand.5 The concept that the reduction in CP/ATP ratio
(as an indication of increase of myocardial free ADP31 )
relates to a mismatch in energy supply and demand is further supported
by our previous observation that adenosine, which both reduced workload
and improved coronary flow in this model, led to an improvement in the
CP/ATP ratio.9
A fetal shift of creatine kinase (CK) isoenzyme and decreased total creatine (a feature of fetal heart) were found in hypertrophied hearts with or without congestive heart failure.21 32 Myocardial CK MM (a CK isoenzyme found mainly in developed normal heart), CP, and total creatine increase as neonatal heart develops.33 Therefore, the decreased CP/ATP ratio observed in remodeled, hypertrophied, or failing hearts may reflect a common feature of fetal shift in the myocyte of these hearts. This change may be an adaptation to the repetitive episode of subendocardial ischemia as observed in the present study during rapid pacing.
In the present
studies, a significant correlation was found between
the subendocardial CP/ATP ratio and the increase in LV mass or
end-diastolic volume (Fig 4; r=-.77 and
r=-.70, respectively). Therefore, the reduction in
subendocardial CP/ATP ratio is correlated with severity of LV
remodeling. This finding is in agreement with the previous observation
of an inverse relation between the CP/ATP ratio and severity of LV
hypertrophy in response to pressure overload produced by banding the
ascending aorta21 and a normal CP/ATP ratio in moderate
and well-compensated hypertrophied hearts.20 It is
interesting to note that the lower CP/ATP ratio was also observed in
the volume-overloaded LV hypertrophied heart34 35 and
severely hypertrophied human hearts.36 Thus, a lower
CP/ATP ratio may be a common feature of severely hypertrophied
hearts.
One possible mechanism responsible for the reduction in CP/ATP ratio is that the substrate preference is altered in these hearts. Previous studies have shown that long-chain fatty acid metabolic capacity is decreased in the hypertrophied myocardium.37 38 Other studies have demonstrated that the concentrations of certain glycolytic metabolism enzymes were significantly increased in hypertrophied myocardium.39 40 We41 and others38 42 have also found that glucose uptake levels were significantly increased in the hypertrophied heart. These studies strongly indicate that the hypertrophied myocardium has increased dependence on glucose metabolism for chemical energy supply under basal conditions. The mechanisms for this altered pattern of substrate preference are unknown. One result of this alteration is the decrease of CP/ATP ratio. Myocardial redox potential (reflected by NADH/NAD+) increases as fatty acid utilization becomes more prominent and decreases as glucose utilization increases.31 43 44 45 It is well known that myocardial CP/ATP increases and decreases as NADH/NAD+ increases and decreases.31 43 44 45 46 Therefore, the reduction of CP/ATP ratio in these different models of hearts with LV hypertrophy may reflect an altered pattern of substrate utilization.
HEP Levels During Rapid Pacing
A pronounced and progressive
decrease of the CP/ATP ratio and an
increase of Pi/CP ratio in the inner layers of
the LV wall were observed in remodeled hearts during rapid pacing.
Together with the progressive redistribution of blood flow away from
the subendocardium as the pacing rate was increased (Table 2),
as well
as the findings of correlation between the decrease of Endo/Epi blood
flow ratio and subendocardial CP/ATP and increase of
Pi/CP (Fig 5), the present results strongly
suggest that remodeled myocardium experiences subendocardial
ischemia during pacing-induced tachycardia that was not
observed in normal hearts. Although the systolic contractile function
was not examined in the present study, the increased LVEDP and
decreased LV systolic pressure probably reflect LV dysfunction during
tachycardia. Subendocardial ischemia during tachycardia could
result in an increase in ventricular stiffness.47 The
decrease in the subendocardial compliance would act to amplify the
subendocardial ischemia, resulting in a further alteration in
HEP levels, which may further compromise contractile function, thereby
forming a "vicious circle." This hypothesis is supported by the
observations that during tachycardia in remodeled hearts, the decrease
of subendocardial and CP/ATP ratio and the increase of
Pi/CP ratio correlated with the Endo/Epi flow ratio
(Fig 5), which also correlated with the increase of LVEDP (Fig
1).
In conclusion, the present findings demonstrate that in hearts with LV remodeling, subendocardial bioenergetic alterations exist under basal conditions. This bioenergetic abnormality is correlated with the severity of LV remodeling. In the remodeled left ventricle, the subendocardium is especially vulnerable to ischemic injury during pacing-induced tachycardia.
|
Acknowledgments |
|---|
This work was supported by US Public Health Service grants HL-21872, HL-32427, HL-33600, and HL-50470 (Dr Zhang); a Program Project Grant (PO-132427) from the National Heart, Lung, and Blood Institute; and a Grant-in-Aid from the Minnesota Affiliate of the American Heart Association. The authors express appreciation to Drs Jay N. Cohn and Robert J. Bache for their guidance and critical review of the data. We thank Dr Thomas Rector for statistical advice. We are also appreciative of the technical assistance of Kate Hauer, Lynn Hartman, Tracy Elbers, and Yi Zhang and for the editorial assistance of Andrea Dahl.
Received September 28, 1994; revision received January 24, 1995; accepted February 8, 1995.
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