(Circulation. 1997;96:2969-2977.)
© 1997 American Heart Association, Inc.
Articles |
Metabolic Response of Normal Human Myocardium to High-Dose Atropine-Dobutamine Stress Studied by 31P-MRS
From the Department of Radiology (H.J.L., J.D., A. de R.) and the Department of Cardiology (H.P.B., B.M.P., E.E. van der W., A. van der L.), Leiden University Medical Center, and the Heart Lung Institute, Utrecht University Hospital (R.O.), The Netherlands.
Correspondence to Hildo J. Lamb, Department of Radiology, Building 1, C2-S, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden/2333 ZA Leiden, The Netherlands. E-mail lamb{at}rullf2.medfac.leidenuniv.nl
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Abstract |
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Background 31P-MRS during cardiac stress may provide (patho)physiological insights into the high-energy phosphate metabolism of the myocardium. Accordingly, the purpose of the present study was to determine the metabolic response of normal human myocardium to severe atropine-dobutamine (A-D) stress. To corroborate the results from the present in vivo study, a 31P-MRS experiment was performed with a moving phantom to simulate respiratory motion.
Methods and Results The phantom experiment showed no relation (P=.371) between the intensity ratio of two separate phosphate peaks and amplitude of phantom excursions. The phosphocreatine (PCr) and ATP signal strength and the PCr/ATP ratio were determined from the left ventricular wall in 20 healthy subjects (posttest likelihood for coronary artery disease was <2.5%) with 31P-MRS at rest and during high-dose A-D stress (rate-pressure product increased threefold). Stress-induced changes were -21% for PCr (P<.001) and -9% for ATP (P<.05). The average PCr/ATP value at rest was 1.42±0.18 and decreased by 14% to 1.22±0.20 during stress (P<.001).
Conclusions The phantom experiment shows that the in vivo decrease of myocardial PCr/ATP due to high-dose A-D stress we observed is not a motion artifact. Consequently, this indicates that myocardial high-energy phosphate metabolism of the normal human heart is altered at high workloads.
Key Words: spectroscopy • phosphates • metabolism • stress • inotropic agents
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Introduction |
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Phosphorus-31 MRS is a unique noninvasive tool to study myocardial HEP metabolism. For example, ATP and PCr, which represent the body's fundamental energy currency and a reservoir of cellular energy, respectively, can be detected by 31P-MRS.1 Acquisition of 31P-MR spectra during cardiac stress testing may provide new (patho)physiological insights into the HEP metabolism of the myocardium.2-5
Spectral acquisition during exercise-induced cardiac stress is most desirable but is subject to several limitations. The main limitations are possible motion artifacts introduced by physical exercise and a relatively low level of attainable cardiac stress. Moreover, many patients are unable to perform an adequate intensity of physical exercise, for various reasons.6 Pharmacologically induced stress has proved to be an attractive alternative for physical exercise.6-12 For example, A-D–induced stress is commonly used in conjunction with 2D echocardiography.6,7,13 A-D stress eliminates the above-mentioned problems of the physical exercise test. In previous animal and human 31P-MRS studies using surface coils, exercise and pharmacological cardiac stress testing were applied. In previous human 31P-MRS studies, cardiac stress was induced mainly by handgrip or leg exercise,14-16 whereas only one 31P-MRS study applied dobutamine stress.17 In these studies, a relatively low stress level was reached. In animal studies,3-5,18,19 however, higher stress levels were applied. In these animal studies, a decrease in the myocardial PCr/ATP ratio of normal hearts was observed if the heart was stressed severely.
The purpose of the present study was to determine the effects of severe pharmacological positive inotropic and positive chronotropic stimulation of the heart on the HEP metabolism of normal human myocardium with 31P-MRS. To investigate the possible effects of motion artifacts on the outcome of these experiments, the motion sensitivity of 3D-ISIS20 was determined separately with a moving multicompartment phantom to simulate breathing motion. Moreover, in volunteers, the 3D-ISIS volume was shifted deliberately to determine the reproducibility of the myocardial PCr/ATP ratio in the presence of small variations in the position of the ISIS volume. We also propose a semiquantitative approach to assess stress-induced changes in myocardial Pi signal intensity. The present study contributes to a better understanding concerning the metabolic response of normal human myocardium to a significant increase in cardiac workload.
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Methods |
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31P-MRS Technique
A Philips 1.5-T Gyroscan S15 MR system (Philips Medical Systems International) and a 100-mm-diameter surface coil were used to acquire 31P-MR spectra. Subjects were positioned in the supine position, then volumes of interest were selected by image-guided spectroscopy with 3D-ISIS based on transverse and sagittal spin-echo MR scout images. Typical in vivo size of the volume of interest was 60 (caudocranial)x70x70 mm3. Localized homogeneity adjustment was performed with the body coil and an automatic procedure optimizing the 1H-MRS water signal obtained with a volume-selective 90°-180°-180° pulse sequence.21 The radiofrequency level was adjusted to obtain a 180° pulse of 40 µs for the reference sample (methyl-phosphonate) at the center of the 31P surface coil. Other technical details were similar, as described previously.22 All human myocardial 31P-MR spectra were acquired 200 ms after the R wave of the ECG. After each excitation, a 3-second relaxation delay was inserted, and the first R wave to occur triggered the next acquisition. The mean TR was 3.7±0.06 seconds at rest and 3.4±0.02 seconds during stress. Total acquisition time for a single in vivo spectrum was
10
minutes for 192 averaged free-induction decays. Phantom compartments
were selected by adjusting the volume of interest to their boundaries
based on MR images of the phantom acquired at stationary situation.
Total acquisition time for a single in vitro spectrum was 3 minutes,
with 64 free induction decays to be averaged at a TR of 3 seconds.
Spectral Quantification
31P-MR spectra were transferred to a
remote SUN-SPARC workstation to be quantified
automatically23 by model function
analysis in the time domain, using a priori spectroscopic
knowledge to improve the accuracy of the spectral
parameters.24-26 Signal modeling and
prior knowledge were performed as in previous
studies.22,27
Correction for Partial Saturation and Blood Contamination
The above-mentioned TRs for rest and stress acquisitions result
in saturation correction factors of 1.34 for rest spectra and 1.36 for
stress spectra.28 For the sake of clinical
applicability, we applied a standard saturation correction factor of
1.35 to all 31P-MR spectra acquired, which value
was based on a TR of 3.6 seconds as reported
previously22 (see "Discussion"). The ATP
level in the 31P-MR spectra was corrected for the
ATP contribution from blood in the cardiac chambers on the basis of a
previous study27 in which the
31P-MR spectrum of whole venous blood was
quantified. The ratio of ATP to 2,3-DPG was 0.36 and was used in the
present study to calculate the contribution of blood ATP to the
observed ATP signal in cardiac 31P-NMR spectra
acquired at rest and during stress.
SNR and Pi-e
An estimate of the SNR was obtained from the CRSD calculated for
the myocardial PCr/ATP ratio, which is an indicator of the accuracy of
the spectral quantification.24-26 The CRSD is
based on the statistical theory of maximum-likelihood estimation,
leading to lower bounds on the statistical errors in the
parameter estimates, and is related to measurement noise.
For each 31P-MR spectrum, the CRSD of myocardial
PCr/ATP was divided by the myocardial PCr/ATP ratio, yielding an rCRSD,
which is inversely related to the SNR.22 The
ratio of the two resonance peaks in the spectral region of 2,3-DPG
served as an estimate of the Pi signal intensity
(see "Results" section).
Phantom Experiment
To simulate the heart and surrounding tissues, a phantom was
constructed, consisting of three concentric cubic compartments (Fig 1A
). The compartments were filled with
1% agarose gel containing various phosphorus compounds with resonance
frequencies and T1 values close to the myocardial
in vivo situation. T1 values were measured by the
inversion recovery method.29 Compartment I
(70x70x70 mm3) contained 50
mmol/L Pi at pH 5.0
(T1=9 seconds) and 50 mmol/L
tripolyphosphate (T1=4.5 seconds). Compartment I
was centered in compartment II (100x100x100
mm3), leaving a gap of 15 mm on all sides;
this space was filled with 50 mmol/L phenylphosphonic acid
at pH 7.0 (T1=8 seconds). Compartment II was
centered in compartment III (200x200x200
mm3), leaving a gap between II and the bottom of
III of 10 mm; this space was filled with 25 mmol/L
Pi at pH 11.0 (T1=9
seconds).
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To simulate respiratory motion, the phantom and surface coil were
placed on top of a plateau on rails (Fig 1B
). Motion was introduced by
connecting the plateau to an eccentric pin on a rotating disk. Phantom
excursions (respiratory motion) were 0, 5, 15, 25, 35, and 45 mm,
with variable speed (breathing frequency) of 25, 40, and 50 rounds
per minute. Motion direction was in the caudocranial direction
(z axis), in analogy to the in vivo situation of respiratory
motion of the diaphragm and liver during a
31P-MRS examination because a Velcro band around
the chest (to secure the 31P surface coil in
place) limits the ventrodorsal movement of the chest
wall.22 The 3D-ISIS volume encompassed
compartment I before motion was introduced; this volume selection was
maintained once the phantom started moving. Acquisition
parameters of stationary spectra were identical to those of
spectra acquired during phantom motion.
Healthy Subjects
Reproducibility
A series of 20 volunteers (average age, 50±17 years; 2 women,
18 men) was studied at rest only to determine the reproducibility of
the myocardial PCr/ATP ratio, with small variations in the position of
the 3D-ISIS volume. The first spectral acquisition was made with the
3D-ISIS volume encompassing the LV.22 The second
31P-MR spectrum was acquired after the ISIS
volume was shifted 5 mm in the cranial direction and 5 mm to
the dorsal side. Thereby, the volume of interest was at a suboptimal
position but still included the entire LV while still excluding
skeletal muscle, diaphragm muscle, or liver tissue, which would
otherwise contaminate the myocardial 31P-MR
spectrum. The 5-mm shift was based on the 3D-ISIS sensitivity profile,
which is 5 mm smaller than the cube displayed on MR
images.30 Parameter settings for
spectral acquisitions were identical for preshift and postshift
studies.
Cardiac Stress Testing
Twenty other volunteers (average age, 48±12 years; 5 women, 15
men) were selected for pharmacological stress testing. They were
healthy at clinical examination, showed a normal ECG at rest, were not
obese (height, 1.80±0.07 m; weight, 72±11 kg), and were normotensive
(Table 1), without a history of
cardiovascular disease and without any complaints. The
normal subjects >40 years old had no ECG-based evidence of
ischemia during bicycle exercise testing (3.0±1.2-fold
increase in RPP) and were without anginal
complaints.15 Their posttest likelihood for CAD
was <2.5%.31
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A myocardial 31P-MR spectrum was first acquired at rest. Without the subject being moved, three subsequent doses of 10 µg/kg atropine sulfate were administered intravenously through an infusion line to block the vagal inhibition of heart rate.32 Then, dobutamine infusion was started at a dose of 10 µg · kg-1 · min-1 and was increased every 2 minutes until a steady target heart rate was reached. The highest infusion rate allowed was 40 µg · kg-1 · min-1. The target heart rate (in beats per minute) was based on sex and age (in years) of the subject: men (220-age)x0.85, women (200-age)x0.85.7,13 Blood pressures were recorded every 2 minutes with a Dinamap sphygmomanometer (Criticon) and were not allowed to exceed a systolic/diastolic blood pressure of 220/100 mm Hg, although these levels were never reached (see "Results" section). As soon as the acquisition of a 31P-MR spectrum during A-D stress was finished, infusion of dobutamine was stopped. In 4 volunteers, a third 31P-MR spectrum was acquired after a 15-minute recovery period. Acquisition parameters of 31P-MR rest spectra were identical to those of stress and recovery spectra.
Informed consent was obtained from all 40 subjects before the examination, and the study was approved by our institutional committee on human research.
Statistical Analysis
Paired t tests were used to test the hypothesis that
observed differences between, for example, rest and stress spectra are
not significantly different from zero for a group of subjects. Linear
regression analysis was performed to study relations between
signal strength of phosphorus compounds in the phantom and phantom
excursion or phantom speed and to study the relation between change in
RPP and percentage change in myocardial PCr/ATP based on previously
reported values. A value of P<.05 was considered to be
significant. All t tests passed tests of normality and equal
variance.
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Results |
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Phantom Experiment
Fig 1
shows 31P-MR spectra of the phantom at
stationary situation and during motion (Fig 1C) and the derived signal
changes due to phantom motion (Fig 1D). Before and during motion of the
phantom, virtually no contaminating signal was detected from
phenylphosphonic acid (compartment II) when the 3D-ISIS volume
encompassed compartment I at stationary situation (Fig 1C, panels 3 and
4). It was not possible to discriminate between the small
phenylphosphonic acid resonance peak and noise in the spectral fitting
procedure. Pi at pH 11.0 (compartment III) was
not detected before or after motion was introduced when the volume of
interest encompassed compartment I at baseline (Fig 1C, panels 3 and
4).
If the phantom excursion was kept constant at 45 mm,
spectral signal strengths were unaffected by changes in phantom speed
(P>.05). Consequently, there are no arguments to presume
that a change in breathing frequency could affect the outcome of in
vivo spectroscopic measurements. The tripolyphosphate-
and
Pi at pH 5.0 resonance signals were chosen as
examples (Fig 1D); the same results hold true for the
tripolyphosphate-ß resonance peak inside compartment I (not
shown).
Healthy Subjects
Reproducibility of the myocardial PCr/ATP ratio acquired before
and after the 3D-ISIS volume was shifted was good; differences between
the two acquisitions were 0.11±0.31 (P=.14) on average.
Spectra of sufficient quality for automated quantification were
obtained at rest, during stress, and after 15 minutes of recovery. The
rCRSD was 12±3% on average at rest and changed to 15±4% during
stress (P<.001); after 15 minutes of recovery, the rCRSD
was 10±2% and similar to rest values (P=.30). Spectral
line widths for PCr were unchanged when rest values (0.41±0.07 ppm, or
11±2 Hz at 1.5 T) and stress values (0.44±0.09 ppm, P=.08)
were compared or when rest and recovery values (0.38±0.02,
P=.98) were compared.
Hemodynamic changes are presented in Table 1
and Fig 2. Heart rate during A-D stress
(147±12 bpm) was 102±8% of the calculated target heart rate (143±8
bpm, P=.22). An example of in vivo
31P-MR spectra acquired before, during, and 15
minutes after A-D stress is shown in Fig 3. Quantification of the average
metabolic response of normal human myocardium
to severe A-D stress and the 15-minute recovery period is shown in
Table 1 and Fig 4. With a threefold
increase in RPP from rest to A-D stress, observed changes were -21%
for PCr (P<.001) and -9% for ATP (P<.05). The
average myocardial PCr/ATP ratio at rest was 1.42±0.18 and decreased
to 1.22±0.20 (-14%) during stress (P<.001). After a
15-minute recovery period, the myocardial PCr/ATP ratio was 1.31±0.06
and comparable to baseline values (P>.05). The
semiquantitative assessment of Pi using
Pi-e yielded values of 1.44±0.27 at rest,
1.87±0.37 during stress (+33±26%, P<.001), and
1.75±0.18 after a 15-minute recovery period (+24±17% compared with
rest, P<.05).
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Discussion |
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The main conclusion from the present study is that myocardial HEP metabolism may change in the normal human heart under high-level pharmacological stress conditions. The stress-induced reduction in myocardial PCr/ATP by 14% presently observed in the normal heart has not been reported previously in human studies,14-17 although similar changes have been observed in normal animal hearts using 31P-MRS under high-level stress (Table 2
).3-5,18,19
Probably the decrease in myocardial PCr/ATP we observed in the normal
heart becomes evident only if the level of induced pharmacological
stress is high; a threefold increase in the RPP was not attained in
previous human studies (Table 2, Fig 5).14-17 That the
relatively high stress level is the most likely explanation for the
present findings is corroborated by the present spectroscopic
results obtained during the recovery phase after stress. Note that the
myocardial PCr/ATP ratio is similar to its resting value when acquired
after a 15-minute recovery period; at that time, the remaining level of
stress equals about 1.3 times the RPP at rest (Table 1), which is a
stress level comparable to those reported in previous human studies
(Table 2).14-17
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The decrease in PCr and ATP signal due to severe pharmacological stress
observed here is in agreement with previous animal
studies,3,4 in which cardiac stress was also
induced by infusion of dobutamine (Table 2).
Phantom Experiment
To exclude the possibility that the metabolic changes
observed here are caused by motion artifacts related to increased
respiration during stress, a phantom experiment was designed to
simulate the effect of motion on the acquisition of spectroscopic data.
At stationary situation and during phantom motion, contamination of the
3D-ISIS volume by signals originating from compartments II and III was
virtually absent, most likely because of the conservative 3D-ISIS
sensitivity profile.30 Even so, excursions of up
to 45 mm should have introduced some signal from compartments II
and III in the 3D-ISIS volume positioned around compartment I (Fig 1C, panel 4). This signal was probably averaged out because the
add-subtract scheme of 3D-ISIS was out of phase with phantom motion.
Therefore, in the in vivo situation, with careful selection of
myocardium within the volume of interest, in combination
with the conservative 3D-ISIS sensitivity profile, it is unlikely that
the myocardial spectrum is contaminated by skeletal and diaphragm
muscle or liver tissue resulting from increased respiratory motion
during the stress test.9 Furthermore, the phantom
experiment shows that signal intensities of, for example,
Pi at pH 5.0 and tripolyphosphate-, are
inversely related to the amplitude of phantom excursion, whereas their
ratio is not affected by increased motion (Fig 1D). Consequently, the
in vivo decrease of the myocardial PCr/ATP ratio of the normal heart
during severe stress observed here is not a motion artifact.
The phantom results are in accordance with what can be expected
on the basis of simple calculations. When compartment I of the phantom
is entirely encompassed by the 3D-ISIS volume, signal intensity is
maximal. Moving the phantom outside this volume causes a partial signal
loss. At an excursion of 45 mm, the maximal excursion in one
direction (caudal or cranial) is 45/2=22.5 mm; consequently, at least
70-22.5=47.5 mm of compartment I is inside the 3D-ISIS volume,
resulting in detection of 47.5/70x100=68% of the original signal
strength. When the phantom is moving at an excursion of 45 mm, the
predicted signal strength is (100+68)/2=84% of the available signal in
compartment I, which is in accordance with the present results (Fig 1D).
Healthy Subjects
Several in vivo results from the present study also exclude
the possibility that motion-related artifacts determine the decrease in
the PCr/ATP ratio in normal human myocardium during severe
stress. First, rCRSDs determined from in vivo acquisitions were low and
spectral line widths were small, implying high-quality
31P-MR spectra before, during, and after A-D
stress. The high spectral quality during all acquisitions indicates
that the 3D-ISIS volume encompassed the LV at all times. The average
rCRSD determined for the myocardial PCr/ATP ratio increased during
stress, possibly because of signal loss associated with the observed
decrease in myocardial PCr/ATP.
Second, the reproducibility of the myocardial PCr/ATP ratio was studied when the 3D-ISIS volume was shifted deliberately. The average myocardial PCr/ATP ratio acquired before and after the volume of interest was shifted was not statistically significantly different. Therefore, small changes in position of the currently applied 3D-ISIS volume do not significantly affect the myocardial PCr/ATP ratio as long as the volume of interest is selecting the entire LV anterior wall and blood only. In analogy to the present volume shift experiment, a previous 3D-ISIS study22 showed that serial spectroscopic examinations in the same subject with a 1-week interval yielded similar myocardial PCr/ATP ratios at both occasions (small interexamination variability). Consequently, the currently applied 3D-ISIS volume selection technique has proved to be highly reproducible.22
Furthermore, there are several in vivo 31P
spectroscopic results that suggest that severe stress of the heart
induces a genuine metabolic change in the
myocardium. First, the commonly observed change in
myocardial Pi in animal
studies3-5,19,33 due to stress of the normal
heart indicates a real change in the in vivo myocardial
31P-MR spectrum. Second, the myocardial PCr/ATP
ratio fully recovers within 15 minutes after infusion of
dobutamine ceases. Therefore, it is unlikely that observed
changes in signal intensities between rest and stress are due to
movement of the subject. Third, it appears that changes in, for
example, the myocardial PCr/ATP ratio are inversely proportional to the
change in RPP from rest to stress (Table 2, Fig 5). By itself, this
could be caused by an increase in respiratory motion, but in most
animal studies, which showed similar stress-induced changes in
myocardial PCr/ATP (Table 2), the phosphorus surface coil was sutured
to the myocardium, excluding a direct effect of respiratory
motion.
Possible Physiological Explanations
The fall in the myocardial PCr/ATP ratio during severe stress may
suggest inadequate adaptation of oxidative
phosphorylation of the normal human heart to high work
states. This may be secondary to limited coronary reserve under
high-work-state conditions, referred to as demand
ischemia.4,5 In addition, an increase in
Pi and decrease in PCr is not always associated
with imminent heart failure.34 The decrease in
ATP signal strength observed here may be partly due to an overall ATP
utilization that is incompletely matched by ATP synthesis, as reported
earlier for the normal canine heart.4
Conversely, a shift in substrate utilization by myocardium from, for example, free fatty acids to glucose may also lead to different steady-state levels of HEP metabolites.35 Also, regulatory mechanisms may change under different physiological conditions, such as increased mechanical loading.36 The latter two issues may also be related to the type of stress.2 Pharmacologically induced or exercise-induced increases in cardiac workload may have differential effects on steady-state levels of myocardial HEP metabolites. Furthermore, the changes in myocardial PCr/ATP we observed could be a transient phenomenon in the presence of adaptation to high stress levels.
Another explanation is that a higher exchange rate of phosphates between PCr and ATP during cardiac stress may lead to changes in T1 relaxation times of the metabolites studied. In a rat heart study,37 it was found that after the phosphoryl exchange between PCr and ATP was inhibited, the apparent T1 values were changed. A consequence of this phenomenon could be that the currently applied partial saturation correction factor for myocardial PCr/ATP determined at rest is not applicable to PCr/ATP ratios acquired during A-D stress. This theory is not supported by saturation transfer experiments in canine hearts,36,38 the results of which indicated that infusion of norepinephrine did not significantly affect the flux of PCr to ATP. On the other hand, even if the higher exchange rate of phosphates between PCr and ATP were to be the only cause of the observed changes in myocardial PCr/ATP due to an increase in cardiac workload, it would still be a stress-induced biochemical change that could be of diagnostic value.
Limitations of the Present Study
To completely rule out the presence of CAD in the healthy control
subjects, a cardiac catheterization would be the
preferred method, but this is obviously impossible for ethical reasons.
Therefore, subjects were submitted to ECG bicycle exercise testing, a
noninvasive technique for possible diagnosis of CAD. The pretest
probability for CAD in the age group studied here is <10%, and it
decreases to a posttest likelihood of <2.5% after ECG bicycle
exercise testing with negative results.31 In
addition, the eight youngest healthy subjects presently studied
(35±7 years old), who had a pretest likelihood for CAD <2.0%, also
showed a statistically significant decrease in myocardial PCr/ATP
(-11±13%, P<.05) when rest and stress acquisitions were
compared. Moreover, all healthy control subjects were without anginal
complaints during severe bicycle or A-D stress testing, whereas the
increase in RPP was comparable for the two stress tests (threefold).
Therefore, the likelihood that the decrease in myocardial PCr/ATP
observed here in the normal human heart during severe cardiac stress
testing can be explained by unknown CAD is practically zero.
The difference in heart rate between rest and stress affects the TR and therefore the saturation correction factor for the myocardial PCr/ATP ratio. To determine this effect, we recalculated our myocardial PCr/ATP ratios with different saturation correction factors for rest and stress acquisitions based on the actual TRs (see "Methods"). Myocardial PCr/ATP ratios changed from 1.42±0.18 at rest and 1.22±0.20 during stress (P<.001) to 1.41±0.18 at rest and 1.23±0.20 during stress (P<.001) when different saturation correction factors were applied for rest and stress spectra (see "Methods"). Clearly, the small variations in TR between rest and stress cannot explain the observed changes in myocardial PCr/ATP between rest and stress.
In human cardiac 31P-MRS at 1.5 T, it is
difficult to discriminate between 2,3-DPG and Pi,
even when proton decoupling is applied.27 Instead
of a qualitative description of the stress-induced changes in
Pi observed here, a semiquantitative estimate for
changes in Pi is proposed
(Pi-e). At rest, this estimate may be dominated
by the 2,3-DPG signal, but in stress spectra,
Pi-e may serve as a good indicator of
Pi, although changes in LV blood volume due to
stress testing may affect the values of Pi-e.
This limitation of Pi-e should be taken into
consideration when the data are interpreted
physiologically. The change in
Pi-e found here in normal human
myocardium induced by severe myocardial stress seems to be
in agreement with previous animal studies,3-5,19
which reported cardiac stress–related changes in
Pi content in normal myocardium
(Table 2). In contrast to PCr and ATP signal intensities, myocardial
Pi-e did not fully recover to its baseline level
in the first 15 minutes. Because of the limitations of
Pi-e mentioned above, it is not possible to draw
firm physiological conclusions regarding this lack
of Pi-e recovery after severe cardiac stress. The
limitations of Pi-e do not weaken the conclusion
that myocardial PCr/ATP is decreased reversibly in the normal human
heart during severe cardiac stress.
Future Considerations
Because it appears that high work states of the heart change the
level of HEP metabolites (Table 2, Fig 5), it would be interesting to
determine the threshold value for a change in RPP at which the PCr/ATP
ratio in normal human myocardium is significantly different
from baseline values. This may lead to criteria for abnormal HEP
metabolism in patients at rest and may provide a sensitive
diagnostic tool to detect differences between patients and
healthy control subjects concerning myocardial HEP
metabolism.
The 95% tolerance interval for normal values39 of myocardial PCr/ATP at rest obtained in the present study ranges from 1.03 to 1.81 (n=20). This means that when a PCr/ATP ratio determined in a single patient is <1.03, there is a statistically significant difference with the normal value. In previous studies, differences of this order of magnitude have been reported in, for example, hypertrophic cardiomyopathy.1 For myocardial PCr/ATP determined during severe stress in the present study, this tolerance interval is from 0.79 to 1.65, which implies a significant difference from the normal value if the PCr/ATP ratio during cardiac stress is <0.79. The tolerance interval for the percentage change in PCr/ATP due to A-D stress ranges from -42% to +14%. Consequently, the PCr/ATP ratio of a subject should drop more than 42% during A-D stress to indicate an abnormal response to cardiac stress. Previous studies did not report such low PCr/ATP values during cardiac stress.
Conclusions
The phantom experiment strongly supports the hypothesis that the
in vivo decrease in PCr and ATP signal strengths as observed in the
present study during cardiac stress is partly caused by increased
respiratory motion. Because all phosphate signals decreased to the same
extent with increasing excursion of the phantom, the observed decrease
of the myocardial PCr/ATP ratio in vivo is not a motion artifact but
rather a metabolic adaptation of the normal human heart to
severe cardiac stress. This indicates that myocardial HEP
metabolism of the normal heart is altered at high
workloads.
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Selected Abbreviations and Acronyms |
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Received June 11, 1997; revision received July 29, 1997; accepted August 13, 1997.
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