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(Circulation. 1999;99:942-948.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Myocardial Oxygenation During High Work States in Hearts With Postinfarction Remodeling

Yo Murakami, MD, PhD; Yi Zhang, MD; Yong K. Cho, PhD; Abdul M. Mansoor, MD, PhD; Jun K. Chung, MD; Cuixia Chu, MD; Gary Francis, MD; Kamil Ugurbil, PhD; Robert J. Bache, MD; Arthur H. L. From, MD; Michael Jerosch-Herold, PhD; Norbert Wilke, MD; Jianyi Zhang, MD, PhD

From the Departments of Medicine, Biochemistry, and Radiology and the Center for Magnetic Resonance Research, University of Minnesota, and the Department of Veterans Affairs Medical Center, Minneapolis, Minn.

Correspondence to Jianyi Zhang, MD, PhD, Box 508, University of Minnesota Health Science Center, 420 Delaware St SE, Minneapolis, MN 55455. E-mail zhang047{at}maroon.tc.umn.edu

	Abstract

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Background—Postinfarction left ventricular remodeling (LVR) is associated with reductions in myocardial high-energy phosphate (HEP) levels, which are more severe in animals that develop overt congestive heart failure (CHF). During high work states, further HEP loss occurs, which suggests demand-induced ischemia. This study tested the hypothesis that inadequate myocyte oxygen availability is the basis for these HEP abnormalities.

Methods and Results—Myocardial infarction was produced by left circumflex coronary artery ligation in swine. Studies were performed in 20 normal animals, 14 animals with compensated LVR, and 9 animals with CHF. Phosphocreatine (PCr)/ATP was determined with ³¹P NMR and deoxymyoglobin (Mb-) with ¹H NMR in myocardium remote from the infarct. Basal PCr/ATP tended to be decreased in postinfarct hearts, and this was significant in animals with CHF. Infusion of dobutamine (20 µg · kg^-1 · min^-1 IV) caused doubling of the rate-pressure product in both normal and LVR hearts and resulted in comparable significant decreases of PCr/ATP in both groups. This decrease in PCr/ATP was not associated with detectable Mb-. In CHF hearts, rate-pressure product increased only 40% in response to dobutamine; this attenuated response also was not associated with detectable Mb-.

Conclusions—Thus, the decrease of PCr/ATP during dobutamine infusion is not the result of insufficient myocardial oxygen availability. Furthermore, in CHF hearts, the low basal PCr/ATP and the attenuated response to dobutamine occurred in the absence of myocardial hypoxia, indicating that the HEP and contractile abnormalities were not the result of insufficient oxygen availability.

Key Words: myocardial infarction • phosphates • myoglobin • dobutamine • heart failure

	Introduction

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In the failing heart, the increased systolic wall stress of the dilated left ventricle (LV) would be expected to increase energy demands, whereas oxygen delivery may be limited by an impaired coronary flow reserve. These considerations have led to the suggestion that an imbalance of the energy supply/demand relationship might contribute to impaired contractile performance in the failing heart.¹ We have described a porcine model of myocardial infarction that results in LV dilation and reduced systolic performance.² In the remodeled heart, the noninfarcted myocardium manifests high-energy phosphate (HEP) abnormalities, including decreases of creatine phosphate (PCr), ATP, the PCr/ATP ratio, and total creatine, which are most prominent in animals that develop overt congestive heart failure (CHF). Knowledge of the intracellular O₂ level is necessary to understand whether oxygen limitation contributes to these HEP abnormalities in remodeled myocardium.

¹H NMR spectroscopic measurements of myocardial deoxymyoglobin (Mb-) have been used to assess mitochondrial oxygen availability in isolated, perfused rodent hearts.^{3 4} We have adapted this technique for use in canine hearts in vivo and found no evidence of myoglobin desaturation under basal conditions.⁵ However, graded coronary stenoses caused increases of Mb- that were linearly related to the decreases of myocardial blood flow.⁵ The purpose of this study was to examine whether limited myocyte oxygen availability contributes to the HEP changes in normal or remodeled hearts at high work states. ³¹P and ¹H NMR spectroscopy were used to evaluate myocardial HEP and Mb- levels under basal conditions, during pacing, and during dobutamine infusion.

	Methods

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Studies were performed in 29 swine with left circumflex coronary artery (LCx) occlusion and 20 normal animals. All experimental procedures conformed to 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 Myocardial Infarct
Young Yorkshire swine (45 days old; weight, 10 kg) were anesthetized with sodium pentobarbital 30 mg/kg IV, intubated, and ventilated with a respirator. A left thoracotomy was performed, and the proximal LCx was ligated to produce total coronary occlusion.² If ventricular fibrillation occurred, electrical defibrillation was performed immediately. The chest was then closed, and the animals were allowed to recover. Of the 29 pigs that underwent LCx ligation, 3 died before recovery from anesthesia, 3 died during the first 2 days after surgery, and the remaining 23 animals underwent a terminal physiological study 6 weeks later or sooner if CHF developed. MRI was performed 24 to 72 hours before the terminal physiological study to characterize cardiac performance.

Magnetic Resonance Imaging
MRI studies were performed on a Siemens Medical Vision System operating at 1.5 T. A detailed account of the imaging and analysis methodologies, including determination of LV chamber volumes and ejection fractions, has been reported.²

Experimental Preparation
The swine were premedicated with ketamine HCl 20 mg/kg IM and anesthetized with -chloralose 100 mg/kg followed by 20 mg · kg^-1 · h^-1 IV, intubated, and ventilated with a respirator with supplemental oxygen. A catheter, 3.0-mm OD, was introduced into the ascending aorta via a femoral artery. A sternotomy was performed, and catheters were placed in the LV and the anterior interventricular vein. A pacing electrode was sutured to the right atrial appendage. In 5 normal pigs and 6 pigs with LCx ligation, hydraulic occluders were placed around the left anterior descending coronary artery (LAD). A double-tuned (³¹P and ¹H) 25-mm-diameter NMR surface coil was sutured onto the LV anterior wall distant from the infarct. The surface coil leads were connected to a balanced-tuned circuit, and the animals were positioned in the magnet.

³¹P NMR Spectroscopy
Measurements were performed in a 40-cm-bore, 4.7-T magnet interfaced with a computer console (Sisco). NMR data acquisition was gated to the cardiac cycle.⁶ Radiofrequency transmission and signal detection were performed with the surface coil. A capillary containing 15 µL of 3 mol/L phosphonoacetic acid at the coil center served as a reference. Chemical shifts were measured relative to PCr, which was assigned a chemical shift of -2.55 ppm relative to 85% phosphoric acid. Spatial localization across the LV wall was performed with the RAPP-ISIS/FSW method.^{6 7} Signal origin was restricted to a 17x17-mm column across the LV wall; within this column, the signal was localized to 5 transmural voxels by use of the B₁ gradient.^{6 7 31}P 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 inorganic phosphate (P_i) resonances and 90% relaxation for the PCr resonance.^{6 7} PCr resonance intensities were corrected for this minor saturation. Spectra consisted of 96 scans accumulated in a 10-minute block. Resonance intensities were integrated by use of Sisco software. The numerical values for PCr and ATP were expressed as ratios of PCr/ATP. P_i levels were measured as changes from baseline values (P_i).

¹H NMR Spectroscopy
The technique of in vivo ¹H MRS detection of Mb- has been described previously.⁵ Briefly, a single-pulse collection sequence with a frequency-selective gauss excitation pulse (1 ms) was used to excite the N- proton signal of the proximal histidine of Mb-.⁸ The NMR signal was optimized by adjusting the RF pulse power using the water signal as a reference. A short repetition time (TR=25 ms) was used because of the short T₁ of Mb-.⁹ Although the short T₁ of Mb- and fast acquisition prevent gating to the cardiac cycle, the signal loss due to motion is negligible because of the inherently broad line width of the Mb- peak. Although the N- proton signal is temperature-sensitive, a pilot study showed that the chemical shift of this resonance, which appeared at 71 to 72 ppm (relative to H₂O), remained constant during periods of coronary occlusion. Mb- data were acquired in 5 minutes (10 000 free induction decay) immediately before HEP data acquisition.

Myocardial Blood Flow, Myocardial Oxygen Consumption, and Lactate Measurements
Myocardial blood flow was measured with radioactive microspheres, 15 µm in diameter, labeled with ¹⁴¹Ce, ⁵¹Cr, ⁹⁵Nb, ⁸⁵Sr, or ⁴⁶Sc (NEN Corp).¹⁰ Myocardial oxygen consumption (MO₂) and lactate uptake were obtained by measuring oxygen and lactate contents in aortic and anterior interventricular vein blood. Arteriovenous oxygen and lactate differences were multiplied by blood flow to obtain MO₂ and net lactate uptake.

Tissue Preparation
At the end of the study, hearts were quickly removed, and 1 branch of the LAD was cannulated and perfused with ice-cold saline for preparation of isolated myocytes (see below). The remainder of the heart was fixed in 10% buffered formalin. The LV and the scar were weighed. The region of myocardium beneath the surface coil was sectioned into 3 transmural layers from epicardium to endocardium, weighed, and placed into vials for counting.

Disaggregated Myocyte Measurements
To assess LV remodeling at the cellular level, myocytes from 5 hearts with left ventricular remodeling (LVR), 3 hearts with CHF, and 7 normal hearts were isolated.^{11 12} The excised specimen was perfused with calcium-free buffer gassed with 95% O₂ and 5% CO₂, followed by recirculating perfusion with 205 U/mL collagenase (type II, Worthington Biochemical Co; 0.1% BSA, fraction V, ICN Immuno-Biologicals) in 50 mL buffer for 20 minutes at 37°C. The perfused tissue was gently minced with a scissors and filtered through 20-mm nylon mesh. Cells were fixed in 25% glutaraldehyde. The yield of rod-shaped cells was 70% to 90%.

Fifty cells (rod-shaped, with clear sarcomere striation and without membrane blebs) were used for each sample. Cell length was defined as the longest length parallel to the longitudinal axis of the cells. Cell volume was determined with a Coulter Channelyzer (model 256) connected to a Coulter Counter (model ZM). Cell cross-sectional area was calculated as cell volume divided by cell length.

Experimental Protocol
CHF was defined by the appearance of peripheral cyanosis, ascites, and decreased activity. The remodeled group without CHF (LVR; n=14) was studied 6 weeks after LCx ligation. Animals that developed CHF (n=9) were studied shortly after the appearance of CHF; earlier study was required because these animals generally died within a few days after the appearance of CHF. Because the LVR and CHF groups differed with respect to age and weight, each group was compared with separate weight-matched control animals.

Aortic and LV pressures were measured with fluid-filled transducers. Hemodynamic measurements and ³¹P and ¹H MRS spectra were first obtained under basal conditions. Midway through the 20-minute data acquisition period, a microsphere injection was performed, and blood samples were obtained for MO₂ and lactate. The response to atrial pacing at 240 bpm was then assessed with a physiological stimulator (model S-88, Grass Instruments). After 10 minutes of pacing, all measurements were repeated. Pacing was then discontinued, and the animal was allowed to recover for 15 to 20 minutes.

The response to dobutamine 20 µg · kg^-1 · min^-1 IV was then examined. After 10 minutes to achieve steady-state conditions, all measurements were repeated. After completion of the above protocol, in 5 normal pigs and 6 animals with LCx ligation, the LAD was occluded and Mb- measurements were repeated. The hearts were then prepared for blood flow measurements and myocyte morphological studies.

Data Analysis
Hemodynamic data were measured from the chart recordings. Integral numerical values for PCr, ATP, and P_i resonances were expressed as PCr/ATP and P_i/ATP ratios. ³¹P NMR spectra from the first, third, and fifth voxels were taken to represent subepicardium, midmyocardium, and subendocardium, respectively.

Data were compared by 1-way ANOVA with replications. A value of P<0.05 was required for significance. When a significant result was found, individual comparisons were made by the method of Scheffé. The unpaired t test was used for the comparison of data between groups. All values are expressed as mean±SEM.

	Results

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Anatomic Data
The anatomic data are summarized in Table 1. The ratio of LV weight to body weight (LVW/BW) was increased 19% in LVR animals and 33% in CHF compared with the respective controls (each P<0.05). Scar accounted for 9% of the LV mass in the LVR group and 12% of LV mass in the CHF group. Ratios of right ventricular weight to body weight were increased in both experimental groups (P<0.01).

View this table: [in this window] [in a new window]   Table 1. Anatomic Data

Arterial Substrate Levels
Arterial blood levels of glucose, lactate, and free fatty acids were not significantly different from normal in animals with remodeled hearts (Table 2).

View this table: [in this window] [in a new window]   Table 2. Arterial Levels of Free Fatty Acids, Glucose, and Lactate

LV Volumes
LV systolic and end-diastolic volumes were significantly increased in the remodeled groups (Table 3). Because the ejection fractions of the 2 control groups were comparable, these data were pooled. Ejection fractions were significantly reduced in the infarcted hearts (51±3%, 41±3%, and 33±6% in the control, LVR, and CHF groups, respectively), and the difference between LVR and CHF groups was significant (each P<0.05, Table 3).

View this table: [in this window] [in a new window]   Table 3. LV Volumes and Ejection Fraction

Isolated Myocyte Data
In LVR hearts, mean cell length, cell volume, and cell cross-sectional area were increased in myocytes remote from the scar (Table 4). Myocytes from hearts with CHF showed the greatest elongation, with no increase in cross-sectional area.

View this table: [in this window] [in a new window]   Table 4. Disaggregated Myocyte Dimensions from 5 Hearts With LVR and 3 Hearts With CHF Compared With 9 Body Size–Matched Normals

Hemodynamic Data
Hemodynamic variables were similar in the normal and LVR groups, although LV end-diastolic pressure tended to be higher in the LVR group (Table 5). Dobutamine caused comparable increases of the rate-pressure product in the normal and LVR groups (Table 5). CHF animals had significantly lower aortic and LV systolic pressures and higher LV end-diastolic pressure during the basal state (Table 5). Pacing caused a rapid increase in LV end-diastolic pressure and a decrease of LV systolic pressure in most of the CHF hearts, which made complete data acquisition impossible, so that pacing data from only 2 stable preparations were obtained (data not shown). In response to dobutamine, the CHF hearts underwent a smaller increase of rate-pressure product than did the other groups (P<0.05).

View this table: [in this window] [in a new window]   Table 5. Hemodynamic Data

Blood Flow, Lactate, and Oxygen Measurements
Myocardial blood flows were not different among the 3 groups under basal conditions. In the normal and compensated LVR groups, blood flow increased similarly during pacing and during dobutamine (Table 6). The inner/outer layer blood flow ratios (endocardial/epicardial) were not different among the groups at baseline and remained unchanged during pacing and dobutamine infusion. In CHF hearts, myocardial blood flow tended to increase in response to dobutamine, but this was not significant.

View this table: [in this window] [in a new window]   Table 6. Myocardial Blood Flow, mL · min-1 · g-1

Myocardial oxygen consumption (MO₂) was not different between groups during basal conditions (Table 7). In the normal and LVR hearts, MO₂ increased to similar levels in response to pacing and dobutamine. In CHF hearts, MO₂ did not increase significantly in response to dobutamine. Lactate uptake was similar in normal and LVR hearts under basal conditions and did not change in response to pacing or dobutamine. Lactate measurements obtained in 1 heart with CHF were similar to the other groups.

View this table: [in this window] [in a new window]   Table 7. MO2 and Net Lactate Uptake Data

Transmural HEP and P_i Levels
Myocardial HEP and P_i data are shown in Table 8. Baseline spectra were characterized by high PCr and ATP levels, whereas P_i was too low to be detected. Dobutamine significantly increased P_i and decreased PCr. PCr/ATP ratios in all myocardial layers were comparable in normal and compensated LVR hearts during baseline and paced states. In CHF hearts, basal PCr/ATP ratios were significantly decreased. In the 2 CHF animals that completed the pacing protocol, there were no changes in PCr/ATP ratio during pacing (data not shown). In normal and LVR hearts, dobutamine caused significant decrease of PCr in the epicardial and midmyocardial layers, but not in endocardium (Table 8). In CHF hearts, PCr did not change significantly from the already reduced baseline levels during dobutamine, and P_i also did not change.

View this table: [in this window] [in a new window]   Table 8. Myocardial CP/ATP and Pi/CP Ratios

Myoglobin Saturation
The Figure shows typical ¹H MRS spectra from normal, LVR, and CHF hearts. No Mb- resonance was detected in any heart of any group under basal conditions (panel A) or during pacing (data not shown) or dobutamine infusion (panel B). During coronary artery occlusion (panel C), done as a positive control to verify that Mb- could be detected, a Mb- resonance appeared at 71 ppm upfield of the water resonance with a high signal-to-noise ratio.

View larger version (10K): [in this window] [in a new window]   Figure 1. 1H NMR spectra for myocardial Mb- during baseline (A), dobutamine infusion (B), and coronary artery occlusion (C) from a normal heart, a heart with LVR, and a heart with CHF. No Mb- resonance was detected during basal or dobutamine infusion conditions in normal or LVR hearts. During coronary occlusion, Mb- appeared 70 to 71 ppm downfield from the water resonance, with a high signal-to-noise ratio.

	Discussion

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The main findings of this study can be summarized as follows. The decrease of PCr/ATP in normal and LVR hearts during dobutamine infusion was not associated with detectable myoglobin desaturation. Furthermore, the abnormally decreased PCr/ATP during basal conditions in CHF hearts was not associated with myoglobin desaturation. The data thus indicate that oxygen limitation is not the basis for the HEP abnormalities present under basal conditions in the CHF group and cannot account for the HEP changes during dobutamine stimulation in the normal and LVR groups. Taken together, the findings do not support the hypothesis that limited myocyte oxygen availability is the basis for the bioenergetic or contractile abnormalities in remodeled myocardium.

Anatomic Characteristics of the Model
Isolated myocytes remote from the scar confirmed the presence of cellular hypertrophy in infarcted hearts, which was most severe in the CHF group. The increased myocyte volume resulted primarily from a striking increase in cell length, whereas cross-sectional area was modestly increased in LVR hearts and unchanged in CHF hearts. The predominant increase in myocyte length with little change in diameter is in agreement with the concept that postinfarct remodeling results in a volume-overload-type stimulus.¹³

Myocardial Blood Flow and Oxygen Consumption
Both mean myocardial blood flow and the transmural distribution of blood flow during rapid pacing were normal in hearts with LVR. During dobutamine infusion, blood flow increased normally in LVR hearts. The similar oxygen consumption per gram of myocardium in normal and LVR hearts under basal conditions and during dobutamine in the absence of myoglobin desaturation indicates that blood flow was not limiting in these hearts. In animals with CHF, dobutamine caused a subnormal increase in myocardial blood flow. Our previous demonstration of normal coronary flow reserve in this model of CHF suggests that failure of coronary flow to increase during dobutamine infusion was the result of failure of myocardial demands to increase rather than inability of coronary flow to increase.² This is further supported by the absence of myoglobin desaturation in these animals.

Myocyte Oxygenation
No Mb- was detected at baseline, during pacing, or during dobutamine in any group, although significant decreases of PCr/ATP and increases of P_i/PCr were observed in normal and LVR groups during dobutamine. A linear relationship between the severity of ischemia/hypoxia and the increase of Mb- has been observed in earlier in vitro studies.^{4 5 8} Furthermore, during ischemia, myoglobin desaturation was strongly correlated with the severity of the blood flow reduction and occurred in concert with decreases of PCr/ATP and increases of P_i/PCr.⁵ NMR sensitivity for detecting Mb- by ¹H MRS and PCr by ³¹P MRS is comparable.⁹ Also, Mb- NMR visibility in muscle is near 100%.^{8 9 14 15} These considerations suggest that an Mb- resonance should be detectable when myoglobin desaturation exceeds 10%. The P₅₀ for myoglobin O₂ saturation at physiological temperatures is 2.5 to 5 mm Hg.^{3 4 16 17} If we assume that 10% desaturation went undetected and the P₅₀ for myoglobin is 2.5 mm Hg, our findings indicate that the intracellular PO₂ would not have fallen below 22 mm Hg during any intervention. Because the K_m value for O₂ with respect to cytochrome oxidase is <1 mm Hg, this PO₂ level would be expected to make mitochondrial oxygen availability nonlimiting.¹⁸

Although Mb- was not detected during dobutamine infusion, it is possible that an initial period of myoglobin desaturation at the onset of increased work could have been missed. To achieve adequate sensitivity for detection of Mb- required summing of ¹H NMR spectra over a period of 5 minutes. Furthermore, measurements were not obtained until steady-state hemodynamic conditions had been achieved. If oxygen limitation occurred at the onset of dobutamine infusion, this might have triggered a feedback loop that would adjust contractile activity and metabolic demands downward to match oxygen availability. Such feedback control of HEP has been demonstrated during acute reductions in coronary perfusion, in which the initial loss of PCr recovers to near normal levels despite continuing hypoperfusion.^{19 20} At the present time, ¹H NMR technology for in vivo detection of Mb- does not allow sufficient temporal resolution to examine the initial time course of the response to dobutamine.

Basal-State HEP Levels
Basal PCr/ATP ratios tended to be lower than control in the LVR group and were substantially reduced in CHF hearts.^{2 21} Myocardial PCr levels are related to cytosolic [ADP] levels, because creatine kinase is a near-equilibrium enzyme and the concentrations of the other substrates generally exceed their respective K_m values.²² Hence, the decreased PCr/ATP in the CHF hearts probably resulted from elevated ADP levels. However, the hypothesis that the reduction in PCr/ATP ratio resulted from elevation of ADP secondary to a mismatch between oxygen supply and demand is not supported by the current data. The mechanism of this abnormality remains to be determined.

HEP Responses to Increased Work States
The increase of myocardial work during dobutamine infusion in normal and LVR hearts resulted in significant increases of blood flow and MO₂, with no detectable myoglobin desaturation. Thus, the decreased PCr/ATP ratios during dobutamine infusion probably reflect a change in the kinetics of oxidative phosphorylation or intermediary metabolic steps rather than a myocyte oxygenation–related limitation of ATP synthetic capacity.²³ In normal pigs, Massie et al²⁴ reported that PCr/ATP ratios were decreased at moderately high work states in association with a decreased endocardial-to-epicardial blood flow ratio and lactate release. They suggested that these changes reflected demand ischemia,²⁴ but the present data demonstrate that HEP changes can occur during moderately high work states in well-oxygenated myocardium. The reduced response to dobutamine in the CHF group may be related to ß-adrenergic receptor downregulation²⁵ or to a primary decrease in myocyte contractile performance, as in pacing-induced heart failure.²⁶ Nevertheless, the response of the CHF hearts to dobutamine, although reduced, was not associated with myoglobin desaturation or changes in the already low PCr/ATP ratios. Similarly, Schaefer et al²⁷ observed that dobutamine caused no change in phosphorus metabolites in patients with dilated cardiomyopathy. The lack of reduction of the PCr/ATP ratio or myoglobin desaturation during dobutamine supports the view that the ability to utilize ATP, rather than the ability to produce ATP, limited function in the CHF group during dobutamine stimulation.

Conclusions
The decreases of PCr/ATP that occur during dobutamine stimulation in normal and LVR hearts are not caused by insufficient myocyte oxygen availability. In hearts with CHF, the decreased basal PCr/ATP ratios and the reduced response to dobutamine also were not associated with myocyte deoxygenation, indicating that decreased oxygen availability did not constrain function or cause the observed HEP abnormalities.

	Acknowledgments

 
This work was supported by US Public Health Service grants HL-21872, HL-33600, HL-50470, and HL-57994 and a Grant-in-Aid from the American Heart Association. Dr Zhang is the recipient of an Established Investigator Award from the American Heart Association.

Received June 5, 1998; revision received September 18, 1998; accepted September 25, 1998.

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