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(Circulation. 1995;92:1274-1283.)
© 1995 American Heart Association, Inc.

Articles

Effect of Left Ventricular Hypertrophy Secondary to Chronic Pressure Overload on Transmural Myocardial 2-Deoxyglucose Uptake

A ³¹P NMR Spectroscopic Study

Jianyi Zhang, MD, PhD; Dirk J. Duncker, MD, PhD; Xu Ya, MD; Yi Zhang, MD; Todd Pavek, BA; Horan Wei, PhD; Hellmut Merkle, PhD; Kâmil Ugurbil, PhD; Arthur H. L. From, MD; Robert J. Bache, MD

From the Departments of Medicine (J.Z., D.J.D., T.P., A.H.L.F., R.J.B.), Biochemistry (K.U.), and Radiology (K.U.) and the Center for Magnetic Resonance Research (J.Z., X.Y., Y.Z., H.W., H.M., K.U.), University of Minnesota Health Sciences Center and the Department of Veterans Affairs Medical Center (A.H.L.F.), Minneapolis.

Correspondence to Robert J. Bache, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508, UMHC, Minneapolis, MN 55455.

	Abstract

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Background This study tested the hypothesis that ³¹P nuclear magnetic resonance (NMR)–detectable 2-deoxyglucose (2DG) uptake is increased in chronically pressure-overloaded hypertrophied left ventricular myocardium.

Methods and Results ³¹P NMR spectroscopy was used to determine the transmural distribution of high-energy phosphate levels and 2-deoxyglucose-6-phosphate (2DGP) accumulation during intracoronary infusion of 2DG (15 µmol · kg body wt^-1 · min^-1) in eight normal dogs and in eight dogs with severe left ventricular hypertrophy (LVH) produced by ascending aortic banding. The ratio of LV weight to body weight was 8.25±0.65 g/kg in the LVH group compared with 4.35±0.11 g/kg in the normal group (P<.01). Myocardial ATP content was decreased by 40% and phosphocreatine (PCr) by 60% in LVH hearts. ATP values were transmurally uniform in LVH and normal hearts, whereas PCr was lower in the subendocardium (Endo) than the subepicardium (Epi) of both groups. The PCr/ATP ratio was lower in LVH hearts (1.72±0.05, 1.64±0.07, and 1.53±0.10 in Epi, midwall, and Endo, respectively) compared with normal hearts (2.36±0.05, 2.09±0.06, and 1.96±0.06; each P<.01 normal versus LVH). Arterial blood levels of glucose, insulin, and free fatty acids were comparable between groups, whereas arterial lactate and norepinephrine levels were significantly higher in the LVH group. 2DG infusion did not affect systemic hemodynamics or myocardial high-energy phosphate or inorganic phosphate levels in either group. At the end of 60 minutes of 2DG infusion, there was no detectable accumulation of 2DGP in the normal hearts. However, seven of the eight LVH hearts showed time-dependent accumulation of 2DGP, which was linearly related to the severity of hypertrophy (r=.90 for subendocardial 2DGP versus LV weight/body weight). A transmural gradient of 2DGP was present, with greatest accumulation in the subendocardium (3.3±1.6, 5.8±2.3, and 7.9±2.2 µmol/g in Epi, midwall, and Endo of the LVH hearts, respectively; P<.05 Epi versus Endo).

Conclusions The pressure-overloaded hypertrophied left ventricle demonstrated increased accumulation of 2DGP detected with ³¹P NMR spectroscopy. Accumulation of 2DGP was positively correlated with the degree of hypertrophy and was most marked in the subendocardium.

Key Words: hypertrophy • aorta • stenosis • glucose • magnetic resonance imaging

	Introduction

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We previously reported that severe left ventricular hypertrophy (LVH) secondary to chronic pressure overload is associated with transmural reductions of myocardial ATP, phosphocreatine (PCr), and creatine and a substantial elevation of free ADP.¹ These abnormalities were not improved by pharmacological coronary vasodilation, indicating that persistent myocardial underperfusion was not the cause of the high-energy phosphate (HEP) abnormalities.¹ In the hypertrophied hearts, pacing-induced tachycardia caused relative hypoperfusion and worsening of HEP abnormalities in the subendocardium, whereas in the subepicardium, blood flow was maintained and HEP content was not further altered.¹ The finding that subepicardial HEP content is depressed, even though perfusion in this layer is not limited either under control conditions or during pacing stress, suggests the presence of a primary alteration of myocardial metabolic characteristics in the hypertrophied heart.

Previous investigators reported that the concentrations of several glycolytic enzymes are increased in hypertrophied myocardium.^{2 3} Furthermore, there is evidence that glucose uptake is greater in hearts from hypertensive rats than in normal rat hearts.^{4 5} On the basis of these previous reports, we hypothesized that the in vivo uptake of glucose in hypertrophied myocardium would be increased and that this change would be most prominent in the subendocardium. We further hypothesized that alterations in the magnitude and distribution of glucose uptake could be detected in vivo by means of spatially localized ³¹P nuclear magnetic resonance (NMR) spectroscopy.^{6 7} To test these hypotheses, myocardial HEP content and 2-deoxyglucose-6-phosphate (2DGP) accumulation were measured by ³¹P NMR spectroscopy during intracoronary infusion of 2-deoxyglucose (2DG) in normal and LVH hearts. Arterial blood levels of competing carbon substrates (lactate and free fatty acids) as well as glucose, insulin, and norepinephrine were monitored.

	Methods

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Studies were performed in accordance with the "Position of the American Heart Association on Research Animal Use," adopted November 11, 1984, and protocols were approved by the Animal Care Committee of the University of Minnesota.

Production of LVH
Eight mongrel dogs 8 weeks of age were anesthetized with sodium pentobarbital (25 to 30 mg/kg IV), intubated, and ventilated with a respirator. A right thoracotomy was performed in the third intercostal space, and the ascending aorta, 1.5 cm above the aortic valve, was mobilized and encircled with a polyethylene band 2.5 mm wide. While left ventricular and distal aortic pressures were measured simultaneously, the band was tightened until a 20 to 30 mm Hg peak systolic pressure gradient was achieved across the narrowing. The chest was then closed, the pneumothorax was evacuated, and the animals were allowed to recover. LVH occurred progressively as the area of aortic constriction remained fixed in the face of normal body growth. At approximately 1 year of age, animals were returned to the laboratory for study.

Experimental Preparation
Eight animals with LVH and 12 normal animals were premedicated with morphine sulfate (1 mg/kg SC) and anesthetized with -chloralose (100 mg/kg IV followed by an infusion of 10 mg · kg^-1 · h^-1). Animals were intubated and ventilated with a respirator with supplemental oxygen; arterial blood gases and pH were maintained within the physiological range. A polyvinyl chloride catheter, 3.0-mm OD, filled with heparin-saline was introduced into the right femoral artery and advanced into the ascending aorta. A left thoracotomy was performed in the fifth intercostal space, and the heart was suspended in a pericardial cradle. In 4 animals used to assess the response to acute left ventricular systolic pressure overload, a hydraulic vascular occluder was placed around the ascending aorta 2 to 3 cm above the aortic valve. A heparin-saline 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. The proximal left anterior descending coronary artery (LAD) was dissected free, and a silicone microcatheter (0.75-mm ID) was introduced into the artery by the method of Gwirtz.⁸ An NMR surface coil was sutured to the anterior left ventricular wall overlying the region perfused by the LAD. The surface coil was constructed of a single turn of copper wire and incorporated a 33-pF capacitor; surface coils for normal and LVH hearts were 28 and 35 mm in diameter, respectively. The surface coil leads were connected to a balanced tuned circuit external and perpendicular to the thoracotomy incision. The pericardial cradle was released, and the heart was allowed to assume its normal position. 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, 3x10⁶ microspheres were administered into the left atrial catheter and flushed with 5 mL of normal saline. A reference sample of arterial blood was withdrawn from the aortic catheter with a roller pump at a rate of 15 mL/min beginning 5 seconds before the 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. Activity in each energy window was corrected for overlapping activity from the associated isotopes as well as for background activity. Knowing the rate of withdrawal of the reference blood specimen (Q_r) and the radioactivity of the reference specimen (C_r), myocardial radioactivity (C_m) was used to compute myocardial blood flow (Q_m) as Q_m=Q_rx(C_m/C_r). Blood flow was expressed as mL · min^-1 · g^-1 myocardium.

NMR Technique
Measurements were performed in a 40-cm-bore, 4.7-T magnet interfaced with a Spectroscopy Imaging Systems Corp console. The left ventricular pressure signal was used to gate NMR data acquisition to the cardiac cycle, and respiratory gating was achieved by triggering the ventilator to the cardiac cycle between data acquisitions.^{6 7 31}P and ¹H resonant 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 inorganic phosphate (P_i) resonances and 95% and 80% relaxation for the PCr and 2DGP resonances, respectively.^{6 7} PCr and 2DGP resonance intensities were corrected for this saturation; the correction factor was determined for each heart from two spectra recorded consecutively without transmural differentiation, one with an 18-second repetition time to allow full relaxation and the other with the 6- to 7-second repetition time used during the study.

Radiofrequency transmission and signal detection were performed with the previously described 35- and 28-mm-diameter surface coils for LVH and normal hearts, respectively. The coil was cemented to a sheet of silicone rubber 0.7 mm thick; 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 accomplished by use of a spin-echo experiment and a readout gradient.⁶ The information gathered in this step was also used to determine the spatial coordinates for spectroscopic localization.⁶ With static magnetic field gradients and adiabatic inversion pulses, signal origin was restricted to a column coaxial with the surface coil and perpendicular to the left ventricular wall; the column dimensions were 23x23 mm in LVH hearts and 18x18 mm in normal hearts. Within this column, the signal was further localized to 5 voxels across the left ventricular wall from epicardium to endocardium with the radiofrequency magnetic field (B₁) gradient centered about 135°, 120°, 90°, 60°, and 45° phase angles.⁹ The details of the adiabatic inversion pulses, the plane rotation adiabatic BIR-4 pulse, the Fourier coefficients, and the multiplication factors used to construct the voxels have been reported elsewhere.^{6 9} When the B₁ gradient is used for localization along the coil axis, an increase in phase angle shifts the voxel further from the surface coil (ie, "deeper" into the left ventricular muscle).^{7 9} Because of the nonlinear nature of the B₁ gradient, voxel width is largest for the 45° ("deepest") voxel; this voxel is centered approximately one radius distant from the coil, with most signal contained between 0.8 and 1.2 radius distance. Despite the nonuniform voxel volume, the detected signal per unit spins is nearly uniform between voxels (<20% variation)¹⁰ because the decreasing sensitivity with increasing distance from the coil compensates for the increasing voxel volume. For this reason, intensities between voxels can be compared directly, except for the innermost voxel, where the metabolite content may be underestimated because of a partial volume effect (ie, the voxel may not contain exclusively subendocardial muscle but rather may be occupied in part by blood in the left ventricular chamber).

Each set of spatially localized spectra consisted of 96 scans accumulated in a 10-minute block of time. Chemical shifts were measured relative to PCr, which was assigned a chemical shift of -2.55 ppm relative to 85% phosphoric acid. Because of off-resonance problems associated with the ATP_ß resonance peak, the ATP resonance was integrated for determination of ATP content by use of Spectroscopy Imaging Systems Corp software. No baseline correction was used. Signal-to-noise ratio for ATP was 25 to 50. Calibration of the epicardial voxel ATP content was performed with chemically determined ATP in an epicardial biopsy obtained at the conclusion of the study.

Tissue Preparation
With a biopsy forceps precooled to -70°C, at the end of the study an epicardial biopsy was taken from 11 normal and 5 LVH ventricles for subsequent analysis of ATP content by high-performance liquid chromatography.¹¹ The animal was then killed, the heart was excised, and a full-thickness myocardial specimen 3 g in weight was taken and frozen for subsequent determination of total creatine content.¹¹ 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 2.0 cm thick contained the region of myocardium located directly beneath the surface coil. The myocardium 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 of radioactivity. Similar myocardial specimens were obtained from the lateral and posterior left ventricular walls to ensure that the measurements from the region beneath the surface coil were typical of the entire left ventricle.

Biochemical Analyses
Plasma glucose was determined with a coupled enzymatic assay (hexokinase and glucose-6-phosphate dehydrogenase method; diagnostic kit, Sigma Chemical Co). Whole-blood lactate was determined by the method of Hohorst (described in Reference 12). Plasma free (nonesterified) fatty acids were measured with a colorimetric assay kit (Wako Chemicals USA). Serum insulin levels were determined with ¹²⁵I radioimmunoassay using an antibody that cross-reacts 100% with human and dog insulin (ICN Biomedicals, Inc, Diagnostics Division). Plasma norepinephrine was measured with a radioenzymatic assay from a commercially available kit (Catecholamine Research Assay System, Amersham Corp).

Hemodynamic Measurements
Aortic and left ventricular pressures were monitored with Spectramed pressure transducers positioned at midchest level. Data were recorded on an 8-channel direct writing recorder (Coulbourne Instrument Co). Left ventricular pressure was recorded at normal and high gains for measurement of end-diastolic pressure. Hemodynamic data were recorded continuously throughout the study. Arterial blood gases were measured every 15 minutes, and the respirator was adjusted to maintain the PO₂, PCO₂, and pH in the physiological range.

Experimental Protocol
Group 1
Studies were performed in eight normal control dogs and all eight animals with LVH to assess myocardial HEP content and 2DGP accumulation during basal conditions. ³¹P NMR spectra were first obtained during control conditions. Midway through the 10-minute NMR data acquisition period, a microsphere injection was performed for determination of myocardial blood flow. Arterial blood samples were obtained for measurement of insulin, norepinephrine, glucose, free fatty acids, and lactate. After completion of the baseline measurements, an infusion of 2DG into the LAD was begun (15 µmol · kg body wt^-1 · min^-1) while NMR data acquisition continued. Transmurally differentiated spectra were acquired (10-minute acquisition time), immediately followed by acquisition of a nontransmurally differentiated spectrum. This NMR data acquisition sequence was repeated every 15 minutes for a total of 60 minutes while the intracoronary 2DG infusion continued. Sixty minutes after the 2DG infusion was begun, arterial blood samples were again obtained for measurement of insulin, glucose, fatty acids, and lactate, and a final injection of microspheres was performed.

Group 2
A second group of four normal dogs was studied to determine whether systolic pressure overload alone (without LVH) would influence myocardial HEP content or 2DGP accumulation. In these animals, hemodynamic measurements and ³¹P NMR spectra were first obtained during basal conditions. The hydraulic ascending aortic occluder was then inflated to increase left ventricular systolic pressure to 170 mm Hg. After 10 minutes was allowed to ensure steady-state conditions, ³¹P NMR spectra were again obtained. Finally, an intracoronary infusion of 2DG (15 µmol · kg body wt^-1 · min^-1) was begun, and all measurements were repeated as described above.

Data Analysis
Hemodynamic data were measured from the chart recordings. Numerical values for PCr and ATP during each experimental condition were expressed as a percentage of the baseline value for each compound. ³¹P NMR spectra from the first, third, and fifth voxels were taken to represent subepicardium, midmyocardium, and subendocardium, respectively.^{9 10} Hemodynamic, biochemical, and blood flow data were analyzed with one-way ANOVA with replications. A value of P<.05 was required for significance. When the ANOVA yielded a significant result, individual comparisons were made by the method of Scheffé. Data are reported as mean±SEM.

	Results

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Group 1
Anatomic data. In the 8 normal control animals, body weights ranged from 18.5 to 24.5 kg (mean, 21.4±0.8 kg), left ventricular weights ranged from 77.9 to 119.1 g (mean, 95.2±5.3 g), and ratios of left ventricular weight to body weight ranged from 3.92 to 4.90 g/kg (mean, 4.35±0.11 g/kg). In animals with aortic banding, body weights ranged from 21.0 to 25.6 kg (mean, 23.1±1.1 kg); left ventricular weights ranged from 141.9 to 250.1 g (mean, 193.6±15.4 g) and were significantly greater than normal (P<.01). Ratios of left ventricular weight to body weight in animals with aortic banding ranged from 6.73 to 11.90 g/kg (mean, 8.25±0.65 g/kg), which averaged 90% greater than in the normal animals (P<.01). None of the animals with LVH had clinical evidence of heart failure.

Hemodynamic data. Hemodynamic measurements are shown in Table 1. During the control state, there was no significant difference in heart rates between normal animals and animals with hypertrophy. In the LVH group, mean aortic pressure distal to the constricting band was similar to that of the normal hearts. Left ventricular systolic and end-diastolic pressures were significantly higher in LVH than in normal hearts (P<.05), and the heart rate–left ventricular systolic pressure product was also significantly higher in the LVH group (P<.05). None of the hemodynamic variables in either group changed significantly during infusion of 2DG.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Data from Eight Normal Control Dogs and Eight Dogs With LVH in Group 1

Myocardial blood flow. In the basal state, mean myocardial blood flow was similar in the two groups (Table 2), but the transmural distribution of perfusion differed, with a significantly lower ratio of subendocardial to subepicardial blood flow in the LVH group (P<.05). 2DG administration did not affect myocardial blood flow in either group.

View this table: [in this window] [in a new window]   Table 2. Myocardial Blood Flow Measurements Obtained During Control Conditions and After a 1-Hour Infusion of 2-Deoxyglucose

Biopsy data. Subepicardial ATP content was approximately 40% lower in LVH (14.6±0.5 µmol/g dry wt) than in normal hearts (24.2±0.9 µmol/g; P<.05). Total tissue creatine was also less in hypertrophied hearts (90.2±5.1 µmol/g dry wt) than in the normal hearts (125.1±7.4 µmol/g; P<.05).

³¹P NMR HEP and 2DGP levels. Transmural sets of ³¹P NMR spectra from a normal heart and from a heart with LVH are shown in Figs 1 and 2, respectively. Spectra were acquired under baseline conditions and during intracoronary infusion of 2DG. The voxel labeled EPI was located over the outer edge of the left ventricular wall, and the voxel most distant from the coil, labeled ENDO, was located over the subendocardium. The voxel labeled MID was located over the midmyocardium. These three voxels have virtually no overlap; there is, however, partial overlap between adjacent voxels in the five-voxel set.^{9 10} Spectra recorded during the control period were characterized by high PCr and ATP levels in both the normal and LVH hearts, but P_i was too low to identify at the signal-to-noise ratio of the spectra. The ATP content across the left ventricular wall of the LVH hearts was examined by comparison of relative intensities after correction for the variation in sensitivities for the different voxels.¹⁰ ATP content relative to the MID voxel is given in Table 3 under baseline conditions and after 2DG infusion. ATP content can be underestimated in the innermost voxel (voxel 5) because of partial volume effects and tended to be lower in the innermost voxel in this study; nevertheless, there was no statistically significant gradient across the LVH heart with respect to ATP content. We have previously reported that the ATP content in normal canine myocardium is also transmurally uniform.¹⁰

View larger version (17K): [in this window] [in a new window]   Figure 1. Tracings showing transmural response of phosphorylated metabolites detected by 31P NMR in a typical normal heart during control conditions (A) and at 45 minutes of intracoronary infusion of 2-deoxyglucose (15 µmol · kg-1 · min-1) (B). Each transmural data set consists of a stack of five spectra extending from epicardium to endocardium. ENDO indicates subendocardium; MID, midwall; EPI, subepicardium; and CP, creatine phosphate.

View larger version (21K): [in this window] [in a new window]   Figure 2. Tracings showing transmural response of phosphorylated metabolites detected by 31P NMR in an animal with left ventricular hypertrophy during control conditions (A) and at 45 minutes of intracoronary infusion of 2-deoxyglucose (15 µmol · kg-1 · min-1) (B). Each transmural data set consists of a stack of five spectra extending from epicardium to endocardium. 2DGP identifies the 2-deoxyglucose-6-phosphate resonance; ENDO, subendocardium; MID, midwall; EPI, subepicardium; and CP, creatine phosphate.

View this table: [in this window] [in a new window]   Table 3. Relative ATP Content Across the Wall of the Left Ventricle in Eight Animals With LVH During Baseline Conditions and After Administration of 2-Deoxyglucose

Absolute values for ATP, PCr, and 2DGP and the PCr/ATP ratios are shown in Table 4. ATP and PCr concentrations and the PCr/ATP ratios were significantly lower in each layer of the hypertrophied hearts than in the corresponding layers of the normal hearts. Subendocardial PCr concentrations and PCr/ATP ratios were lower than those in the subepicardium in both groups (P<.05). In animals with aortic banding, the degree of reduction of the subendocardial PCr/ATP ratios was positively correlated with the severity of hypertrophy (r=.75). Neither ATP nor PCr changed significantly in response to 2DG infusion in either group.

View this table: [in this window] [in a new window]   Table 4. Myocardial ATP, PCr, and 2DGP in Eight Normal Hearts and Eight Hearts With LVH During Baseline Conditions and After a 1-Hour Infusion of 2-Deoxyglucose

There was no NMR-detectable accumulation of 2DGP during 2DG infusion in any myocardial layer in the normal group (Fig 1 and Table 4). In contrast, accumulation of 2DGP was observed in seven of the eight LVH hearts (Fig 2). As shown in Fig 3, significant 2DGP concentrations were seen in the spectra ending at 30 minutes of 2DG infusion. At 45 minutes of 2DG infusion, 2DGP levels had begun to plateau, and there was no further significant increase at 60 minutes.

View larger version (22K): [in this window] [in a new window]   Figure 3. Bar graph showing mean±SEM 2-deoxyglucose-6-phosphate (2DGP) in eight animals with left ventricular hypertrophy. Spectra were accumulated over a 10-minute interval; the time reported indicates the time after the beginning of infusion of 2DGP at which data accumulation was concluded. ENDO indicates subendocardium; MID, midmyocardium; and EPI, subepicardium.

A transmural gradient of 2DGP accumulation was evident, as illustrated in Figs 2B and 3 and Table 4 (subendocardium > subepicardium; P<.05). Accumulation of 2DGP did not affect hemodynamic measurements, transmural blood flow distribution, or the myocardial content of PCr or ATP (Tables 1, 2, and 4). When the subendocardial 2DGP/ATP ratio was plotted against the ratio of left ventricular weight to body weight (Fig 4), a significant positive relation was observed, indicating that 2DG uptake was correlated with the severity of hypertrophy. As shown in Fig 5, the degree of accumulation of 2DGP in the subendocardium of the hypertrophied hearts was negatively correlated with the subendocardial PCr/ATP ratio.

View larger version (12K): [in this window] [in a new window]   Figure 4. Graph showing subendocardial 2-deoxyglucose-6-phosphate (2DGP), expressed relative to ATP, plotted against the relative severity of left ventricular (LV) hypertrophy, expressed as the ratio of LV weight to body weight in eight animals with LV hypertrophy. 2DGP was measured between 45 and 60 minutes of the 2-deoxyglucose infusion.

View larger version (12K): [in this window] [in a new window]   Figure 5. Graph showing subendocardial 2-deoxyglucose-6-phosphate (2DGP), expressed relative to ATP, plotted against subendocardial PCr/ATP in eight animals with left ventricular hypertrophy. 2DGP was measured between 45 and 60 minutes of 2-deoxyglucose infusion. PCr indicates phosphocreatine.

Arterial blood levels of carbon substrates, insulin, and norepinephrine. As shown in Table 5, arterial glucose, fatty acid, and insulin concentrations were comparable in the two groups during the control period and were not significantly changed during 2DG infusion, although glucose levels in the LVH group tended to increase during 2DG infusion. Arterial lactate levels were significantly higher in the LVH group during the control period and during the 2DG infusion period, although they were not significantly affected by the infusion itself. Plasma norepinephrine concentration was significantly higher in the LVH group than in the normal group (P<.05) during the control period; norepinephrine was not measured during 2DG infusion.

View this table: [in this window] [in a new window]   Table 5. Arterial Levels of Norepinephrine, Insulin, Free Fatty Acids, Glucose, and Lactate in Eight Normal Dogs and Eight Dogs With Left Ventricular Hypertrophy During Control Conditions and After Infusion of 2-Deoxyglucose

Because of the possibility that the elevated norepinephrine levels reflected greater sensitivity to the surgical preparation in the hypertrophy group (rather than a chronic neurohumoral alteration), plasma norepinephrine levels were measured in two groups of resting awake dogs. One group was composed of normal animals and the second of animals with LVH of a severity comparable to the group reported here. Plasma norepinephrine levels were significantly higher in awake animals with LVH (406±58 pg/mL) than in the normal dogs (240±27 pg/mL; P<.05). Plasma norepinephrine levels in animals with LVH were higher in the open-chest state than during resting awake conditions (P<.05).

Group 2
Hemodynamic data from four normal dogs in group 2 are shown in Table 6. Constriction of the ascending aorta with the hydraulic occluder increased left ventricular systolic pressure from 107±4 to 168±1 mm Hg (P<.01), with no change in the other measured hemodynamic variables. Left ventricular systolic pressure and rate-pressure product during aortic constriction in the normal dogs in group 2 were similar to those in the dogs with LVH in group 1.

View this table: [in this window] [in a new window]   Table 6. Hemodynamic Data From Four Normal Dogs During Control Conditions, During Ascending Aortic Constriction, and During Aortic Constriction With Infusion of 2-Deoxyglucose

Myocardial ATP and PCr concentration during control conditions, during elevated left ventricular systolic pressure, and during elevated left ventricular systolic pressure after a 1-hour infusion of 2DG are shown in Table 7. Left ventricular systolic pressure overload caused no change in ATP, PCr, or the ATP/PCr ratio. There was no ³¹P NMR–detectable accumulation of 2DGP in any of the normal dogs during systolic pressure overload.

View this table: [in this window] [in a new window]   Table 7. Myocardial ATP and PCr in Four Normal Dogs During Baseline Conditions, During Ascending Aortic Constriction, and During Aortic Constriction With Infusion of 2-Deoxyglucose

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major new findings of this study are that pressure-overloaded hypertrophied myocardium accumulated ³¹P NMR–detectable 2DGP but normal myocardium did not, and that 2DGP accumulation in the hypertrophied hearts was greatest in the subendocardium. Accumulation of 2DGP was related to the presence of myocardial hypertrophy and not to systolic pressure overload alone, since acute elevation of left ventricular systolic pressure in normal hearts did not result in detectable accumulation of 2DGP. The subsequent discussion will examine the experimental methodology used and consider the physiological implications of these results.

Methodological Considerations
2DGP Accumulation as an Indicator of Glucose Utilization
2DG is a glucose analogue that is transported by the sarcolemmal glucose transporter and subsequently phosphorylated in the C6 position by hexokinase to yield 2DGP.¹³ 2DG uptake is subject to insulin control and is increased as blood levels of competing oxidative substrates such as fatty acids and lactate are decreased.^{13 14 15} Because 2DGP (1) cannot undergo further glycolytic metabolism, (2) is hydrophilic and cannot easily diffuse out of the myocyte, and (3) is very slowly dephosphorylated by 6-phosphoglucose phosphatase, the clearance of 2DGP from the heart is extremely slow.¹⁶ In tracer studies, the relation of the uptake and phosphorylation rates between glucose and 2DG is expressed as the "lumped constant."^{13 17} If the lumped constant remains unchanged under a variety of conditions, then the fractional rate of 2DGP accumulation will reflect the fractional rate of glucose uptake. However, a major assumption of 2DG or ¹⁹F-fluorodeoxyglucose methods for estimating glucose uptake is that the glucose analogue is administered in tracer concentrations so that glucose uptake is not affected by competitive inhibition with the 2DG.¹³ Because of competition for transport across the cell membrane in the presence of high levels of 2DG,¹⁸ it is likely that glucose uptake in the present study was substantially lower than would be the case with standard tracer methods. Under the present experimental conditions, 2DG uptake is a component of total hexose uptake, which is the sum of 2DG and glucose uptakes. Thus, the major issue is whether the increased 2DG uptake in the hypertrophy group implies elevated total hexose uptake, which, in the absence of 2DG, would be composed of glucose alone.

During 2DG administration, glucose, free fatty acid, and insulin levels were not significantly different between experimental groups, and the higher lactate levels would be likely to retard (rather than enhance) 2DG uptake in the LVH group.¹⁹ Similarly, the trend toward higher plasma glucose levels in the LVH group, although not statistically significant, would tend to decrease 2DG transport into the cell by simple competition.¹⁸ Coronary blood concentrations of 2DG were lower in LVH than in normal hearts because the coronary blood flow into which the 2DG was diluted was increased in proportion to the degree of hypertrophy. Because the degree of hypertrophy was not known until the heart was weighed, it was not possible to adjust the infusion rate for differences in myocardial mass at the time of study. However, by use of postmortem measurements of the mass of left ventricle perfused by the LAD and myocardial blood flow measured with microspheres, it was possible to compute total coronary blood flow into which the 2DG was diluted. In the normal animals, mean LAD blood flow was 28.4 mL/min while the infusion rate was 0.321 mmol/min, yielding a blood concentration of 11.3 mmol/L during the first pass. In animals with aortic banding, mean LAD blood flow was 61.4 mL/min; 2DG was infused at a rate of 0.347 mmol/min, yielding a coronary blood concentration of 5.65 mmol/L. These represent initial blood concentrations; not all of the 2DG was extracted, so there was some recirculation. However, the recirculated 2DG would be diluted into the total systemic blood volume and taken up by other tissues, so the increase in coronary blood concentration was probably modest and similar in the two groups. The lower arterial blood levels of 2DG would be expected to diminish 2DG accumulation in the LVH group because 2DG blood levels in both groups were near the previously estimated K_m values for the glucose transporter.¹⁸ These considerations support the concept that the higher 2DG accumulation rates indicate higher total hexose uptake rates in the LVH group. Further, it is possible that because of the lower arterial blood levels of 2DG in the LVH group, the difference in total hexose transport rates between the normal and LVH groups is underestimated by the rates of 2DGP accumulation in the LVH group.

The mechanism for the plateau of 2DGP accumulation despite continuing infusion of 2DG is of interest. In rat hearts perfused with comparable concentrations of 2DG but without glucose in the perfusate, 2DGP accumulation continued until the intracellular phosphate became limiting as the ATP and PCr pools fell to extremely low levels.^{14 20} These data indicate that in the presence of adequate alternative carbon substrate (other than glucose), intracellular 2DG and/or 2DGP accumulation does not substantially inhibit hexose transport or hexokinase activity. In contrast, when 2DG was infused with glucose, 2DGP accumulation plateaued at much lower levels than when glucose was absent from the perfusate.¹⁴ Unlike 2DGP, glucose-6-phosphate is known to inhibit hexokinase.²¹ It is also known that 2DGP at least partially inhibits the "downstream" glycolytic pathway because it cannot be (rapidly) metabolized.²² Thus, it is likely that when both glucose and 2DG are transported into the myocyte, the partial inhibition of glycolysis by 2DGP results in an elevation of glucose-6-phosphate levels, which, in turn, inhibits hexokinase and limits further phosphorylation of 2DG. In contrast to the observations in the perfused rat heart,^{14 20} accumulation of 2DGP in the present study was not associated with reductions of PCr or ATP, so that P_i from degraded HEP was not the source of P_i for 2DG phosphorylation. Moreover, the levels of NMR-visible (ie, "free") P_i were extremely low in hypertrophied myocardium. Therefore, the data raise the possibility that there may be a significant pool of NMR-invisible P_i that buffers the NMR-visible pool. However, it is most likely that the source of additional phosphate was from the extracellular phosphate pool, as suggested by recent observations showing rapid transsarcolemmal phosphate transport.²³

Why Was 2DGP Accumulation Not Observed in Normal Hearts?
The failure of the normal hearts to accumulate ³¹P NMR–detectable 2DGP must be reconciled with earlier reports in which glucose uptake was detected in normal canine myocardium by use of arteriovenous difference measurements²⁴ or positron emission tomography.^{15 25} It is likely that the relative insensitivity of ³¹P NMR spectroscopy explains our failure to detect 2DGP uptake in the normal hearts. The threshold of consistently resolvable phosphate metabolite using ³¹P NMR technology is 2 to 4 µmol/g dry wt, whereas the positron emission tomography technique is at least three orders of magnitude more sensitive than this. Unless glucose uptake is enhanced (as by the administration of insulin)¹⁴ or very high concentrations of 2DG are used, 2DGP accumulation may remain below the threshold of NMR detectability. In support of this, we observed that intravenous administration of a much larger dose of 2DG that elicits an increase in plasma insulin can result in NMR-detectable 2DGP accumulation in normal myocardium.²⁶ Nevertheless, the relatively low sensitivity of ³¹P NMR limits the usefulness of this technique in normal myocardium.

Physiological Implications of Increased 2DG Uptake in LVH
Myocardial Energy Requirements in LVH
In response to chronic pressure overload, the left ventricle undergoes compensatory hypertrophy. The resultant increase in wall thickness results in normalization of systolic wall stress (force per unit cross-sectional area) despite persistently elevated intracavitary pressure.²⁷ As a result, oxygen consumption per gram myocardium is similar to that of nonhypertrophied myocardium.²⁸ Consequently, the increased 2DG uptake in the hypertrophied hearts in the present study cannot be explained by a generalized increase in substrate uptake to meet basal energy requirements. Furthermore, increasing left ventricular systolic pressure in normal dogs to a level similar to the animals with hypertrophy did not result in accumulation of ³¹P NMR–detectable 2DGP, indicating that an increased pressure load alone could not account for the difference between normal and aortic-banded dogs. Oxygen requirements per gram myocardium undergo a greater increase during exercise in the pressure-overloaded hypertrophied left ventricle than in the normal heart.²⁹ It is possible that the increased energy expenditure in the hypertrophied hearts during exercise could result in altered patterns of substrate utilization that would persist during basal conditions.

Bioenergetic Abnormalities in Hypertrophied Myocardium
The hypertrophied hearts in the present study demonstrated prominent loss of HEP, with 40% lower ATP and 58% lower PCr concentrations in comparison with the normal hearts. Despite the loss of HEP, the hypertrophied hearts were able to sustain the increased pressure load imposed by the aortic banding procedure without evidence of cardiac failure. This is in agreement with studies in perfused rat hearts in which administration of 2DG to cause depletion of ATP and PCr did not impair contractile function until HEP levels were markedly depressed.²⁰ Similarly, dietary depletion of myocardial PCr in rats did not impair systolic function at basal work loads even when PCr values were decreased to 10% of normal,³⁰ although the ability to respond to an inotropic stimulus was reported to be impaired.³¹ Furthermore, although the ATP loss in postischemic stunned myocardium is associated with depressed contractile function,³² stunned myocardium can respond quite well to inotropic stimulation.³³ These findings suggest that within a broad range, the size of the HEP pool is not critical to contractile performance.

Previously Defined Abnormalities of Intermediary Metabolism in Hypertrophied Myocardium
Earlier investigators reported that the concentrations of a number of glycolytic enzymes are increased in hypertrophied myocardium^{2 3 34} and that the concentrations of these enzymes are highest in the subendocardium of normal hearts.³⁵ Consistent with this finding, glucose uptake has been shown to be greatest in the subendocardium of normal rat and dog left ventricles.^{36 37} There is also evidence that glucose uptake is greater in left ventricles from hypertensive rats than from normotensive rats.^{4 5} Abnormalities of fatty acid metabolism have also been demonstrated in the hypertrophied heart. Cardiac failure secondary to chronic pressure overload has been shown to result in defective long-chain fatty acid metabolism in guinea pig hearts,² whereas chronic volume overload induced a reduction of long-chain fatty acid metabolic capacity in the rat heart.³⁸ Hypertensive Dahl rat hearts also showed reduced long-chain fatty acid uptake compared with normal hearts, although the degree of LVH was not reported.⁴ These previous findings support the concept that hypertrophied myocardium has increased glucose uptake, although the mechanism of this altered pattern of metabolism is unknown.

Transmural Gradient of 2DGP Accumulation
A transmural gradient of 2DGP was observed in the hypertrophied hearts, with greatest accumulation in the subendocardium. As noted earlier, previous reports indicate that subendocardial glucose uptake exceeds subepicardial uptake in both normal and hypertensive rat left ventricle.^{4 36} It is possible that higher levels of glycolytic enzymes in the subendocardium of normal myocardium³ are necessary to support the higher energy requirements in that region and consequently lead to enhanced basal-state glucose consumption. Lowe et al³⁹ and Bladergroen et al⁴⁰ reported that when left ventricular myocardium was removed from normal or hypertrophied canine hearts and incubated under ischemic conditions, ATP levels fell most rapidly in the subendocardium. Because under these incubation conditions there are no transmural gradients of either perfusion or wall stress, the higher rate of ATP hydrolysis in the subendocardium presumably reflects an intrinsic difference in the metabolic characteristics of that region. These investigators also reported that in corresponding myocardial layers, the rate of fall of ATP was greater in hypertrophied than in normal myocardium.⁴⁰ Although normal and hypertrophied ventricles showed similar transmural gradients with regard to the rate of ATP hydrolysis, the overall rates of ATP catabolism were higher in hypertrophied myocardium. These data support the concept that the metabolic characteristics of both normal and hypertrophied myocardium are transmurally nonhomogeneous.

Implications of Increased 2DGP Uptake by Hypertrophied Myocardium
If increased 2DGP accumulation in the hypertrophied hearts reflects enhanced glucose uptake, it is uncertain whether this would reflect increased glucose oxidation or enhanced anaerobic glycolysis. Previous studies using this experimental model of LVH have demonstrated that myocardial hyperperfusion produced by pharmacological coronary vasodilation did not affect HEP levels, thus indicating the absence of tissue ischemia during baseline conditions.¹ However, since we did not examine myocardial lactate kinetics, it is not possible to exclude enhanced anaerobic glycolysis in the hypertrophy group. The elevated blood levels of norepinephrine could have contributed to enhanced glucose uptake in the LVH group. -Adrenergic receptor activation is known to mediate translocation of the glucose transporter to the sarcolemma,⁴¹ and phosphofructokinase, a major rate-limiting enzyme in the glycolytic sequence, is activated by ß- and -adrenergic receptor stimulation.⁴² Other observations also support the concept that the state of adrenergic activation can alter myocardial substrate utilization patterns. For example, in dogs with surgical cardiac denervation, oxidative utilization of glucose was markedly reduced and fructose-6-phosphate levels were elevated.⁴³ An important question in the present study is whether the elevated norepinephrine blood levels represent chronic sympathetic activation in the hypertrophy group or whether this resulted from an exaggerated response to the stress of surgery in that group. To examine this question, we measured plasma norepinephrine levels in a group of awake dogs with a similar degree of LVH produced by banding of the ascending aorta. These animals demonstrated norepinephrine levels significantly higher than normal control animals, although less than in LVH animals studied under open-chest conditions. The finding of significantly increased norepinephrine levels in this model of myocardial hypertrophy even during resting awake conditions suggests that chronically increased sympathetic activation could contribute to increased 2DGP accumulation. The even higher values in the open-chest state suggest that the animals with hypertrophy were more sensitive to the stress of the surgical preparation.

Summary
Hypertrophied myocardium demonstrated increased 2DGP accumulation that was detectable with ³¹P NMR spectroscopy. The increase in 2DG uptake was most marked in the inner layers of the left ventricle and was positively correlated with the severity of hypertrophy. These findings suggest increased dependence on glucose metabolism, especially in the subendocardium of the chronically pressure-overloaded hypertrophied left ventricle.

	Acknowledgments

 
This work was supported by US Public Health Service grants HL-21872, HL-32427, HL-33600, and HL-50470 from the National Heart, Lung, and Blood Institute; a Grant-in-Aid from the Minnesota Affiliate of the American Heart Association; and Department of Veterans Affairs Medical Research Funds. The authors wish to acknowledge the expert technical assistance provided by Paul Lindstrom, Melonie Crampton, and Indulis Rutks.

Received January 12, 1995; accepted February 21, 1995.

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