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(Circulation. 1997;96:334-343.)
© 1997 American Heart Association, Inc.

Articles

Relationships Between Myocardial Bioenergetic and Left Ventricular Function in Hearts With Volume-Overload Hypertrophy

Jianyi Zhang, MD, PhD; Cynthia Toher, MD; Mark Erhard, MD; Yi Zhang, MD; Kamil Ugurbil, PhD; Robert J. Bache, MD; Thomas Lange, BS; ; David C. Homans, MD

From the Departments of Medicine, Cardiology Division (J.Z., C.T., M.E., K.U., R.J.B., T.L. D.C.H.), and Radiology (Y.Z., K.U.), University of Minnesota Medical School, Minneapolis.

Correspondence to Jianyi Zhang, MD, PhD, Cardiovascular Division, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail zhang047{at}maroon.tc.umn.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Left ventricular (LV) hypertrophy secondary to volume overload can result in alterations in myocardial bioenergetics and LV dysfunction. This study examined whether bioenergetic abnormalities contribute to the pump dysfunction.

Methods and Results Severe mitral regurgitation (MR) was produced in 10 dogs by disruption of the chordal apparatus. Hemodynamics and ventricular function were examined 11.7 months later under baseline conditions and during treadmill exercise. Myocardial high-energy phosphates were measured by using magnetic resonance spectroscopy at rest, during coronary vasodilation with adenosine, and during oxidative stress induced by rapid pacing and dobutamine. Chronic MR caused a 30% increase in LV mass and a 65% increase in LV volume. In MR animals, the hemodynamic and LV function were normal at rest, but abnormalities developed during ß-blockade and exercise. Myocardial creatine phosphate–to-ATP ratios were significantly lower in each layer across the LV wall in MR hearts than normal hearts. Myocardial blood flow and coronary reserve were normal in MR hearts. Moreover, hyperperfusion did not correct the abnormal bioenergetics. Despite altered bioenergetics at rest, the MR hearts tolerated rapid pacing and dobutamine infusion well.

Conclusions In volume-overloaded LV hypertrophied hearts, alterations in myocardial high-energy phosphate levels do not induce abnormal mechanical performance at rest but may be related to a decreased contractile reserve during exercise.

Key Words: mitral valve • regurgitation • phosphates • spectroscopy • heart failure

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Chronic severe MR remains a challenging clinical problem primarily because of the LV dysfunction that may ensue. The response to severe VO consists of three phases. Initially, there is acute dilatation with a modest increase in sarcomere length.¹ Shortly thereafter there is rearrangement and "slippage" of myofibrils, reestablishing normal sarcomere length and preload reserve.¹ The second phase consists of compensatory remodeling characterized by further chamber dilation and eccentric hypertrophy. This hypertrophic response, in which sarcomeres are added primarily in series, permits ventricular volume to increase so that an increased stroke volume can be accomplished with normal shortening of each sarcomere, and it also normalizes wall stress.² During this compensated phase patients may remain stable for years with persistence of normal contractile performance. Surgical correction during this phase results in a reduction in LV volume and maintenance of normal systolic performance.^{3 4} In the third phase, progressive dilation and dysfunction occur; surgical correction at this point may not reverse contractile dysfunction or ventricular dilatation.³ The mechanisms responsible for this late deterioration remain obscure, but abnormalities in the kinetics and/or regulation of myocardial ATP production, delivery, and use (bioenergetics) might play a role. Previous studies have demonstrated bioenergetic abnormalities in models of concentric hypertrophy resulting from pressure overload.⁵ In experimental hypertrophy secondary to aortic banding, a decrease in the CP/ATP ratio (indicating increase of myocardial free ADP) has been demonstrated that correlates with the severity of hypertrophy.⁵ In the pressure-overload hypertrophy model, however, tachycardia resulted in a redistribution of blood flow away from the subendocardium and worsening of bioenergetic abnormalities. Thus, in the pressure- overload model, it was not possible to determine whether bioenergetic abnormalities reflected a primary metabolic derangement of hypertrophied myocardium or primarily represented a response to subendocardial hypoperfusion.

Abnormal myocardial CP/ATP ratios have been reported in humans with MR,⁶ raising the possibility that abnormalities of myocardial bioenergetics may play a role in the genesis of the myocardial dysfunction associated with chronic VO. Alternatively, the possibility that the bioenergetic abnormalities are secondary to the hypertrophy or hemodynamic alterations associated with the chronic overload state is difficult to exclude. Interpretation of these clinical data are further hampered by heterogeneity of the patient population with respect to duration and mechanism of MR, other coexistent cardiac disease, limited data regarding LV mechanical function, and lack of data regarding myocardial perfusion. Thus, clinical studies are unlikely to address questions regarding the relationship between bioenergetic abnormalities and myocardial perfusion or the precise relationship between bioenergetic changes and mechanical function. An experimental study of severe MR suggested normal resting blood flow and normal coronary vasodilator reserve in response to exogenous adenosine.⁷ Measurements of bioenergetics were not obtained in that study, however, nor were measurements obtained during the clinically relevant vasodilator stimulus of exercise.

The present study therefore tested the hypothesis that bioenergetic abnormalities exist in eccentric hypertrophy resulting from VO, which could ultimately contribute to impaired mechanical performance. The possibility that bioenergetic abnormalities might be in part related to inadequate perfusion at rest or during stress was excluded by measurements of blood flow at rest and during stress and administration of the potent vasodilator adenosine. These hypotheses were tested by employing ³¹P NMR spectroscopy to obtain measurements of myocardial HEP levels. ³¹P NMR spectroscopy allows repeated nondestructive measurements of the phosphorylated metabolite levels in the myocardium.

NMR experiments were performed in animals with previously normal hearts (ensuring that all abnormalities were in fact due to chronic VO), and MR resulted from a common mechanism (chordal rupture with flail mitral valve leaflet). In addition to NMR studies of myocardial energy metabolism, detailed measurements of LV morphology, blood flow, oxygen consumption, and mechanical performance were obtained as well as measures of the integrated cardiovascular responses to the clinically relevant stress of muscular exercise. This study design permitted a comprehensive assessment of the significance of myocardial bioenergetic abnormalities not possible in clinical observations or limited experimental studies.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Studies were performed on 10 dogs with VO hypertrophy secondary to MR and 8 normal control dogs. All experimental procedures were performed in accordance with the animal use guidelines of the University of Minnesota, and the experimental protocol was approved by the Animal Care Committee of the University of Minnesota. The investigation conformed to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication #85-23, revised 1985).

Production of VO Hypertrophy Secondary to MR
MR was produced by using a modification of the method of Kleaveland et al.⁸ Dogs were sedated with morphine sulfate 1.0 mg/kg IV, anesthetized with sodium thiamylal (10 to 20 mg/kg IV), and intubated. A sterile cutdown was performed on the right side of the neck, and 8F sheaths (Cordis) were inserted into the right internal jugular vein and carotid artery. Esmolol (300 µg·kg^-1·min^-1 IV) and atropine (1.0 mg/IV) were administered. A canine 7F thermodilution catheter (Zeon Medical Corp) was introduced into the right internal jugular vein and advanced to the pulmonary artery. A 7F pigtail catheter was advanced via the right carotid artery to the LV. A 5-MHz single-plane transesophageal echocardiographic transducer (Hewlett Packard) was inserted into the esophagus and advanced until the left atrium and mitral valve were well visualized. Baseline echocardiographic, angiographic, and hemodynamic measurements were recorded, including pulmonary artery wedge pressure, pulmonary artery pressure, thermodilution cardiac output, and transesophageal echocardiographic images of the left atrium, mitral valve flow patterns, and the LV. Left ventriculography was then performed in the 60° left anterior oblique projection, injecting 40 mL diatrizoate meglumine at 20 mL/s.

The 7F pigtail catheter was then replaced by a 7F pediatric J-tipped biopsy sheath (Cordis) that was advanced to the LV. A 5.4F endomyocardial biopsy forceps (Cordis) was advanced via the sheath to the LV. Under fluoroscopic and transesophageal echocardiographic guidance, the mitral cordae tendinae were then grasped and torn by forcible retraction of the biopsy forceps into the sheath. This maneuver was repeated until severe mitral insufficiency was achieved, as judged by the following criteria: (1) severe disruption of the mitral valve apparatus with echocardiographic evidence of a flail leaflet, (2) a broad color Doppler jet of mitral insufficiency extending well into the pulmonary veins, (3) hemodynamic embarrassment as shown by pulmonary artery wedge pressure >20, V-wave >40 mm Hg, and stroke volume <70% of control,⁷ and (4) regurgitant orifice area >0.4 cm².⁸ Echocardiographic, hemodynamic, and angiographic measurements were then repeated. To determine whether metabolic abnormalities might correlate with the severity of LV dilatation or dysfunction, several animals with less severe MR were also included in the study.

Chronic Instrumentation Procedure
Four to 17 (mean, 11.7) months after the induction of severe MR, 10 dogs with chronic VO and 8 control dogs underwent chronic instrumentation. Animals were pretreated with morphine sulfate (1.0 mg/kg) and gentamicin (2 mg/kg IV) and anesthetized with sodium thiamylal (20 to 30 mg/kg IV with supplemental doses to maintain surgical anesthesia). A left thoracotomy was performed in the fifth intercostal space, and the superior and inferior vena cava were dissected free and fitted with silicone elastomer hydraulic occluders. A heparin-filled 3.0-mm-OD PVC catheter was inserted through the right atrial appendage and advanced to the coronary sinus. Heparin-filled PVC catheters were inserted into the aortic arch, left atrium, and LV. A Konigsburg high-fidelity micromanometer was inserted into the LV via the apical dimple. Two pairs of ultrasonic-dimension transducers were sutured to the epicardial surface to measure LV major axis and minor axis diameters. A third pair of ultrasonic microcrystals was placed to measure wall thickness. The proximal left anterior descending coronary artery was dissected free and fitted with a Doppler ultrasonic velocity probe. A bipolar pacing electrode was sutured to the right atrial appendage. A 6.0-mm-OD silicone elastomer catheter with multiple side holes was placed in the left pleural space for fluid evacuation and pressure measurement. The pericardium was closed, and the thoracotomy was closed in layers. All catheters were tunneled dorsally and exteriorized near the base of the neck. The animals received antibiotic prophylaxis and analgesics for the first 3 days postoperatively and were examined daily by a veterinarian. Beginning 4 to 5 days after surgery, animals were exercised daily.

Experimental Protocol for Physiological Studies in Awake Animals
On the day prior to the hemodynamic study, the animals were anesthetized, and an 8F sheath was inserted into the left internal jugular vein. A 7F thermodilution Swan Ganz catheter was advanced to the pulmonary artery and sutured in place. The following day, when the animal was fully recovered from anesthesia, hemodynamic studies were performed. Ultrasonic microcrystals were activated with a four-channel, ultrasonic-dimension system (Triton Technology model 120). Coronary flow velocity was measured by using a Doppler flowmeter (Instrumentation Development Laboratories, Baylor College of Medicine). Fluid-filled catheters were connected to pressure transducers (Viggo-Spectramed Inc) that were maintained at midchest level. Analog data were converted to digital format on-line by using an analog-to-digital converting board (Data Q instruments). Under steady-state resting conditions, the following measurements were recorded: aortic, left atrial, pulmonary artery, and LV pressures, ultrasonic LV dimensions, coronary artery flow velocity, and thermodilution cardiac output. In addition, blood samples were collected anaerobically from the aortic, coronary sinus, and pulmonary artery catheters for determination of pH, PO₂, PCO₂, and hemoglobin. Radionuclide-labeled microspheres (15-µm diameter) were injected into the left atrium for measurement of regional MBF.

The dogs' exercise protocol followed a standard protocol that produced graded increases in heart rate and MOC. Animals exercised at a peak sustainable exercise level that was determined for each animal on the basis of previous training sessions. At peak exercise, all hemodynamic measurements were again recorded, and blood samples were withdrawn for blood gas determinations. Radioactive microspheres were again injected for determination of regional MBF, and thermodilution cardiac output determinations were repeated. Following exercise, animals were transferred to a specially constructed echocardiographic imaging table. All measurements were again recorded during the following steady-state hemodynamic conditions: (1) baseline, (2) autonomic blockade with atropine (15 µg/kg) and esmolol (300 µg·kg^-1·min^-1 IV), (3) dobutamine (15 and 30 µg·kg^-1·min^-1), and (4) right atrial pacing at 200 and 240 bpm. Parasternal short- and long-axis two-dimensional echocardiographic images and two-dimensional directed M-mode echocardiographic recordings were obtained at the chordal level. Care was taken during M-mode imaging to avoid distortion (due to tangential imaging of the LV cavity) and to ensure recordings that depicted the true diameter of the ventricle. M-mode echocardiographic tracings were obtained under control conditions and during each of the experimental interventions except exercise. LV mass was estimated from two-dimensional images by using the formula of Fenely et al.⁹

³¹P NMR Spectroscopy Studies
One to 3 days after completion of physiological studies in the conscious state, the animals were anesthetized with sodium pentobarbital, intubated, and ventilated with a respirator. Supplemental oxygen was used to maintain arterial blood gases within the physiological range. A left thoracotomy was performed in the fourth intercostal space. A 28-mm-diameter NMR surface coil was sutured onto the anterior wall of the LV. The surface-coil leads were connected to a balanced-tuned circuit external and perpendicular to the thoracotomy incision. The animals were then placed in a Lucite cradle and positioned within the magnet.

Measurements were performed in a 40-cm-bore 4.7-T magnet interfaced with a SISCO (Spectroscopy Imaging Systems Corp) console. The LV pressure signal was used to gate NMR data acquisition to the cardiac cycle, and respiratory gating was achieved by triggering the ventilator to the cardiac cycle between data acquisitions.¹⁰ Spectra were recorded in late diastole with a pulse repetition time of 6 or 7 seconds. This repetition time allowed full relaxation for ATP and P_i resonances, and 95% relaxation for the CP resonance.¹⁰ CP resonance intensities were corrected for this minor saturation; the correction factor was determined for each heart from two spectra recorded consecutively without transmural differentiation, one with a 15-second repetition time to allow full relaxation and the other with the 6- or 7-second repetition time used during the study.

Radiofrequency transmission and signal detection were performed with the surface coil. The coil was cemented to a 0.7-mm-thick sheet of silicone rubber that was 50% larger in diameter than the coil itself. A capillary containing 15 µL of 3 mol/L phosphonoacetic acid was placed at the coil center to serve as a reference. The proton signal from water detected with the surface coil was used to homogenize the magnetic field and to adjust the position of the animal in the magnet so that the coil was at or near the magnet and gradient isocenters. This was accomplished by using a spin-echo experiment and a read-out gradient. The information gathered in this step was also used to determine the spatial coordinates for spectroscopic localization.¹⁰ Chemical shifts were measured relative to CP, which was assigned a chemical shift of -2.55 ppm relative to 85% phosphoric acid at 0 ppm.

Spatial localization across the LV wall was performed by using the RAPP-ISIS Fourier series window method.¹¹ Signal origin was restricted by using the B₀ gradient and adiabatic inversion pulses to a column coaxial with the surface coil, which was perpendicular to the LV wall; column dimensions were 18x18 mm. Within this column, the signal was further localized by using the B₁ gradient to five voxels centered about 45°, 60°, 90°, 120°, and 135° spin-rotation increments.^{10 11} The details of the adiabatic inversion pulses and plane-rotation adiabatic BIR-4 pulse in this technique have been reported.^{10 11} Fourier series window localization used a nine-term Fourier series expansion; the Fourier coefficients, number of free induction decays acquired for each term in the Fourier expansion, and the multiplication factors employed to construct the voxels are available.^{10 11} The position of the voxels relative to the coil was set by using the B₁ magnitude at the coil center, which was determined in each case by measuring the 90° pulse length for the phosphonoacetic acid reference located in the coil center. A total of 96 scans acquired in 10 minutes were used to generate each set of spatially localized transmural spectra within each 10-minute period.

³¹P NMR Experimental Protocol
Hemodynamic measurements and ³¹P NMR spectra were first obtained during control conditions. Midway through the 10-minute acquisition period, a microsphere injection was performed for determination of MBF. Animals then underwent a series of interventions designed to produce maximal coronary vasodilation (adenosine 1 mg·kg^-1·min^-1 IV) and to provoke oxidative stress (right atrial pacing at 200 and 240 bpm and dobutamine 15 µg·kg^-1·min^-1 IV). NMR and hemodynamic measurements were obtained 5 minutes into each intervention, ie, once a steady state had been established. Interventions were separated by a 15- to 20-minute recovery period. In order to measure MBF, radioactive microspheres were injected midway into the adenosine, atrial pacing at 240 bpm, and dobutamine interventions.

Tissue Preparation
After completion of the study, a myocardial biopsy was obtained by using a biopsy forceps precooled in liquid nitrogen. Tissue was maintained at -70°C until subsequent analysis of ATP was performed by using a high-performance liquid chromatography technique.¹² Animals were then killed, and the hearts were fixed in 10% buffered formalin. The atria, right ventricle, aorta, and large epicardial vessels were dissected from the LV, which was weighed and sectioned into four transverse rings of approximately equal thickness. The region of myocardium directly beneath the surface coil was removed and sectioned into three transmural layers from epicardium to endocardium, weighed on an analytical balance, and placed into vials for counting. Similar myocardial specimens were obtained from the lateral and posterior LV wall to ensure that the measurements from the region of myocardium corresponding to the surface coil were typical for the entire LV.

MBF and MOC
MBF was measured with 15-µm-diameter microspheres labeled with ¹⁴¹Ce, ⁵¹Cr, ⁹⁵Nb, ⁸⁵Sr, or ⁴⁶Sc (NEN Corp).¹³

MOC was determined from arterial and coronary blood samples that were obtained anaerobically for determination of pH, PO₂, PCO₂, and hemoglobin. Hemoglobin saturation was computed from the blood PO_2, pH, and temperature by using the oxygen desaturation curve for canine blood.¹⁴ Oxygen content was computed as hemoglobinx1.34xpercent oxygen saturation+0.0031xPO₂. Coronary flow measured by the flowmeter probe was divided by the total grams of myocardium perfused by the vessel distal to the probe in order to calculate flow per gram of myocardium. Oxygen consumption was computed by multiplying the arteriovenous oxygen difference by coronary blood flow.

Data Analysis
Of the 10 MR animals undergoing chronic instrumentation, 2 died after physiological studies were completed but before NMR studies could be performed; comparisons of physiological studies were therefore performed using all 10 animals, but only 8 animals were used for the NMR data. Analog physiological data were converted on-line to a digital format by using a commercially available analog-to-digital board (DATAQ) and were stored in digital form. Subsequent analysis was accomplished by using commercial software (Codas and Bioenergy). At least 10 to 15 beats were averaged for each steady-state condition. Because ultrasonic microcrystal placement may not always measure the true LV diameter or full-wall thickness, microcrystal measurements were calibrated to simultaneous M-mode echocardiographic recordings of LV diameter and wall thickness. LV volume was computed from measurements of LV external major and minor axis diameters and wall thickness by using the method of Rankin et al.¹⁵ Meridional wall stress was computed from instantaneous measures of LV pressure, minor axis, and wall thickness.² LV SW was computed by integrating the area within the LV pressure-volume loop. Minimum coronary resistance was calculated as the perfusion pressure (which equals mean aortic pressure minus LVEDP) divided by the maximum coronary blood flow. Pressure-volume area was computed according to a modification of the technique of Suga et al.¹⁶ Since the volume intercept of the end-systolic pressure-volume area is frequently negative in the presence of MR, the volume intercept was defined as 0 for all animals.

CP, ATP, and P_i resonances of the spectra were integrated by using Spectroscopy Imaging Systems Corp integral software. The differences of integral values obtained in the region of P_i resonance between baseline and other experimental conditions were used as the changes of P_i level (P_i). The results were expressed as ratios of CP/ATP and P_i/CP. ³¹P spectra from the first, third, and fifth voxels were taken to represent subepicardium, midmyocardium, and subendocardium, respectively.

Hemodynamic and MBF data were analyzed by using ANOVA with replications. A value of P<.05 was required for significance. When a significant result was found, individual comparisons were made by using the method of Scheffé. Data are reported as mean±SD.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Anatomic Data
The anatomic data comparing the MR and normal groups are summarized in Table 1 and Fig 1. Body weights of the control and MR groups were similar (22.4±0.39 versus 25.7±0.75 kg, respectively). The LV weight/body weight ratio in animals with MR was 5.61±0.48 compared with 4.40±0.15 in controls (P<.01), representing an average 30% increase in LV mass. MR produced significant VO, with an increase in LV end-diastolic volume from 66±14 mL in the normal animals to 109±26 mL in dogs with MR (P<.01). Although LV mass increased 30%, the ratio of LV minor axis radius to wall thickness was increased in MR dogs, consistent with eccentric hypertrophy. The severity of MR, as estimated by the regurgitant fraction, varied but was generally severe (51±15%).

View this table: [in this window] [in a new window]   Table 1. LV Volumes

View larger version (29K): [in this window] [in a new window]   Figure 1. Bar graphs show LV weight, volume, and regurgitant (Regurg) fraction in the control and MR groups. Data are mean±SEM. *P<.05 MR vs control.

Physiological Studies in Awake Animals
Hemodynamic measurements in MR and control animals are summarized in Tables 1 through 4. At rest there were no significant differences in heart rate, LV systolic or diastolic pressure, left atrial pressure, or cardiac output. Mean and peak systolic wall stress tended to be nonsignificantly higher in animals with MR. The mean values for LVEDP and left atrial pressure tended to be higher in the MR group, but these also failed to achieve significance. Indices of systolic function, including EF, maximal dP/dt, and SW divided by end-diastolic volume were similar in MR and normal animals.

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Data

View this table: [in this window] [in a new window]   Table 3. LV Meridional Wall Stress

View this table: [in this window] [in a new window]   Table 4. LV Systolic Function

The two groups did differ in their response to ß-adrenergic blockade. During ß-adrenergic blockade, LVEDP was significantly higher and mean aortic pressure was significantly lower in MR than normal animals. Furthermore, mean systolic, peak systolic, and end-diastolic LV wall stress were increased and cardiac output was lower in MR dogs during ß-adrenergic blockade.

The MR group also failed to respond normally to exercise, achieving lower peak cardiac outputs (9.5±1.6 versus 12.2±0.8 L/min; P<.05). Mixed venous oxygen saturations were similar in the two groups at peak exercise (32.3±2.2% versus 28.8±2.7%, MR versus normal; NS), indicating that MR animals were exercising at their peak capacity. Although mean values for LVEDP and left atrial pressures tended to be higher and peak LV dP/dt tended to be lower in MR dogs during exercise, these differences did not achieve significance. MR dogs responded to dobutamine infusion and right atrial pacing similarly to control dogs, indicating sufficient reserve to respond normally to these milder stresses.

Fig 2 depicts a plot of LV EF versus end-systolic meridional wall stress, both of which were measured in the presence of ß-adrenergic blockade. When the MR group and control group were analyzed separately, both demonstrated significant inverse correlations between wall stress and EF (r=.91, y=-0.597x+68.7, P<.005 for the MR group; r=.82, y=-0.561x+58.4, P<.02 for control). Multivariate analysis was performed using both end-systolic wall stress and group assignment (MR versus control) as independent variables; only end-systolic wall stress was selected as contributing to the variance in EF. Thus, when differences in afterload were accounted for, MR animals did not appear to have impaired systolic function relative to the control group.

View larger version (14K): [in this window] [in a new window]   Figure 2. Plot of LV EF vs end-systolic wall stress in the control and MR groups.

MOC
Measurements of MOC in conscious dogs are summarized in Tables 5 and 6. During resting conditions, coronary artery flow, arterial-coronary sinus oxygen content differences, and MOC were similar in both groups. During right atrial pacing, dobutamine, and exercise, MOC increased in both the normal and MR groups, but no differences emerged between the two groups. Arterial-coronary venous oxygen differences widened during exercise in both groups, but again there were no differences between MR and control. MBF (per gram of myocardium) increased similarly during exercise in both groups, indicating that neither impaired blood flow nor impaired oxygen consumption was responsible for the abnormal hemodynamic responses in the MR group.

View this table: [in this window] [in a new window]   Table 5. MOC in Conscious Dogs

View this table: [in this window] [in a new window]   Table 6. Mechanical Correlates of Oxygen Consumption in Awake Animals

Table 6 summarizes estimates of oxygen consumption derived from mechanical data. The pressure-volume area, which correlates well with oxygen consumption,¹⁶ was consistently larger in the MR group. When normalized for LV mass, however, there were no significant differences. Similarly, there were no significant differences in SW when normalized for LV mass. To obtain an estimate of the efficiency with which oxygen consumption was transduced into mechanical work, the SW/oxygen consumption ratios were compared; again, there was no significant difference between the two groups.

Physiological Studies in Anesthetized Animals
Hemodynamic measurements are shown in Table 7. During basal conditions there were no significant differences in heart rate, aortic or LV systolic pressure, or the rate-pressure product between the normal and MR groups, but LVEDP was higher in the MR group. Heart rate increased more in the normal than the MR group (P<.05) in response to dobutamine. LVEDP did not change significantly with any intervention in either group. The rate-pressure product (heart ratexLV systolic pressure) was similar under basal conditions, but was significantly less than in the MR group during dobutamine infusion.

View this table: [in this window] [in a new window]   Table 7. Hemodynamics During NMR Spectroscopic Studies

MBF
MBF data under baseline conditions, adenosine infusion, and during atrial pacing in anesthetized animals are summarized in Fig 3. MBF was similar under basal conditions; it tended to increase to a similar level in both groups during rapid atrial pacing, and blood flow remained uniformly distributed across the LV wall. Adenosine produced a 400% mean increase of MBF in the normal group, but only a 280% increase of blood flow in the MR group (P<.05). Minimum coronary vascular resistance, however, did not differ between the two groups (25.1±7.1 versus 33.2±6.6 mm Hg·mL^-1·min/g^-1 in normal and hypertrophied hearts, respectively). This is due to the lower mean aortic (perfusion) pressure during adenosine infusion in MR animals.

View larger version (20K): [in this window] [in a new window]   Figure 3. Transmural distribution of MBF at baseline and during right atrial pacing (A) and adenosine infusion (B). Data are mean±SEM. Endo indicates subendocardial layers; Mid, midwall; and Epi, subepicardial layers. *P<.05 MR vs control.

HEP Levels
Examples of typical transmural spectra sets acquired from a normal heart and from a heart with MR under basal conditions are shown in Fig 4. The voxel labeled EPI was over the outer edge of the LV wall, while the voxel most distant from the surface coil, labeled ENDO, was positioned over the subendocardium with little penetration into the LV chamber; consequently, relatively little contribution from the erythrocyte-contained 2,3-diphosphoglycerate within the LV cavity was seen in the ENDO voxel. The voxel labeled MID corresponds to the midmyocardium. The three labeled voxels had virtually no overlap; there was, however, partial overlap between adjacent voxels in the five-voxel set. The transmural CP/ATP ratios obtained from integrals are summarized in Table 8. Because none of the subjects in either group showed detectable changes in P_i level during each intervention, the P_i/CP ratio is not included in Table 8.

View larger version (20K): [in this window] [in a new window]   Figure 4. Transmural distribution of HEP concentrations detected by 31P NMR spectroscopy during baseline conditions from normal hearts (left) and VO hearts with LV hypertrophy (LVH; right). Each transmural data set consists of a stack of five spectra corresponding to voxels centered around phase angles 45°, 60°, 90°, 120°, and 135°. The 135° voxel (subepicardium) and 45° voxel (subendocardium) are the outermost and innermost voxels respective to the surface coil. Spectra were scaled to optimize visualization of the resonance peaks; thus only the CP/ATP ratios can be compared between spectra. The CP/ATP ratio was decreased in MR hearts. ENDO, MID, and EPI indicate subendocardial, midmyocardial, and subepicardial voxels, respectively; 2,3 DPG, 2,3-diphosphoglycerate.

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

Under basal conditions, spectra in both the normal and MR groups were characterized by high CP and ATP levels, while P_i was too low to identify with certainty. The basal CP/ATP ratio was significantly lower across the LV wall in the MR group (P<.01) (Fig 4 and Table 8). Adenosine-induced hyperperfusion did not change CP/ATP ratios in either group, indicating that myocardial ischemia was not responsible for the decrease in the CP/ATP ratio.

Rapid pacing did not change the CP/ATP ratio in either group (Table 8), nor did it result in a significant increase in P_i level in any VO heart. Dobutamine infusion did not result in significant changes in HEP or P_i levels in either group.

Biopsy Data
Myocardial ATP concentration was 21.9±3.9 (range, 18.2 to 25.4) µmol/g dry weight from six normal hearts compared with 20.2±5.4 (range, 15.0 to 25.7) µmol/g dry weight (P=NS) from three MR hearts. Myocardial total creatine concentration was 121.2±10.8 (range, 108.1 to 131.3) µmol/g dry weight from normal hearts compared with 115.1±14.7 (range, 89.6 to 124.4) µmol/g dry weight (P=NS) from hearts with VO hypertrophy.

Correlation of HEP Levels With Physiological Data
There was a weak and nonsignificant correlation between the subendocardial CP/ATP ratio and LV mass (r=.66, P=.07) and peak systolic wall stress (r=.63, P=.10). There were no correlations between the subendocardial CP/ATP ratio and LV volume, mass/volume ratio, resting or exercise EF, end-diastolic pressure, or regurgitant fraction.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
There are four related findings in the current study. First, CP/ATP ratios are significantly lower in eccentrically hypertrophied VO hearts after induced severe MR. Second, this abnormality is unlikely caused by abnormalities of myocardial perfusion. Third, unlike pressure-overload hypertrophy, stresses imposed by exercise, pacing, and dobutamine infusion were well tolerated in chronic MR and did not cause further abnormalities or HEP metabolism. Finally, mechanical performance of the LV in the "basal" state is in part dependent on sympathetic stimulation in chronic severe MR. The current study is unique with respect to its comprehensive assessment of ventricular function and integrated cardiovascular performance with measurements of oxygen consumption and HEP metabolism. Our data suggest that the bioenergetic changes associated with MR and VO do not, within the limits tested, impair MOC, the efficiency with which biochemical energy stores are transduced into mechanical "work," or the mechanical performance of the heart.

Characteristics of the Experimental Model
By experimental design, animals with varying severities of MR were studied. Nevertheless, some differences emerged between normal and MR dogs. LV volume increased 65% in MR dogs, in contrast to a smaller (30%) increase in LV mass. The failure of LV mass to increase as much as LV volume confirms the work of Carabello et al,¹⁷ who have suggested that hypertrophy may be "inadequate," leading to increased wall stress and ultimately to heart failure.

Although baseline values of wall stress were not significantly increased in the current study, ventricular volume and wall stress were increased in the MR group during ß-adrenergic blockade. This suggests that in addition to hypertrophy, increased ß-adrenergic tone is a mechanism by which the VO heart normalizes stress. Our data support the findings of Nagatsu et al,¹⁸ who have also shown increased dependence on sympathetic stimulation to maintain mechanical performance in an animal model of MR. The mechanism of the hemodynamic deterioration noted during ß-adrenergic blockade was not established in this study. It is possible that the severity of MR may have increased due to changes in heart rate, ventricular volume or geometry, or alterations in the contribution of myocardial contraction to the effective mitral regurgitant orifice area. Alternatively, negative lucitropic consequences of ß-adrenergic blockade may have directly increased LV diastolic (hence left atrial) pressures. Finally, ß-adrenergic blockade may have unmasked covert LV systolic mechanical dysfunction. Animals with MR were also unable to respond appropriately to the physiological stress of intense muscular exercise, achieving lower external workloads and reduced cardiac output. Taken together, these findings suggest subtle hemodynamic impairment. The abnormalities of HEP metabolism observed in this model, therefore, occur very early in the process of LV decompensation, prior to the development of overt heart failure or obvious LV systolic dysfunction. It is doubtful that the bioenergetic abnormalities observed are simply the result of increased sympathetic stimulation, since they did not worsen during dobutamine infusion.

Transmural Blood Flow Distribution
In the current study, the eccentric hypertrophy secondary to VO was associated with a normal transmural blood flow distribution under basal conditions, in agreement with previous studies.⁷ Although basal MBF and oxygen consumption were not significantly greater than normal, they tended to be increased in the MR group, consistent with an increased reliance on sympathetic tone in the basal state. During the ß-adrenoreceptor stimulation associated with exercise or dobutamine infusion, however, MOC was slightly (but not significantly) lower in the MR group.

The coronary vasodilator response to adenosine is normal in experimental VO.⁷ Impaired coronary flow reserve has been noted in different models of eccentric hypertrophy and has been explained on an anatomic basis as a result of inadequate vessel growth.¹⁹ In the current study, although the basal flow distribution was normal, blood flow was mildly decreased when maximum coronary vasodilation was produced with adenosine. Minimum coronary resistance was unchanged, however, indicating that major functional or structural abnormalities of the microvasculature are unlikely in this model.

During rapid pacing, a transmurally uniform increase in MBF was maintained in the VO hearts, in contrast to pressure-overload hypertrophy, in which blood flow is distributed away from subendocardium during rapid pacing.^{5 20} This may in part be a function of well-preserved LV diastolic performance in eccentric hypertrophy. Since LV diastolic pressure did not increase during pacing, extravascular compressive forces remained low in the subendocardium, resulting in a normal perfusion-pressure gradient across the myocardial wall and uniform flow distribution.

Oxidative Phosphorylation Regulation and HEP Levels
Biopsy data indicated that subepicardial ATP was normal in the MR hearts. In normal hearts under basal conditions there is a transmural gradient of the CP/ATP ratio with slightly lower values in the subendocardial layers.^{5 21} This CP/ATP gradient results from a uniform distribution of ATP across the wall, with slightly lower CP values in the subendocardium. It has been thought that the lower CP/ATP ratio in the subendocardium might be related to an imbalance in oxygen consumption and supply. Since systolic thickening in the subendocardium exceeds that of the subepicardium and subendocardial blood flow is selectively impeded during systole, the inner layers may be at the threshold of "oxygen limitation" with respect to the ATP synthetic requirements. Furthermore, either increases in blood flow or decreases in oxygen demand an increase in the subendocardial CP/ATP ratio,²¹ resulting in a more uniform transmural distribution of HEP. In the present study, the subendocardial CP/ATP ratio was significantly lower in MR hearts than normal hearts under basal conditions, in agreement with reports of LV remodeling in an animal model^{22 23} and in humans with severe MR.²⁴ Mechanisms responsible for this alteration are not clear. An imbalance between oxygen supply and demand could result from increased wall stress due to chamber dilation or an increase in myofibril content relative to mitochondrial volume. However, wall stress, blood flow, MOC, and minimum coronary resistance were normal in VO hearts. Furthermore, increasing myocardial perfusion by infusion of adenosine to cause a 280% increase in coronary blood flow did not increase the CP/ATP ratio in the MR animals, indicating that the decreased CP/ATP ratio was not the result of persistent underperfusion. Thus, the HEP abnormalities cannot be attributed to inadequate tissue perfusion relative to demand.

Lower CP/ATP ratios have also been reported in diseased human hearts as well as in experimental models of myocardial hypertrophy, cardiac failure, or LV remodeling following regional myocardial injury.^{22 23 24} Using the creatine kinase equilibrium, the lower CP/ATP ratio in the presence of normal levels of total creatine and ATP in the MR hearts indicates an increase in myocardial free ADP. This implies that hearts with myocardial hypertrophy secondary to MR required a higher than normal free ADP level to maintain an adequate ATP synthetic rate. The finding of a higher free ADP level suggests that under basal conditions oxidative phosphorylation regulation is altered in these hearts. The reason for this alteration is unknown. The current data demonstrate that it is not caused by insufficient myocardial oxygen delivery, since increasing blood flow with adenosine had no effect on the CP/ATP ratio. Several investigators have reported that fatty acid utilization is decreased^{25 26} and glucose utilization is increased^{27 28} in hypertrophied hearts with a resultant decrease of NADH level and, consequently, a compensatory need for a higher myocardial free ADP level. Substrate utilization was not examined in the current study and represents an important area for future study.

In response to rapid pacing, pressure-overload hypertrophied hearts demonstrate a decrease in subendocardial CP and increased P_i. This is accompanied by a redistribution of blood flow away from subendocardium, suggesting that subendocardial hypoperfusion is responsible for the bioenergetic abnormalities.²⁹ In contrast, the current VO hearts demonstrated a uniform increase in MBF across the LV wall that was accompanied by a constant transmural HEP distribution. Furthermore, VO hearts tolerated the stress of tachycardia well, without developing an increase in LV end-diastolic or left atrial pressure. Thus, the abnormal CP/ATP ratios observed under resting control conditions did not prevent the VO hearts from responding normally to tachycardia.

The decreased myocardial CP/ATP ratio reported in diseased human hearts as well as in experimental models of myocardial hypertrophy and cardiac failure has been proposed by previous investigators to support the hypothesis that "energy starvation" in the overloaded heart can result in cardiac pump failure.³⁰ We are not aware of any previous study that has examined myocardial HEP levels and LV contractile function in VO hearts. The results of the present study demonstrate for the first time that the decreased myocardial CP/ATP ratio in VO hypertrophy is not associated with impairment of mechanical performance either under basal conditions or during the increased workload produced by cardiac pacing or dobutamine.

We have found²⁹ that ß-adrenergic stimulation causes an exaggerated increase in the rate-pressure product in pressure-overloaded hearts. This higher rate-pressure product (and therefore a higher workstate) of the hypertrophied hearts is accompanied by decreased CP and increased P_i levels, and we hypothesized that dobutamine induced "demand-" mediated ischemia in those hearts. This change was not observed in the current study. The finding that under basal conditions the hemodynamic performance of these hearts appears to be dependent on a higher basal level of ß-adrenergic stimulation raises the possibility that higher basal levels of sympathetic stimulation desensitize VO hearts to additional exogenous catecholamines, which has been shown in the VO state produced by aortocaval fistula.³¹

Conclusions
The present findings demonstrate that primary changes occur in the regulation of HEP metabolism in eccentric LV hypertrophy that are not due to inadequate blood perfusion and occur before overt heart failure develops. Within the limits tested, this abnormality does not appear to restrain the heart from responding normally to the oxidative stresses of tachycardia or sympathetic stimulation, but it may related to a decreased contractile reserve during exercise.

	Selected Abbreviations and Acronyms

 

CP = creatine phosphate EF = ejection fraction HEP = high-energy phosphate LV = left ventricular LVEDP = left ventricular end-diastolic pressure MBF = myocardial blood flow MOC = myocardial oxygen consumption MR = mitral regurgitation NMR = nuclear magnetic resonance Pi = inorganic phosphate SW = stroke work VO = volume overload

	Acknowledgments

 
This work was supported by US Public Health Service grants HL21872, HL33600, HL32427, and HL50470 (J.Z.) from the National Heart, Lung, and Blood Institute and a Grant-in-Aid (J.Z.) and an Established Investigator Award (J.Z.) from the American Heart Association. The authors wish to acknowledge the expert technical assistance provided by Todd Pavek, Melanie Crampton, Paul Lindstrom, Indulis Rutes, and Mike Dennis, and the secretarial assistance of Susan Quirt.

Received September 4, 1996; revision received December 17, 1996; accepted January 9, 1997.

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