Original Article

Regional Myocardial Metabolism of High-Energy Phosphates during Isometric Exercise in Patients with Coronary Artery Disease

Robert G. Weiss, M.D., Paul A. Bottomley, Ph.D., Christopher J. Hardy, Ph.D., and Gary Gerstenblith, M.D.

N Engl J Med 1990; 323:1593-1600December 6, 1990

Abstract

Abstract

Background.

The maintenance of cellular levels of high-energy phosphates is required for myocardial function and preservation. In animals, severe myocardial ischemia is characterized by the rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP.

Full Text of Background....

Methods.

To determine whether ischemic metabolic changes are detectable in humans, we recorded spatially localized phosphorus-31 nuclear-magnetic-resonance (³¹P NMR) spectra from the anterior myocardium before, during, and after isometric hand-grip exercise.

Full Text of Methods....

Results.

The mean (±SD) ratio of phosphocreatine to ATP in the left ventricular wall when subjects were at rest was 1.72±0.15 in normal subjects (n = 11) and 1.59±0.31 in patients with nonischemic heart disease (n = 9), and the ratio did not change during hand-grip exercise in either group. However, in patients with coronary heart disease and ischemia due to severe stenosis (≥70 percent) of the left anterior descending or left main coronary arteries (n = 16), the ratio decreased from 1.45±0.31 at rest to 0.91±0.24 during exercise (P<0.001) and recovered to 1.27±0.38 two minutes after exercise. Only three patients with coronary heart disease had clinical symptoms of ischemia during exercise. Repeat exercise testing in five patients after revascularization yielded values of 1.60±0.20 at rest and 1.62±0.18 during exercise (P not significant), as compared with 1.51±0.19 at rest and 1.02±0.26 during exercise before revascularization (P<0.02).

Full Text of Results....

Conclusions.

The decrease in the ratio of phosphocreatine to ATP during hand-grip exercise in patients with myocardial ischemia reflects a transient imbalance between oxygen supply and demand in myocardium with compromised blood flow. Exercise testing with ³¹P NMR is a useful method of assessing the effect of ischemia on myocardial metabolism of high-energy phosphates and of monitoring the response to treatment. (N Engl J Med 1990; 323:1593–600.)

Full Text of Conclusions....

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Figure 1Axial Surface-Coil ¹H NMR Image Acquired through the Chest and Heart of Patient 7 at Rest (Top) and ³¹P NMR Spectra (Bottom) Corresponding to the 10-mm—Thick Coronal Sections Indicated in the ¹H Image.

Figure 2Axial ¹H NMR Image (Top) and Corresponding ³¹P Spectra (Bottom) from Adjacent 10-mm—Thick Coronal Slices in the Anterior Myocardial Wall of a Normal Subject before, during, and after Isometric Exercise (Heart Rates of 64, 77, and 66 Beats per Minute, Respectively).

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Article

ALTERED cardiac metabolism is the primary pathophysiologic consequence of myocardial ischemia in humans. To date, however, both investigative and routine characterizations of the presence and severity of myocardial ischemia and its response to therapy have focused on coronary anatomy and on the symptomatic, electrocardiographic, and functional results of changes in myocardial metabolism rather than on the metabolic changes themselves. Positron-emission tomography has been used to evaluate the effects of ischemia and infarction on myocardial substrate uptake but cannot quantify myocardial high-energy phosphate metabolites,1 2 3 which are required for the functioning and viability of myocardial cells.

Phosphorus-31 nuclear-magnetic-resonance (³¹P NMR) spectroscopy permits direct biochemical quantification of cardiac high-energy phosphates. Studies in isolated and surgically exposed animal hearts show that an early change in high-energy phosphate metabolism accompanying the onset of severe ischemia is a decrease in phosphocreatine and in the ratio of phosphocreatine to ATP.4 5 6 Spatially localized ³¹P NMR allows noninvasive measurement and monitoring of phosphorus metabolites in the human heart.7 8 9 We therefore applied this technique to study the effect of a transient increase in cardiac work induced by isometric hand-grip exercise on myocardial high-energy phosphates in a group of patients with confirmed coronary artery disease and in normal subjects. To assess the specificity of the findings, the studies were also performed in a group of patients with nonischemic cardiac disease and were repeated in a subgroup of the patients with ischemic disease after successful myocardial revascularization.

Methods

Subjects

The group of patients with coronary heart disease and ischemia consisted of 16 patients 40 to 79 years old (mean ±SD, 57±11). All had severe stenosis of either the left anterior descending or the left main coronary arteries (≥70 percent), which supply the anterior wall (Table 1Table 1Stenosis in the Patients with Coronary Artery Disease and Ischemia.). The degree of stenosis was determined by visual assessment of cardiac-catheterization films by at least one independent cardiologist. All 16 patients had a history of chest pain, and 13 had electrocardiographic or thallium-201 (²⁰¹Tl)—scintigraphic evidence of transient ischemia. All were taking anti-ischemic medications at the time of study; 9 patients were taking beta-blocking agents, 13 were taking a calcium-channel blocker, and 12 were taking nitrates. No medications were withheld before evaluation with NMR. Seven patients had evidence of a myocardial infarction in the past; in six the infarct was located in the anterior distribution and was associated with wall-motion abnormalities. Six patients had anterior hypokinesis, but only two had echocardiographic or left-ventriculographic evidence of anterior-wall akinesis or dyskinesis, which was focal in both.

The control group consisted of 11 normal subjects 24 to 83 years old (mean, 42±19), none of whom had any clinical history of heart disease. The normal subjects more than 40 years old had no electrocardiographic or ²⁰¹Tl tomographic evidence of ischemia during treadmill testing.

Two additional groups of patients were studied to assess the specificity of the findings for critical coronary artery disease. Five patients with ischemia were restudied after they underwent successful revascularization by either percutaneous transluminal coronary angioplasty (three patients) or coronary-artery bypass grafting (two patients). In addition, nine patients with nonischemic heart disease who were 41 to 88 years old (mean, 66±15) were also studied. These patients had no evidence of ischemia on treadmill testing with ²⁰¹Tl scintigraphy but did have documented severe valvular disease (aortic or mitral insufficiency, three patients), hypertrophic cardiomyopathy (five patients), or dilated cardiomyopathy (one patient).

All subjects gave informed consent for the study, which was approved by the Johns Hopkins Joint Committee on Clinical Investigation.

NMR Techniques

Experiments were performed with an unmodified, commercially available 1.5-T imaging—spectroscopy system (General Electric Medical Systems).10 The subjects lay prone but rotated slightly to the left on a set of three custom-built coaxial coplanar NMR surface coils, on which the surface of the chest anterior to the heart had been positioned.11 , 12 Conventional proton (¹H) NMR images were acquired with a figure 8—shaped surface coil 80 by 130 mm11 to confirm the location of the coil relative to the heart and to identify the anatomy corresponding to each localized ³¹P spectrum. A square surface transmitter coil 0.4 by 0.4 m then uniformly excited ³¹P spectra from the sensitive volume of a circular coaxial 65-mm surface detection coil.12 To minimize motion artifacts, spectra and images were acquired synchronously with the diastolic cardiac phase, with the use of an optical peripheral-gating transducer. Spectra were spatially encoded into 32 10-mm—thick coronal slices through the chest with a one-dimensional phase-encoding gradient sequence.13 The acquisition delay was 1 msec. Since the ¹H image and the ³¹P spectral localization sequences were acquired with the same scanning magnetic-field gradients, the 16th slice corresponded to the center of each image and the geometric center of the NMR magnet. The localization of ³¹P spectra relative to the ¹H image was confirmed by studying test objects and by including a ³¹P reference compound (phosphonitrilic chloride trimer) in the plane of the surface coil during scanning of each subject. The acquisition time ranged from 9 to 14 minutes per set of spectra before exercise and from 5 to 8 minutes during and after exercise. The total NMR examination time ranged from 45 to 75 minutes. NMR saturation factors for phosphate metabolites were measured in each subject at rest by acquiring unlocalized surface-coil spectra at the heart rate and at 15-second intervals. This correction assumes that muscle and heart metabolites have the same relative spin-lattice relaxation times.12 Imaging, spectroscopy, and exercise were all performed without moving the subject. The ratio of phosphocreatine to ATP metabolites was derived from the integrated areas of the resonances of phosphocreatine and the β-phosphate peak of ATP, after application of a 12-Hz line-broadening exponential filter, fitting of the peaks to gaussian or lorentzian lines to within the spectral noise level, and then correction for saturation. The fitting of overlapping peaks assumes that the line shape of the resolved portion reflects that of the entire peak, so that overlap principally contributes to and is included as random error. Phosphocreatine line widths were 0.2 to 1.0 ppm (mean, 0.3±0.2) and varied between subjects but not during stress testing of each subject.

Exercise Protocol

Before the subjects were positioned in the magnet, their maximal force production was measured while they squeezed the lever on a nonmagnetic hand dynamometer (Stoelting, Chicago). ³¹P NMR spectra were collected before, during, and after a seven- to eight-minute period of continuous isometric hand-grip exercise at a constant 30 percent of each subject's maximal force. The dynamometer was continuously observed by an investigator to prompt compliance. If one hand became fatigued, the other hand was used at once and continuous isometric contraction was resumed.14 , 15 The acquisition of spectra commenced one to two minutes after exercise began and again one to three minutes after exercise ended.

Statistical Analysis

A two-way repeated-measures analysis of variance with interaction among the three groups (normal subjects, patients with coronary artery disease, and patients with nonischemic heart disease) before and during exercise was performed on ³¹P NMR data. Changes between individual means were analyzed by means of t-tests with the Bonferroni correction for multiple comparisons. A variable expressing the exercise-induced difference was also generated, and a one-way analysis of variance performed, to analyze the differences in the three groups. In addition, Bonferroni t-tests were again applied to the individual means.16

Results

During exercise, heart rates increased from a mean (±SD) of 67±12 at rest to 81±10 beats per minute in the normal subjects, from 77±13 to 89±16 beats per minute in the patients with coronary artery disease, and from 75±13 to 85±14 beats per minute in the patients with nonischemic heart disease; there were no significant differences among the groups. Blood pressure could not be monitored during hand-grip exercise while the subjects were in the magnet, but it was measured in 31 of the 36 subjects during identical isometric hand-grip exercise conducted outside the magnet. The mean double product (heart rate × systolic blood pressure) at rest was 9600±2800 mm Hg · beats per minute in the normal subjects, 10,200±3300 mm Hg · beats per minute in the patients with coronary artery disease, and 9900±2800 mm Hg · beats per minute in the patients with nonischemic disease, and increased during exercise to mean peak values of 12,600±3700, 13,400±3700, and 13,500±3800 mm Hg · beats per minute, respectively; there were no significant differences among the groups in the values obtained at rest or during exercise. Although anxiety may have contributed to the level of stress experienced by the subjects during the NMR study, the changes in heart rate induced by exercise performed inside or outside of the magnet did not differ significantly. During exercise, chest pain or dyspnea developed in three patients with coronary artery disease, and dyspnea developed in the patient with idiopathic dilated cardiomyopathy.

Figure 1Figure 1Axial Surface-Coil ¹H NMR Image Acquired through the Chest and Heart of Patient 7 at Rest (Top) and ³¹P NMR Spectra (Bottom) Corresponding to the 10-mm—Thick Coronal Sections Indicated in the ¹H Image. shows a typical ¹H image and nine ³¹P spectra acquired at different depths through the chest and heart. The spectra correspond to slices as annotated in the ¹H image: the reference falls in slice 10, with a contribution of less than 10 percent to the adjacent slice 9; adipose tissue in slice 11 contributes a negligible high-energy phosphate signal; and skeletal muscle in slices 12 and 13 has a higher phosphocreatine/ATP ratio than myocardium in slice 14 and slices above — observations consistent with earlier findings.7 8 9

Figures 2Figure 2Axial ¹H NMR Image (Top) and Corresponding ³¹P Spectra (Bottom) from Adjacent 10-mm—Thick Coronal Slices in the Anterior Myocardial Wall of a Normal Subject before, during, and after Isometric Exercise (Heart Rates of 64, 77, and 66 Beats per Minute, Respectively). and 3Figure 3Axial Image (Top) and Corresponding ³¹P Spectra (Bottom) from Adjacent Coronal Slices in the Anterior Myocardial Wall of Patient 11 before, during, and after Exercise (Heart Rates of 84, 94, and 88 Beats per Minute, Respectively). show ³¹P spectra from the anterior left ventricle before, during, and after exercise in a normal subject and a patient with coronary artery disease, respectively. In the normal subject the phosphocreatine/ATP ratio was not significantly changed by exercise, but in the patient with coronary disease it decreased from 1.7 to 0.9 and the level of inorganic phosphate increased during exercise in the slice containing predominantly endocardium (Fig. 3).

The averaged values for the phosphocreatine/ATP ratio in the anterior left ventricular wall of the normal subjects and patients with coronary artery disease are shown in Figure 4Figure 4Transient Change in the Phosphocreatine/ATP Ratio in the Anterior Myocardium in Response to Isometric Exercise at 30 Percent of Maximal Force in Controls and Patients with Coronary Artery Disease.; inorganic phosphate could not be measured reliably because the resonances for blood 2,3-diphosphoglycerate overlapped.7 8 9 In normal subjects, the mean ratios were unchanged — 1.72±0.15, 1.74±0.17, and 1.77±0.16 before, during, and after exercise, respectively. In the patients with coronary artery disease, the mean ratio before exercise was 1.45±0.31, and it fell significantly during exercise by 37 percent, to 0.91±0.24. The 95 percent confidence interval for the phosphocreatine/ATP ratio in the myocardium of patients with coronary artery disease was 1.29 to 1.62 at rest and 0.78 to 1.04 during exercise. This decrease was not due to increased saturation effects associated with the higher heart rate caused by exercise, because changes in heart rate were similar in the normal subjects and the patients and because phosphocreatine/ATP ratios in adjacent slices were unchanged by exercise in the patients (e.g., in adjacent superficial slices containing mostly chest muscle, the ratio was 2.83±0.79 before exercise and 2.63±0.64 during exercise [P not significant]). The exercise-induced decrease in the phosphocreatine/ATP ratio was similar in the limited number of patients with coronary artery disease who had had an infarction and those who had not. After exercise, the mean phosphocreatine/ATP ratio increased in the group with coronary artery disease to 1.27±0.38, which was significantly higher than the value during exercise but not different from that measured before exercise. Thus, the changes in cardiac-metabolite ratios produced by isometric exercise were transient.

The mean myocardial phosphocreatine/ATP ratio in the nine patients with nonischemic heart disease did not change during isometric exercise. The ratio was 1.59±0.31 at rest, 1.55±0.24 during exercise, and 1.54±0.28 during recovery (Fig. 5Figure 5Transient Change in the Phosphocreatine/ATP Ratio in Response to Isometric Exercise at 30 Percent Maximal Continuous Isometric Force in Nine Patients with Nonischemic Heart Disease.).

The results of the two-way analysis of variance showed that the difference among the three study groups in the phosphocreatine/ATP ratio at rest approached significance (P = 0.052); t-tests with Bonferroni's correction showed that this was due to a slightly lower mean ratio in the group with coronary heart disease than in the control group or the group with nonischemic heart disease. The difference in the ratio among the groups during exercise was significant (P<0.001). This difference was entirely due to a lower value in the group with coronary artery disease. The mean phosphocreatine/ATP ratios determined during isometric exercise in the control group and the group with nonischemic heart disease did not differ from each other. The change in the ratio between rest and exercise in the three groups also differed significantly (P<0.001), and again this difference was due entirely to a significant change in the group with coronary artery disease. There was no correlation between age and the phosphocreatine/ATP ratio at rest or during exercise. Thus, isometric hand-grip exercise induced transient changes in the mean myocardial phosphocreatine/ATP ratio only in the patients with coronary artery disease and not in either the normal subjects or the patients with nonischemic heart disease.

As in the entire group of patients with coronary artery disease, the mean myocardial phosphocreatine/ATP ratio before revascularization in the subgroup of five of these patients decreased from a mean of 1.51±0.19 at rest to 1.02±0.26 during exercise (P<0.02). However, after revascularization the ratio did not change during identical exercise: the values were 1.60±0.20 at rest and 1.62±0.18 during exercise (Fig. 6Figure 6Transient Response of the Phosphocreatine/ATP Ratio in Response to Isometric Exercise at 30 Percent Maximal Isometric Force in Five Patients before and after Successful Revascularization.). Thus, isometric-exercise-induced changes in the myocardial phosphocreatine/ATP ratios in patients with coronary artery disease resolved after successful revascularization.

Discussion

The diagnosis and prognosis for patients with coronary artery disease depend on an objective recognition and assessment of the severity of myocardial ischemia. Established indexes of disease severity, including the number of electrocardiographic leads that show ST-segment changes, the magnitude of ST-segment depression, and changes in left ventricular function,17 , 20 only indirectly measure the metabolic changes induced by imbalances between myocardial oxygen supply and demand. Direct measurement of ischemia-induced metabolic change in human myocardium has been limited to invasive sampling of lactate and succinate in coronary-sinus effluent.21 22 23 Positron-emitting radionuclides, including fluorine-18 deoxyglucose, nitrogen-13 ammonia, and carbon-11 palmitate, have been used to identify ischemic myocardium and to determine the potential reversibility of left ventricular wall-motion abnormalities.1 2 3 Although these techniques can estimate the delivery and transport of glucose and fatty acid analogues into the cell, they do not provide information regarding high-energy phosphate levels.

We have demonstrated that myocardial levels of high-energy phosphate metabolites, which are critical for both contraction and cellular integrity, are transiently altered during exercise in patients with flow-limiting coronary-artery lesions but not in normal subjects or in patients with nonischemic heart disease. Previous studies of the effect of increased cardiac work on classic biochemical measures of myocardial high-energy phosphate levels in isolated hearts have produced conflicting results.24 25 26 The finding in the present study — that ratios of high-energy phosphates remain unchanged in normal subjects during a period of increased cardiac workload produced by isometric exercise — is consistent with the results of ³¹P NMR studies in dogs, in which phosphocreatine/ATP ratios were unchanged over a range of heart rate—blood pressure products (from 5000 to 25,000 mm Hg · beats per minute) produced by pacing,27 and preliminary results in normal subjects, in whom ratios did not seem to change during aerobic leg exercise that produced rate—pressure products of up to 12,000 mm Hg · beats per minute.28 Thus, in the absence of severe reductions in coronary flow, the heart can regulate and maintain high-energy phosphate levels over a range of workloads. Also, since the phosphocreatine/ATP ratio is sensitive to alterations in the concentration of free cellular ADP,27 the absence of change in the myocardial phosphocreatine/ ATP ratio suggests that ADP is not the primary regulator of the increased metabolism needed to meet higher cardiac workload during isometric exercise in normal subjects.

Although ³¹P NMR was used in this study to measure high-energy phosphate levels and not flux rates, the transient decrease in the phosphocreatine/ATP ratio in the patients suggests that coronary artery disease can restrict oxygen delivery to the heart to such an extent that a transient imbalance between oxygen supply and demand can be induced by the added stress of isometric exercise, resulting in transient excess consumption of high-energy metabolites. ³¹P NMR studies of animals have also shown significant decreases in the myocardial phosphocreatine/ATP ratio when coronary blood flow was reduced by occluding the left anterior descending coronary artery by 70 to 80 percent.29 , 30 These metabolic changes were greatest in the endocardium and similar in extent to the changes we observed in exercising patients. It is noteworthy that symptoms of ischemia did not develop in most patients despite demonstrable changes in the myocardial phosphocreatine/ATP ratios, suggesting a metabolic correlate of previously described "silent myocardial ischemia" syndromes, in which transient abnormalities in flow, electrocardiographic changes, and rises in left ventricular diastolic and pulmonary artery pressures occur in the absence of symptoms of ischemia.20 , 31 32 33 34 35 36 The resolution of exercise-induced metabolic changes in the subgroup of patients who underwent revascularization, and the absence of change in the patients with nonischemic heart disease, suggest that these findings are specific for ischemic heart disease.

In addition to producing elevated heart rate and systolic blood pressure in both normal subjects and patients with heart disease, continuous isometric hand-grip exercise significantly decreases the stroke-work index and increases left ventricular end-diastolic pressure in patients with ischemia, as compared with normal subjects.14 , 15 Reflex coronary vasoconstriction can also occur at critical levels of coronary stenosis during isometric hand-grip exercise and may have an important role in inducing ischemic sequelae during such stress testing.37 Isometric exercise is ideally suited for studies in the bore of an NMR instrument because such exercise produces these hemodynamic responses without the thoracic movement that normally accompanies aerobic or dynamic exercise of large muscle groups. It can be performed safely and without the modification of existing clinical machines. The patient's ability to tolerate exercise, however, limits scanning time to less than 10 minutes during exercise. This restriction, combined with the necessity of maintaining spatial resolution comparable to that of the thickness of the anterior myocardial wall to avoid contamination of metabolite measurements by other tissues, is a major factor limiting the sensitivity of spectral acquisition.

The scatter of values for the resting myocardial phosphocreatine/ATP ratio in patients with coronary artery disease may represent differences in the profile of high-energy phosphate metabolism in ischemic, reperfused "stunned," and infarcted myocardium,38 , 39 all of which were probably present in the diverse patient population studied. The greater variability in response to stress in this group probably relates also to differences in the degree or the extent (or both) of ischemia induced by any given increase in the determinants of demand. These include differences in the amount of viable tissue served by the stenotic vessel, the presence and extent of collateral flow to the region, the severity of fixed obstruction, and the degree of vasoconstriction induced by hand-grip stress. All our patients with coronary artery disease had critical coronary lesions, and it is not known whether similar metabolic disturbances would occur during similar exercise in patients with less severe coronary disease. In addition, our protocols for study of the anterior myocardium may not be directly applicable to study of the inferior or posterior myocardium. Nevertheless, the recent proliferation of clinical magnetic-resonance-imaging systems capable of ³¹P NMR enhances the applicability of these techniques to selected groups of patients. In addition, the advent of 4-T whole-body NMR systems40 offers further scope for improvements in sensitivity, spatial resolution, and scanning times.

Thus, image-guided, spatially localized ³¹P NMR spectroscopy with isometric-exercise stress testing may markedly improve noninvasive means of recognizing and evaluating myocardial ischemia in patients with suspected coronary artery disease. Quantification of myocardial levels of high-energy phosphate during exercise can also provide an important means of determining the efficacy of novel as well as established strategies and interventions for treating ischemia.

Supported by a Specialized Center of Research Grant (HL-17655–16) from the National Heart, Lung, and Blood Institute and by research funds from the General Electric Research and Development Center. This work was also done in part while Dr. Weiss was the recipient of a Clinician Scientist award from the American Heart Association and a Merck Clinician Scientist award from the Johns Hopkins University.

In accordance with the Journal's policy, Dr. Bottomley has stated that he holds stock or stock options in General Electric Company.

Source Information

From the Peter Belfer Laboratory of the Division of Cardiology, Department of Medicine, the Johns Hopkins Hospital, Baltimore (R.G.W., G.G.), and the General Electric Research and Development Center, Schenectady, N.Y. (P.A.B., C.J.H.). Address reprint requests to Dr. Bottomley at the General Electric Research and Development Center, P.O. Box 8, Schenectady, NY 12301.

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