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(Circulation. 1997;95:2060-2067.)
© 1997 American Heart Association, Inc.

Articles

Effect of Exercise Training on Myocardial Remodeling in Patients With Reduced Left Ventricular Function After Myocardial Infarction

Application of Magnetic Resonance Imaging

Paul Dubach, MD; Jonathan Myers, PhD; Gerald Dziekan, MD; Ute Goebbels, MD; Walter Reinhart, MD; Paul Vogt, MD; Reto Ratti, MD; Peter Muller, MD; Risto Miettunen, MD; Peter Buser, MD

From the Cardiology Divisions, Kantonsspital, Chur (P.D., G.D., U.G., W.R., R.R., P.M.), Basel (R.M., P.B.), and Zürich (P.V.), Switzerland, and Palo Alto Veterans Affairs Medical Center and Stanford University (J.M.), Palo Alto, Calif.

Correspondence to Jonathan Myers, PhD, Palo Alto Veterans Affairs Health Care System, Cardiology, 111-C, 3801 Miranda Ave, Palo Alto, CA 94304.

	Abstract

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Background There are conflicting reports on the effects of training on the remodeling process in post–myocardial infarction patients with ventricular damage.

Methods and Results Twenty-five patients with reduced ventricular function (mean ejection fraction, 32.3±6%) after an anteroseptal or inferolateral myocardial infarction were randomized to an exercise group (n=12) or a control group (n=13). Patients in the exercise group resided in a rehabilitation center for 2 months and underwent a training program consisting of two 1-hour sessions of walking daily, along with four monitored 45-minute sessions of stationary cycling weekly. Before and after the study period, maximal exercise testing and cardiac MRI were performed. Oxygen uptake increased 26% at maximal exercise (19.7±3 to 23.9±5, P<.05) and 39% at the lactate threshold (P<.01) in the exercise group, whereas control values did not change. No differences were observed within or between groups in MRI measures of end-diastolic (187±47 pre versus 196±35 mL post in the exercise group and 179±52 pre versus 180±51 mL post in the control group), end-systolic volume (118±41 pre versus 121±33 mL post in the exercise group and 119±54 pre versus 116±56 mL post in the control group), or ejection fraction (38.0±9 pre versus 38.2±10% post in the exercise group and 37.0±10 pre versus 38.3±13% post in the control group). Myocardial wall thickness measurements at end diastole and end systole and their difference in 80 myocardial segments determined by MRI yielded no significant interactions between groups. When myocardial wall thickness measurements were classified by infarct or noninfarct areas, no differences were observed between groups over the study period.

Conclusions A high-intensity, 2-month residential cardiac rehabilitation program resulted in substantial increases in exercise capacity among patients with reduced left ventricular function. In contrast to some recent reports, the training program had no deleterious effects on left ventricular volume, function, or wall thickness regardless of infarct area.

Key Words: exercise • magnetic resonance imaging • heart failure • remodeling

	Introduction

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Substantial clinical and experimental evidence exists demonstrating that progressive left ventricular dilation can occur after a myocardial infarction.^{1 2 3 4} The combination of myocardial wall thinning, aneurysm formation, expansion of the infarct area, and an increase in the radius of the left ventricle has been termed "myocardial remodeling" and appears to represent an important prognostic marker after an infarction^{5 6} and a precursor to heart failure.^{1 2 3 4} The mechanism for myocardial remodeling after an infarct is unknown, but several factors appear to be involved, including chronic diastolic volume overload causing increased wall stress and compensatory eccentric hypertrophy^{7 8 9} and bioenergetic alterations.¹⁰

Several factors appear to influence the extent of the remodeling process, including attenuation by ACE inhibition therapy, extent and site of the infarction, hypertension, and continued ischemia.^{1 2 3 4 11} The body of evidence documenting the physiological benefits of exercise training after an infarct is substantial,¹² but recently a debate has arisen regarding the influence of exercise training on the remodeling process. For example, animal studies have demonstrated further ventricular dilatation with training after experimentally induced infarctions.^{13 14} Jugdutt and associates,¹⁵ using echocardiography, suggested that exercise training in patients with reduced left ventricular function after a myocardial infarction leads to further myocardial damage, including wall thinning, infarct expansion, further asynergy, and a reduction in ejection fraction. Several subsequent studies published in preliminary form failed to confirm these findings.^{16 17 18} Giannuzzi and associates¹⁹ studied patients before and after 1 year of exercise training who had sustained an anterior myocardial infarction. Echocardiographic measures of ventricular size, regional dilatation, and shape distortion did not change in either the control or trained groups. However, patients with ejection fractions of <40% had more significant ventricular enlargement initially and demonstrated further global and regional dilatation after 6 months in both groups. Training did not influence this spontaneous deterioration. A more recent analysis from these investigators suggested that training actually has a beneficial effect on the remodeling process.²⁰ This issue continues to generate significant debate.²¹

The differences in the findings among studies may be due to differences in patient populations (ie, presence, type, and severity of infarct), intensity of training, measurement techniques, or a combination of these factors. It has been argued that measurement techniques used in previous studies lacked the precision necessary to evaluate the effect of exercise training in this context. In the present study, we used MRI to evaluate changes in myocardial wall thinning, thickness, global left ventricular size, volumes, and ejection fraction in response to exercise training. MRI is uniquely suited for the study of left ventricular size and function because unlike echocardiography, it does not depend on geometric assumptions and provides superior contrast between the heart and blood pool.²² Numerous studies are available documenting the superior precision and reproducibility of MRI relative to other imaging techniques.^{23 24 25} To more clearly separate the exercise intervention from the spontaneous evolution of myocardial size and function after the infarction, we used a high-intensity training stimulus in a randomized, controlled design.

	Methods

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Patients
Twelve male patients (mean age, 56±5 years) participated in the exercise group, and 13 male patients (mean age, 55±7 years) participated in the control group, all after having given written informed consent. The clinical characteristics of the two groups are outlined in Table 1. All patients had sustained a recent myocardial infarction, and their hospital course included the diagnosis of heart failure. Before their hospitalization, none of the patients had had a previous history of heart failure. The presence of heart failure was documented by signs, symptoms, and angiographic evidence of reduced left ventricular function (ejection fraction, <40%) due to coronary artery disease. All patients had stable symptoms after their myocardial infarction before randomization. The duration between the myocardial event and the initial test was 36.1±14 days for patients randomized to the trained group and 35.0±6 days for the control group. All were limited by fatigue or dyspnea on baseline exercise testing, and none had clinical evidence of pulmonary disease.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Study Design
Group assignment was randomized, with the study period lasting 8 weeks. Randomization was accomplished using a list of random numbers. Patients in both groups underwent nuclear magnetic resonance evaluations initially and after 2 months. Cardiopulmonary exercise testing, pulmonary function tests, and quality-of-life assessments were performed initially and after 1 and 2 months.

Exercise Training
After stabilization and initial testing, patients in the exercise group resided in a rehabilitation center in Seewis, Switzerland, for a period of 8 weeks. Seewis is a small village in the mountains at an elevation of 3500 feet. The center has its own staff of physicians consisting of a medical director and three interns/residents. Program components included education, exercise, and low-fat meals prepared three times daily by the center's cook. Two outdoor walking sessions daily for a duration of 1 hour were performed, once in the morning and once in the afternoon. Walking intensity was stratified into four levels on the basis of clinical status, exercise capacity, and performance on a 500-m walking test (50-m increase in altitude) on a nearby hill. The patients were accompanied by a physician during these walking sessions. Exercise leaders carried two-way radios for communication with the center in case of emergency. A van equipped with emergency equipment followed the group.

In addition to these walking periods, the 12 patients in the exercise group performed four 45-minute periods of monitored stationary cycling per week. The cycling sessions were designed to elicit an intensity equal to 60% to 70% of the patient's heart rate reserve and were increased progressively over the 2 months as tolerated. Each of these sessions was monitored closely by a medical resident at the Center. Heart rate, workload, and perceived exertion were recorded every 5 minutes; adjustments were made in exercise intensity as appropriate. Control patients received the usual clinical follow-up and were encouraged not to exercise beyond a level associated with normal activities of daily living.

Exercise Testing
On the day of testing, patients in both groups were requested to abstain from food, coffee, and cigarettes for 3 hours before the test. Standard pulmonary function tests were performed. Maximal exercise testing was performed on an electrically braked cycle ergometer using an individualized ramp protocol. Briefly, this test entails choosing an individualized ramp rate to yield a test duration of 10 minutes.²⁶ Arterial blood lactate samples were drawn every minute throughout the test. A 12-lead ECG was monitored continuously, and blood pressure was measured manually every minute during exercise and throughout the recovery period. The patient's subjective level of exertion was quantified every minute using the Borg 6-20 scale.²⁷ All tests were continued to volitional fatigue/dyspnea. Respiratory gas exchange variables were acquired continuously throughout exercise using the Schiller CS-100 metabolic system. Gas exchange variables analyzed were oxygen uptake, carbon dioxide production, minute ventilation, respiratory rate, tidal volume, oxygen pulse, and respiratory exchange ratio.

MRI
Cine-MRI was performed using a commercially available 1.5-T MRI scanner in the supine position. ECG electrodes were placed on the back to obtain an optimal ECG signal. With T1-weighted spin-echo sequences, the angulation of the left ventricular long-axis view was defined in a transverse and a parasagittal scout image. The left ventricular short-axis view was defined as imaging planes perpendicular to the left ventricular long axis. The four-chamber view was defined as an imaging plane encompassing the insertion of the anterior mitral leaflet and the apex in an oblique coronal view parallel to the interventricular septum. Cine-MRI was performed using ECG-gated gradient refocused echo sequences with a flip angle of 30° and an echo time of 6 milliseconds. Slice thickness was 8 mm, and 14 to 16 frames per RR interval were acquired in a single imaging plane. The entire heart was continuously encompassed from the base to the apex in a short axis, and four additional cine-MRI sequences were performed in the four-chamber view, thus allowing for correction of partial volume effects and for regional wall motion analysis of the apex. The total imaging time was 20 minutes.

To obtain reproducible contrast between muscle and blood, a statistical analysis of pixel intensities with subsequent adaptation of the dynamic range (window and level of gray scale) was performed automatically. This permitted alterations in contrast between myocardium and blood pool to be minimized as well as differences in display parameters on images between the two MRI studies in each patient. For images with poor contrast (30% of the images), manual adjustment of the intensity level and width was performed subjectively to recognize the internal ventricular morphology.

All cine-MR images were analyzed by a cardiologist (P.B.) and a radiologist (R.M.) who had extensive experience with cardiovascular MRI and who were blinded to the randomization of the patients. In all cine-MRI loops, regional wall motion and global left ventricular ejection fraction were visually estimated by both investigators. In addition, regional systolic wall thickening was measured in eight segments of the left ventricular myocardium in all short-axis planes as previously described.²⁸ Left ventricular volumes were calculated as the sum of the measured cavity area multiplied by the slice thickness of all slices covering the left ventricle. Left ventricular mass was calculated as the sum of the ventricular cavity area times the slice thickness multiplied by the specific myocardial gravity (1.05). Left ventricular stroke volume and ejection fraction were calculated from end-systolic and end-diastolic volumes. Interobserver and intraobserver variabilities in our laboratory have been shown to be 6.6±3.2% and 5.1±2.9%, respectively, for left ventricular end-diastolic volume and 6.2±3.3% and 4.8±2.2%, respectively, for left ventricular mass. These values are similar to those recently reported elsewhere using MRI.²⁴

The myocardium was measured in 10 short-axis planes (cross-sectionally), each of which was divided into eight segments around the circumference as illustrated in Fig 1 (yielding a total of 80 segments per heart). Myocardial wall thickness was quantified in each segment at end diastole and end systole, and the difference (end-systolic minus end-diastolic wall thickness) was determined. The infarct areas that were predominantly anteroseptal (short-axis segments 1, 2, 6, 7, and 8) were summed to determine whether training caused thinning or thickening in an infarct-related or non–infarct-related area. Likewise, among patients who had sustained an infarct that was predominantly inferolateral, segments 3, 4, and 5 were summed, and differences between infarct and noninfarct areas were determined.

View larger version (34K): [in this window] [in a new window]   Figure 1. Illustration showing the cross-sectional and longitudinal MRI measurements. Each patient's myocardium was measured in 80 segments and divided into anteroseptal (segments 1, 2, 6, 7, and 8) and inferolateral areas (shaded segments 3, 4, and 5).

Statistical Analysis
Statistical Graphics Corporation Software was used to perform multivariate ANOVA procedures comparing hemodynamic, gas exchange, and MRI results between groups. Data are presented as mean±SD.

	Results

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No differences were observed between the two groups initially in clinical or demographic data, including age, height, weight, resting blood pressure, pulmonary function, ejection fraction, or maximal oxygen uptake (Table 2). No untoward events occurred during any of the exercise testing or training procedures. Patients in the exercise group were closely monitored by heart rate, workload, and perceived exertion during their stationary cycling sessions and only generally during walking sessions. During monitored cycling over the 2 months, the mean percentage of maximal heart rate maintained was 83±6%, the mean percentage of maximal workload was 78±7%, and perceived exertion averaged 15.2±2.

View this table: [in this window] [in a new window]   Table 2. Exercise and Gas Exchange Data

Maximal Exercise Testing
Both groups achieved mean maximal respiratory exchange ratios of >1.20 and mean perceived exertion levels of 19 on all three tests, suggesting that maximal efforts were generally achieved (Table 2). No differences were observed within or between groups in maximal heart rate or blood pressure. The exercise group demonstrated a 26% increase in maximal oxygen uptake from test 1 to test 2 (19.3±3.0 to 23.9±4.8 mL·kg^-1·min^-1, P<.01) and a further 5% increase from test 2 to test 3 (Fig 2). Concomitant increases in maximal minute ventilation, CO₂ production, exercise time, and Watts achieved were observed in the exercise group. No differences between pretests and posttests were observed among control patients in maximal oxygen uptake, exercise time, or Watts achieved.

View larger version (13K): [in this window] [in a new window]   Figure 2. Oxygen uptake at maximal exercise (VO2) and at the ventilatory threshold (VO2Lt) for the exercise and control groups on tests 1 (baseline), 2 (after 1 month of training), and 3 (after 2 months of training).

Oxygen uptake at the lactate threshold increased significantly between all three tests in the exercise group (39% overall from test 1 to test 3), whereas small but insignificant decreases were observed among control subjects (Fig 2). Similar increases in exercise time and Watts achieved at the lactate threshold were observed among patients in the exercise group, whereas the control group demonstrated small decreases in these variables. No differences were observed within or between groups for heart rate, systolic or diastolic blood pressure, minute ventilation, CO₂ production, respiratory exchange ratio, lactate, or perceived exertion at this point.

MRI
Left ventricular volume, mass, and ejection fraction values in the two groups are presented in Table 3. There were no differences observed within or between groups in end-systolic or end-diastolic volumes or mass during the study period. Likewise, changes in ejection fraction were similar between groups (38.0±9% pre versus 38.2±10% post in the exercise group and 37.0±10% pre versus 38.3±13% post in the control group).

View this table: [in this window] [in a new window]   Table 3. MRI Measures of Ventricular Volume and Mass Initially (Pre) and After (Post) the Study Period

Initially, ANOVA was performed on the myocardial wall thickness measurements at end systole and end diastole and the difference between them in all 80 myocardial segments using group (exercise versus control) and test (pre versus post) as independent factors. This analysis yielded no significant interactions between groups. The data were then summed by infarct- and non–infarct-related segments among the anteroseptal and inferolateral infarct subgroups (Fig 1). The infarct areas for the anteroseptal infarct patients in the trained group are presented in Fig 3, and those for control patients are presented in Fig 4. Myocardial wall thickness measurements for the anteroseptal infarct patients in the noninfarct areas for the trained and control groups are illustrated in Figs 5 and 6, respectively. No significant differences were observed between exercise and control groups in end-diastolic wall thickness, end-systolic wall thickness, or their difference in either the infarct or noninfarct areas. Although the inferolateral groups were smaller (4 patients in the exercise group and 3 in the control group), the myocardial wall thickness measurements in these patients were also similar between groups throughout the study period.

View larger version (15K): [in this window] [in a new window]   Figure 3. Myocardial wall thickness (mm, ±SD) among anteroseptal infarct patients in the infarct areas, summed for each of the eight cross-sectional segments, in the exercise group (n=7).

View larger version (16K): [in this window] [in a new window]   Figure 4. Myocardial wall thickness (mm, ±SD) among anteroseptal infarct patients in the infarct areas, summed for each of the eight cross-sectional segments, in the control group (n=8).

View larger version (16K): [in this window] [in a new window]   Figure 5. Myocardial wall thickness (mm, ±SD) among anteroseptal infarct patients in the noninfarct areas, summed for each of the eight cross-sectional segments, in the exercise group (n=7).

View larger version (15K): [in this window] [in a new window]   Figure 6. Myocardial wall thickness (mm, ±SD) among anteroseptal infarct patients in the noninfarct areas, summed for each of the eight cross-sectional segments, in the control group (n=8).

	Discussion

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Progressive left ventricular enlargement, dilatation, and global or regional left ventricular dysfunction are important prognostic factors in the clinical course of chronic heart failure, particularly after a myocardial infarction. These changes ("remodeling") can precede a deterioration in exercise capacity, and ventricular dilatation is associated with a significant reduction in cardiac performance.^{1 3 4} Some studies have in fact suggested that left ventricular volume is the most important determinant of survival in patients after an infarction.^{5 29}

The benefits of exercise training in the recovery period after a myocardial infarction are well established.³⁰ In recent years, these benefits have been extended to include patients with reduced ventricular function.^{30 31 32 33} However, a rather lively debate has recently arisen concerning the role of exercise training in the remodeling process among patients with reduced left ventricular function. One study using echocardiography reported marked left ventricular wall thinning, regional distortion, reduced ejection fraction, and global dysfunction among patients participating in a training program, whereas these variables remained unchanged among control patients.¹⁵ These observations have been confirmed experimentally in animals in some studies^{14 34} although not in others.^{35 36} Studies among humans have also been mixed. Two recent studies reported abnormal remodeling among some patients, although training did not appear to have any effect on this process.^{19 37} Giannuzzi et al²⁰ recently reported in preliminary form that training actually lessened left ventricular dilatation and regional dysfunction.

MRI is uniquely suited for quantifying changes caused by remodeling because it can noninvasively image the entire left ventricle. MRI measurements are independent of geometric assumptions and therefore currently considered the most accurate and reproducible method for quantifying left ventricular morphology.³⁸ Several recent studies have observed superior interobserver reproducibility of MRI compared with echocardiographic and radionuclide techniques.^{23 24 25} Moreover, MRI is capable of imaging using three-dimensional reconstructions of the heart, something that is not possible with echocardiography. Three-dimensional imaging is central to the issue of myocardial remodeling because it permits the measurement of myocardium in very specific areas. In the present study, the heart was imaged in 80 sections, permitting the quantification of expansion or thinning in infarct- and non–infarct-related areas.

We did not observe any differences within or between groups in ventricular volumes or ejection fraction (Table 3). Moreover, no differences were observed in measures of regional expansion or thinning by MRI, in both the infarcted and noninfarcted zones (Figs 3 through 6). To our knowledge, these are the first such observations using MRI technology to evaluate the effects of exercise training in humans. These findings sharply contrast with those of Jugdutt et al,¹⁵ who reported increases in ventricular asynergy, expansion, peak shape distortion, thinning, and a reduction in ejection fraction after 12 weeks of training in a subgroup of patients initially found to have ventricular asynergy by echocardiography. No differences were found in these variables among their patients in the trained group who had normal ventricular function initially or among control subjects who did not train. It is noteworthy that the study of Jugdutt and associates¹⁵ differed from ours in several respects. First, all of their patients had moderate-sized anterior Q-wave infarctions, whereas approximately two thirds of our patients had anterior infarcts, with the remainder having inferolateral infarcts. Second, in the former study, patients began rehabilitation at a mean of 15 weeks after infarction, with a range of 6 to 32 weeks; all of our patients were enrolled in the study at 1 month (mean, 36±12 days) after infarction. Last, none of our patients were receiving ß-blockade therapy during the study period, but all were receiving ACE inhibitors. In contrast, the majority of patients in the study of Jugdutt et al¹⁵ were receiving ß-blockers, but none were receiving ACE inhibitors. Both of these agents are known to influence the remodeling process. Although it is difficult to extrapolate observations made among animals to humans in this context, ACE inhibition has been demonstrated to attenuate abnormal remodeling,³ whereas ß-blockade has been shown to be detrimental.¹³

It is noteworthy that resting heart rate was reduced by 15 bpm from test 1 to test 3, which is to be expected after exercise training (Table 2). Had the serial MRI measures of ventricular volume been performed at matching heart rates, it would have optimized the comparison. Although the reduction in heart rate was not statistically significant, it may have influenced resting volumes and, therefore, wall thickness. We are unaware of any validated method to correct MRI measures based on changes in heart rate. However, DeMaria and colleagues³⁹ evaluated the effect of alterations in heart rate by atrial pacing in humans on ventricular volumes. Not surprisingly, these investigators observed that changes in heart rate were linearly related to changes in ventricular volume and developed a regression equation to correct volumes based on heart rate. Out of interest, we performed the same analysis in our population using the regression equation of DeMaria et al.³⁹ Although the reduction in resting heart rate after training resulted in small (10%) increases in corrected resting end-diastolic and end-systolic volumes, there remained no significant differences within or between groups. We are therefore confident that our data represent reasonably precise reflections of volumes and wall thickness and that exercise training did not influence these measurements.

The proper place and safety of high-intensity training among patients early in the course of heart failure are presently unclear. We did not observe any adverse events in the present study, and we are unaware of any previous studies that have trained similar patients at such a high level. As in similar studies among patients with reduced left ventricular function and coronary artery disease,^{12 40} we did not observe differences in left ventricular ejection fraction with training. There was a marked training effect demonstrated among the exercise group (26% increase in peak VO₂), which likely reflects a widening of the a-VO₂ difference via enhanced oxidative capacity of the skeletal muscle. Hambrecht and associates³³ recently confirmed noninvasive spectroscopy studies of the skeletal muscle³¹ by evaluating biopsy samples of the leg mitochondria and skeletal muscle ultrastructure before and after training among patients with congestive heart failure. These studies have consistently demonstrated enhanced oxidative capacity of the skeletal muscle after training. Based on studies published during the past decade, the beneficial peripheral adaptations to exercise training in patients with congestive heart failure appear to be indisputable.^{16 30 31 32 33}

Clinical Implications
In the present study, high-intensity training among postinfarction patients with an initial diagnosis of stable heart failure was effective in improving maximal oxygen uptake and caused a significant delay in the lactate threshold. Importantly, and in contrast to some recent reports, training did not cause further myocardial damage (ie, wall thinning, infarct expansion, changes in ejection fraction, or increases in ventricular volume). Presumably, the application of MRI represents a significant advance in precision over previous studies. It should be noted that our population differed somewhat from previous studies in that all patients had newly diagnosed reduced ventricular function after either anterior or inferior myocardial infarctions. The findings may differ in the presence of larger or more severe infarctions or if training were performed during a different time course in the healing process. MRI appears to be an optimal tool for the assessment of adaptations of the myocardium to exercise training.

	Acknowledgments

 
This work was supported in part by grants from the Schweizerische Herzstiftung, Switzerland, and the Roche Research Foundation. The authors gratefully acknowledge the administrative and technical assistance of A. Koloz, MD (Seewis, Switzerland), and U. Gadola, A. Camerisch, V. Anigoni, A. Sauter, and M. Arvai (Chur, Switzerland).

Received September 23, 1996; revision received November 4, 1996; accepted November 23, 1996.

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