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(Circulation. 1996;94:978-982.)
© 1996 American Heart Association, Inc.

Articles

Interaction Between Exercise Training and Ejection Fraction in Predicting Prognosis After a First Myocardial Infarction

Giuseppe Specchia, MD; Stefano De Servi, MD; Aldo Scire, MD; Jole Assandri, MD; Carlo Berzuini, PhD; Luigi Angoli, MD; Maria Teresa La Rovere, MD; Franco Cobelli, MD

the Divisione di Cardiologia, IRCCS Policlinico S. Matteo (G.S., S. De S., A.S., L.A.); the Centro di Riabilitazione di Montescano (J.A., M.T. La R., F.C.); and the Dipartimento di Informatica e Sistemistica, Universita degli Studi (C.B.), Pavia, Italy.

Correspondence to Prof Giuseppe Specchia, Divisione di Cardiologia, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.

	Abstract

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Background Although recent meta-analysis trials have shown that exercise training may improve survival after myocardial infarction, the mechanism of this beneficial effect is still unknown. The purpose of this study was to detect possible interactions between exercise training and predictors of prognosis after a first myocardial infarction.

Methods and Results Patients with uneventful clinical courses after a first myocardial infarction were randomly assigned to a 4-week training period (125 patients, group 1) or to a control group (131 patients, group 2). Before randomization, all patients underwent a symptom-limited exercise test (28±2 days after myocardial infarction), 24-hour Holter monitoring, and coronary arteriography (31±3 days after the acute episode). After a mean follow-up period of 34.5 months, 18 patients had cardiac deaths (5 in group 1 and 13 in group 2). Multivariate analysis by Cox regression model showed that ejection fraction was the only independent prognostic indicator (P=.03). Evidence existed of an interaction between ejection fraction and exercise training, showing an effect of physical training on survival that depended on the patient's ejection fraction. Among patients with ejection fractions <41%, the relative risk for an untrained patient was 8.63 times higher than for a trained patient (P=.04), whereas for ejection fractions >40%, the estimated risks for trained and untrained patients were similar.

Conclusions These data show that exercise training may prolong survival in post-myocardial infarction patients with depressed left ventricular function. A randomized trial in such patients seems warranted.

Key Words: myocardial infarction • exercise • prognosis • ventricles

	Introduction

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Recent meta-analysis trials have shown that exercise training reduces cardiac mortality after acute myocardial infarction.^{1 2} However, the mechanism of this beneficial effect is still uncertain because it is not known whether cardiac rehabilitation interacts with variables predictive of survival after myocardial infarction, particularly left ventricular function, which is the most powerful prognostic indicator in such patients. This question has practical implications because it would be desirable to identify patient subsets with various degrees of myocardial dysfunction who would take advantage of or would not benefit from an exercise training program.^{3 4 5} Thus, we undertook a prospective study of 256 patients recovering from a first myocardial infarction who were randomized either to a 4-week training period or a control group. The long-term follow-up data were analyzed to identify prognostic indicators and to assess the possible interaction of exercise-based cardiac rehabilitation with variables found to be predictive of survival in this population.

	Methods

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Patient Population
Over a 40-month period, 450 consecutive patients <65 years of age who had not had previous myocardial infarctions were admitted to the Cardiac Care Unit because of chest pain lasting >30 minutes and because they had a diagnosis of acute myocardial infarction based on evolutionary ECG changes and serum kinase elevation. We excluded 88 patients from the study: 40 patients did not survive the acute episode and 48 had a complicated in-hospital clinical course. Of these patients, 21 had early postinfarction angina requiring urgent coronary revascularization procedures, and 27 had evidence of congestive heart failure after the first 48 hours that demanded aggressive medical therapy, including digitalis and diuretics. Another 68 patients were excluded because of chronic concomitant illnesses or musculoskeletal handicaps that would have prevented them from finishing the exercise training period. Of the remaining 294 patients, 38 did not consent to enter the study. The remaining 256 patients were included in the study.

Study Design
At hospital discharge, after a mean hospitalization period of 12±4 days, the 256 patients were randomized either to a 4-week training period (125 patients, group 1) or a control group (131 patients, group 2). At discharge, medical treatment consisted of ß-blockers in 17 group 1 patients and 13 group 2 patients (P=NS), nitrates or calcium antagonists in 107 group 1 patients and 113 group 2 patients (P=NS), and low doses of diuretics in 11 group 1 patients and 13 group 2 patients (P=NS). No patient was taking digitalis. All patients went to the Rehabilitation Center of Montescano (Pavia, Italy), where they remained for 3 weeks. During this period of time, all patients underwent a symptom-limited exercise test (28±2 days after myocardial infarction), 24-hour Holter monitoring, and coronary arteriography (31±3 days after the acute episode). Moreover, all patients attended colloquial sessions, held by a cardiologist and a psychologist, dealing with secondary prevention of cardiovascular diseases and stressing dietary changes and smoking cessation. The 131 group 2 patients were then discharged and were clinically re-examined 1 month later when they underwent a second symptom-limited exercise test. On the other hand, the 125 group 1 patients underwent a 4-week physical training period consisting of supervised training sessions of 30 minutes of bicycle ergometry five times a week combined with calisthenics. Training intensity was graded according to 75% of maximal work capacity reached in the previous exercise test. At the end of the 4-week training period, a second symptom-limited exercise test was performed. Patients were then discharged with the instructions to continue the calisthenics daily and to walk for 30 minutes every 2 days.

Exercise Testing
The maximal symptom-limited bicycle exercise test was performed with patients in the sitting position beginning at 25 W with subsequent 25-W increments every 3 minutes. The test was terminated at the point of physical exhaustion, severe angina, ST-segment depression >3 mm, a decline in systolic blood pressure >20 mm Hg, complex ventricular arrhythmia, severe dyspnea, or claudication. An ischemic response was defined as ST-segment depression of at least 1 mm 80 milliseconds beyond the J-point. Medical treatment was not discontinued before the test.

Total exercise time, time to ischemia, heart rate, blood pressure, and double product at the onset of ischemia, and at peak exercise, maximal ST-segment depression and development of angina during exercise were recorded.

Holter Monitoring
All patients underwent 24-hour Holter monitoring before exercise testing. Holter ECGs were performed with a portable Aviotronics tape recorder (model 445B) to obtain two leads corresponding to modified lead II and V₅. The tapes were analyzed on a Trendsetter Aviotronics (model 9060) by an experienced nurse. All rhythm disturbances and ST-sloping periods were printed at 25 mm/s and reviewed by a cardiologist. Arrythmias, according to Lown classification, maximal heart rate achieved, mean daily and nightly heart rates, and episodes of ST-segment depression, were tabulated.

Coronary Arteriography
Selective coronary arteriography was performed in multiple views by use of the Sones or Judkins technique. When a lesion was noted, the vessel was filmed again after sublingual nitroglycerin administration. A coronary stenosis was considered significant when the lesion reduced the luminal vessel diameter in the projection obtained after sublingual nitroglycerin administration by >50%. Left ventriculograms were performed in 30° right anterior oblique projection before coronary arteriography. Left ventricular ejection fraction was calculated according to the single-plane area-length method.

Follow-up and Statistical Analysis
All patients were followed at 3- to 4-month intervals from the time of entry into the study. At each visit, detailed clinical information was obtained and evaluations were made to document the occurrence of any clinical event. Descriptions of the cause and circumstances of all deaths were obtained from relatives or physicians. Cardiac death was the only event considered in the analysis. Student's t test was used to compare mean values, and a ² test was used to compare the incidence of discrete variables between the two groups. Univariate analysis was carried out by the Kaplan-Meier method, and significance was tested by the log-rank test. A total of 86 variables were considered. Multivariate analysis was performed by use of the Cox regression model for censored survival data. Interactions between exercise training and prognostic indicators also were searched for to assess whether the impact of treatment in a given patient would depend in some way on the value of one or more prognostic indicators.

	Results

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Clinical and Angiographic Variables
Table 1 lists the clinical variables in the two groups of patients. There were no differences in sex prevalence, risk factors, preinfarction angina, type and location of myocardial infarction, or arrhythmic disturbances in the acute phase. There was a small but significant difference in age between the two groups (51.5±5 in group 1 versus 54.3±6 in group 2, P<.01). Streptokinase was used in a similar percentage of patients in the two groups. Table 2 shows the angiographic findings. Extent of coronary disease was similar in the two groups. Likewise, no difference was found between mean values of ejection fraction, left ventricular end-diastolic pressure, and left ventricular end-diastolic volume index.

View this table: [in this window] [in a new window]   Table 1. Clinical and ECG Findings in the Two Groups

View this table: [in this window] [in a new window]   Table 2. Angiographic Findings in the Two Groups

Exercise Testing
Table 3 gives the results of the exercise test performed 28 days after acute myocardial infarction. No differences were found in exercise duration, heart rate, and double product at peak exercise and in the value of double product at 1-mm ST-segment depression between the two groups. The percentage of patients who developed ST-segment depression or elevation during the test also was similar.

View this table: [in this window] [in a new window]   Table 3. Exercise Testing Results at 28 Days After Myocardial Infarction in the Two Groups

The exercise duration of the test performed 2 months after acute myocardial infarction (Table 4) was increased compared with the first exercise test in both groups (group 1, 13.4±3.6 versus 11.7±3.4 minutes, P<.001; group 2, 12.4±3.6 versus 11.8±3.6 minutes, P<.001). However, group 1 patients exercised for a longer time than group 2 patients (P<.05).

View this table: [in this window] [in a new window]   Table 4. Exercise Testing Results at 2 Months After Myocardial Infarction in the Two Groups

Holter Monitoring
Table 5 gives the results of the Holter monitoring. No differences were found between the two groups in Lown class of ventricular arrhythmias, number of episodes showing ST-segment depression, or maximal and mean daily and nightly heart rates.

View this table: [in this window] [in a new window]   Table 5. Results of Holter Monitoring

Follow-up
After a mean follow-up period of 34.5 months, 18 patients (5 in group 1 and 13 in group 2) had cardiac deaths (14 had sudden deaths; 4 had fatal myocardial infarctions). Eighteen patients underwent bypass surgery (11 patients in group 1 and 7 in group 2). Patients were operated on because of chest pain that was unresponsive to medical treatment (15 patients) or because of a significant left main disease (3 patients) after a mean time period of 8.4 months (range, 1 to 38 months) from randomization. No patients died because of operation or in the subsequent follow-up period. Two patients (1 in group 1 and 1 in group 2) underwent successful coronary angioplasty. To avoid any potential effect of these revascularization procedures on survival, these patients were excluded from survival analysis at the time of bypass surgery or coronary angioplasty.

Kaplan-Meier analysis revealed that five variables were significantly related to cumulative probability of cardiac death: persistence of ST-segment elevation (>1 mm) in the ECG leads showing abnormal Q waves (P<.05), cardiomegaly on radiographic examination (P<.05), an exercise duration <9 minutes (P<.05), a blood pressure increase of <30 mm Hg during exercise testing (P<.01), and ejection fraction (P<.001).

In the multivariate analysis, the five variables that were univariate predictors of prognosis and age were included in the model. Ejection fraction turned out to be the only independent prognostic indicator (P=.03). However, there was evidence of interaction between ejection fraction and exercise training that showed that the effect of physical training on survival depended on the patient's ejection fraction. For instance, among 51 patients with ejection fraction <41%, the relative risk for the 27 untrained patients was 8.63 times higher than for the 24 trained ones (95% CI, 1.2 to 65, P=.04). By contrast, when ejection fraction exceeded 40%, the estimated risk for an untrained patient was 1.07 times higher than for a trained person (P=NS). Figs 1 and 2 show survival curves for trained and untrained patients with ejection fractions <41% and >40%, respectively.

View larger version (9K): [in this window] [in a new window]   Figure 1. Survival curves in patients with ejection fractions <41% show a statistically significantly better survival for patients who had an exercise training period after myocardial infarction than those assigned to a control group.

View larger version (8K): [in this window] [in a new window]   Figure 2. No difference in survival was found between the two groups of patients with ejection fractions >40%.

	Discussion

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Patients with a first myocardial infarction represent the majority of all patients with acute infarction (60% to 80%).⁶ Although these patients have less mechanical dysfunction than patients without previous infarctions,⁷ the most potent prognostic variables are those relating to the extent of myocardial damage after the infarction.^{8 9 10 11} In a study by Ahnve et al,¹² stepwise logistic-regression analysis revealed that age, ejection fraction, and infarct location were the independent predictors of cardiac mortality. Patients <71 years of age who had ejection fractions >40% had a 2.5% 1-year mortality rate, whereas those >70 years of age with ejection fractions <41% had a 1-year mortality rate of 38%. Similar findings were reported by Norris et al¹³ in a population of 325 men <60 years of age who were followed up for 1 to 6 years after a first myocardial infarction: all the independent predictors of cardiac death except age were related to the extent of myocardial damage after the initial infarction. In the present study, we report on 256 patients with uneventful clinical courses after a first myocardial infarction and without clinical or physical contraindications to the accomplishment of an exercise training program. Patients randomly assigned to a 4-week training period or to a control group were followed up for a mean period of 35 months. Five variables were found to be univariate predictors of long-term outcome, but multivariate analysis revealed that ejection fraction was the only independent prognostic variable in this selected population. Interestingly, in the multivariate model, exercise training interacted with ejection fraction in predicting prognosis. Among patients with ejection fractions <41%, the relative risk was 8.7 times higher for an untrained patient than for a trained patient, whereas the estimated risk was nearly the same for trained and untrained patients when ejection fraction exceeded 40%.

The effects of exercise-based cardiac rehabilitation on mortality after myocardial infarction remain unclear because difficulties in study design (lack of randomization and control groups, inadequate study group size) have precluded definite conclusions.¹⁴ May et al,¹⁵ in a review of various interventions after myocardial infarction, found that maintaining an exercise program induces a significant 19% decrease in mortality, an effect similar to that achieved by ß-adrenergic blockade. Recently, O'Connor et al² overviewed 22 randomized trials of exercise-based cardiac rehabilitation after myocardial infarction involving 4554 patients. After an average of 3 years of follow-up, odds ratios concerning total and cardiac mortalities were significantly lower in the rehabilitation than in the comparison group. The odds ratio for sudden death was significantly lower in the rehabilitation group at 1 year and was compatible with a benefit at 2 and 3 years. These authors concluded that the overview of randomized trials of cardiac rehabilitation with exercise indicates a moderate reduction of 20% in total and cardiovascular mortalities that is apparent 1 year after randomization and persists throughout the follow-up. Similar data were reported by Oldridge et al,¹ who found a significantly lower pooled odds ratio of 0.75 (95% CI, 0.62 to 0.93) for cardiovascular mortality in the exercise-based rehabilitation group.

The correct identification of patients who might benefit most from an exercise program is still a subject of controversy. Early studies suggested that patients with poor left ventricular function were least likely to benefit from training because of their inability to increase cardiac output. Recent research, however, has provided evidence to the contrary.^{16 17} Sullivan et al¹⁷ found that training induced an increase in peak oxygen consumption together with important peripheral adaptations, resulting in improved exercise performance in 12 stable patients with chronic heart failure caused by left ventricular dysfunction. Similar data were reported by Froelicher et al,¹⁸ who found that infarct expansion is an unlikely outcome of exercise training. Moreover, in a multicenter randomized trial,¹⁹ exercise training was found to have no additional negative effect on the spontaneous ventricular enlargement that occurs in patients with large infarcts and depressed left ventricular function. The authors concluded that such patients can undergo a long-term exercise training program without further deterioration of ventricular volumes and function. Indeed, the data of the present study indicate that such patients may benefit most from an exercise-based cardiac rehabilitation.

Study Limitations
The present investigation was not designed to assess whether cardiac rehabilitation can reduce mortality in patients with previous myocardial infarctions. The purpose of our study was to detect possible interactions between exercise training and predictors of prognosis after a first myocardial infarction. However, because trained patients with ejection fractions <41% had better outcomes than untrained patients with similar left ventricular dysfunction, a randomized trial aimed at assessing whether exercise training may improve survival in post-myocardial infarction patients with low ejection fractions seems warranted. It must be remembered, however, that our population represents a selected group of patients with depressed left ventricular function because only patients without symptoms of congestive heart failure who could perform a symptom-limited exercise test were enrolled in the trial. The inability to perform a maximal exercise test represents an indicator of a worse prognosis in patients with a recent myocardial infarction.²⁰

Our study does not elucidate the mechanism whereby exercise training may prolong survival in post-myocardial infarction patients with low ejection fractions. Exercise training could exert a beneficial effect by inducing a change in the autonomic balance of the heart. Strong evidence links the autonomic nervous system to cardiovascular mortality after myocardial infarction.²¹ Myocardial ischemia and infarction can impair autonomic innervation to and from the heart, thus modulating the development of cardiac arrhythmias.^{22 23} Specifically, in the setting of acute myocardial ischemia, dominance of sympathetic reflexes facilitates the onset of malignant arrhythmias, whereas dominance of vagal reflexes can exert an antifibrillatory effect.²⁴ Exercise training modifies the sympathovagal balance toward a condition of parasympathetic dominance.²⁵ In high-risk dogs with and without healed myocardial infarctions, exercise induces an increase in markers of vagal activity and prevents ventricular fibrillation.^{26 27}

The change in the autonomic balance induced by physical training may be beneficial in other ways besides preventing life-threatening arrhythmias in high-risk patients. Elevated sympathetic activity, by increasing the wall stress and loading condition of the myocardium, further deteriorates cardiac function²⁸ by worsening the process of ventricular remodeling. Training-induced increases in parasympathetic activity may limit the deleterious effects of sympathetic hyperactivity on left ventricular performance, particularly in patients with low ejection fractions.

Received November 3, 1995; revision received February 27, 1996; accepted March 4, 1996.

	References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Specchia, G. Articles by Cobelli, F. Search for Related Content PubMed PubMed Citation Articles by Specchia, G. Articles by Cobelli, F. Pubmed/NCBI databases Medline Plus Health Information Heart Attack