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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:713-717 (2006)
© 2006 The Gerontological Society of America

Exercise-Based Cardiac Rehabilitation Improves Heart Rate Recovery in Elderly Patients After Acute Myocardial Infarction

Francesco Giallauria, Rosa Lucci, Marco Pietrosante, Gaetano Gargiulo, Anna De Lorenzo, Mariantonietta D'Agostino, Giusto Gerundo, Pasquale Abete, Franco Rengo and Carlo Vigorito

Department of Clinical Medicine, Cardiovascular and Immunological Sciences, School of Medicine, University of Naples Federico II, Italy.

Address correspondence to Francesco Giallauria, MD, Department of Clinical Medicine, Cardiovascular and Immunological Sciences School of Medicine, University of Naples Federico II, Via S. Pansini, 5, 80131 Naples, Italy. E-mail: giallauria{at}libero.it


   Abstract
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Methods
 Results
 Discussion
 References
 
Background. Heart rate recovery (HRR), defined as the fall in HR during the first minute after exercise, is a marker of vagal tone, which is a powerful predictor of mortality in patients with coronary artery disease and in older patients. Whether exercise training (ET) modifies HRR in elderly patients recovering from acute myocardial infarction (AMI) is still unknown. Therefore, this study aims at evaluating the effect of ET on HRR in elderly AMI patients.

Methods. This was a prospective observational study including 268 older patients after AMI (217 men, 51 women), subdivided in two groups: Group A (n = 104), enrolled in an ET program; Group B (n = 164), discharged with generic instructions to continue physical activity. At baseline and at 3-month follow-up, all Group A and 54/164 Group B patients underwent a cardiopulmonary exercise stress test, whereas 110/164 Group B patients underwent an exercise stress test.

Results. After completion of the ET program, in Group A we observed an improvement in oxygen consumption at peak exercise (VO2peak; from 14.7 ± 1.3 to 17.6 ± 1.9 mL/kg/min, p <.001), in the rate of increase of ventilation per unit of increase of carbon dioxide production (VE/VCO2slope; from 34.2 ± 3.8 to 30.4 ± 3.0, p <.001), and in HRR (from 13.5 ± 3.7 to 18.7 ± 3.5 beats/min, p <.001). The changes in VO2peak and in VE/VCO2slope after ET were correlated with the improvement of HRR (r = –0.865, p <.01; r = –0.594, p <.01, respectively). No changes in these parameters were observed in Group B patients.

Conclusions. In older AMI patients, ET results in HRR improvement, which was correlated to the improvement in cardiopulmonary parameters. These findings may shed additional light on the possible mechanisms of the beneficial prognostic effects of ET in this patient population.

EXERCISE-BASED cardiac rehabilitation results in improved exercise capacity (1) and in a reduction in mortality in patients after acute myocardial infarction (AMI) (2–4).

Exercise training (ET) has been associated with improvement in cardiovascular functional capacity in older patients after AMI (5–8). Oxygen consumption at peak exercise (VO2peak), a recognized parameter of exercise capacity, is an independent predictor of long-term survival both in young and older persons, and in both healthy persons and in patients with coronary artery disease (CAD) (9).

Heart rate recovery (HRR), defined as the fall in HR during the first minute after exercise, is a marker of vagal tone, which is a powerful predictor of mortality in patients with CAD (10–12) and in older patients (13), even after taking into account the angiographic severity of CAD, left ventricular function, and exercise capacity (14).

Measurements of HR variability after ET have demonstrated, in AMI patients, an increase in high-frequency spectra that can be related to increased parasympathetic tone (15), which has been associated with reduced mortality after myocardial infarction (16).

In older persons, Pichot and colleagues (17) have recently reported that interval training increases two major indices of autonomic nervous system activity, HR variability and baroreflex activity. More recently, we demonstrated that ET improves HRR in older persons (18).

However, whether ET modifies HRR in older patients recovering from AMI is still unknown. Therefore, this study was performed to investigate the effect of ET on HRR in older patients recovering from AMI, to evaluate whether an improvement in sympathovagal balance, as derived by HRR, with its associated favorable prognostic implications, may be obtained also in this patient population.


   METHODS
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Results
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Study Population
A total of 268 patients 65 years old or older recovering from AMI were subdivided into two groups (A and B), similar for age, severity of CAD, coronary risk factors, type of coronary event, and left ventricular ejection fraction (LVEF) (Table 1). We excluded patients with postinfarction residual myocardial ischemia, severe ventricular arrhythmias, atrioventricular block, severe reduction of LVEF (≤25%), hypertrophic cardiomyopathy, valvular disease requiring surgery, pericarditis, severe renal dysfunction (i.e., creatinine > 2.5 mg/dL), or severe disabling comorbidity.


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  		Table 1. Demographic and Clinical Characteristics of Study Patients.

 
At a mean distance of 10 ± 4 days from AMI, Group A patients (n = 104; 81 men, 23 women) were enrolled in a 3-month ET program as a part of a comprehensive cardiac rehabilitation program including patient education and counselling, risk factor intervention, optimal pharmacological therapy, and psychological intervention. Group B patients (n = 164, 136 men, 28 women; control group) were not enrolled in any ET program (mostly for logistical reasons), and were discharged with only routine recommendations.

At baseline and at 3-month follow-up, Group A patients and 54/164 (32.9%) Group B patients underwent a cardiopulmonary exercise test (CPX), whereas 110/164 (67.1%) Group B patients underwent an exercise stress test. No patient was lost at follow-up in either group. Cardiovascular treatment was kept constant throughout the study (Table 1). The study was approved by the Ethical Committee of our institution. All patients gave their written informed consent.

Training Protocol
Group A patients attended the ET program in the hospital on an ambulatory-based regimen 3 times per week. Training sessions, performed under continuous electrocardiogram monitoring, were supervised by a cardiologist and a graduate nurse. Each session, preceded by a 5-minute warm-up and followed by a 5-minute cool-down, was performed by pedalling for 30 minutes on a bicycle ergometer at the level of 60% of VO2peak achieved at the initial symptom-limited cardiopulmonary exercise test (CPX1), or at 60% of peak HR reached at the initial symptom-limited exercise stress test (in Group B patients not performing CPX).

CPX
All patients underwent a symptom-limited CPX or exercise stress test with Bruce treadmill protocol (19). HR and blood pressure at baseline and peak exercise, HR 1 minute into a walking cool-down period (1.7 mph at 0% grade), and treadmill speed and grade at peak exercise were recorded. HR recovery (HRR) was calculated as the difference between HR at peak exercise and at 1 minute of the cool-down period. Before each test, oxygen and carbon dioxide analyzers and a flow mass sensor were calibrated by use of available precision gas mixtures and a 3 L syringe, respectively. To stabilize gas measurements, patients were asked to remain still on the treadmill for at least 3 minutes before starting to exercise. A 12-lead electrocardiogram was monitored continuously during the test, and cuff blood pressure was manually recorded every 2 minutes. Respiratory gas exchange measurements were obtained breath-by-breath with use of a computerized metabolic cart (Vmax 29C; Sensormedics, Yorba Linda, CA). VO2peak was recorded as the mean value of VO2 during the last 20 seconds of the test and was expressed in milliliters per kilogram per minute. At the end of the CPX, patients were asked to identify the primary reason for stopping. Medical treatment administered the day of exercise testing was recorded. Predicted VO2peak was determined by use of a sex-, age-, height-, and weight-adjusted and protocol-specific formula outlined by Wassermann and colleagues (20). The ventilatory anaerobic threshold (VAT) was detected by two experienced reviewers (C.V. and F.G.) by use of the V-slope method (21). The ventilation versus carbon dioxide production (VE vs VCO2) relationship was measured by plotting VE against VCO2 obtained every 10 seconds of exercise (VE/VCO2slope): Both VE and VCO2 were measured in liters per minute. The VE/VCO2slope was calculated as a linear regression function, excluding the nonlinear part of the relationship after the onset of acidotic drive to ventilation.

Statistics
Descriptive statistics are given in terms of means ± standard deviation. Comparison between groups for continuous variables were made using Student's t test. Pearson's correlation coefficient was used to assess the association between HRR and cardiopulmonary parameters. Statistical significance was set at level p <.05, for two-tailed probability independent samples. All statistical analyses were performed using the software package SPSS (version 11.0; SPSS Inc., Chicago, IL).


   RESULTS
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Table 2 shows all clinical and exercise parameters in both Group A and B patients at baseline and at 3-month follow-up. Trained elderly patients (Group A) showed significant improvement in cardiopulmonary parameters and in HRR at 3-month follow-up (Table 2). The mean value of HRR and of VO2peak at the end of ET was significantly higher than the value observed at 3 months in elderly patients not enrolled in the ET program (Group B; p <.001). In trained elderly patients, the changes of VO2peak and of VE/VCO2slope after ET were correlated with the improvement of HRR (r = –0.865, p <.01, Figure 1; r = –0.594, p <.01, Figure 2, respectively). In trained patients there was also a correlation between age and changes in HRR after ET (r = 0.412, p <.01, Figure 3).


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  		Table 2. Clinical, Cardiopulmonary, and Exercise Parameters in Group A and Group B Patients at Baseline and After 3 Months.

 

Figure 01
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  		Figure 1. Relationship between changes in heart rate recovery (HRR) and in oxygen consumption at peak exercise (VO2peak; mL/kg/min) after exercise training in Group A

 

Figure 02
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  		Figure 2. Relationship between changes in heart rate recovery (HRR; beats/min) and in the rate of increase of ventilation per unit of increase of carbon dioxide production (VE/VCO2slope) after exercise training in Group A

 

Figure 03
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  		Figure 3. Relationship between age (years) and changes in heart rate recovery (HRR; beats/min) after exercise training in Group A

 

   DISCUSSION
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ET is an important component of the standard comprehensive cardiac rehabilitation program in patients after an acute cardiovascular event (22,23). Pooled data from clinical trials have shown significant reductions in all-cause and cardiovascular mortality in patients with CAD enrolled in an exercise-based cardiac rehabilitation program (2–4). Even compared with other established risk factors for cardiovascular disease, exercise capacity is a powerful predictor of mortality in patients with CAD (9). The mechanisms by which physical training exerts its beneficial effects on mortality and cardiovascular disease are poorly understood but probably include favorable effects on atherosclerosis progression, risk factor profile, myocardial ischemia, and autonomic balance (15,24,25).

HRR in the first minute after exercise is correlated with long-term prognosis in patients with cardiovascular disease (10,11,16), even after taking into account the angiographic severity of CAD, left ventricular function, and exercise capacity (14).

There are a number of plausible mechanisms to explain this powerful vagal influence on long-term prognosis. The most obvious beneficial effect of cardiac vagal activity is to decrease cardiac work by reducing resting HR and contractility. In fact, in Group A there was a small but significant reduction of resting HR after 3 months of ET (Table 2). Although it is widely held that vagal innervations of human ventricular myocardium are sparse, recent work has demonstrated a significant negative inotropic effect by stimulation of the human vagus nerve in vivo (26). The combination of this reduction in contractility with a reduction in cardiac work and myocardial oxygen demand may be advantageous in the context of CAD and left ventricular dysfunction. In addition, stimulation of the vagus nerve results not only in direct effects on the sinus node and myocardium but also inhibits sympathetic nerve activity via peripheral pre- (27) and postsynaptic interactions (28). The adverse effects of prolonged sympathetic nervous overactivity on the heart are well recognized. Experimental data suggest that myocardial exposure to high levels of noradrenalin results in ß receptor-mediated cytotoxic effects and apoptosis as well as {alpha} receptor-mediated hypertrophic effects (29,30). The prevention of such effects by "indirect" vagal activity is of clear potential importance.

These observations may constitute the pathophysiological basis for understanding the beneficial prognostic effects of improving sympathovagal balance after AMI. Therefore, it appears as the changes in vagal tone can be used as an outcome tool for improving risk stratification for cardiovascular events both in patients with and in persons without cardiovascular disease. However, although extensive evidence demonstrates the prognostic value of HRR in a variety of populations with cardiovascular disease, it is unknown whether HRR improves after ET in older patients, a population often denied the benefits of an exercise-based cardiac rehabilitation program (31).

This study shows that an exercise-based cardiac rehabilitation program in elderly patients after AMI is associated with a significant improvement in HRR. This improvement was not observed in comparable nonexercising older AMI patients chosen as the control group. These findings are consistent with those from other studies that have demonstrated a favorable effect of an exercise-based cardiac rehabilitation program on autonomic tone in a younger population with CAD (15,25,32). The direct relationship between HRR and age found in Group A patients suggests that the oldest patients derive the most benefit from ET (Figure 3).

In addition, this study confirms that, in older AMI patients, ET improves cardiovascular functional capacity (5,6), as expressed by the increase in VO2peak (8). Functional capacity is a well-established predictor of cardiovascular risk in adults and older patients with and without known coronary disease (9). VE/VCO2slope is a CPX-derived parameter that can confer additional prognostic significance to the value of VO2peak (33,34). The decrease in VE/VCO2slope observed in older training patients may reflect exercise-induced improvement in ventilation drive.

The significant correlations found between the improvement in HRR and in VO2peak (Figure 2) and in VE/VCO2slope (Figure 3) suggest that the same pathophysiological mechanisms activated by ET underlie the favorable changes in cardiac functional capacity and in sympathovagal balance observed in trained older AMI patients. Although we have no specific data, we can hypothesize that an improved exercise-induced endothelial function may be the common pathophysiological mechanism of these changes. In fact, increase in endothelium-dependent arteriolar peripheral dilation is associated with increase in cardiac functional capacity in patients with CAD (35), and vascular endothelium, through nitric oxide and other chemical mediators, modulates the effects of sympathetic adrenergic activation at the vascular and myocardial level (36). In addition, cross-sectional studies have demonstrated a positive linear relationship between maximal oxygen consumption and parasympathetic activity (37).

Because we did not measure the endothelium-dependent vasodilatation, we cannot confirm this hypothesis in our patients; other mechanisms may be at the base of the direct relationship between changes in VO2peak and HRR. However, both changes may be synergic in improving long-term cardiac prognosis in older AMI patients.

Finally, this study, because of its limited statistical power, was not aimed at evaluating the long-term beneficial prognostic effects of the observed improvement in HRR and cardiopulmonary parameters. It suggests, however, that ET might represent an effective therapeutic option for reducing cardiovascular risk associated with abnormal HRR in older patients recovering from AMI.


   Acknowledgments
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We thank Mr. Mario Rosario Eliseo, Mr. Mario Aurino, and Mrs. Maria Calabrese for their technical support in the collection of CPX data and in the conduction of the study.


   Footnotes
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Decision Editor: Luigi Ferrucci, MD, PhD

Received January 11, 2006

Accepted January 12, 2006


   References
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