Effects of a Residential Exercise Training on Baroreflex Sensitivity and Heart Rate Variability in Patients With Coronary Artery Disease

Methods

The study population consisted of patients with coronary artery disease referred after myocardial revascularization surgery to our cardiac rehabilitation center between January and December 1997. Patients had undergone CABG on the basis of symptomatic and/or abnormal findings on diagnostic procedures and arteriographically documented coronary artery disease. All patients came from the same cardiac surgery division, so that they had undergone the same surgical procedures and preoperative and postoperative clinical management.

Criteria for eligibility were male sex, in sinus rhythm, and with left ventricular ejection fraction ≥50%, as determined by preoperative cardiac catheterization and by echocardiographic examination before hospital discharge and at the rehabilitation center. Exclusion criteria were age >70 years, coexisting valvular and/or peripheral vascular diseases, concomitant endarterectomy, contraindications to exercise stress testing, frequent atrial or ventricular premature beats, conduction defects, insulin-dependent diabetes, arterial blood pressure >160/90 mm Hg, pericarditis, peripheral neuropathy, orthopedic or neurological limitations, and perioperative MI or any serious postoperative complication.

The patients were admitted to the rehabilitation center during the first postoperative week, and after the initial screening, which included a 24-hour Holter recording, they were randomly assigned to a supervised, residential exercise training program (TR) or to an untrained group (UTR). Initially, 97 patients met the study criteria, but 7 dropped out from the study because of personal reasons (n=5) or intercurrent illness (n=2). Four patients were also excluded because of discomfort in breathing within the face mask that prevented measurements of gas exchange during the exercise stress test (n=2) or for unexpected frequent premature beats at the time of recordings for autonomic evaluation (n=2).

Eighty-six patients (45 TR and 41 UTR) completed the study. In post-MI patients, the time elapsed after MI ranged from 9 years to 2 months. However, in 66% of patients, MI occurred in the last year before the study. Clinical characteristics of the patients are summarized in Table 1⇓. Medications were not altered throughout the study. All patients gave written informed consent to participate in this study, which was approved by the Scientific and Ethical Committee of the rehabilitation center.

Results

There were no significant differences in baseline characteristics between TR and UTR patients with respect to all variables, including peak V̇o₂, arterial pressure, R-R interval, RRSD, and BRS (Tables 1⇑ and 2⇓).

Exercise training resulted in a significant increase in peak V̇o₂ (Table 2⇑). A small increase in peak V̇o₂ was also observed in the UTR group and can be explained in part by normal recovery from surgery and by the fact that our controls performed some amount of daily physical activity. However, the magnitude of V̇o₂ increase was significantly and markedly greater in the TR group (181.3±27.2 versus 73.9±18.0 mL/min, P=0.001). In TR patients, resting R-R interval was significantly increased by 7%, BRS by 73%, and RRSD by 26%. No significant changes in these variables were observed in UTR patients (Table 2⇑).

No correlations were found between peak V̇o₂ and BRS either at baseline for the study population as a whole (r=0.18, P=0.10) or after training in the TR group (r=0.09, P=0.55). Similarly, no relationships were found between peak V̇o₂ and RRSD at baseline in the whole population or after training in the TR group (r=0.15, P=0.16 and r=0.11, P=0.49, respectively).

No significant differences were observed in baseline BRS and RRSD between MI and non-MI patients in the overall population. BRS was 3.4±0.4 versus 3.0±0.3 ms/mm Hg and RRSD was 18.0±1.3 versus 17.9±1.3 ms in MI and non-MI patients, respectively. Mean age did not differ significantly between MI and non-MI patients (59.0±6.6 versus 58.9±8.5 years), nor did the number of coronary vessels with a critical stenosis (2.4±0.7 versus 2.6±0.6). BRS increased significantly in both MI and non-MI trained patients, as did RRSD (Figure⇓), and the magnitude of the increase in both variables did not differ significantly between the 2 groups (2.8±1.0 versus 1.7±0.5 ms/mm Hg, P=0.53 and 5.4±2.3 versus 4.3±1.8 ms, P=0.72, for BRS and RRSD, respectively).

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Figure 1.

Effects of exercise training on BRS (top) and RRSD (SDRR; bottom) in post-MI patients (n=22, solid lines) and in patients without previous MI (n=23, dashed lines). *P<0.05, †P<0.01, and ‡P<0.001 vs baseline. Rehab indicates rehabilitation.

No significant cardiovascular events occurred during the training sessions.

Discussion

The present study indicates that a structured exercise training program is able to enhance BRS and increase HRV in patients with coronary artery disease. The relevance of this finding should be placed in the context of the growing evidence indicating the adverse effect of a depressed vagal cardiac modulation and the protective role exerted by high vagal activity in the setting of ischemic heart disease.

Animal studies have clearly indicated that the presence of depressed vagal reflexes and enhanced sympathetic activation is associated with a greater risk for life-threatening arrhythmias during myocardial ischemia.^{6 8 9 10} Clinical studies confirmed the adverse effect of impaired vagal modulation by showing that both BRS and HRV are reduced early after MI^{11 12 13} and that this has an independent prognostic value.¹⁶ Moreover, a depressed BRS may play a role in the occurrence of malignant arrhythmias, even long after MI.^{29 30}

Conversely, interventions capable of increasing vagal activity exert a protective effect against ischemia-related arrhythmias.^{31 32} Among these interventions, exercise training has been shown to increase both BRS and HRV and to prevent ventricular fibrillation, concomitantly improving cardiac electrical stability, in conscious dogs with and without healed MI.^{19 20} Thus, exercise training might be an effective nonpharmacological tool to increase the vagal contribution to autonomic control of the heart in patients with coronary artery disease, as has been observed in other pathological states.^{33 34} Indeed, recent studies have suggested the effectiveness of exercise training in improving HRV in post-MI patients,^{21 22} and this was confirmed by the present investigation. However, the potential for exercise training to improve BRS in patients with coronary artery disease had not been clearly established. One small study²² reported an improvement in BRS after exercise training in post-MI patients, but the lack of an untrained control group prevented a definitive conclusion from being reached. Thus, this is the first randomized, controlled study obtained in a relatively large population showing that exercise training results in marked enhancement of both BRS and HRV in patients with coronary artery disease. This is important information, because BRS and HRV reflect different, although possibly related,³⁵ aspects of the autonomic modulation of the heart and are not clinically redundant.^{16 36} Although both BRS and HRV effectively discriminate individuals at high and low risk for cardiac mortality,¹⁶ experimental and clinical studies have indicated that BRS is more useful in the prediction of future events. In an animal model, analysis of BRS before MI was able to predict outcome during ischemic episodes that occurred after MI, whereas HRV was not.^{6 10} Similarly, BRS but not HRV was reduced in patients who developed malignant arrhythmias long after MI.^{29 30} Thus, the increase in BRS induced by exercise training, reflecting more powerful vagally mediated baroreflex responses, might result in a condition less favorable for the development of malignant arrhythmias in the event of ischemic episodes by conferring protection against increases in sympathetic activity.^{4 19 20}

The results of the present study also indicate that the improvement of BRS associated with exercise training is not limited to patients with prior MI but extends to coronary patients without MI, in whom measures that could reduce the risk of subsequent lethal events might be of paramount importance.^{1 37} The potential clinical relevance of increasing BRS in coronary patients without MI is also outlined by the observation that a depressed BRS present before MI affected the susceptibility to ventricular fibrillation during myocardial ischemia that occurred after MI in an animal model of sudden death.⁶

No significant differences were observed in baseline BRS between patients with and without a previous MI. This finding could be explained by the severity of coronary artery disease, which was similar in MI and non-MI patients, as evaluated by the number of vessels with critical stenosis, because the extent of coronary narrowing negatively affects BRS.^{11 12 38}

Our study confirms the improvement in cardiovascular performance induced by exercise, and the 14% increase in peak V̇o₂ obtained after this short-term yet intensive, concentrated endurance exercise training is in line with expectations. However, no relationship was observed between changes in functional capacity and indexes of autonomic function after training, a finding that is in line with the hypothesis that the mechanisms responsible for the improvements may differ for each variable.³⁹ The mechanisms through which exercise training affects these markers of cardiac vagal modulation are still unclear and cannot be defined by the present investigation. They may involve adaptations in peripheral and central neural pathways, although modifications in the responsiveness of the heart might also contribute.

Some possible limitations of the present investigation deserve comment. The first is the generalization of the reported effects to other coronary patient populations, namely, those who have not undergone CABG. However, it is reasonable to speculate that the benefits of exercise training should also extend to patients who have not undergone CABG but are eligible for a formal exercise training program. Moreover, there are no data indicative that CABG per se positively affects BRS and HRV in patients without MI or in the recovery phase after MI. Consistent with this assumption is the lack of spontaneous increase in BRS and HRV in the control group. In any case, the patients of the present study are representative of a large population of ischemic patients for whom cardiac rehabilitation is highly recommended⁴⁰ and who could benefit from improved cardiac autonomic function.

Second, we do not know whether improving markers of autonomic activity by exercise actually affects the outcome of patients with coronary artery disease. The present study was not designed for this purpose. Instead, it was aimed at addressing the question of whether exercise training improves autonomic markers that have been shown to carry adverse effects and negative prognosis in ischemic heart disease. The answer to this question is affirmative. In fact, the increase in BRS is in a direction that has been associated with a better outcome in coronary patients.^{11 16 29 30} However, the potential for exercise-induced enhancement of BRS and HRV to improve the risk profile in coronary artery patients remains to be demonstrated. This would require a large, multicenter trial. Nevertheless, among the many beneficial effects of exercise training in secondary prevention of ischemic heart disease, improvement in markers of cardiac autonomic function should also be considered.