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The Effect of Residential Exercise Training on Baroreflex Control of Heart Rate and Sympathetic Nerve Activity in Patients With Acute Myocardial Infarction*

Posted on: Wednesday, 27 April 2005, 03:00 CDT

Study objectives: Exercise training has been shown to favorably affect the prognosis after acute myocardial infarction (AMI), but the mechanisms of such favorable effects remain speculative. The aim of this study was to determine whether exercise training improves baroreflex control of heart rate and muscle sympathetic nerve activity (MSNA) in patients with AMI.

Design: Prospective randomized clinical study.

Participants: Thirty patients with an uncomplicated AMI were randomized into trained or untrained groups. Arterial BP, heart rate, and MSNA were measured at rest, and during baroreceptor stimulation (phenylephrine infusion) and baroreceptor deactivation (nitroprusside infusion). These measurements were performed at baseline and after 4 weeks of exercise training.

Measurements and results: Peak oxygen uptake increased significantly (12.3 10.7% [mean SD]) with exercise training. Resting MSNA reduced from 34 12 to 27 8 bursts/min in the trained group but not in the untrained group. Arterial baroreflex sensitivity (BRS) [from 8.9 3.0 to 10.3 3.0 ms/mm Hg, p < 0.05] and MSNA response to baroreceptor stimulation (change of integrated MSNA from - 47 23 to - 70 21%, p < 0.01) improved significantly in the trained group, but not in the untrained group. Despite baroreceptor deactivation improving MSNA response in both groups, there was no significant difference between the two groups.

Conclusions: Exercise training increased arterial BRS and decreased sympathetic nerve traffic after AMI, which indicate that the sympathoinhibitory effect of exercise training may, at least in part, contribute to the beneficial effect of exercise training in patients with AMI.

(CHEST 2005; 127:1108-1115)

Key words: baroreceptors; exercise; muscle sympathetic nerve activity; myocardial infarction

Abbreviations: AMI = acute myocardial infarction; BRS = baroreflex sensitivity; LV = left ventricular; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; MSNA = muscle sympathetic nerve activity

Exercise training has been shown to improve mortality and morbidity rates in patients after acute myocardial infarction (AMI).1-3 Although the mechanisms related to the beneficial effect of exercise training remain speculative, there is evidence that benefits of exercise training are achieved through an altered cardiovascular autonomic tone.4-9 An experimental study by Billman et al4 suggested a linkage of exercise training to the change in baroreflex sensitivity (BRS) and improved outcome. A study in humans by La Rovere et al8 found that baroreflexes are depressed after AMI and improved by exercise training. These findings suggested that exercise training shifts the autonomic balance toward increased vagal activity and decreased sympathetic activity, which contributes to the improved prognosis after AMI. Thus, the effects of exercise training on autonomic function in patients with AMI have been studied using heart rate variability and BRS, considered as a measure of the tonic vagal control of the heart. The purpose of this study was to examine the effects of exercise training on baroreflex control of heart rate and sympathetic nerve activity using direct microneurographic recording of muscle sympathetic nerve activity (MSNA) in patients with AMI.

MATERIALS AND METHODS

Patient Population

We evaluated 30 consecutive patients (mean age, 56 10 years [ SD]) who not only underwent exercise testing and coronary angiography, but also had a patent infarct-related coronary artery and negative exercise testing results. All the patients included in this study had had their first AMI 2 weeks before the study, and none of the patients had postinfarction angina, critical arrhythmia, or uncontrolled congestive heart failure for at least 1 week prior to the study. Before entry into the study, each patient underwent a complete physical examination, and patients were excluded from the study if they had mitral regurgitation, physical or radiographic signs of obstructive lung disease, or intermittent claudication that limited their exercise capacity. All medications were discontinued for at least 48 h before the study. The risks of the study were fully explained, and informed consent was obtained from each patient before the study. This study complies with the Declaration of Helsinki, and the protocol was approved by the Ethical Committee of Kansai Medical University.

Study Protocol

After a symptom-limited exercise test and baroreflex function evaluation, patients were randomly assigned into two groups: an exercise training group (n = 15) and an untrained group (n = 15). Clinical characteristics of the two groups are outlined in Table 1. There were no differences in the clinical variables between the two groups. In the training group, each participant was given an individual exercise prescription consisting of a home walking training. The exercise intensity was 60% of their determined heart rate at peak oxygen uptake. Patients exercised four times per week for 4 weeks, and the duration of each exercise was 40 min. Pulse- controlled exercise training was performed at home and recorded in a diary. All of the patients in the trained group completed the prescribed physical training for 4 weeks. No patient dropped out of the training program. Patients randomized to the untrained group were advised to follow the home activity program and avoid any other moderate-intensity exertion during the study period. Cardiopulmonary exercise testing and baroreflex function evaluation were repeated at 4 weeks in both groups.

Table 1-Clinical Characteristics*

Arterial BRS

Studies were carried out in the morning after 30 min of supine rest. Arterial BRS was assessed by the phenylephrine and nitroprusside bolus methods.10,11 Arterial BP (Jentow 7700, OM- J77EX-RO1; Colin; Tokyo, Japan) and heart rate were continuously recorded. Phenylephrine (80 to 120 g) or nitroprusside (80 to 120 g) was injected IV to pertubate 15 to 30 mm Hg systolic arterial pressure by at least three bolus injections separated by 10-min intervals. The R-R intervals were plotted against the preceding arterial systolic pressure, and a linear regression was obtained from the points included between the beginning and the end of first significant change in systolic arterial pressure. Only regression lines with a correlation coefficient ≥ 0.90 and p < 0.05 were used. The mean of at least three measurements was calculated.

Sympathetic Nerve Traffic

Multiunit recordings of efferent postganglionic sympathetic nerve activity to the muscle bed were obtained with a tungsten microelectrode with a tip diameter of a few micrometers inserted into a muscle fascicle of the peroneal nerve posterior to the fibular head. A low-impedance reference electrode was inserted subcutaneously a few centimeters away. Details of the nerve recording technique and criteria for MSNA were reported previously.12-14 The original nerve signal was amplified with a gain of 50,000 and fed through a band-pass filter with a band width of 500 to 3,000 Hz, and then through an integrating network with a time constant of 0.1 s to obtain a mean voltage display of the nerve activity. Integrated nerve activity was monitored by a loudspeaker, displayed on a storage oscilloscope (VC-6725; Hitachi; Tokyo, Japan), and stored in a personal computer for later analysis (AcqKnowledge III for the MPlOOWS; Biopak Systems; Santa Barbara, CA). Sympathetic bursts were identified by inspection of the mean voltage neurogram. Resting MSNA was quantified as bursts per minute. It was quantified as percentage changes of integrated activity (bursts per minute times mean burst amplitude expressed in arbitrary units) during baroreceptor function testing.

Baroreflex Function

Baroreceptor modulation of MSNA and heart rate was assessed by the technique based on infusion of phenylephrine and nitroprusside. Phenylephrine (80 to 120 g) was infused as a bolus through the cannula placed in the antecubital vein. Nitroprusside (80 to 120 g) was also infused in the antecubital vein. Arterial BP, heart rate, and MSNA were collected for 5 min before infusion and for 5 min of each infusion. Baroreceptor modulation of MSNA was estimated by calculating the absolute and percentage change in MSNA induced by baroreceptor stimulation and deactivation. Data were analyzed at rest and 1 min of the baroreceptor stimulus or suppressant. This was taken as the measure of baroreflex function during baroreceptor stimulation and deactivation.

Exercise Testing and Expired Gas Analysis

Symptom-limited exercise test using a ramp protocol (1W/6 s) with a cycle ergometer (CPE 2000; MedGraphics; Minneapolis, MN) was performed with monitoring 12-lead ECG (ML-5000 Stress Test System; Fukuda Denshi; Tokyo Japan), expired gas analyzer (Aerometer AE- 280s; Minato Medical Science; Osaka, Japan), and BP at baseline and 4 weeks. From these data, oxygen uptake was displayed on a monitor of a personal computer (PC-9821; NEC; Tokyo, Japan). Peak oxygen uptake was calculated by averaging the value recorded during the final 30 s of a ramp exercise.

Echocardiographic Measurements

An echocardiogram (Sonos 2500; Philips Medical Syste\ms; Andover, MA) was obtained in each patient before and after the program. LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) were derived using the Simpson rule by manual endocardial tracing of the apical four-chamber and apical two-chamber views; LV ejection fraction (LVEF) was calculated as follows: 100 ([LVEDV - LVESV]/ LVEDV).

Table 2-Change in Hemodynamic and Echocardiographic Indices*

Neurohumoral Variables

Plasma norepinephrine concentrations were measured by using high- performance liquid chromatography, and plasma renin activity and plasma angiotensin II concentrations were measured by radioimmunoassay.15,16 The measurements were obtained from a blood sample drawn from a cannula placed in the antecubital vein of the arm contralateral to that used for BP measurements.

Statistical Analysis

Data were analyzed by a single investigator. Values from individual subjects were averaged for the group as a whole and expressed as mean SD. Comparisons between the data obtained at baseline and at 4 weeks were made by two-way analysis of variance. The Student t test was used to identify the difference between the two groups; p < 0.05 was taken as statistical significance.

RESULTS

In all patients, bicycle exercise was limited by exercising muscle fatigue. Angina or ischemic ST-segment changes during exercise did not develop in any patient.

There were no significant changes in arterial BP, heart rate, LVEDV, LVESV, and LVEF at baseline and 4 weeks in both groups (Table 2). Although there was no significant change in peak oxygen uptake in the untrained group, there was a significant increase in peak oxygen uptake in the trained group.

Effects of Training on MSNA and Neurohumoral Indexes

There were no significant differences in MSNA and plasma norepinephrine at baseline between the two groups, but exercise training caused a significant reduction in MSNA and plasma norepinephrine in the trained group (Table 3). Plasma renin activity and angiotensin II decreased after training, but there were no significant changes in plasma renin activity and angiotensin II in the untrained group.

Table 3-Change in MSNA and Neurohumoral Indices*

Effect of Training on Arterial BRS Response to Bradycardia and Tachycardia

The effects of phenylephrine and nitroprusside infusion on arterial BP, heart rate, and MSNA are shown as examples in Figures 1 and 2. No serious adverse event was observed during phenylephrine and nitroprusside infusion. Infusion of phenylephrine caused a progressive increase in arterial BP and a progressive decrease in heart rate, whereas infusion of nitroprusside had opposite effects. The same doses of phenylephrine and nitroprusside were administrated at 4 weeks, which resulted in a similar arterial BP change in both groups. At baseline, there was no significant difference in arterial BRS to bradycardia and tachycardia between the two groups. Although arterial BRS to bradycardia and tachycardia did not change at 4 weeks in the untrained group, BRS increased significantly to bradycardia (from 8.9 3.0 to 10.3 3.0 ms/mm Hg, p < 0.05) and to tachycardia (from 7.7 3.1 to 9.1 3.8 ms/mm Hg, p < 0.01) in the trained group (Fig 3).

FIGURE 1. Comparative experimental recordings during baroreceptor stimulation with IV phenylephrine at baseline (upper panel) and 4 weeks (lower panes) in the trained group.

Effects of Phenylephrine and Nitroprusside Infusion on MSNA at Baseline and 4 Weeks

Figures 4 and 5 show the MSNA response to phenylephrine and nitroprusside baroreflex function tests at baseline and 4 weeks. Infusion of phenylephrine caused a progressive reduction in MSNA, whereas infusion of nitroprusside caused a progressive increase in MSNA. The percentage of changes of MSNA response to phenylephrine did not change at 4 weeks in the untrained group, but was significantly greater in the trained group (from - 47 23 to - 70 21%, p < 0.01). In contrast, the percentage changes of MSNA response to nitroprusside increased significantly at 4 weeks in both groups (trained group, 86 51 to 210 159%, p < 0.01; untrained group, 108 95 to 152 129%, p < 0.05).

FIGURE 2. Comparative experimental recordings during baroreceptor deactivation with IV nitroprusside at baseline (upper panel) and 4 weeks (lower panel) in the trained group.

DISCUSSION

This study demonstrated that exercise training improved arterial BRS in patients with AMI. This is consistent findings in previous studies4-9 that exercise training is associated with a shift of autonomic balance toward an increase in vagal activity in patients with AMI. We extended these observations by demonstrating that plasma norepinephrine levels and MSNA with microneurography were favorably affected by exercise training after AMI. These findings indicate that exercise training increased BRS and decreased sympathetic activity and, hence, contributed to the beneficial effect of exercise training after AMI.

Our observations provided information on the effect of exercise training on sympathetic nerve activity after AMI. Although there were no significant changes in resting arterial BP and heart rate after exercise training, exercise training decreased directly measured resting MSNA and plasma norepinephrine levels, which suggests that the sympathoinhibitory effect of exercise training was not due to hemodynamic improvement. The present study confirms that exercise training decreases central sympathetic outflow and may result in beneficial outcome in patients with AMI.

The mechanism responsible for the decrease in sympathetic nerve activity after exercise training is not entirely clear. It is likely that changes in central sympathetic outflow after exercise training are responsible for the change in BRS. Therefore, restoration of autonomic function should also enhance BRS. Although the present study revealed an increase in MSNA response to phenylephrine after exercise training, many other factors responsible for alterations in sympathetic outflow may operate to increase BRS after exercise training. Previous experimental studies17-19 have indicated that angiotensin II acts centrally to attenuate baroreflex control of the sympathetic activity. Therefore, the reduction in circulating angiotensin II levels most likely is responsible for the decrease in sympathetic nerve activity after exercise training. However, exercise training did not affect the baroreflex response to nitroprusside infusion after AMI. Considering the fact that central muscarinic receptor activation has an important role in mediating the baroreflex in rats,20 one explanation may be that the change in muscarinic receptor sensitivity following exercise training is primarily responsible for increased high-pressure baroreceptor stimulation.

FIGURE 3. Arterial BRS with phenylephrine and nitroprusside methods in trained group (closed circle) and untrained group (open circle) at baseline and 4 weeks. Data are shown as individual and mean values.

FIGURE 4. Percentage changes of integrated MSNA during arterial baroreflex function testing with phenylephrine method in trained and untrained groups. Data are expressed as mean value SD.

FIGURE 5. Percentage changes of integrated MSNA during arterial baroreflex function testing with nitroprusside method in trained and untrained groups. Data are expressed as mean value SD.

Reduced arterial BRS and increased sympathetic nerve activity have prognostic value for cardiac mortality and cardiac events after AMI.21 Our study as well as previous studies4-9 confirmed that exercise training improved arterial BRS and this in turn had a sympathoinhibitory effect. Furthermore, our study showed that directly measured sympathetic nerve activity is favorably affected by exercise training. Indeed, La Rovere et al8 demonstrated that exercise-induced increase in BRS improved prognosis after AMI; our data add importantly to the existing knowledge of exercise training on autonomie balance and to the clinical management after AMI.

In conclusion, exercise training decreases directly measured central sympathetic nerve outflow in patients with AMI. The sympathoinhibitory effect of exercise training may, at least in part, contribute to the known beneficial effects of exercise training on survival in patients with umcomplicated AMI.

* From the Second Department of Internal Medicine (Drs. Mimura, Yuasa, Yutama, Kawamura, Iwasaki, and Iwasaka), Kansai Medical University, Osaka; and Department of Clinical Laboratory Medicine (Dr. Sugiura), Kochi Medical School, Kochi, Japan.

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Jun Mimura, MD; Fumio Yuasa, MD; Reisuke Yuyama, MD; Akihiro Kawamura, MD; Masayoshi Iwasaki, MD; Tetsuro Sugiura, MD, FCCP; and Toshiji Iwasaka, MD

Manuscript received May 5, 2004; revision accepted November 1, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Jun Mimura, MD, CCU, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka, Japan; e- mail: mimuraj@takii.kmu.ac.jp

Copyright American College of Chest Physicians Apr 2005

Source: Chest

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