Antihypertensive Effects of Aerobic Exercise in Middle-Aged Normotensive Men with Exaggerated Blood Pressure Response to Exercise

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1 507 Original Article Antihypertensive Effects of Aerobic Exercise in Middle-Aged Normotensive Men with Exaggerated Blood Pressure Response to Exercise Nobuyuki MIYAI, Mikio ARITA, Kazuhisa MIYASHITA, Ikuharu MORIOKA, Tatsuo SHIRAISHI, Ichiro NISHIO, and Shintaro TAKEDA An exaggerated blood pressure (BP) response to physical exertion among normotensive subjects is considered a significant risk factor for future hypertension. The purpose of this study was to examine whether regular aerobic exercise can lead to a reduction in hypertensive risks in patients with such a high-risk profile. Thirty-five sedentary men (46 2 years old) with normal BP at rest but an exaggerated BP response during exercise were randomly assigned to an exercise or control group for 12 weeks followed by an 8-week washout period. The subjects were then crossed over to the alternate group for an additional 12-week period. The exercise training consisted of 3 days per week of stationary bicycling for 45 min at 50 60% of the heart rate reserve. The treatment effects were evaluated using the method of Hills and Armitage. The training-induced reduction in resting BP was not statistically significant. In ambulatory BP monitoring, the averages of 24-h and daytime systolic and diastolic BP were significantly lower, but nighttime BP remained unchanged after training. During ergometric exercise, significant decreases were observed in systolic and diastolic BP and plasma norepinephrine concentration measured at the submaximal workloads. M-mode echocardiographic and Doppler-derived left ventricular variables were not significantly affected by training. These findings suggest that regular aerobic exercise attenuates BP elevations during physical exertion and daytime activities mainly as a result of the reduction in enhanced sympathetic nervous tonus, which may in turn play a role in lowering the risk for hypertension in normotensive subjects with an exaggerated BP response to exercise. (Hypertens Res 2002; 25: ) Key Words: blood pressure, exercise, normotension, men, sympathetic nervous system Introduction Hypertension is one of the leading health problems in both industrialized and developing societies (1). Knowledge of the adverse effects that hypertension has on cardiovascular organ systems and the fact that these effects worsen with time make early detection and treatment of hypertension a priority (2). Exercise testing is generally accepted as an important diagnostic and prognostic procedure in the assessment of patients with hypertension. Emerging evidence has suggested that an exaggerated blood pressure (BP) response during exercise among normotensive subjects is associated with increased risk for developing hypertension (3, 4). Addi- From the Department of Hygiene, Nursing College, and Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No ), by a grant from Chiyoda Mutual Life Foundation, Tokyo, Japan, and by a grant from the Descent and Ishimoto Memorial Foundation, Osaka, Japan. Address for Reprints: Nobuyuki Miyai, Ph.D., Department of Hygiene, Wakayama Medical University, Kimiidera, Wakayama , Japan. miyain@wakayama-med.ac.jp Received January 28, 2002; Accepted in revised form March 13, 2002.

2 508 Hypertens Res Vol. 25, No. 4 (2002) tionally, it has been indicated that individuals exhibiting such abnormal pressor reactivity show some other hemodynamic, metabolic, and hormonal features that may be considered as markers of a predisposition to hypertension or promoters of the development of hypertension (5 7). These findings lead to the idea that such high-risk subjects should frequently be counseled and that nonpharmacological strategies should be investigated for their ability to prevent hypertension. Several long-term epidemiological studies have provided evidence that levels of physical activity and fitness are inversely related to the incidence and severity of hypertension (8, 9). A number of intervention studies have reported BP reductions in hypertensive patients undergoing a regular program of aerobic exercise (10, 11). Consequently, it has been concluded that physical training can be beneficial as a nonpharmacological treatment of hypertension (12). However, in normotensive subjects, the possible antihypertensive action still remains a matter of debate (13). In particular, information regarding whether regular aerobic exercise can reduce the hypertensive risks in those who have an exaggerated BP response to exercise is lacking. We therefore undertook this study to assess the effects of endurance training on 24-h BP monitoring, hemodynamic and hormonal reactions to physical exertion, and functional and morphological changes of the heart by echocardiography in sedentary normotensive adults with an exaggerated BP response to exercise. Study Population Methods A total of 921 men underwent a bicycle ergometric test conducted at our laboratory from 1998 to Subjects were excluded if they 1) had a history of cardiovascular or renal diseases or diabetes mellitus; 2) had electrocardiographic evidence of coronary heart disease or cardiac arrhythmia; 3) were hypertensive, as defined by current use of any antihypertensive medications or an average resting BP of 140/90 mmhg on three separate visits; 4) were 30 years or 59 years of age; or 5) were obese, as defined by a body mass index of 25. Also excluded were any individuals who regularly practiced sports or had undergone instructional programs concerning lifestyle modification. After this screening, 431 healthy, sedentary normotensive men were selected. Based on their exercise testing data, BP response to exercise was evaluated with respect to heart rate increment using our previously described method (14, 15). Sixty-two subjects showed an exaggerated BP response, as indicated by either systolic or diastolic BP above the 95th percentile values. These subjects were invited back for a screening examination consisting of standard BP measurement and symptomlimited maximum exercise test. After strict assessment, 54 subjects were still eligible for this study and were asked to participate in the 12-week aerobic-exercise trial. Out of the 54, 39 subjects agreed to participate and signed a written informed consent form after receiving a detailed explanation of the study aims and procedures. The protocol of this study was approved by the Ethics Committee of the Wakayama Medical University. Study Design After completion of the baseline assessment, the subjects were randomly divided into 2 groups of similar age and weight distribution (group 1, n 20; group 2, n 19) and assigned to a randomized two-way crossover trial. At the first phase, group 1 started the 12-week training program, and group 2 continued their normal daily sedentary life and served as controls. At the second phase after the 8-week washout period, group 2 was assigned to the training regimen, and group 1 served as controls. The program consisted of 48 sessions of 1 h each at a frequency of 3 sessions per week. Each session began with a 5-min warm-up period, was followed by 45 min of stationary bicycling, and ended with a 5- to 10-min cooling-down period. The training was supervised by physicians and a fitness instructor, and the exercise intensity was adjusted to maintain a constant heart rate between 50% and 60% of the heart rate reserve (12), which was calculated by the following formula: (maximum heart rate resting heart rate) 0.5 or 0.6 resting heart rate (16). Maximum heart rate was derived from the screening examination, and resting heart rate was measured after 15 min of supine rest. Throughout the two experimental periods, the subjects were repeatedly instructed to keep dietary, drinking, and smoking habits and physical activity (except for the prescribed training periods) as stable as possible. The subjects received clinical examinations consisting of anthropometric, physiological and blood biochemical measurements at baseline and at the end of the representative control and training periods. The measurements were performed in a controlled, quiet room between 9 AM and 12 AM after an overnight fast and abstinence from smoking or caffeine for at least 6 h. Brachial BP was measured 3 times after 5 min of sitting rest at baseline and 15 min of supine rest at the end of the two periods by well-trained physicians using a mercury sphygmomanometer. The average of the second and third measurements in each position was used as the representative value. Ambulatory Blood Pressure Monitoring Twenty-four-hour ambulatory BP monitoring was carried out with a noninvasive automated device (TM-2425; A&D, Tokyo, Japan) using an auscultatory technique, with the cuff fitted on the nondominant arm. The subjects were instructed to keep the same day and night rhythm and to stop muscular activity and keep their arms entirely still during BP measurements. The BP monitor was programmed to measure BP at

3 Miyai et al: Aerobic Exercise and Exaggerated BP Response 509 intervals of 15 min between 6 AM and 10 PM and intervals of 30 min between 10 PM and 6 AM. Each BP reading was edited by a computer and rejected if the systolic BP was less than 80 mmhg or more than 250 mmhg and the diastolic BP was less than 40 mmhg or more than 140 mmhg. Recordings for each subject were accepted if more than 80% of the raw data were valid. Average values were calculated for 2 periods making up a whole day: a 6-h period between 12 AM and 6 AM (nighttime) and a 12-h period between 8 AM and 8 PM (daytime). Ergometer Exercise Test After the subjects had rested in the supine position for 15 min, a graded submaximal exercise test was performed on a bicycle ergometer (ML-1400; Fukuda Denshi, Tokyo, Japan). With subjects in the sitting position, the workload was progressively increased to 100 W using the step-wise method at a rate of 25 W every 2 min. Throughout the test, electrocardiogram lead V3 and heart rates were monitored continuously, and systolic and diastolic BP were recorded every minute noninvasively with an automated BP monitor (STBP-780B; Nippon Colin, Komaki, Japan). After the supine rest period and after the end of the last stage of the incremental exercise, a blood sample was drawn from the antecubital vein for a catecholamine assay. Blood was collected in ethylenediamine tetraccetic acid (EDTA)-treated tubes. Samples were immediately cold-centrifuged, and the plasma was frozen and stored at 80ºC until the time of the assay. Plasma concentrations of epinephrine and norepinephrine were determined by high-performance liquid chromatography. Echocardiographic Examination M-mode and Pulsed-Doppler two-dimensional echocardiograms were obtained with the subject in the left lateral decubitus position using the standard techniques (SSD-1700; Aloka, Tokyo, Japan). Measurements of the left ventricular (LV) interventricular septal thickness (IVSTd), posterior wall thickness (PWTd), end-diastolic LV internal diameter (LVDd), and end-systolic LV internal diameter (LVDs) were made according to the recommendations of the American Society of Echocardiography and the Penn Convention (17). The LV mass (LVM) was calculated according to the following formula: 1.04 [(LVDd PWTd IVSTd) 3 LVDd 3 ] 13.6 and indexed for body surface area (LVMI) (18). The LV fractional shortening and ejection fractions were determined as a systolic functional index. The late-to-early peak transmittal flow velocity ratio (A/E) was calculated as a prameter of diastolic function. Statistical Analyses Data are expressed as the mean SEM. Statistical significance of the treatment effect was evaluated using the method of Hills and Armitage (19) by combining all participants for the two experimental periods. This method was the standard approach used throughout the two-period crossover controlled trial. The null hypothesis was rejected at p 0.05 as the level of statistical significance. All statistical analyses were performed using the SPSS statistical package 10.0 for Windows (SPSS Software). Results Of the 39 subjects who attended the baseline examination, four subjects did not complete the training regimen; one subject was referred for medical treatment, and three subjects dropped out because of lack of motivation. Consequently, data analyses were performed on 35 subjects (group 1, n 17; group 2, n 18). Additionally, due to technical failures affecting three subjects who completed the program, more than 20% of the recordings of ambulatory BP were unsuccessful. Therefore, complete ambulatory BP data were available for 32 subjects. The clinical characteristics of the subjects at baseline are shown in Table 1. Comparisons of the two groups revealed no baseline differences in any clinical variables, except for slightly higher body mass index, total cholesterol concentration, and fasting blood glucose in group 1 than in group 2. Compared with the values at the end of the control period, the body weight showed a slight but not significant decrease of 1.2 kg after training ( kg vs kg, p 0.09). The physical working capacity at a heart rate of 75% of the maximal heart rate significantly increased by 14% ( W vs W, p 0.001). Based on the values measured after 15 min of supine rest, no significant exercise-induced reduction in resting BP was found for either systolic ( mmhg vs mmhg, p 0.22) or diastolic BP ( mmhg vs mmhg, p 0.18). The plasma lipid and lipoprotein levels did not differ between the two study periods, except for an 11% reduction in triglycerides ( mmol/l vs mmol/l, p 0.010). The fasting blood glucose showed a significant decrease of 7% ( mmol/l vs mmol/l, p 0.027). The time courses of ambulatory BP over 24 h at the end of the control and training periods are represented in Fig. 1. The average absolute values for BP and heart rate over 24 h and the daytime and nighttime periods are listed in Table 2. Training significantly lowered systolic ( 2.9 mmhg, p 0.014) and diastolic BP ( 3.1 mmhg, p 0.007) during the day, while no significant BP reductions were found at night either for systolic ( 1.5 mmhg, p 0.114) or diastolic BP ( 0.4 mmhg, p 0.291). The heart rate showed a significant decrease of 5 beats/min during the day ( p 0.001) and of 2 beats/min at night ( p 0.034). The pressor responses during bicycle ergometric exercise after the two experimental periods are shown in Fig. 2. Com-

4 510 Hypertens Res Vol. 25, No. 4 (2002) Table 1. Clinical Characteristics of the Subjects at Baseline Variables Group 1 Group 2 p-value Number Age (years) Height (cm) Body weight (kg) Body mass index (kg/m 2 ) Systolic BP (mmhg) Diastolic BP (mmhg) Heart rate (beats/min) Total cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l) Fasting blood glucose (mmol/l) Alcohol consumption (g/week) Current smoker (%) Parental hypertension (%) BP, blood pressure; Parental hypertension, paternal or maternal history of hypertension. Values are shown as percentage of the subjects and mean SEM. Table 2. Ambulatory Blood Pressure and Heart Rate of 32 Subjects at the End of the Control and Training Periods Variables Control Training p-value 24-h Systolic BP Diastolic BP Heart rate Daytime Systolic BP Diastolic BP Heart rate Nighttime Systolic BP Diastolic BP Heart rate Daytime, from 8 AM to 8 PM; nighttime, from 12 PM to 6 AM. Abbreviations are as in Table 1. Values are shown as mean SEM. Fig. 1. Twenty-four-hour time courses of ambulatory systolic (A) and diastolic blood pressures (B) of 32 subjects at the end of the control (open circles) and training periods (closed circles). Values are shown as the mean SEM. pared with the control values, systolic and diastolic BP measured during submaximal workload of exercise and at the 3- min-recovery phase were significantly lower after training. Similarly, significant reductions in heart rate were found during both the exercise and recovery periods. Plasma catecholamine levels measured during supine rest and immediately after the incremental exercise are shown in Fig. 3. A significant reduction in resting plasma norepinephrine level was found at the end of the training period compared with the control period ( p 0.022). Additionally, bicycle ergometric exercise caused remarkable elevation in the plasma norepinephrine level. Training led to a significant decrease in the plasma norepinephrine response to physical exertion ( p 0.009). The levels of plasma epinephrine at rest and during exercise were not significantly different between the

5 Miyai et al: Aerobic Exercise and Exaggerated BP Response 511 Table 3. Echocardiographic Parameters of 35 Subjects at the End of the Control and Training Periods Fig. 2. Systolic and diastolic blood pressures measured during the submaximal bicycle ergometric test of 35 subjects at the end of the control (open circles) and training periods (closed circles). Values are shown as mean SEM. p 0.05; p Fig. 3. Plasma noradrenaline (A) and epinephrine concentrations (B) measured after the supine rest period and after the last stage of the bicycle ergometric test for 35 subjects at the end of the control (open bars) and training periods (shaded bars). Values are shown as mean SEM. p 0.05; p two periods. The echocardiographic features of subjects at the end of the control and training periods are listed in Table 3. There were no significant differences in any echocardiographic variable of morphological change after training compared with the control values. The functional variables were also not affected by training, except for a slight but not significant decrease in the A/E ( p 0.091). Discussion Variables Control Training p-value IVSTd (mm) PWTd (mm) LVDd (mm) LVDs (mm) LVMI (g/m 2 ) FS (%) EF (%) A/E IVSTd, left ventricular interventricular septal thickness; PWTd, posterior wall thickness; LVDd, end-diastolic left ventricular internal diameter; LVDs, end-systolic left ventricular internal diameter; LVMI, left ventricular mass index; FS, left ventricular fractional shortening, EF, left ventricular ejection fraction; A/E, the late to early peak transmittal flow velocity ratio. Values are shown as mean SEM. The results of our randomized controlled trial have demonstrated that a program of moderate aerobic exercise for 12 weeks significantly attenuates BP elevations during laboratory exercise stress and daily physical activities in sedentary, normotensive adults with exaggerated BP response to exercise. These antihypertensive actions may mainly account for the reduction in the enhanced sympathetic nervous tonus of subjects, which is considered to play a pivotal role in the etiology of hypertension. It has been thoroughly established that an exaggerated BP response to physical exertion poses a considerable risk factor for future hypertension (3, 4). In addition, it has been shown that total peripheral resistance in individuals with such abnormal pressor response does not fall adequately to compensate for the rise in cardiac output during exercise, suggesting increased resting peripheral vascular resistance and impaired capacity for exercise-induced vasodilatation (5 7). This hemodynamic behavior can be explained by a hyperreactivity of the sympathetic nerves and an increased vascular response to adrenergic stimulation or by a thickening of the arteriolar wall that alters its ability to respond to vasoconstrictor stimuli. Abnormalities of autonomic control and vasoreactivity have been found to contribute to the pathogenesis of hypertension at the early phase (20). Thus, individuals with such high-risk profile should be encouraged to engage in preventive measures even if their resting BP is within the normotensive range. Endurance exercise training is generally recommended as a nonpharmacological therapy in patients with mild-to-moderate hypertension (12). Conversely, several controlled studies have shown no BP lowering effect in normotensive subjects, and even in studies in which trained subjects showed a significant BP change, the reduction in normotensive subjects was only slight (13). In addition, scant information is available regarding the efficacy of endurance training for pa-

6 512 Hypertens Res Vol. 25, No. 4 (2002) tients with an exaggerated pressor reactivity to behavioral stress. In this study, resting BP in normotensive subjects who were hyperreactive to physical exertion tended to decrease after a 12-week training regimen, but the decrease was not statistically significant. This lack of change in resting BP following exercise conditioning is consistent with the result in an earlier report describing the BP response to a 6-week endurance training in normotensive African-American adults, who have been shown to be more hyperreactive to physical and mental tasks than other racial groups (21). It has been shown that the effects of physical training on BP in normotensive subjects are more pronounced under certain stress conditions (22). In our study, endurance training led to significant decreases in systolic and diastolic BP responses at the submaximal absolute levels of exercise and during the subsequent recovery phase. These BP reductions were slightly greater than those in individuals with normal response to exercise (22, 23). These results suggest that regular aerobic exercise can attenuate an excessive rise in BP during physical exertion even if it results in only a modest reduction in resting BP. The mechanisms responsible for the observed attenuation in pressor reactivity to physical exertion after the training regimen are not clear. Arakawa et al. (24) demonstrated that the antihypertensive mechanism of exercise is a multifactorial one involving sympathicolytic as well as diuretic actions through activation of relevant metabolic pathways; that is, a decrease in endogenous ouabain-like substances and an increase in plasma taurine, prostaglandin E and urinary dopamine, and kallikrein excretion. We cannot attribute the attenuated pressor reactivity of the present study to any of these mechanisms. However, our results showed a significant reduction in plasma norepinephrine levels measured at rest and during submaximal incremental exercise after the endurance training. Venous plasma catecholamine levels are generally considered an index of whole-body sympathetic and adrenomedullar activities. In particular, individuals with an exaggerated response to physical exertion show signs of enhanced sympathetic nervous activity and increased vascular response to adrenergic stimulation. This would suggest that the abnormalities of autonomic control and vasoreactivity that bring about the pressor hyperreactivity might be improved after exercise conditioning. It has also been well confirmed that reduction in sympathetic nervous tonus plays an important role in the antihypertensive mechanism (25 27). These findings lead to the idea that the attenuated pressor reactivity to physical exertion may mainly be caused by the reduction in the enhanced sympathetic and adrenomedullar activities of subjects. Other metabolic changes, such as sugar and lipid metabolism and insulin resistance, also seem to contribute antihypertensive effects (24). Thus a further possibility is that the attenuated pressor reactivity observed in the present study may have been partly due to the reductions in plasma triglycerides and fasting blood glucose concentrations after the training regimen. The increased pressor response to experimental physical exertion may translate to enhanced activation in response to daily physical stress. Indeed, previous reports have found significant correlations between exercise BP and the ambulatory daytime BP (6). Further, in agreement with two earlier reports (5, 6), the average ambulatory BP in our subjects with elevated exercise BP tended to be higher than the values reported in the literature as normal. In this study, training-induced BP-lowering effects during exercise in a laboratory setting extended to ambulatory BP over daytime activities, while no significant changes were observed during the night. At night, the plasma norepinephrine level and, presumably, the sympathetic nervous activity are low in nontrained subjects, as described by Stern et al. (28). During the day, however, the overall sympathetic nervous activity is higher, and the effectiveness of exercise training could thus be more pronounced. Our study also showed significant reductions in heart rate during both the day and night. These findings are in line with previous reports that examined the antihypertensive effect of regular aerobic exercise in normotensive sedentary subjects (22, 23). It is known that heart rate is affected dominantly by parasympathetic nervous activity. For example, Dixon et al. (29) showed that parasympathetic nervous activity significantly increased after exercise training and was greater in athletes than in sedentary controls. Echocardiography-determined LV hypertrophy is an independent risk factor for cardiovascular complications (30). Gottdiener et al. (31) reported that, even in the absence of hypertension, an exaggerated BP response during exercise is associated with the presence of LV hypertrophy as well as with the subsequent development of hypertension. It has been suggested that individuals with such pressor hyperreactivity may also experience increased stress in response to daily physical and emotional stimuli, eventually leading to the development of sustained hypertension, which, in turn, would lead to even worse LV hypertrophy (32). Regression of LV hypertrophy after a reduction in BP has been reported with most antihypertensive medications (33). In contrast, the effects of prolonged exercise on ventricular structure and function are unclear. In this study, a 12-week training regimen did not affect any of the echocardiographic, morphological and functional measurements. However, it is quite possible that the action by which aerobic training attenuates BP reactivity to physical exertion may contribute to decreased LV wall stress in response to daily physical or emotional stimuli. A long-term intervention study will be needed to determine the efficacy of regularly performed exercise in reducing LV hypertrophy. To reduce the impact of subsequent cardiovascular complications, the early identification of subgroups more likely to develop hypertension is a critical concern. Although routine mass exercise testing is not recommended to identify future hypertensive individuals, the use of exercise tests is more feasible, since these tests are now widely utilized for

7 Miyai et al: Aerobic Exercise and Exaggerated BP Response 513 detecting coronary artery disease or levels of physical fitness. Such data may provide important information about a hypertensive risk profile in the population of apparently healthy normotensive adults. Additionally, our results have shown that the antihypertensive efficacy of moderate endurance training extends to normotensive subjects who show an exaggerated BP response to physical exertion. These findings lead to the notion that regular physical activity interventions may be useful for attenuating excessive BP elevations during normal daily physical activities, thereby lowering a subject s relative risk of developing hypertension. There are potential limitations to this study. Because the study sample consisted of middle-aged men, it is possible that our results may not be fully generalizable to the younger population or to women. In addition, we focused on the effects of endurance training on factors that may be considered as markers of a predisposition to hypertension or promoters of the development of hypertension. A further controlled longitudinal study will be needed to examine whether regularly performed aerobic exercise can reduce the prevalence of hypertension in a normotensive subgroup showing exaggerated pressor reactivity to physical stress. In conclusion, regular aerobic exercise, which produces an increase in aerobic fitness, appears to attenuate BP elevations during physical exertion and daytime activities. This may result mainly from the reduction of enhanced sympathetic nervous tonus, which may in turn play a role in lowering the risk for hypertension in normotensive adults with an exaggerated BP response to exercise. References 1. 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