In the past, attention was given to educating patients

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1 AJH 2000;13: Aerobic Exercise Training Fails to Reduce Blood Pressure in Nondipper-Type Hypertension Renato Nami, Sergio Mondillo, Eustachio Agricola, Salvatore Lenti, Giuseppe Ferro, Niccolò Nami, Maria Tarantino, Gianni Glauco, Emilia Spanò, and Carlo Gennari To assess whether aerobic exercise training is an effective and an alternative method to control blood pressure (BP) in hypertension, 32 uncomplicated, never treated patients suffering from mild-to-moderate essential arterial hypertension (EAH) were included in an aerobic exercise training program using a regular standardized cycle ergometer exercise for 3 months. In all EAH patients, before and after the exercise training period, ambulatory BP monitoring (ABPM) was performed and several metabolic variables were assessed. Before exercise, in 20 EAH patients, a 48-h ABPM showed a normal day night rhythm, with nocturnal BP decrease, according to a dipper-type hypertension, whereas in 12 EAH patients 48-h ABPM profile indicated a nondippertype hypertension. After exercise, EAH dippers presented a significant decrease in the daytime systolic and diastolic BP, whereas EAH nondippers did not show any change in daytime and nighttime systolic and diastolic BP. Our study confirms the controversy about the postulated BP lowering effect of dynamic exercise in EAH patients, in the sense that only EAH dipper patients seem to obtain a beneficial diurnal lowering BP effect deriving from exercise, possibly through a reduction in sympathetic tone. On the contrary, physical activity seems to fail in reducing diurnal and nocturnal BP values in EAH nondippers, suggesting that in nondipper-type hypertension, other masking endogenous or exogenous factors could interfere with and prevail over the adrenergic vagal balance that modulates the day night BP synchronism. Am J Hypertens 2000; 13: American Journal of Hypertension, Ltd. KEY WORDS: Aerobic dynamic exercise training, cycle ergometer test, essential arterial hypertension, 24- hour ambulatory blood pressure monitoring, dippers and nondippers. In the past, attention was given to educating patients with hypertension, or at risk for hypertension, about nonpharmacologic measures to control blood pressure (BP). 1 Nondrug treatment of hypertension can be classified into three categories: nutrition, aerobic exercise, and change of life style. Of the many nutritional approaches that have been studied, 2 sodium restriction in sodium-sensitive individuals, weight loss in the obese, and limiting alcohol intake in heavy drinkers have all been shown to re- Received March 12, Accepted November 2, From the Department of Cardiology, Institute of Internal Medicine, University of Siena, Siena, Italy. Address correspondence and reprint requests to Prof. Renato Nami, Cattedra di Cardiologia, Istituto di Clinica Medica, Università di Siena, Policlinico Le Scotte, Viale Bracci,2, Siena, Italy; nami@unisi.it 2000 by the American Journal of Hypertension, Ltd /00/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 594 NAMI ET AL AJH JUNE 2000 VOL. 13, NO. 6, PART 1 duce BP. With regard to exercise, there is evidence that aerobic exercise may prevent hypertension and reduce BP 3,4 and mortality in hypertensive patients and those at high risk for coronary artery disease. 5 Results of several trials indicate that aerobic exercise of large muscle groups can be used to correct hypertension, whereas other researchers 6 do not confirm the beneficial effect of aerobic exercise. These differences might be due to different methods of studying BP in the various trials and to the heterogeneity of the hypertensive population studied. Conventional clinical measurement of BP is influenced by many factors that make it unsuitable for the assessment of antihypertensive treatment. There is increasing evidence that noninvasive ambulatory BP monitoring (ABPM) is more physiologically valid and more reliable than office or clinical BP measurement. 7 Using this method, it is possible to differentiate populations of hypertensive individuals at different degrees of risk according to the circadian variations in BP. Therefore, the reduction or inversion of the physiologic day night rhythm in the 24-h BP profile is now recognized to have a different prognostic value. In fact, it has been suggested that the reduced decline in day night BP, typical of nondipper hypertensive patients, is associated with a higher degree of cardiovascular complications 8 10 and could be more closely correlated with future cardiovascular events than random office or home BP measurements, because these patients are exposed longer to high BP levels in the 24-h period Therefore, the aim of the present study was to evaluate the effect of aerobic exercise training on 24-h BP profile, cardiac morphology, and some metabolic variables, in two groups of never treated and uncomplicated hypertensive patients suffering from mild-tomoderate essential arterial hypertension (EAH), presenting respectively a dipper-type hypertension or a nondipper-type hypertension. SUBJECTS AND METHODS Subjects Thirty-two, uncomplicated, never-treated patients suffering from mild-to-moderate EAH were recruited from our outpatient Hypertension Centre. All subjects had mild-to-moderate EAH, based on the World Health Organization (WHO) hypertension criteria and presented a WHO stage I, without any cardiovascular complications or signs of end-organ damages because of hypertension. Attention was given to the following inclusion criteria: 1) no sign on electrocardiogram or echocardiography of left ventricular hypertrophy; 2) no history of coronary artery disease or congestive heart failure; 3) no clinical evidence of idiopathic or secondary orthostatic hypotension, sleep apnea syndrome, diabetic dysautonomia, insomnia, depression, alcohol or drug abuse; 4) no smoking; 5) no previous fitness program at least 3 months before the recruitment in the study, 6) good compliance and adherence to protocol. Dietary habit (salt intake, alcohol consumption, and total caloric intake) was recognized by an anamnestic interview before and after the training program. In addition, neither antihypertensive drugs were administered nor dietary fibers or dietary Ca 2,K,orMg 2 supplements were added to patients in their diet during the entire study period. The study was performed in accordance with the Second Declaration of Helsinki and was approved by a Local Committee on Clinical Research. All subjects gave written informed consent. Protocol In the morning after a 12-h overnight fasting and resting period, in all subjects body weight and height were measured and body mass index (BMI) was calculated as weight (kg)/height (m 2 ). Moreover, a blood sample was drawn from the antecubital vein to measure serum glucose, total cholesterol, triglycerides, uric acid (by enzymatic method, automatic analyser), HDL cholesterol and calculated LDL cholesterol levels. Serum HDL cholesterol was determined enzymatically after LDL- and very low-density lipoprotein cholesterol were selectively removed from the plasma sample by heparin and magnesium chloride precipitation. 13 LDL cholesterol was estimated by the Friedewald formula (LDL cholesterol total cholesterol [HDL cholesterol (triglyceride 0.2]) for triglycerides 400 mg/dl (4.52 mmol/l. 14 No patient exhibited plasma triglyceride values 400 mg/dl, therefore, ultracentrifugation for assessing plasma LDL cholesterol values was not necessary. In the morning M-mode, B-mode-guided echocardiography (ECHO) was performed in all subjects, using an ESAOTE-Biomedica SIM 7000 PLUS ultrasound imaging system (ESAOTE-Biomedica, Florence, Italy). Measurements were made according to the American Society of Echocardiography recommendations. 15 Left ventricular mass index (LVMI) was calculated according to the formula of Devereux et al 16 (LVMI normal range: men 134 g/m 2, women 110 g/m 2 ). Then, in the morning, between 10:00 and 12:00 am, an automatic ambulatory BP monitoring (ABPM) was performed with a noninvasive recorder (SpaceLabs Paris, France) using an oscillometric method. BP and heart rate (HR) values were monitored every 15 min, night and day, for 2 consecutive working days (48 h) of normal typical activity. Validation of ambulatory BP measuring device was previously done according to the British Hypertension Society recommendations. 17 Each subject recorded a diary of action, from which information as to exact times of falling asleep and waking up were obtained. The night BP was defined as the mean BP for the interval from the

3 AJH JUNE 2000 VOL. 13, NO. 6, PART 1 EXERCISE IN DIPPER- AND NONDIPPER-TYPE HYPERTENSION 595 TABLE 1. CLINICAL CHARACTERISTICS OF DIPPER AND NONDIPPER HYPERTENSIVE PATIENTS, BEFORE AND AFTER A 3-MONTH AEROBIC EXERCISE PERIOD Before Exercise* After Exercise Number Dippers (n 20) Nondippers (n 12) Dippers 21 (P within the group) Nondippers 11 Gender (male/female) 12/8 8/4 13/8 7/4 Age (yr) BW (kg) BMI (kg/m 2 ) Duration of hypertension (yr) BW body weight; BMI body mass index. * Between groups, P is not significant; Pis not significant within group. time that the patient went to bed until the patient awoke and the day BP as the mean BP from awakening until the patient went to bed. Conventional statistical methods were used to calculate the individual mean values of BP and HR for 48-h period, the day period, and the night period. According to the reduction of the average BP values from day to night, patients were arbitrarily divided into two groups based on the presence (dipper) or absence (nondipper) of a reduction in both systolic and diastolic BP during the night by an average of 10% of the daytime pressure. 18 According to this definition, 20 patients had a nocturnal dipper-type pattern and 12 had a nocturnal nondipper pattern. All patients included in the study had ABPM recordings of good technical quality and data lost due to technical artifacts were 10% of the total measurements. Physical aerobic activity in all subjects consisted in a regular fitness program with cycle ergometer submaximal exercise, standardized for sex and age, at 40% to 60% of peak power output, for 1 h, three times a week, for 3 months. At the end of the 3-month exercise period, blood chemistry, ECHO recordings, and 48-h ABPM were repeated, the day following the last exercise session, observing the same above mentioned procedure. Statistical Analysis Results are expressed as mean the error standard of the mean. Statistical analysis was performed using Student s t test for paired data for assessing the significance of the differences within the groups, while comparisons between the groups were performed using two-way analysis of variance (ANOVA). The strength of correlation between variables was tested by univariate linear regression analysis using Pearson s test. A P.05 was considered significant. RESULTS Our EAH patients were arbitrarily divided in two groups, dippers (n 20) and nondippers (n 12), according to their nocturnal to diurnal ABPM reduction rate. The two groups, on basal conditions, had comparable demographic characteristics, duration of hypertension (Table 1), casual BP values, daytime ABPM values, sleeptime duration, left ventricular cardiac morphology (Table 2), and metabolic lipid profile (Table 3). Moreover, dietary habit, salt intake, alcohol consumption, caloric intake, working times, mean morning wake-up times, mean bedtimes, sleep duration, and dairy activities, assessed by an anamnestic interview, were similar between the two groups at the start of the study and they did not change during and after the aerobic exercise training program. Only nocturnal ABPM values, and consequently the mean 48-h ABPM values in EAH nondippers were significantly higher than those of EAH dippers (Table 1). In EAH dipper patients, physical fitness induced a significant decrease in diurnal systolic and diastolic BP values, without affecting nocturnal systolic and diastolic BP ones (Figure 1). In nondipper EAH patients no significant change in diurnal and nocturnal systolic and diastolic BP was found after the third month of physical exercise training, when compared to the basal values (Figure 2). Aerobic exercise training caused a significant decrease in diurnal heart rate (HR) in both the groups, whereas no significant change, when compared to the basal values, was observed in nocturnal HR in both the groups, after physical fitness (Figures 1 and 2, Table 2). In dipper hypertensive patients, BW, serum total cholesterol, and LDL cholesterol levels were significantly reduced and serum HDL cholesterol was significantly increased after 3 months of aerobic physical fitness (Table 3). A comparable trend in reduction of serum total cholesterol, LDL cholesterol levels, and an increase in serum HDL cholesterol was registered in nondipper hypertensive patients, but not significantly, likely because of the small number of cases represented in this group (Table 3). LVMI resulted in the normal range before training, and it did not change

4 596 NAMI ET AL AJH JUNE 2000 VOL. 13, NO. 6, PART 1 TABLE 2. CASUAL BP, AMBULATORY BP, AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF DIPPER AND NONDIPPER HYPERTENSIVE PATIENTS, BEFORE AND AFTER A 3-MONTH AEROBIC EXERCISE PERIOD Before Exercise After Exercise Characteristics Dippers Nondippers (P between the groups) Dippers (P within the group) Nondippers (P within the group) Casual SBP (mm Hg) NS NS Casual DBP (mm Hg) NS NS Casual HR (beats/min) NS h SBP (mm Hg) NS 48-h DBP (mm Hg) NS 48-h HR (beats/min) NS Day SBP (mm Hg) NS NS Day DBP (mm Hg) NS NS Day HR (beats/min) NS Night SBP (mm Hg) NS NS Night DBP (mm Hg) NS NS Night HR (beats/min) NS NS NS Sleep time (h) NS NS NS LVMI (g/m 2 ) NS NS NS SBP, systolic BP; DBP, diastolic BP; LVMI, left ventricular mass index; NS, not statistically significant. after the 3-month physical training period in both groups. Finally, in dipper hypertensives an univariate linear regression analysis did not give evidence of any significant relation between the percentage decrease in diurnal systolic and diastolic BP and the percentage changes in body weight, serum total cholesterol, LDL cholesterol, HDL cholesterol levels, after 3 months of aerobic exercise training. DISCUSSION Physical fitness when performed by aerobic exercise training is considered to be effective in reducing BP in a large amount of patients with established hypertension and in subjects considered to be at high risk for hypertension. 19 However, data in literature concerning this beneficial effect of exercise in hypertensive patients are not conclusive. 6 The results of the present study seem to confirm and partially explain this controversy: in fact, a 3-month aerobic fitness induced a significant decrease in systolic and diastolic BP, only during the daytime period in dipper hypertensives, but not in nondipper hypertensives. Conversely, diurnal HR values significantly decreased at the same extent, after exercise, in dipper and nondipper hypertensives. Our results are in agreement with the hypothesis that regular aerobic exercise induces a BP lowering effect in dipper hypertensives mainly acting on the sympathetic/parasympathetic balance, that is, reducing the sympathetic tone or enhancing the parasympathetic one. Such neurovegetative changes pro- TABLE 3. METABOLIC PROFILE OF DIPPER AND NONDIPPER HYPERTENSIVE PATIENTS, BEFORE AND AFTER A 3-MONTH AEROBIC EXERCISE PERIOD Variables Before Exercise* Dippers Nondippers Dippers After Exercise (P within the group) Nondippers Serum glucose (mg/dl) NS Serum total cholesterol (mg/dl) Serum LDL cholesterol (mg/dl) Serum HDL cholesterol (mg/dl) Serum triglycerides (mg/dl) NS Serum uric acid (mg/dl) NS NS, not statistically significant. *P not significant between groups; P not significant within group.

5 AJH JUNE 2000 VOL. 13, NO. 6, PART 1 EXERCISE IN DIPPER- AND NONDIPPER-TYPE HYPERTENSION 597 FIGURE 1. Diurnal ambulatory blood pressure (BP) and heart rate (HR) profile in hypertensive dippers. Average hourly systolic and diastolic BP and HR before (f f) and after (# #) a 3-month aerobic exercise training period are shown. (Mean SEM; *P.01, P.001.) moted by exercise training have been well documented in borderline hypertensives. 20 The BPlowering effect of aerobic exercise did not seem to be influenced by other environmental factors such as diurnal activity, dietary habit, daytime, working time, nighttime, sleep duration of dipper and nondipper hypertensives. In fact, no significant difference in FIGURE 2. Diurnal ambulatory blood pressure (BP) and heart rate (HR) profile in nondipper hypertensive dippers. Average hourly systolic and diastolic BP and HR before (f f) and after (# #) a 3-month aerobic exercise training period are shown. (Mean SEM; *P.01, P.001.) these variables, assessed by an anamnestic interview, was observed, before and after exercise, within the group and between the two groups. Particularly, results were not affected by any pretraining level of fitness in our hypertensives, because none of them had followed any previous fitness program for at least 3 months before the start of the study. Moreover, no significant difference in nocturnal waking-up episodes and in their duration was registered in dipper and nondipper hypertensives, before and after exercise. In addition, the fact that nocturnal HR was reduced in all patients, indicates indirectly a good index of nocturnal rest reached by every patient, before and after exercise. Therefore, sleep duration and sleep quality were comparable between the two groups, and did not affect per se abnormal nocturnal BP responses, especially in the nondipper hypertensives. Interestingly, aerobic exercise training lowered systolic and diastolic BP in dipper hypertensives only throughout the day, without interfering with nocturnal BP profile. This hypotensive effect contrasts with that of the longlasting antihypertensive drugs, which, when taken in the morning, prolong their effect into the night, and, sometimes, many hours beyond the day after. It is well known that a direct vasodilation occurs immediately, during exercise, secondarily to the augmented tissue oxygen demand and to the increased catabolite accumulation, 21 but this vasodilation is transient and lasting for only a few hours after physical activity. Concerning this aspect, recently the magnitude and duration of ambulatory BP reduction following acute exercise has been assessed, and in hypertensives a significant reduction in systolic and diastolic BP was documented, after exercise, mostly during the time of day that typically exhibits higher diurnal pressures. 22 These data appear consistent with those of the present study, although in the setting of a different experimental design that investigated only the short-term effects of exercise on ABPM. However, another vasodilation, more tardive but more prolonged and responsible for the BP hypotensive effect lasting in our dipper hypertensives all day, occurs more appropriately, subsequently to the postulated sympathetic vagal balance change. Then, to exclude the interference of the first immediate vasodilation related to exercise-induced aerobic metabolic changes, ABPM monitoring was performed in all patients at least 24 h after the last physical activity session. Recently, it has been demonstrated that long-term aerobic exercise, through increased release of nitric oxide (NO), restores the impaired endothelium-dependent vasorelaxation in the forearm circulation of patients with essential hypertension. 23,24 Concerning the possible mechanism of action by which aerobic exercise improves endothelial function in essential hypertension, some hypotheses have been formulated. First, aerobic exercise increases

6 598 NAMI ET AL AJH JUNE 2000 VOL. 13, NO. 6, PART 1 blood flow and shear stress, which may enhance release and production of NO in the vascular endothelium. 25,26 Increased blood flow and shear stress induced by exercise also have been shown to exert beneficial effects on vascular structure and reactivity. 27 The present study did not investigate the NOrelated antihypertensive effects of exercise, which remain to be further elucidated. However, according to our data, the exercise-induced vasodilation evident in the hypertensive dippers in the diurnal period did not induce a further BP decrease in the nocturnal period. A possible explanation of this phenomenon can be related to the nocturnal sympathetic vagal balance change that physiologically occurs in dipper hypertensives. The effect of exercise on nocturnal BP decrease in these patients could be still present but less evident than in the day, because in the night, sympathetic tone spontaneously reduces and the parasympathetic tone predominates. 20 However, even if the BP-lowering property of exercise in our dipper hypertensives is limited to the diurnal period, this limitation could represent an advantage, when compared with the long-lasting antihypertensive drugs, which, unlike exercise, also act in the night and may provoke, in dipper and even more in extreme dipper hypertensives an excessive nocturnal hypotension. 28 In dipper and nondipper hypertensives aerobic exercise training induced a comparable diurnal resting bradycardia, indicating that in both groups sympathetic tone was reduced. Our data agree with previous observation that in humans exercise training induces resting bradycardia and attenuates the tachycardic response during exercise because a lower sympathetic activity is released with simultaneously increased vagal activity. 29 However, in nondipper hypertensives, sympathetic activity reduction after aerobic exercise was not accompanied by a concomitant diurnal systolic and diastolic BP decrease. The mechanism of the abnormal BP variation pattern in nondipper-type hypertension remains unclear. A nondipper pattern have been reported in secondary hypertensive patients with endocrine abnormality and in those with autonomic nervous abnormality such as diabetic neuropathy. 30 According to the inclusion criteria established for the recruitment of our hypertensive patients, attention was given to avoid any condition of secondary hypertension or autonomic dysfunction. However, modification in autonomic nervous function may explain the nondipper phenomenon also in essential hypertension, as suggested by studies using power spectral analysis that indicated that nondipper hypertensive subjects were characterized by a decreased physiologic circadian fluctuation in autonomic function. 31 In addition, it has been recently demonstrated that in nondipper hypertensives the sympathetic nervous activity is lower during the daytime, whereas the parasympathetic nervous activity is diminished during the nighttime, thus conditioning a lesser nocturnal BP decrease. 32 However, other pathophysiologic conditions or confounding factors (metabolic, hormonal, genetic) cannot be excluded in nondipper-type hypertension. In fact, exogenous or endogenous factors could theoretically interfere with the diurnal BP variation and be responsible for the lesser or absent nocturnal BP decrease as well as for the failure of exercise to reduce diurnal BP in hypertensive nondippers. Therefore, the difference in BP response to aerobic exercise, based on the dipper or nondipper-type hypertension of the subjects included in the study, may explain, at least in part, why some previous trials recruiting hypertensive patients who were not preventively selected according to these criteria failed to confirm the BP-lowering effect of exercise in a general hypertensive population. 6 Physical activity induced in hypertensive dippers a significant decrease in body weight, serum total and LDL cholesterol, and a significant increase in serum HDL cholesterol, while a comparable, even if not significant, trend in body weight reduction and in the lipid profile amelioration was observed in nondipper hypertensives. These results give further evidence of the well-known beneficial effects of aerobic exercise on obesity and lipid metabolism in hypertensive patients. 33,34 However, in dipper hypertensives, the BPlowering effect of exercise does not seem to be related to weight loss or metabolic changes. In fact, no significant correlation was found between the percentage decrease in BP and the percentage changes in body weight, serum total cholesterol, LDL, HDL cholesterol, and triglyceride levels after 3 months of aerobic training. These results indicate that the documented antihypertensive effect of aerobic exercise in our dipper hypertensives is independent from its proven beneficial influence on weight loss and lipid metabolism. 3 An other point of controversy is that reproducibility of the dipper/nondipper phenomenon has been many times discussed and is usually reported to be low, about 35% to 40%. 35 On the contrary, our data indicate a reproducibility of 91.6%, because only 1 of 12 nondipper hypertensive patients after aerobic exercise changed from nondipper to dipper-type BP profile. Our study is certainly limited by the small sample size. According to an ideal study design, patients should have been randomly assigned to exercise or to a sedentary condition. Therefore, each group of patients, dipper and nondipper hypertensives, should have been divided into two groups, according to sedentary or exercise training program. Then, because of the small number of subjects in each group, results would not been comparable and conclusive. In addition, the duration of study planned would have lasted more than 6 months, a period too long and not ethi-

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