Effect of betaxolol hydrochloride on heart rate variability indices during exercise stress testing in patients with hypertension

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Biomedicine & Pharmacotherapy 59 (2005) S158-S162 http://france.elsevier.com/direct/B IOPHA/

Effect of betaxolol hydrochloride on heart rate variability indices during exercise stress testing in patients with hypertension B. Takase a, ,, y . Abe c, M. Nagata c, T. Matsui a, H. Hattori a, F. O h s u z u b, M. Ishihara a, A. Kurita a a Division of Biomedical Engineering, National Defense"Medical College Research Institute, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan b Internal Medicine-I, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan c lruma Heart Hospital, 1258-1, Koyatag lnuma, Saitama, 358-0026, Japan

Abstract Betaxolol hydrochloride is a ~l-selective antagonist that produces vasodilation in patients with hypertension and ischemic heart disease. The goal of the present study was to characterize the effect of betaxolol on heart rate variability indices (HRV), a well-established prognostic marker. Symptom limited-treadmill exercise testing was performed in 17 hypertensive patients (60.9 _+14.8 years-old) before and immediately a 3 weeks course of betaxolol hydrochloride (5 mg daily). Frequency domain HRV (high frequency spectra, HF; 0.15-0.40 Hz: low frequency spectra, LF; 0.04-0.15 Hz) was measured during exercise treadmill testing using MemCalc software. Betaxolol hydrochloride significantly decreased the maximal systolic blood pressure and heart rate (184 _+29 vs. 156 _+26 mmHg, P < 0.01; 132 _+21 vs. 113 _+ 15 bpm, P < 0.01) and significantly increased HF and LF during exercise treadmill testing (HF, 32 -+ 36 vs. 56 _+55 ms2/Hz, P < 0.01; LF, 64 _+58 vs. 95 -+ 86 ms2/Hz, P < 0.01). Thus, treatment with betaxolol hydrochloride resulted in a decrease in blood pressure during exercise treadmill testing and in an increase in HRV. This suggests that this agent could have beneficial effects on long-term prognosis in patients with hypertension. © 2005 Elsevier SAS. All rights reserved. Keywords: Anti-hypertensive therapy; Exercise-induced hypertension; Blood pressure; Heart rate

1. Introduction Among the several classes of effective cardiovascular medications, [3-blockers are widely used for treatment of a variety of cardiovascular disorders such as hypertension, coronary artery disease, heart failure and arrhythmias. Betaxolol hydrochloride is a [31-selective antagonist that produces vasodilation [1-4] and is effective for the treatment of hypertension and coronary artery disease [5,6]. Heart rate variability indices (HRV) are well-recognized prognostic parameters in patients with cardiovascular disease, including hypertensive heart disease [7-9]. However,

* Corresponding author. E-mail address: [email protected], [email protected] (B. Takase). © 2005 Elsevier SAS. All rights reserved.

there are few reports on the effects of betaxolol hydrochloride on HRV and the effects of betaxolol hydrochloride on exercise-induced hypertension have not been fully investigated. Thus, the goal of the present study was to characterize the effect of betaxolol on heart rate variability as well as on exercise-induced hypertension in hypertensive patients. 2. Methods

2.1. Study population The study population consisted of 17 hypertensive patients (12 men and 5 women; average age, 60.9 ___14.8 years; age range, 47-78 years) that were referred to the National Defense Medical College Hospital or Iruma Heart Hospital due to poor control of blood pressure despite initiation of anti-

B. Takase et al. / Biomedicine & Pharmacotherapy 59 (2005) S158-S162

hypertensive medication. Hypertension was defined as a history of high blood pressure (casual systolic blood pressure > 140 mmHg and/or diastolic pressure > 95 mmHg). Written informed consent was obtained from each patient before the start of the study. The study protocol was approved by the institutional Investigation Review Board. 2.2. Study protocol The study protocol was similar to that of our previous study [10]. Briefly, it consisted of a single-blind, 2-4-week open label trial. Treatment included a control observational phase for 7-14 days followed by betaxolol hydrochloride treatment (5 mg daily) for 2-4 weeks (average, 23 __. 8 days). The 5 mg/day dosage was used based on reports that this dosage represents the minimum optimal dose in Japanese patients [11]. Exercise treadmill testing was performed and HRV indices were measured on the last day of the control observation phase and the treatment phase. 2.3. Exercise treadmill testing Maximum symptom-limited treadmill testing was performed using the standard Bruce protocol. Throughout the study, 12-lead electrocardiogram (ECG) was continuously monitored and recorded at 1-min intervals using a Fukuda Denshi Stress System (Fukuda Denshi Inc., Stress System ML-6500, Tokyo, Japan). ST-segment depression was assessed 80 ms after the J-points. A horizontal or downsloping ST-segment depression of at least 1 mm was considered an indicator of exercise-induced ischemia. Blood pressure was measured by Korotkoff's method at 1-min intervals. End points for the termination of exercise testing included typical angina, dyspnea, extreme fatigue, leg fatigue or exercise-induced ST-depression exceeding 2 mm. Physicians who supervised the exercise testing in each phase were unaware of the phase of the betaxolol hydrochloride therapy. 2.4. Measurement of the HRV indices HRV indices were measured using commercial software (MemCalc/Tarawa, Suwa Trust Inc., Tokyo, Japan), based on the RR intervals of normal sinus beats obtained through exercise treadmill testing-Stress System's ECG monitoring. All RR intervals were transferred to a personal computer for frequency domain analysis with commercial software (MemCalc/Tarawa). Online analysis was performed for five consecutive RR intervals using the modified maximum entropy method. Low frequency spectra (0.04-0.15 Hz) and high frequency spectra (0.15-0.40 Hz) were continuously calculated. Thereafter, these values were averaged for 5 min at rest (rest mean values for 5 min), during exercise treadmill testing [during exercise (mean values)] and during recovery phase [during recovery (mean values)]. The ratio

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of low frequency spectra and high frequency spectra was measured as LF/HF. 2.5. Statistical analysis Data are expressed as mean _ standard deviation. Paired Student's t-tests were used to compare data before and after betaxolol hydrochloride therapy. Effects of exercise treadmill testing on each parameter were compared by repeated measure of one-way analysis of variance, and subsequent alpha values were corrected using Scheffe methods. Differences were considered significant at P _<0.05. 3. Results

Coronary risk factors and selected clinical characteristics were as follows: cigarette smoking (n = 4), hyperlipidemia (total cholesterol > 230 mg/dl; n = 7), family history of premature atherosclerosis (n = 4), diabetes mellitus (n = 0), and complicated with coronary artery disease (n = 4). Patient medication profiles included aspirin (n = 7), statins (n = 5), angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers (n = 6) and calcium channel blockers (n = 4). All patients with coronary artery disease had undergone revascularization procedures prior to entering this study. No exercise-induced ischemia was noted in any of the patients. Betaxolol hydrochloride therapy resulted in improved exercise tolerance time and decreased systolic and diastolic blood pressure during rest, peak exercise and recovery (5 min after exercise) (Table 1). In addition, betaxolol hydrochloride therapy significantly decreased heart rate during rest, peak exercise and recovery (5 min after exercise). Low frequency spectra and high frequency spectra increased at rest and during exercise, while high frequency spectra increased and low frequency spectra tended to increase during recovery (Table 2). However, betaxolol hydrochloride therapy did not change LF/HF. Exercise itself resulted in decreased low frequency spectra and high frequency spectra, and exercise tended to increase LF/HF. The effects of the betaxolol hydrochloride therapy on low frequency spectra, high frequency spectra and LF/HF in individual patients are illustrated in Figs. 1-3. 4. Discussion

The present study demonstrated that betaxolol hydrochloride increased heart rate variability indices at rest and during exercise. Further betaxolol hydrochloride attenuated exercise-induced hypertension. Although exercise stress resulted in decreased absolute values of HRV indices, betaxolol hydrochloride significantly increased low and high frequency spectra. In addition, betaxolol hydrochloride significantly decreased systolic and diastolic blood pressure as well as heart rate during both rest and exercise.

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B. Takase et al. / Biomedicine & Pharmacotherapy 59 (2005) S158-S162

Table 1. Effect of betaxololhydrochlorideon blood pressure responSeto exercise treadmilltesting Before betaxolol Duringbetaxolol P value therapy therapy Exercise treadmilltesting 373 ± 132 exercise time (s)

417 ± 112

<0.05

Systolic blood pressure (mmHg) Rest

140 ± 17

127 + 19

<0.01

Peak exercise

184 ± 29

156 ± 26

<0.01

Recovery (5 rain after exercise)

161 + 25

145 + 22

<0.01

Rest

88 ± 18

75 ± 13

<0.01

Peak exercise

90 _+19

78 ± 14

<0.01

Recovery (5 min after exercise)

93 ± 15

- 88 ± 12

Diastolic blood pressure (mmHg)

0.07

Mean _+S.D.; betaxolol, betaxolol hydrochloride.

Table 2. Effect of betaxolol hydrochlorideon heart rate and heart rate variabilityindicesin exercise treadmilltesting Before betaxolol therapy

Duringbetaxo- P value lol therapy

Rest

68 __.15

58±7

<0.01

Peak exercise

132 ± 21

113±15

<0.01

66±7

<0.01

449 _+608

<0.05

During exercise (meanvalues) 64 _+58*

95 ± 86*

<0.01

During recovery (mean values) 163 _+201

215 ± 198

NS

357 ± 536

<0.05

During exercise (mean values) 32 _+36*

56 _+55*

<0.01

During recovery (mean values) 78 _+108

123 _+129

<0.01

2.3,,,1.3

NS

During exercise (meanvalues) 3.8 _+2.8

4.4±3.8*

NS

During recovery (mean values) 3.9 ± 2.3

3.3±2.9

NS

Heart rate (beats/rain)

Recovery (5 min after exercise) 79 ± 13 Low frequencyspectra (ms2/Hz) Rest (mean values for 5 min)

272 ± 392

High frequencyspectra (ms2/Hz) Rest (meanvaluesfor 5 min)

177 ± 212

LF/HF Rest (mean values for 5 min)

2.6 ± 2.4

Mean ± S.D.; betaxolol,betaxololhydrochloride;LF/HF,low frequencyand high frequencyspectraratio; NS, no significantdifferences;*P < 0.05 vs. rest.

The beneficial effects of betaxolol hydrochloride on HRV indices may result from its ability to prevent hypertension-induced organ damage. Previous reports have demonstrated that decreased HRV indices in patients with hypertension reflected the presence of either left ventricular hypertrophy [7,8] or coronary artery disease [9] and that decreased HRV indices are associated with poor prognosis in patients with cardiovascular disease [12-14]. Further prospective study would be of benefit to determine whether improvements in HRV secondary to the incremental effect of betaxolol hydrochloride treatment result in more favorable patient outcomes. Investigators have reported that exercise-induced tachycardia and sympathetic activation result in decreases in HRV indices [15-17], but the incremental effects of betaxolol hydrochloride on HRV indices especially during exercise represent a novel finding. Although many previous studies have demonstrated that [3-blocking agents increase HRV indices measured at rest and/or during daily activity [18], some studies have indicated that [3-blocking agents other than betaxolol hydrochloride could not prevent the exercise-induced decrease in HRV indices [19]. Recent studies show that exercise tolerance is closely associated with vascular endothelial function [20] and that betaxolol hydrochloride produces vasodilatation in arterioles, potentially via promoting endothelial function [21]. This may provide a mechanistic explanation for the beneficial effect on betaxolol hydrochloride on HRV indices. The present study also demonstrated another important finding that betaxolol hydrochloride treatment can prevent exercise-induced hypertension. Exercise-induced hypertension correlates with subsequent cardiac events [22], and the hypertensive blood pressure response to exercise in healthy subjects can predict the future development of hypertension [23]. These results suggest that blood pressure changes during exercise might be associated with the pathophysiology of hypertension. Thus, the effect of the betaxolol hydrochloride on exercise-induced hypertension may be associated with better patient outcomes. This study has several limitations. First, this study was performed with a small cohort and was not performed in a placebo-controlled double blind fashion. Thus, this should be duplicated in the larger study populations with more sophisticated study design. Second, this study did not investigate the relationship between long-term prognosis and the betaxolol hydrochloride-mediated improvement in HRV indices and exercise-induced hypertension. However, our results are worth considering in clinical practice particularly because of the current lack of knowledge on the effects of betaxolol hydrochloride on HRV indices and blood pressure response to exercise. Third, the effect of respiration on HRV indices during exercise was not assessed. There are some conflicting reports about this subject [24,25]. However, HRV indices were compared within the same patients before and after betaxolol hydrochloride therapy, thereby minimizing the effects of respiration on HRV indices during

B. Takase et al. / Biomedicine & Pharmacotherapy 59 (2005) S158-S162

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Effect of betaxolol hydrochloride on low frequency spectra •~ Mean d:SD

(ms21Hz)

/

2750 2500 2250 2000 17~0

p<0.05 vs Pre

1500 1250 1000 750 500 250 0

P~LFzaR~t

PestLFatP-~xt

PteLFatE~i~e P~tLFatExeltke

PreLFat~ry

PestLFatReco~xF

Fig. 1. Effect of betaxolol hydrochloride on low frequency spectra. Betaxolol hydrochloride increased low frequency spectra at rest and during exercise in most patients and tended to increase low frequency spectra during recovery. Mean -+ S.D., *P < 0.05 vs. Pre; Pre indicates before betaxolol hydrochloride therapy.

Effect of betaxolol hydrocl-doride on high frequency spectra .L M e a n ± S D

(ms2/Hz) 2000

p<0.05 vs Pre

1750 1500 1250 1000 750 50O

PI~J~Fat Exer¢~sePost HTat ]~xerfi~

I ~ ] : ~ at Recovery PostH]~ at Re~ely

Fig. 2. Effect of betaxolol hydrochloride on high frequency spectra. Betaxolol hydrochlofide increased high frequency spectra at rest, during exercise, and during recovery in most patients. Format and abbreviations are the same as those in Fig. 1.

Effect of betaxolol hydrochloride on LF/HF

~. Mean+_SO 14

12 10 9 8

5 4

I

2 1 0

P~LFftlFatP~est P~tIA~m~tl~st

PrvLF/HFxtE~t~.tsepe~thFMFat~I~ise

P~LF/HFa~P.eeo,yex T P~tI,F/HFQ~Ref*~z7

Fig. 3. Effect of betaxolol hydrochlofide on LF/HF. Betaxolol hydrochloride did not have significant effect on LF/HF during any phase. Format and abbre, viations are the same as those in Fig. 1.

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B. Takase et al./Biomedicine & Pharmacotherapy 59 (2005) $158-$162

e x e r c i s e , b e c a u s e t h e p a t t e r n o f r e s p i r a t i o n is p r e s u m e d to be similar when compared within the same individuals. In conclusion, treatment with betaxolol hydrochloride r e s u l t e d in a d e c r e a s e in b l o o d p r e s s u r e d u r i n g e x e r c i s e t r e a d m i l l t e s t i n g a n d a n i n c r e a s e in H R V . T h i s s u g g e s t s that this a g e n t c o u l d h a v e b e n e f i c i a l e f f e c t s o n l o n g - t e r m p r o g n o s i s in p a t i e n t s w i t h h y p e r t e n s i o n .

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