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(Chest. 2005;128:1136-1139.)
© 2005 American College of Chest Physicians

Comparison of the Short-term Effects of Salmeterol and Formoterol on Heart Rate Variability in Adult Asthmatic Patients*

Beyhan Eryonucu, MD; Kürsat Uzun, MD; Niyazi Güler, MD; Mustafa Tuncer, MD and Cengizhan Sezgi, MD

* From the Departments of Cardiology (Drs. Eryonucu, Güler, and Tuncer) and Chest Diseases (Drs. Uzun and Sezgi), Medical Faculty, Yüzüncü Yil University, Van, Turkey.

Correspondance to: Beyhan Eryonucu, MD, Yüzüncü Yil dUniversitesi, Tip Fakültesi Kardiyoloji AD, 65200 Van, Turkey; e-mail: drbeyhan{at}yahoo.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: We investigated the effects of ß2-adrenergic agonists salmeterol and formoterol on heart rate variability (HRV) in adult asthmatic patients using time-domain measures of HRV.

Patients: Thirty-nine adult patients with asthma were studied. All patients showed a mild-to-moderate decrease in baseline FEV1. Any diseases that might have influenced the autonomic function were excluded. All patients underwent a complete physical examination and medical history that revealed no cardiovascular disease or medication.

Methods: The ß2-adrenergic inhaled agonists salmeterol, 50 µg, and formoterol, 12 µg, were used in the study. HRV analysis was performed for each 5-min segment: 5 min and 10 min before inhalation of the study drug, and 5, 10, 15, 20, 25, and 30 min after inhalation. Time-domain parameters of HRV were calculated: (1) the SD all normal-to-normal intervals; (2) the SD of the mean of all normal-to-normal intervals in all 5-min segments of the entire recording; (3) the root mean square of differences between adjacent normal-to-normal intervals; (4) the mean of the SD of all normal-to-normal intervals in all the 5-min intervals; and (5) the SD of the SD of all normal-to-normal intervals in all the 5-min intervals.

Results: Baseline HRV parameters were not significantly different between formoterol and salmeterol groups. There were no significant differences in HRV parameters after formoterol and salmeterol inhalation. The HRV parameters in each 5-min segment in the formoterol group were not statistically significant different when compared to the same segment in the salmeterol group.

Conclusion: Salmeterol and formoterol have no short-term adverse effects on HRV.

Key Words: asthma • heart rate • inhalation • therapeutics


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heart rate variability (HRV) is a reliable indicator for assessment of autonomic cardiovascular function. Indexes of the HRV reflect cardiac autonomic tone.12 Decreased HRV is associated with increased mortality and morbidity with various forms of heart disease including myocardial infarction, cardiomyopathy, congestive heart failure, and chronic mitral regurgitation.3456789

Sympathetic/parasympathetic regulation of heart rate in subjects with bronchial asthma differs from that of normal subjects.1011 Sympathetically mediated HRV was significantly lower in both asymptomatic and acute asthma patients compared to healthy control subjects.12

Formoterol and salmeterol are two, inhaled, long-acting, ß2-adrenergic agonists.13 Both of these drugs have become the most effective bronchodilator agents in the regular treatment of asthmatic patients. Side effects of ß-agonists, which are quite rare, are numerous, and most stem from activation of ß1-receptors. ß2-adrenergic agonists may interfere with autonomic cardiovascular function.14

To our knowledge, although the effects of salmeterol on HRV in asthmatic children have been established, the effects of salmeterol and formoterol therapy on HRV in asthmatic adult patients have not been established.15 Our aim was to assess and compare the short-term effects of salmeterol and formoterol therapy on HRV in patients with asthma by using time-domain measures of HRV.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
Thirty-nine patients (mean age, 35 ± 7 years [± SD]; range, 23 to 48 years) with newly diagnosed or known cases of bronchial asthma were studied. Asthmatic patients were selected consecutively according to the American Thoracic Society guidelines.16 None of the patients were receiving oral and inhaled asthma medications (ß2-agonists and corticosteroids) for the previous 1 month. All patients showed a mild-to-moderate decrease in baseline FEV1. Patients with diabetes mellitus, renal disorders, or any diseases that might have influenced the autonomic function were excluded. The patients all underwent a complete physical examination and medical history that revealed no cardiovascular disease or medication. Blood chemistry and urine test results were within the normal range. The patients also had normal BP, ECG, and transthoracic echocardiography findings. The clinical characteristics of the patients are shown in Table 1 . All patients gave informed consent to the study, which was approved by the hospital ethical committee.


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  		Table 1.. Clinical Characteristics of Patients*

 
Study Design
If all inclusion criteria were fulfilled, the patients were included in the study. The study followed a randomized design. The patients were studied once. The studies were done between 9 AM and 12 noon to avoid circadian variation of HRV parameters.

Study Drugs
The drugs used were inhaled salmeterol, 30 µg (Serevent; Glaxo Wellcome; Birmingham, UK) and inhaled formoterol, 12 µg (Oxis Turbohaler; Astra; Södertälje, Sweden). The subjects directly inhaled the drug without a spacer device after full expiration and then held their breath for 10 s.

Holter Monitoring and HRV Analysis
The ambulatory ECGs were recorded by a recorder (Del Mar Avionics 483 Digicorder; Del Mar Medical Systems; Irvine, CA) 30 min before and 1 h after drug inhalation. All Holter recordings were obtained at rest in the supine position. The patients quietly breathed during the Holter recordings. Thus, the effect of respiration on HRV was minimized. These recordings were analyzed with special computer software (Del Mar Holter Analysis System; Del Mar Medical Systems). All recordings were visually examined and manually overread to verify beat classification. Abnormal beats and areas of artifact were automatically and manually identified and excluded from the analysis. All patients were in sinus rhythm throughout the recordings. The time-domain analysis of HRV was performed. HRV analysis were performed, and the mean heart rate was calculated for 5 min before inhalation of the study drug and six sequential, 5-min intervals starting after the inhalation of study drugs.

The following parameters were used in evaluation of HRV in time domain: (1) SD of all normal-to-normal intervals (SDNN [milliseconds]); (2) SD of mean of all normal-to-normal intervals in all consecutive 5-min segments of the entire recording (SDANN [milliseconds]); (3) the root mean square of differences between adjacent normal-to-normal intervals (RMSSD [milliseconds]); (4) mean of the SD in all 5-min intervals (HRVM [milliseconds]); and (5) SD in all 5-min intervals (SDHRV [milliseconds]).

Statistical Analysis
Results are expressed as the mean ± SD. The normal distribution of the variables was evaluated using Kolmogorov-Smirnov tests. Data between the groups were compared with {chi}2 test or Fisher Exact Test and Student unpaired two-tailed t test. The changes of HRV parameters after inhalation of the study drugs were compared with paired t tests. A two-tailed p value < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
HRV parameters before and after inhalation of the study drugs are shown in Table 2 and Figure . Baseline HRV parameters were not significantly different between formoterol and salmeterol groups. There were no significant differences in HRV parameters after the formoterol and salmeterol inhalation. The HRV parameters in each 5-min segment in the formoterol group were not statistically significant different when compared to the same segment in the salmeterol group.


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  		Table 2.. Changes of HRV Parameters After Formoterol and Salmeterol Inhalation*

 


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  		Figure 1.. Changes of HRV parameters after formoterol and salmeterol.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study showed that both formoterol and salmeterol have no short-term effects on autonomic cardiovascular function in asthmatic adult patients. Time-domain parameters of HRV did not change in the short-term period after formoterol and salmeterol inhalation.

HRV analysis can be used for assessment of autonomic cardiovascular activity.12 This analysis showed that the asthmatic children have an increased parasympathetic and sympathetic activity as compared to healthy children. The different autonomic nervous function of asthmatic children is related to severity of the asthma.111213

In the previous studies,151718 acute salbutamol and fenoterol inhalation showed increased adrenergic activity in asthmatic children. Similarly, we showed that acute salbutamol and terbutalin inhalation produce similar effects on HRV and increase sympathetic modulation in the cardiac autonomic activity in adult asthmatic patients.19 The cardiovascular actions of ß-adrenergic agonists result from direct myocardial effects and from indirect rate effects that result from baroreceptor reflexes to peripheral dilation. The observed ß2-agonist–induced changes of HRV result from increased ß-receptor stimulation.

Jartti et al15 compared heart rate, HRV, and arterial pressure variability in baseline and after a 4-week salmeterol treatment period, and found that salmeterol therapy in asthmatic children increases sympathetic dominance in the cardiovascular autonomic balance. We did not find acute HRV changes after salmeterol and formoterol inhalation in the 30-min period. HRV analysis of the long-term period may elicit a chronic effect of salmeterol and formoterol inhalation on HRV parameters in adult asthmatic patients.

Increased sympathetic activity may be implicated in the pathogenesis of a number of cardiovascular risk factors, including insulin resistance, hypertension, and cardiovascular hypertrophy.2021 In addition, increased sympathetic activity assessing by HRV analysis is related to increase cardiac mortality, morbidity, and sudden death in patients with heart disease.3456789 Therefore, although formoterol and salmeterol are safe drugs in the short-term period in patients without heart disease, further studies are needed to evaluate the long-term effects of these drugs on HRV in asthmatic patients with heart disease.


   Footnotes
 
Abbreviations: HRV = heart rate variability; HRVM = mean of the SD of all normal-to-normal intervals in all 5-min intervals; RMSSD = root mean square of differences between adjacent normal-to-normal intervals; SDANN = SD of mean of all normal-to-normal intervals in all consecutive 5-min segments of the entire recording; SDHRV = SD of all normal-to-normal intervals in all 5-min intervals; SDNN = SD of all normal-to-normal intervals

Received for publication November 29, 2004. Accepted for publication January 4, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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This Article
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