Formoterol

Study objectives: We investigated the effects of [[beta].sub.2]-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 FE[V.sub.1]. 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 [[beta].sub.2]-adrenergic inhaled agonists salmeterol, 50 [micro]g, and formoterol, 12 [micro]g, 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

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

**********

Heart rate variability (HRV) is a reliable indicator for assessment of autonomic cardiovascular function. Indexes of the HRV reflect cardiac autonomic tone.1-2 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. (3-9)

Sympathetic/parasympathetic regulation of heart rate in subjects with bronchial asthma differs from that of normal subjects. (10,11) 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, [[beta].sub.2]-adrenergic agonists. (13) Both of these drugs have become the most effective bronchodilator agents in the regular treatment of asthmatic patients. Side effects of [beta]-agonists, which are quite rare, are numerous, and most stem from activation of [[beta].sub.1]-receptors. [[beta].sub.2]-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

Study Subjects

Thirty-nine patients (mean age, 35 [+ or -] 7 years [[+ or -] 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 ([[beta].sub.2]-agonists and corticosteroids) for the previous 1 month. All patients showed a mild-to-moderate decrease in baseline FE[V.sub.1]. 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.

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 [micro]g (Serevent; Glaxo Wellcome; Birmingham, UK) and inhaled formoterol, 12 [micro]g (Oxis Turbohaler; Astra; Sodertalje, 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 [+ or -] SD. The normal distribution of the variables was evaluated using Kolmogorov-Smirnov tests. Data between the groups were compared with [chi square] 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

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.

DISCUSSION

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. (1,2) 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. (11-13)

In the previous studies, (15,17,18) 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 [beta]-adrenergic agonists result from direct myocardial effects and from indirect rate effects that result from baroreeeptor reflexes to peripheral dilation. The observed [[beta].sub.2]-agonist-induced changes of HRV result from increased [beta]-receptor stimulation.

Jartti et al (15) 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 autonomie 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. (20-21) In addition, increased sympathetic activity assessing by HRV analysis is related to increase cardiac mortality, morbidity, and sudden death in patients with heart disease. (3-9) 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.

REFERENCES

(1) Task Force of European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation and clinical use. Circulation 1996; 93:1043-1065

(2) Aubert AE, Ramaekers D. Neurocardiology: the benefits of irregularity; the basics of methodology, physiology and current clinical applications. Acta Cardiol 1999; 54:107-120

(3) Stein PK, Domitrovich PP, Kleiger RE, et al. Including patients with diabetes mellitus or coronary artery bypass grafting decreases the association between heart rate variability and mortality after myocardial infarction. Am Heart J 2004; 147:309-316

(4) Wennerblom B, Lurje L, Tygesen H, et al. Patients with uncomplicated coronary artery disease have reduced heart rate variability mainly affecting vagal tone. Heart 2000; 83:290-294

(5) Karez M, Chojnowska L, Zareba W, et al. Prognostic significance of heart rate variability in dilated cardiomyopathy. Int J Cardiol 2003; 87:75-81

(6) Singh N, Mironov D, Armstrong PW, et al. Heart rate variability assessment early after acute myocardial infarction: pathophysiological and prognostic correlates. Circulation 1996; 93:1388-1395

(7) Nolan J, Batin PD, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure. Circulation 1998; 98:1510-1516

(8) Ponikowski P, Anker SD, Tuan PC, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997; 79: 1645-1650

(9) Stein KM, Borer JS, Hochreiter C, et al. Prognostic value and physiological correlates of heart rate variability in chronic severe mitral regurgitation. Circulation 1993; 88:127-135

(10) Fujii H, Fukutomi O, Inoue R, et al. Autonomic regulation after exercise evidenced by spectral analysis of heart rate variability in asthmatic children. Ann Allergy Asthma Immunol 2000; 85:233-237

(11) Kazuma N, Otsuka K, Matsuoka I, et al. Heart rate variability during 24 hours in asthmatic children. Chronobiol Int 1997; 14:597-606

(12) Garrard CS, Seidler A, McKibben A, et al. Spectral analysis of heart rate variability in bronchial asthma. Clin Auton Res 1992; 2:105-111

(13) Sovani MP, Whale CI, Tattersfield AE. A benefit-risk assessment of inhaled long-acting [[beta].sub.2]-agunists in the management of obstructive pulmonary disease. Drug Saf 2004; 27:689-715

(14) Salpeter SR. Cardiovascular safety of [[beta].sub.2]-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review. Drugs Aging 2004; 21:405-414

(15) Jartti TT, Kaila TJ, Tahvanainen KU, et al. Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children. Clin Physiol 1998; 18:345-353

(16) American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease and asthma. Am Rev Respir Dis 1987; 136:225-244

(17) Jartti TT, Kaila TJ, Tahvanainen KUO, et al. Altered cardiovascular autonomic regulation after 2-week inhaled salbutamol treatment in asthmatic children. Eur J Pediatr 1997; 156:883-888

(18) Jartti T, Kaila T, Tahvanainen K, et al. The acute effects of inhaled salbutamol on the beat-to-beat variability of heart rate and blood pressure assessed by spectral analysis. Br J Clin Pharmacol 1997; 43:421-428

(19) Eryonucu B, Uzun K, Guler N, et al. Comparison of the acute effects of salbutamol and terbutaline on heart rate variability in adult asthmatic patients. Eur Respir J 2001; 17:863-867

(20) Palatini P, Julius s. Heart rate and cardiovascular risk. J Hypertens 1997; 15:3-17

(21) Barron HV, Lesh MD. Autonomic nervous system and sudden cardiac death. J Am Coll Cardiol 1996; 27:1053-1060

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

Manuscript received November 29, 2004; revision accepted January 4, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondance to: Beyhan Eryonucu, MD, Yuzuncu Yil Universitesi, Tip Fakultesi Kardiyoloji AD, 65200 Van, Turkey; e-mail: drbeyhan@yahoo.com

COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group