Left ventricular systolic function after inhalation of beta-2 agonists in healthy athletes.
Humans
Male
Female
Adrenergic beta-2 Receptor Agonists
/ administration & dosage
Ventricular Function, Left
/ drug effects
Adult
Young Adult
Albuterol
/ administration & dosage
Administration, Inhalation
Athletes
Double-Blind Method
Formoterol Fumarate
/ administration & dosage
Echocardiography
Cross-Over Studies
Systole
/ drug effects
Bronchodilator Agents
/ administration & dosage
Anti-doping
Athlete
Beta-2 agonists
Echocardiography
Global longitudinal strain
Left ventricular function
Sex-specific thresholds
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 10 2024
08 10 2024
Historique:
received:
04
03
2024
accepted:
23
09
2024
medline:
9
10
2024
pubmed:
9
10
2024
entrez:
8
10
2024
Statut:
epublish
Résumé
Inhaled beta-2 adrenoceptor agonists (iβ2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iβ2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iβ2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iβ2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of β2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021).
Identifiants
pubmed: 39379505
doi: 10.1038/s41598-024-74095-z
pii: 10.1038/s41598-024-74095-z
doi:
Substances chimiques
Adrenergic beta-2 Receptor Agonists
0
Albuterol
QF8SVZ843E
Formoterol Fumarate
W34SHF8J2K
Bronchodilator Agents
0
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
23437Informations de copyright
© 2024. The Author(s).
Références
Fitch, K. D. An overview of asthma and airway hyper-responsiveness in olympic athletes. Br. J. Sports Med. 46, 413–416 (2012).
pubmed: 22228581
doi: 10.1136/bjsports-2011-090814
Price, O. J. et al. Prevalence of lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus group on ‘acute respiratory illness in the athlete’. Br. J. Sports Med. 56, 213–222 (2022).
pubmed: 34872908
doi: 10.1136/bjsports-2021-104601
Cote, A., Turmel, J. & Boulet, L. P. Exercise and asthma. Semin. Respir. Crit. Care Med. 39, 19–28 (2018).
pubmed: 29427982
doi: 10.1055/s-0037-1606215
Irewall, T., Soderstrom, L., Lindberg, A. & Stenfors, N. High incidence rate of asthma among elite endurance athletes: a prospective 4-year survey. J. Asthma. 58, 735–741 (2021).
pubmed: 32077348
doi: 10.1080/02770903.2020.1728769
Levy, M. L. et al. Key recommendations for primary care from the 2022 Global Initiative for Asthma (GINA) update. NPJ Prim. Care Respir. Med. 33, 7 (2023).
pubmed: 36754956
pmcid: 9907191
doi: 10.1038/s41533-023-00330-1
Asthma, G. I. F. Global strategy for asthma management and prevention. 2024 GINA Report (update 22.05.2024) (2024).
Krings, J. G. & Beasley, R. The role of ICS-containing rescue therapy versus SABA alone in asthma management today. J. Allergy Clin. Immunol. Pract. 12, 870–879 (2024).
pubmed: 38237858
doi: 10.1016/j.jaip.2024.01.011
Hostrup, M. et al., Inhaled salbutamol induces leanness in well-trained healthy females but not males during a period of endurance training: a randomised controlled trial. ERJ Open Res. 9 (2023).
Ferrari, M. et al. Evidence of the rapid protective effect of formoterol dry-powder inhalation against exercise-induced bronchospasm in athletes with asthma. Respiration. 67, 510–513 (2000).
pubmed: 11070454
doi: 10.1159/000067465
Nials, A. T. et al. Effects of beta-adrenoceptor agonists in human bronchial smooth muscle. Br. J. Pharmacol. 110, 1112–1116 (1993).
pubmed: 7905340
pmcid: 2175821
doi: 10.1111/j.1476-5381.1993.tb13929.x
Adami, P. E. et al. Cardiovascular effects of doping substances, commonly prescribed medications and ergogenic aids in relation to sports: a position statement of the sport cardiology and exercise nucleus of the European Association of Preventive Cardiology. Eur. J. Prev. Cardiol. 29, 559–575 (2022).
pubmed: 35081615
doi: 10.1093/eurjpc/zwab198
Abosamak, N. R. & Shahin, M. H. Beta2 receptor agonists and antagonists. (2024).
Bizjak, D. A. et al. Acute effects of single Versus Combined inhaled beta2-Agonists salbutamol and formoterol on time trial performance, lung function, metabolic and endocrine variables. Sports Med. Open. 9, 79 (2023).
pubmed: 37640958
pmcid: 10462601
doi: 10.1186/s40798-023-00630-3
Decorte, N. et al. Effect of salbutamol on neuromuscular function in endurance athletes. Med. Sci. Sports Exerc. 45, 1925–1932 (2013).
pubmed: 23559124
doi: 10.1249/MSS.0b013e3182951d2d
Elers, J., Morkeberg, J., Jansen, T., Belhage, B. & Backer, V. High-dose inhaled salbutamol has no acute effects on aerobic capacity or oxygen uptake kinetics in healthy trained men. Scand. J. Med. Sci. Sports. 22, 232–239 (2012).
pubmed: 21083771
doi: 10.1111/j.1600-0838.2010.01251.x
Martineau, L., Horan, M. A., Rothwell, N. J. & Little, R. A. Salbutamol, a beta 2-adrenoceptor agonist, increases skeletal muscle strength in young men. Clin. Sci. (London). 83, 615–621 (1992).
pubmed: 1335400
doi: 10.1042/cs0830615
Parr, M. & Müller-Schöll, A. Pharmacology of doping agents—mechanisms promoting muscle hypertrophy. AIMS Mol. Sci. 5, 131–159 (2018).
Pearen, M. A. et al. The nuclear receptor, Nor-1, markedly increases type II oxidative muscle fibers and resistance to fatigue. Mol. Endocrinol. 26, 372–384 (2012).
pubmed: 22282471
pmcid: 5417129
doi: 10.1210/me.2011-1274
Pearen, M. A. et al. The orphan nuclear receptor, NOR-1, a target of beta-adrenergic signaling, regulates gene expression that controls oxidative metabolism in skeletal muscle. Endocrinology. 149, 2853–2865 (2008).
pubmed: 18325999
doi: 10.1210/en.2007-1202
Pluim, B. M. et al. beta(2)-agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials. Sports Med. 41, 39–57 (2011).
pubmed: 21142283
doi: 10.2165/11537540-000000000-00000
Riiser, A., Stensrud, T., Stang, J. & Andersen, L. B. Can beta2-agonists have an ergogenic effect on strength, sprint or power performance? Systematic review and meta-analysis of RCTs. Br. J. Sports Med. 54, 1351–1359 (2020).
pubmed: 32747344
doi: 10.1136/bjsports-2019-100708
Riiser, A., Stensrud, T., Stang, J. & Andersen, L. B. Aerobic performance among healthy (non-asthmatic) adults using beta2-agonists: a systematic review and meta-analysis of randomised controlled trials. Br. J. Sports Med. 55, 975–983 (2021).
pubmed: 32816795
doi: 10.1136/bjsports-2019-100984
Ryall, J. G., Sillence, M. N. & Lynch, G. S. Systemic administration of beta2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses. Br. J. Pharmacol. 147, 587–595 (2006).
pubmed: 16432501
pmcid: 1751341
doi: 10.1038/sj.bjp.0706669
World Anti-Doping Agency (WADA), WADA`s Executive Committee. The 2024 prohibited list - world anti-doping code. (2024).
Wang, M. T., Lai, J. H., Tsai, C. L. & Liou, J. T. Risk of adverse cardiovascular events with use of inhaled long-acting bronchodilators in management of chronic obstructive pulmonary disease. J. Food Drug Anal. 27, 657–670 (2019).
pubmed: 31324282
pmcid: 9307027
doi: 10.1016/j.jfda.2018.12.006
Janson, C., Wiklund, F., Telg, G., Stratelis, G. & Sandelowsky, H. High use of short-acting beta(2)-agonists in COPD is associated with an increased risk of exacerbations and mortality. ERJ Open Res.9 (2023).
Amegadzie, J. E., Gamble, J. M., Farrell, J. & Gao, Z. Association between Inhaled beta(2)-agonists initiation and risk of major adverse cardiovascular events: a population-based nested case-control study. Int. J. Chron. Obstruct. Pulmon. Dis. 17, 1205–1217 (2022).
pubmed: 35645559
pmcid: 9130098
doi: 10.2147/COPD.S358927
Cazzola, M., Matera, M. G. & Donner, C. F. Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs. 65, 1595–1610 (2005).
pubmed: 16060696
doi: 10.2165/00003495-200565120-00001
Salpeter, S. R., Ormiston, T. M. & Salpeter, E. E. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest. 125, 2309–2321 (2004).
pubmed: 15189956
doi: 10.1378/chest.125.6.2309
Sears, M. R. Adverse effects of beta-agonists. J. Allergy Clin. Immunol. 110, S322–328 (2002).
pubmed: 12464943
doi: 10.1067/mai.2002.129966
Kallergis, E. M. et al. Acute electrophysiologic effects of inhaled salbutamol in humans. Chest. 127, 2057–2063 (2005).
pubmed: 15947320
doi: 10.1378/chest.127.6.2057
Brodde, O. E. Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol. Rev. 43, 203–242 (1991).
pubmed: 1677200
Newton, G. E. & Parker, J. D. Acute effects of beta 1-selective and nonselective beta-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation. 94, 353–358 (1996).
pubmed: 8759076
doi: 10.1161/01.CIR.94.3.353
Furlanello, F., Serdoz, L. V., Cappato, R. & De Ambroggi, L. Illicit drugs and cardiac arrhythmias in athletes. Eur. J. Cardiovasc. Prev. Rehabilit. 14, 487–494 (2007).
pubmed: 17667636
doi: 10.1097/HJR.0b013e3280ecfe3e
Snyder, E. M. et al. Effects of an inhaled beta2-agonist on cardiovascular function and sympathetic activity in healthy subjects. Pharmacotherapy. 31, 748–756 (2011).
pubmed: 21923601
doi: 10.1592/phco.31.8.748
Syed, S. A. et al. Short-term effect of inhaled salbutamol on heart rate in healthy volunteers. Cureus. 13, e13672 (2021).
pubmed: 33824823
pmcid: 8018588
Simon, P., Neuberger, E. W., Wang, G. & Pitsiladis, Y. P. Antidoping Science: important lessons from the medical sciences. Curr. Sports Med. Rep. 17, 326–331 (2018).
pubmed: 30300193
doi: 10.1249/JSR.0000000000000521
Martin, L. et al. New insights for identification of doping with recombinant human erythropoietin micro-doses after high hydration. Drug Test Anal. 8, 1119–1130 (2016).
pubmed: 27390252
doi: 10.1002/dta.2004
Schamasch, P. & Rabin, O. Challenges and perspectives in anti-doping testing. Bioanalysis. 4, 1691–1701 (2012).
pubmed: 22831484
doi: 10.4155/bio.12.145
Kalsen, A., Hostrup, M., Bangsbo, J. & Backer, V. Combined inhalation of beta2 -agonists improves swim ergometer sprint performance but not high-intensity swim performance. Scand. J. Med. Sci. Sports. 24, 814–822 (2014).
pubmed: 23834392
doi: 10.1111/sms.12096
Gaus, W. & Hogel, J. Balanced designs for multiple crossover studies. Arzneimittel-Forschung. 42, 163–172 (1992).
pubmed: 1610429
Zugel, M. et al. The ELSA trial: single versus combinatory effects of non-prohibited beta-2 agonists on skeletal muscle metabolism, cardio-pulmonary function and endurance performance-study protocol for a randomized 4-way balanced cross-over trial. Trials. 22, 903 (2021).
pubmed: 34895300
pmcid: 8665595
doi: 10.1186/s13063-021-05862-w
Lang, R. M. et al., Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr. 28 (1–39), e14 (2015).
Negishi, K. et al. Practical guidance in echocardiographic assessment of global longitudinal strain. JACC Cardiovasc. Imaging. 8, 489–492 (2015).
pubmed: 25129519
doi: 10.1016/j.jcmg.2014.06.013
Voigt, J. U. et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. J. Am. Soc. Echocardiogr. 28, 183–193 (2015).
pubmed: 25623220
doi: 10.1016/j.echo.2014.11.003
Harps, L. et al. Quantitation of formoterol, salbutamol and salbutamol-4’-O-sulfate in human urine and serum by UHPLC-MS/MS. Separations. 10, 368 (2023).
doi: 10.3390/separations10070368
Maack, C. et al. Treatments targeting inotropy. Eur. Heart J. 40, 3626–3644 (2019).
pubmed: 30295807
doi: 10.1093/eurheartj/ehy600
Van Eenoo, P. & Delbeke, F. T. beta-adrenergic stimulation. Handb. Exp. Pharmacol., 227–249 (2010).
Milano, G., Chiappini, S., Mattioli, F., Martelli, A. & Schifano, F. beta-2 agonists as misusing drugs? Assessment of both clenbuterol- and salbutamol-related European medicines agency pharmacovigilance database reports. Basic Clin. Pharmacol. Toxicol. 123, 182–187 (2018).
pubmed: 29498199
doi: 10.1111/bcpt.12991
Boucher, A. et al. Salbutamol misuse or abuse with fatal outcome: a case-report. Hum. Exp. Toxicol. 30, 1869–1871 (2011).
pubmed: 21138987
doi: 10.1177/0960327110388957
Ferrua, S., Varbella, F. & Conte, M. R. Images in cardiology. Acute myocardial infarction due to coronary vasospasm and salbutamol abuse. Heart. 95, 673 (2009).
pubmed: 19329721
doi: 10.1136/hrt.2008.161638
Winter, R. J., Langford, J. A. & Rudd, R. M. Effects of oral and inhaled salbutamol and oral pirbuterol on right and left ventricular function in chronic bronchitis. Br. Med. J. (Clin. Res. Ed.). 288, 824–825 (1984).
pubmed: 6142748
doi: 10.1136/bmj.288.6420.824
Hohlfeld, J. M. et al. Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial. Lancet Respir. Med. 6, 368–378 (2018).
pubmed: 29477448
doi: 10.1016/S2213-2600(18)30054-7
Tedjasaputra, V., Bouwsema, M. M. & Stickland, M. K. Effect of aerobic fitness on capillary blood volume and diffusing membrane capacity responses to exercise. J. Physiol. 594, 4359–4370 (2016).
pubmed: 26959808
pmcid: 4967759
doi: 10.1113/JP272037
Taylor, N. E. et al. Albuterol improves alveolar-capillary membrane conductance in healthy humans. Clin. Med. Insights Circ. Respir. Pulm Med. 10, 19–25 (2016).
pubmed: 27773996
pmcid: 5063752
doi: 10.4137/CCRPM.S30251
Lazovic, B. et al. Comparison of lung diffusing capacity in young elite athletes and their counterparts. Rev. Port. Pneumol. (2006). (2017).
Iversen, E. T., Sorensen, T., Heckscher, T. & Jensen, J. I. Effect of terbutaline on exercise capacity and pulmonary function in patients with chronic obstructive pulmonary disease. Lung. 177, 263–271 (1999).
pubmed: 10384064
doi: 10.1007/PL00007646
Erbel, R. et al. Effects of heart rate changes on left ventricular volume and ejection fraction: a 2-dimensional echocardiographic study. Am. J. Cardiol. 53, 590–597 (1984).
pubmed: 6695789
doi: 10.1016/0002-9149(84)90036-5
Gruca, M. M. et al. Strain echocardiography to describe left ventricular function pre- and postexercise in elite basketball athletes: a feasibility study. Echocardiography. 38, 1165–1172 (2021).
pubmed: 34028863
doi: 10.1111/echo.15121
Alexandre, J. et al. Cardiovascular toxicity related to cancer treatment: A pragmatic approach to the American and European cardio-oncology guidelines. J. Am. Heart Assoc. 9, e018403 (2020).
pubmed: 32893704
pmcid: 7727003
doi: 10.1161/JAHA.120.018403
Luis, S. A., Chan, J. & Pellikka, P. A. Echocardiographic assessment of left ventricular systolic function: an overview of contemporary techniques, including speckle-tracking echocardiography. Mayo Clin. Proc. 94, 125–138 (2019).
pubmed: 30611439
doi: 10.1016/j.mayocp.2018.07.017
Lyon, A. R. et al. ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur. Heart J. 43, 4229–4361 (2022).
pubmed: 36017568
doi: 10.1093/eurheartj/ehac244
Bjork Ingul, C., Rozis, E., Slordahl, S. A. & Marwick, T. H. Incremental value of strain rate imaging to wall motion analysis for prediction of outcome in patients undergoing dobutamine stress echocardiography. Circulation. 115, 1252–1259 (2007).
pubmed: 17325245
doi: 10.1161/CIRCULATIONAHA.106.640334
Ng, A. C. et al. Incremental value of 2-dimensional speckle tracking strain imaging to wall motion analysis for detection of coronary artery disease in patients undergoing dobutamine stress echocardiography. Am. Heart J. 158, 836–844 (2009).
pubmed: 19853706
doi: 10.1016/j.ahj.2009.09.010
Bizjak, D., Dreyhaupt, J., Steinacker, J. & Parr, M. Acute effects of single vs. combinatory inhaled β2-agonists salbutamol and formoterol on time trial performance, lung function, metabolic and endocrine variables. (2023).