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Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults
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Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults ¨ Cem Ozde MD , Adnan Kaya MD , Ismail Hakkı Akbudak , Guls¸ah Akture ¨ , Osman Kayapinar MD PII: DOI: Reference:
S0002-9149(19)31314-1 https://doi.org/10.1016/j.amjcard.2019.11.020 AJC 24310
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
8 October 2019 11 November 2019 13 November 2019
¨ Please cite this article as: Cem Ozde MD , Adnan Kaya MD , Ismail Hakkı Akbudak , Guls¸ah Akture ¨ , Osman Kayapinar MD , Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults, The American Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.amjcard.2019.11.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults
Cem Özde1, MD, Adnan Kaya1, MD, İsmail Hakkı Akbudak2, Gulşah Aktüre1, Osman Kayapinar1, MD. 1
Department of Cardiology, Düzce University Training and Research Hospital, Düzce, Turkey 2
Department of İnternal Medicine, Pamukkale University Training and Research Hospital, Denizli, Turkey
Corresponding Author: Osman Kayapinar, MD Department of Cardiology, Düzce University Faculty of Medicine, 8100 Konuralp, Düzce Turkey E-mail: [email protected] GSM: +90 532 419 07 00 Fax: +90 380 542 14 16
1
Abstract Energy drinks (EDs) are widely consumed by adolescents and young adults. Almost all kinds of arrhythmias have been reported following EDs consumption, most of which is atrial fibrillation (AF). Atrial conduction time prolongation and heterogeneous sinusal impulses propagation to the atriums are the key electrophysiological mechanisms leading AF. We aimed to evaluate the acute effects of Red Bull ED ingestion on atrial electromechanical conduction times in healthy young adults. After a 12hour fasting, 54 healthy young adults consumed 330 mL of Red Bull ED. Atrial electromechanical coupling (PA), intra-atrial electromechanical delay (intra-AEMD), and inter-atrial electromechanical delay (inter-AEMD) were measured at baseline and 2-hour after Red Bull ED ingestion by echocardiographic tissue-Doppler imaging (TDI) method. PA-lateral (49.7 ± 11.2 vs. 54.1 ± 11.0 msn, p=0.001) and PA-septal (40.8 ± 9.1 vs. 43.7 ± 10.5 msn, p=0.032) times were statistically significantly prolonged after Red Bull ED ingestion. There was also a statistically significant increase in the duration of inter-AEMD (14.4 ± 10.6 vs. 18.1 ± 8.5 msn, p=0.010) after ED ingestion. It was showed that even a single can of ED can acutely increase atrial electromechanical conduction times in young adults. These findings may be the cause of ED-associated AF.
Key words: energy drink, Red Bull, atrial electromechanical functions, atrial fibrillation
2
Introduction Energy drinks (EDs) are widely consumed by adolescents and young adults and Red Bull is among the most popular one with annual global sales (1, 2). EDs mainly differ from other soft drinks regarding their high level caffeine and taurine content and possible effects on physical and cognitive performance. Despite the potential beneficial effects, EDs have been accused of causing abnormal heart rhythms and heart attacks (3). The numerous reported cases indicate the association of energy drinks with adverse cardiac events. Besides, a review showed association of EDs with adverse cardiovascular events, cardiac arrhythmias such as malign ventricular arrhythmias, ST segment elevation myocardial infarction, QT interval prolongation and atrial fibrillations (4, 5). Recent increase in the number of atrial fibrillation (AF) cases associated with energy drinks is remarkable (6-10). However, the mechanisms for AF in this setting have not been fully elucidated. Delay in the intra- and interatrial conduction times and heterogeneous propagation of sinus impulses are well-known electrophysiological characteristic for AF predisposition. There is a lack of evidence about the effect of EDs on atrial electromechanical conduction times which could explain the AF mechanism in this setting. In this study, we aimed to investigate the acute effect of Red Bull on atrial electromechanical conduction times by tissue Doppler imaging (TDI). Methods This is a prospective, observational and open-label study. The study population consisted of 54 healthy young adults (mean age: 23.3 ± 4.2 years). All subjects were self-described as healthy, with no history of cardiovascular diseases including hypertension and diabetes mellitus. All subjects had normal findings on physical examination and electrocardiography (ECG). None of the subjects had smoking, alcohol or drug use, and none of them used a regular medication. All subjects were familiar with Red Bull® and some participants have previously consumed this beverage in their daily lives. However, four subjects were very rarely consumers of energy drinks (no more than 1 energy drink per month). Sixty volunteers were included in the study. However, six volunteers had nausea while drinking Red Bull and could not finish one can (330 cc) of Red Bull. These volunteers were excluded 3
from the study. Other subjects completed the study without any problems. Informed consent was obtained from all the patients prior to the study. The local ethics committee approved the study protocol, and all the patients signed written informed consent. All subjects abstained from caffeinated products (such as coffee or coke) for at least 3 days before study initiation. All evaluations took place in a quiet, dimly lit, temperature-controlled (20°C– 24°C) echocardiography room and started between 8:00 am and 10:00 am. After a 12-hour fast, all subjects consumed a 330 mL of Red Bull ED containing caffeine (114 mg), taurine (1.42 mg), glucuronolactone (84.2 mg), and sucrose and glucose (39.1 g) at room temperature. All patients drank their own drinks in about 5 minutes. Baseline echocardiography was performed, and a subsequent echocardiography was performed 2 hours after ingestion of Red Bull. On average, three cases were evaluated every day and the data of all cases were collected in approximately twenty days. Afterwards, all data were analyzed. All the echocardiographic measurements (2-D echocardiography, M-mode echocardiography, pulsed wave Doppler, color flow Doppler) were performed and recorded by a cardiologist blinded to the clinical details and outcomes of the study. Records were analyzed by another physician, who was blinded to the study. Transthoracic echocardiography (TTE) recordings were performed while the patients were in the left lateral decubitus position. Apical four-chamber views (A4CW), as well as two-chamber and parasternal images, were recorded at expiratory apnea for three consecutive cardiac cycles using a 3.0 MHz phased-array transducer with an echocardiography (Vivid 7 Pro, GE, Horten, Norway) device. The echocardiography evaluation was performed with combination of surface ECG (DII) monitoring. All the measurements were performed according to the American Society of Echocardiography (11). Left atrial dimension, left ventricle (LV) end systolic dimension, LV end diastolic dimension, LV ejection fraction (EF), interventricular septal thickness, and posterior wall thickness were measured. A transducer of 3.5-4.0 MHz of frequencies was used for TDI adjusted for a nyquist limit of 15-20 cm/s while gaining the examples. A monitor sweep of 50-100 mm/s was used to optimize the
4
gain. The pulsed wave Doppler measurements were acquired from the lateral mitral annulus, the septal mitral annulus, and the lateral tricuspid annulus. The sample window was positioned as parallel as possible to the target area to obtain the most accurate measurements. Atrial electromechanical coupling time which is calculated from the beginning of the surface P wave to the beginning of the late diastolic wave (Am wave) was calculated for lateral mitral annulus (PA lateral), the septal mitral annulus (PA septal), and the lateral tricuspid annulus (PA tricuspid) (Figure 1). All the measurements were averaged over four consecutive beats and corrected for heart rate. The inter-atrial electromechanical delay (AEMD) was calculated with subtraction of PA tricuspid from the PA lateral. The intra-AEMD was calculated with subtraction of PA tricuspid from the PA septal (12, 13). The intraobserver variability was assessed in fifteen subjects by repeating the measurements under the same conditions. The cardiologist, blinded to previously obtained data, separately measured atrial electromechanical coupling time from fifteen random patients for intra-observer variability analysis. Additionally, an experienced observer calculated PA-lateral, PA-septal and PA-tricuspidal values twice on two consecutive days for analysis of intra-observer variability. We employed intra-observer variability to determine the interclass coefficient. Statistical analyses were performed using SPSS software version 20 (SPSS Inc, Chicago, Illinois). The Kolmogorov-Smirnov test was used to assess the distribution of the data. Continuous data are expressed as means ± standard deviation and categorical data as percentages. The paired sample t-test was used to assess differences between variables before and after Red Bull® consumption. A P value <0.05 was considered significant. Results The main characteristics of all subjects are presented in table 1. Blood pressure and heart rate values before and after Red Bull consumption are presented in table 2. There was a statistically significant increase in systolic blood pressure and heart rate in the second hour after Red Bull consumption, but no significant change in diastolic blood pressure. The results of two-dimensional conventional and Doppler echocardiography parameters are presented in table 3. There was no
5
significant change in basic echocardiographic parameters after energy drink consumption. Atrial electromechanical function parameters of different sites measured by tissue Doppler imaging are presented in table 4. Some atrial electromechanical conduction time parameters statistically significantly altered after Red Bull consumption. PA-lateral and PA-septal durations were statistically significantly prolonged at the second hour after Red Bull consumption. The results are summarized in figure 2. However, no significant change was observed in PA-tricuspid duration. There was also a statistically significant increase in the duration of inter-AEMD. However, there was no significant change in left and right intra-AEMD durations. Discussion In the present study, we investigated the acute effect of Red Bull, a well-known ED, on the atrial electromechanical conduction times in young adults. We found that consumption of a can of Red Bull in young adults is associated with prolongation of atrial electromechanical conduction times in the acute phase. We found that the left atrial electromechanical coupling time was prolonged temporally and the inter-AEMD was prolonged. Additionally, we have found that the heart rate and systolic blood pressure increased after Red Bull consumption in acute period. To the best of our knowledge, this is the first study to investigate the relationship between ED and atrial electromechanical conduction times. Red Bull consumption in young adults seems to be associated with deterioration of atrial electromechanical functions which may be a predisposing factor for new AF development in acute period. Energy Drinks include some of the fastest-growing products of the beverage industry mostly targets young adults (1). EDs are soft drinks that contain high amount of caffeine, taurine, glucuronolactone, herbal supplements, vitamins, minerals, and carbohydrates; and they are marketed with the claim that they improve cognitive and physical performance (14). The performance enhancing effect of EDs is thought to be primarily related to caffeine which is approximately four-fold more than an ordinary soda contains. Caffeine is a well-known stimulant molecule that has been studied over long periods of time. It has a potent stimulant effect especially at high doses. Direct adenosine receptor
6
stimulation in addition to the impacts on monoamine neurotransmitters are the main mechanisms (15). Caffeine mimics the inotropic and chronotropic effects of epinephrine on cardiomyocytes through βadrenergic stimulation (15). Hence, it enhances periphery vasodilatation and stimulates positively cardiac functions simultaneously which increase systemic blood pressure. It is also showed that caffeine may increase circulating catecholamine level in normal healthy individuals (16). Large quantity and rapid manner of caffeine ingestion with EDs may cause massive fluctuations in the circulating catecholamine levels and so arrhythmia (17). Additionally, taurine, ginseng and guarana may be found in variant quantities in EDs, which may cause addition unclear interactions (4) Taurine, may have detrimental impacts on myocardial sodium channels and may lead to arrhythmia (18). High amounts of taurine can shorten the duration of cardiac action potential and may provoke both atrial and ventricular arrhythmia by slowing down the terminal repolarization of cardiac action potential (19). Additionally, many brands of EDs may contain more caffeine than the calculated caffeine, as they may not indicate the immeasurable additional caffeine from substances, such as cola nut, yerba mate and guarana, which contain significant amounts of caffeine. Another one, young adults who thought to be the target consumer population of EDs are more vulnerable to caffeine-related adverse events. The reason for this is that the pharmacological tolerance over time to caffeine is not present in these young-adults yet (4, 17). A relationship between AF and atrial electromechanical conduction delay has been shown (13, 20). Patients with a history of paroxysmal AF, even those with a history of isolated AF (lone AF), have abnormal atrial refractoriness and conduction as compared to patients without AF. Moreover, there are clinical studies suggesting an association between prolongation of atrial conduction times and the risk of developing new AF (21, 22). Electrophysiological maps of AF in humans suggest that AF is caused by multiple wandering wavelets, and these may be due to heterogeneity of atrial conduction and refractoriness. So that conduction abnormalities may create a favorable microenvironment for re-entry mechanism (23). In this context, AEMDs constitute an important substrate for the development of atrial arrhythmias. Conduction delays decrease the atrial tissue wavelength, increase refractory period dispersion, and promote spatiotemporal heterogeneities in atrial 7
electrophysiology. These are well known substrates of reentry in AF patients. Moreover, AEMDs are associated with an increased incidence of atrial premature beats, thus facilitating the starting of the reentry likely due to abnormal tissue activation such as retrograde left atrial activation (24-26). Noninvasive atrial electromechanical coupling assessment by echocardiographic TDI is performed by calculation of electromechanical intervals easily (13, 22). By this method, we showed increased atrial electromechanical (AEM) conduction times with ED ingestion which in turn may be accepted as a substrate for AF development. This study was limited by the relatively small number of healthy volunteer young adults. Our results are limited to young healthy volunteers and require confirmation in other more vulnerable cohorts, such as those with underlying cardiovascular disease. We evaluated only the effects of a single can of ED consumption. At higher doses the results may be differ. The PA measurement method may have influenced our results. The results could be different with invasive electrophysiological evaluation. However, the major limitation of electrophysiologic method is that such a procedure may not be approved by the local ethics committee. In addition to these, the electrophysiologic modalities cannot be reached easily, are more expensive, require more advanced expertise and reside a complication risks. Conducting more frequent blood pressure measurements and serial ECGs to identify the timing of the greatest change in blood pressure and each electrocardiographic parameter may provide additional insights. Volunteers included in the study did not receive a standard diet program before the study. Different diets may have an impact on the results. We have concluded that even a single can of Red Bull can acutely increase atrial electromechanical conduction time in healthy young adults. These findings may be the cause of EDassociated AF. However, randomized controlled studies are needed to confirm the current hypothesis. Disclosures The authors have no conflicts of interest to disclose. Acknowledgements None 8
1. Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T, Barber-Heidal K. A survey of energy drink consumption patterns among college students. Nutr J 2007; 6:35. 2. Red Bull company figures. https://energydrink.redbull.com/company. Accessed April 5, 2019. 3. Lattouf A, Vukovic D (2017) Energy drinks could be deadly for young people with heart conditions, study finds. ABC (16 February 2017), Sydney. https://www.abc.net.au/news/2017-0216/energy-drinks-dangers-for-young-unaware-of-heart-problems/8275484 Accessed 30 Dec 2018 4. Higgins JP, Tuttle TD, Higgins CL. Energy beverages: content and safety. Mayo Clin Proc 2010; 85: 1033-1041. 5. Goldfarb M, Tellier C, Thanassoulis G. Review of published cases of adverse cardiovascular events after ingestion of energy drinks. Am J Cardiol 2014; 113: 168-172. 6. Thyagarajan B, Alagusundaramoorthy SS, Agrawal A. Atrial fibrillation due to over the counter stimulant drugs in a young adult. J Clin Diagn Res 2015; 8: 5-7. 7. Di Rocco JR, During A, Morelli PJ, Heyden M, Biancaniello TA. Atrial fibrillation in healthy adolescents after highly caffeinated beverage consumption: two case reports. J Med Case Rep 2011; 5:18. 8. Sattari M, Sattari A, Kazory A. Energy drink consumption and cardiac complications: a case for caution. J Addict Med 2016; 10: 280-282. 9. Mattioli AV, Pennella S, Farinetti A, Manenti A. Energy drinks and atrial fibrillation in young adults. Clin Nutr 2018; 37: 1073-1074. 10. Izquierdo Fos I, Vázquez Gomis RM, Vázquez Gomis C, Piernas R, Climent Forner E, Llaguno Salvador MD, Vargas Torcal F. Atrial fibrillation after ingestion of a high energy drink. An Pediatr 2012; 77: 417-419. 9
11. Rein AJ, O’Donnell CP, Colan SD, Marx GR. Tissue velocity Doppler assessment of atrial and ventricular electromechanical coupling and atrioventricular time intervals in normal subjects. Am J Cardiol 2003; 92: 1347-1350 12. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440-1463. 13. Omi W, Nagai H, Takamura M, Okura S, Okajima M, Furusho H, Maruyama M, Sakagami S, Takata S, Kaneko S. Doppler tissue analysis of atrialel ectromechanical coupling in paroxysmal atrial fibrillation. J Am Soc Echocardiogr 2005; 18: 39–44. 14. Seifert SM, Schaechter JL, Hershorin ER, Lipshultz SE. Health effects of energy drinks on children, adolescents, and young adults. Pediatrics 2011; 127: 511-528. 15. Cannon ME, Cooke CT, McCarthy JS. Caffeine-induced cardiac arrhythmia: an unrecognized danger of health food products. Med J Aust 2001; 174: 520-521. 16. Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, Oates JA. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978; 298: 181186. 17. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks--a growing problem. Drug Alcohol Depend 2009; 99:1-10. 18. Satoh H. Cardiac actions of taurine as a modulator of the ion channels. Adv Exp Med Biol 1998; 442: 121-128. 19. Read WO, Byrne JE. Effect of taurine on the refractory period of heart muscle. Physiologist 1966; 9: 273. 10
20. Platonov PG, Yuan S, Hertervig E, Kongstad O, Roijer A, Vygovsky AB, Chireikin LV, Olsson SB. Further evidence of localized posterior interatrial conduction delay in lone paroxysmal atrial fibrillation. Europace 2001; 3: 100-107. 21. Daubert JC, Pavin D, Jauvert G, Mabo P. Intra- and interatrial conduction delay: implications for cardiac pacing. Pacing Clin Electrophysiol 2004; 27: 507-525. 22. Cui QQ, Zhang W, Wang H, Sun X, Wang R, Yang HY, Meng XQ, Zhang Y, Wang H. Assessment of atrial electromechanical coupling and influential factors in nonrheumatic paroxysmal atrial fibrillation. Clin Cardiol 2008; 31: 74-78. 23. Atienza F, Almendral J, Moreno J, Vaidyanathan R, Talkachou A, Kalifa J, Arenal A, Villacastín JP, Torrecilla EG, Sánchez A, Ploutz-Snyder R, Jalife J, Berenfeld O. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation 2006; 114: 2434-2442. 24. Martínez-Sellés M, Martínez-Sellés M, Massó-van Roessel A, Álvarez-García J, García de la Villa B, Cruz-Jentoft AJ, Vidán MT, López Díaz J, Felix Redondo FJ, Durán Guerrero JM, Bayes-Genis A, Bayes de Luna A; Investigators of the Cardiac and Clinical Characterization of Centenarians (4C) registry. Interatrial block and atrial arrhythmias in centenarians: prevalence, associations, and clinical implications. Heart Rhythm 2016; 13: 645-651. 25. Bayés De Luna A, Cladellas M, Oter R, Torner P, Guindo J, Martí V, Rivera I, Iturralde P. Interatrial conduction block and retrograde activation of the left atrium and paroxysmal supraventricular tachyarrhythmia. Eur Heart J 1988; 9: 1112-1118. 26. Johner N, Namdar M, Shah DC. Intra- and interatrial conduction abnormalities: hemodynamic and arrhythmic significance. J Interv Card Electrophysiol 2018; 52: 293-302.
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Figure 1. Atrial electromechanical coupling time.
Figure 2. Atrial electromechanical conduction times before and after Red Bull. Table 1. Demographic Characteristics and Laboratory Findings of the Subjects (n=54)
Age (year) Male Female Body mass index (kg/m2) Smoke (-) (+) Fasting blood glucose (mg/dl) Creatinine (mg/dl) Blood urea nitrogen Thyroid-stimulating hormone (mIU/L) Aspartate transaminase (U/L) Hemoglobin (g/dl)
Mean value ± standard deviation (n=54) 23.3 ± 4.2 34 (63.0%) 20 (37.0%) 24.3 ± 4.5 26 (48.1%) 28 (51.9%) 83.6 ± 8.0 0.7 ± 0.1 12.8 ± 2.1 1.4 ± 1.3 22.1 ± 3.7 13.7 ± 1.2
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Table 2. Blood pressure and heart rate findings Before Red Bull (n=54) Systolic blood pressure (mmHg) 109.9 ± 4.0 Diastolic blood pressure (mmHg) 73.1 ± 3.0 Mean blood pressure (mmHg) 85.5 ± 4.0 Heart Rate (beat per minute) 74.7 ± 10.8
After Red Bull (n=54) 113.1 ± 2.6 72.2 ± 4.8 86.4 ± 5.5 80.7 ± 11.9
p value <0.001 0.8 0.1 <0.001
Table 3. Basic Echocardiographic Characteristics
Left atrial diameter (mm) Trans-mitral flow velocity during early ventricular filling (E) (cm/s) Trans-mitral flow velocity during atrial contraction (A) (cm/s) Mitral deceleration time (ms) Mitral E/A ratio Tissue Doppler velocity at the mitral annulus during early ventricular filling (E’) Tissue Doppler velocity at the mitral annulus during atrial contraction (A’) (cm/s) Mitral lateral E’/A’ ratio (cm/s) Mitral lateral isovolumetric relaxation time (ms) Right atrial diameter Systolic pulmonary artery pressure (mmHg) Left ventricle interventricular septum thickness (mm) Left ventricle posterior wall thickness (mm) Left ventricle end-diastolic diameter (mm) Left ventricle end-systolic diameter (mm) Left ventricle ejection fraction (%)
Before Red Bull (n =54) 29.5 ± 1.1 0.8 ± 0.1 0.6 ± 0.0
After Red Bull (n = 54) 29.4 ± 1.2 0.84 ± 0.1 0.6 ± 0.2
p value
163.1 ± 4.7 1.2 ± 0.1 18.3 ± 0.4
161 ± 4.0 1.22 ± 0.0 18.8 ± 0.1
0.1 0.6 0.07
11.8 ± 0.8
12.0 ± 0.1
0.1
1.6 ± 0.1 58.4 ± 2.7 28.4 ± 0.8 20.2 ± 4.2
1.6 ± 0.4 58.5 ± 2.1 28.5 ± 0.2 21.1 ± 5.8
0.9 0.1 0.8 0.09
7.7 ± 0.7 6.8 ± 0.5 42.2 ± 1.6 27.4 ± 1.2 66.1 ± 1.7
7.7 ± 0.7 6.8 ± 0.4 41.7 ± 2.4 27.8 ± 5.6 67.2 ± 3.8
1.0 0.9 0.6 0.8 0.06
0.5 0.5 0.8
Table 4. Atrial electromechanical functions
Lateral-atrial electromechanical coupling (ms) Septal-atrial electromechanical coupling (ms) Tricuspidal-atrial electromechanical coupling (ms) Inter-atrial electromechanical delay (ms) Left intra- atrial electromechanical delay (ms) Right intra- atrial electromechanical delay (ms)
Before Red Bull (n = 54) 49.7 ± 11.2 40.8 ± 9.1 34.7 ± 7.9 14.4 ± 10.6 8.1 ± 7.6 6.1 ± 6.8
After Red Bull (n = 54) 54.1 ± 11.0 43.7 ± 10.5 35.7 ± 9.9 18.1 ± 8.5 8.2 ± 6.6 7.9 ± 7.2
p value 0.001 0.032 0.4 0.01 0.9 0.1
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Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults ¨ Cem Ozde MD , Adnan Kaya MD , Ismail Hakkı Akbudak , Guls¸ah Akture ¨ , Osman Kayapinar MD PII: DOI: Reference:
S0002-9149(19)31314-1 https://doi.org/10.1016/j.amjcard.2019.11.020 AJC 24310
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
8 October 2019 11 November 2019 13 November 2019
¨ Please cite this article as: Cem Ozde MD , Adnan Kaya MD , Ismail Hakkı Akbudak , Guls¸ah Akture ¨ , Osman Kayapinar MD , Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults, The American Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.amjcard.2019.11.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Acute Effects of Red Bull Energy Drinks on Atrial Electromechanical Function in Healthy Young Adults
Cem Özde1, MD, Adnan Kaya1, MD, İsmail Hakkı Akbudak2, Gulşah Aktüre1, Osman Kayapinar1, MD. 1
Department of Cardiology, Düzce University Training and Research Hospital, Düzce, Turkey 2
Department of İnternal Medicine, Pamukkale University Training and Research Hospital, Denizli, Turkey
Corresponding Author: Osman Kayapinar, MD Department of Cardiology, Düzce University Faculty of Medicine, 8100 Konuralp, Düzce Turkey E-mail: [email protected] GSM: +90 532 419 07 00 Fax: +90 380 542 14 16
1
Abstract Energy drinks (EDs) are widely consumed by adolescents and young adults. Almost all kinds of arrhythmias have been reported following EDs consumption, most of which is atrial fibrillation (AF). Atrial conduction time prolongation and heterogeneous sinusal impulses propagation to the atriums are the key electrophysiological mechanisms leading AF. We aimed to evaluate the acute effects of Red Bull ED ingestion on atrial electromechanical conduction times in healthy young adults. After a 12hour fasting, 54 healthy young adults consumed 330 mL of Red Bull ED. Atrial electromechanical coupling (PA), intra-atrial electromechanical delay (intra-AEMD), and inter-atrial electromechanical delay (inter-AEMD) were measured at baseline and 2-hour after Red Bull ED ingestion by echocardiographic tissue-Doppler imaging (TDI) method. PA-lateral (49.7 ± 11.2 vs. 54.1 ± 11.0 msn, p=0.001) and PA-septal (40.8 ± 9.1 vs. 43.7 ± 10.5 msn, p=0.032) times were statistically significantly prolonged after Red Bull ED ingestion. There was also a statistically significant increase in the duration of inter-AEMD (14.4 ± 10.6 vs. 18.1 ± 8.5 msn, p=0.010) after ED ingestion. It was showed that even a single can of ED can acutely increase atrial electromechanical conduction times in young adults. These findings may be the cause of ED-associated AF.
Key words: energy drink, Red Bull, atrial electromechanical functions, atrial fibrillation
2
Introduction Energy drinks (EDs) are widely consumed by adolescents and young adults and Red Bull is among the most popular one with annual global sales (1, 2). EDs mainly differ from other soft drinks regarding their high level caffeine and taurine content and possible effects on physical and cognitive performance. Despite the potential beneficial effects, EDs have been accused of causing abnormal heart rhythms and heart attacks (3). The numerous reported cases indicate the association of energy drinks with adverse cardiac events. Besides, a review showed association of EDs with adverse cardiovascular events, cardiac arrhythmias such as malign ventricular arrhythmias, ST segment elevation myocardial infarction, QT interval prolongation and atrial fibrillations (4, 5). Recent increase in the number of atrial fibrillation (AF) cases associated with energy drinks is remarkable (6-10). However, the mechanisms for AF in this setting have not been fully elucidated. Delay in the intra- and interatrial conduction times and heterogeneous propagation of sinus impulses are well-known electrophysiological characteristic for AF predisposition. There is a lack of evidence about the effect of EDs on atrial electromechanical conduction times which could explain the AF mechanism in this setting. In this study, we aimed to investigate the acute effect of Red Bull on atrial electromechanical conduction times by tissue Doppler imaging (TDI). Methods This is a prospective, observational and open-label study. The study population consisted of 54 healthy young adults (mean age: 23.3 ± 4.2 years). All subjects were self-described as healthy, with no history of cardiovascular diseases including hypertension and diabetes mellitus. All subjects had normal findings on physical examination and electrocardiography (ECG). None of the subjects had smoking, alcohol or drug use, and none of them used a regular medication. All subjects were familiar with Red Bull® and some participants have previously consumed this beverage in their daily lives. However, four subjects were very rarely consumers of energy drinks (no more than 1 energy drink per month). Sixty volunteers were included in the study. However, six volunteers had nausea while drinking Red Bull and could not finish one can (330 cc) of Red Bull. These volunteers were excluded 3
from the study. Other subjects completed the study without any problems. Informed consent was obtained from all the patients prior to the study. The local ethics committee approved the study protocol, and all the patients signed written informed consent. All subjects abstained from caffeinated products (such as coffee or coke) for at least 3 days before study initiation. All evaluations took place in a quiet, dimly lit, temperature-controlled (20°C– 24°C) echocardiography room and started between 8:00 am and 10:00 am. After a 12-hour fast, all subjects consumed a 330 mL of Red Bull ED containing caffeine (114 mg), taurine (1.42 mg), glucuronolactone (84.2 mg), and sucrose and glucose (39.1 g) at room temperature. All patients drank their own drinks in about 5 minutes. Baseline echocardiography was performed, and a subsequent echocardiography was performed 2 hours after ingestion of Red Bull. On average, three cases were evaluated every day and the data of all cases were collected in approximately twenty days. Afterwards, all data were analyzed. All the echocardiographic measurements (2-D echocardiography, M-mode echocardiography, pulsed wave Doppler, color flow Doppler) were performed and recorded by a cardiologist blinded to the clinical details and outcomes of the study. Records were analyzed by another physician, who was blinded to the study. Transthoracic echocardiography (TTE) recordings were performed while the patients were in the left lateral decubitus position. Apical four-chamber views (A4CW), as well as two-chamber and parasternal images, were recorded at expiratory apnea for three consecutive cardiac cycles using a 3.0 MHz phased-array transducer with an echocardiography (Vivid 7 Pro, GE, Horten, Norway) device. The echocardiography evaluation was performed with combination of surface ECG (DII) monitoring. All the measurements were performed according to the American Society of Echocardiography (11). Left atrial dimension, left ventricle (LV) end systolic dimension, LV end diastolic dimension, LV ejection fraction (EF), interventricular septal thickness, and posterior wall thickness were measured. A transducer of 3.5-4.0 MHz of frequencies was used for TDI adjusted for a nyquist limit of 15-20 cm/s while gaining the examples. A monitor sweep of 50-100 mm/s was used to optimize the
4
gain. The pulsed wave Doppler measurements were acquired from the lateral mitral annulus, the septal mitral annulus, and the lateral tricuspid annulus. The sample window was positioned as parallel as possible to the target area to obtain the most accurate measurements. Atrial electromechanical coupling time which is calculated from the beginning of the surface P wave to the beginning of the late diastolic wave (Am wave) was calculated for lateral mitral annulus (PA lateral), the septal mitral annulus (PA septal), and the lateral tricuspid annulus (PA tricuspid) (Figure 1). All the measurements were averaged over four consecutive beats and corrected for heart rate. The inter-atrial electromechanical delay (AEMD) was calculated with subtraction of PA tricuspid from the PA lateral. The intra-AEMD was calculated with subtraction of PA tricuspid from the PA septal (12, 13). The intraobserver variability was assessed in fifteen subjects by repeating the measurements under the same conditions. The cardiologist, blinded to previously obtained data, separately measured atrial electromechanical coupling time from fifteen random patients for intra-observer variability analysis. Additionally, an experienced observer calculated PA-lateral, PA-septal and PA-tricuspidal values twice on two consecutive days for analysis of intra-observer variability. We employed intra-observer variability to determine the interclass coefficient. Statistical analyses were performed using SPSS software version 20 (SPSS Inc, Chicago, Illinois). The Kolmogorov-Smirnov test was used to assess the distribution of the data. Continuous data are expressed as means ± standard deviation and categorical data as percentages. The paired sample t-test was used to assess differences between variables before and after Red Bull® consumption. A P value <0.05 was considered significant. Results The main characteristics of all subjects are presented in table 1. Blood pressure and heart rate values before and after Red Bull consumption are presented in table 2. There was a statistically significant increase in systolic blood pressure and heart rate in the second hour after Red Bull consumption, but no significant change in diastolic blood pressure. The results of two-dimensional conventional and Doppler echocardiography parameters are presented in table 3. There was no
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significant change in basic echocardiographic parameters after energy drink consumption. Atrial electromechanical function parameters of different sites measured by tissue Doppler imaging are presented in table 4. Some atrial electromechanical conduction time parameters statistically significantly altered after Red Bull consumption. PA-lateral and PA-septal durations were statistically significantly prolonged at the second hour after Red Bull consumption. The results are summarized in figure 2. However, no significant change was observed in PA-tricuspid duration. There was also a statistically significant increase in the duration of inter-AEMD. However, there was no significant change in left and right intra-AEMD durations. Discussion In the present study, we investigated the acute effect of Red Bull, a well-known ED, on the atrial electromechanical conduction times in young adults. We found that consumption of a can of Red Bull in young adults is associated with prolongation of atrial electromechanical conduction times in the acute phase. We found that the left atrial electromechanical coupling time was prolonged temporally and the inter-AEMD was prolonged. Additionally, we have found that the heart rate and systolic blood pressure increased after Red Bull consumption in acute period. To the best of our knowledge, this is the first study to investigate the relationship between ED and atrial electromechanical conduction times. Red Bull consumption in young adults seems to be associated with deterioration of atrial electromechanical functions which may be a predisposing factor for new AF development in acute period. Energy Drinks include some of the fastest-growing products of the beverage industry mostly targets young adults (1). EDs are soft drinks that contain high amount of caffeine, taurine, glucuronolactone, herbal supplements, vitamins, minerals, and carbohydrates; and they are marketed with the claim that they improve cognitive and physical performance (14). The performance enhancing effect of EDs is thought to be primarily related to caffeine which is approximately four-fold more than an ordinary soda contains. Caffeine is a well-known stimulant molecule that has been studied over long periods of time. It has a potent stimulant effect especially at high doses. Direct adenosine receptor
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stimulation in addition to the impacts on monoamine neurotransmitters are the main mechanisms (15). Caffeine mimics the inotropic and chronotropic effects of epinephrine on cardiomyocytes through βadrenergic stimulation (15). Hence, it enhances periphery vasodilatation and stimulates positively cardiac functions simultaneously which increase systemic blood pressure. It is also showed that caffeine may increase circulating catecholamine level in normal healthy individuals (16). Large quantity and rapid manner of caffeine ingestion with EDs may cause massive fluctuations in the circulating catecholamine levels and so arrhythmia (17). Additionally, taurine, ginseng and guarana may be found in variant quantities in EDs, which may cause addition unclear interactions (4) Taurine, may have detrimental impacts on myocardial sodium channels and may lead to arrhythmia (18). High amounts of taurine can shorten the duration of cardiac action potential and may provoke both atrial and ventricular arrhythmia by slowing down the terminal repolarization of cardiac action potential (19). Additionally, many brands of EDs may contain more caffeine than the calculated caffeine, as they may not indicate the immeasurable additional caffeine from substances, such as cola nut, yerba mate and guarana, which contain significant amounts of caffeine. Another one, young adults who thought to be the target consumer population of EDs are more vulnerable to caffeine-related adverse events. The reason for this is that the pharmacological tolerance over time to caffeine is not present in these young-adults yet (4, 17). A relationship between AF and atrial electromechanical conduction delay has been shown (13, 20). Patients with a history of paroxysmal AF, even those with a history of isolated AF (lone AF), have abnormal atrial refractoriness and conduction as compared to patients without AF. Moreover, there are clinical studies suggesting an association between prolongation of atrial conduction times and the risk of developing new AF (21, 22). Electrophysiological maps of AF in humans suggest that AF is caused by multiple wandering wavelets, and these may be due to heterogeneity of atrial conduction and refractoriness. So that conduction abnormalities may create a favorable microenvironment for re-entry mechanism (23). In this context, AEMDs constitute an important substrate for the development of atrial arrhythmias. Conduction delays decrease the atrial tissue wavelength, increase refractory period dispersion, and promote spatiotemporal heterogeneities in atrial 7
electrophysiology. These are well known substrates of reentry in AF patients. Moreover, AEMDs are associated with an increased incidence of atrial premature beats, thus facilitating the starting of the reentry likely due to abnormal tissue activation such as retrograde left atrial activation (24-26). Noninvasive atrial electromechanical coupling assessment by echocardiographic TDI is performed by calculation of electromechanical intervals easily (13, 22). By this method, we showed increased atrial electromechanical (AEM) conduction times with ED ingestion which in turn may be accepted as a substrate for AF development. This study was limited by the relatively small number of healthy volunteer young adults. Our results are limited to young healthy volunteers and require confirmation in other more vulnerable cohorts, such as those with underlying cardiovascular disease. We evaluated only the effects of a single can of ED consumption. At higher doses the results may be differ. The PA measurement method may have influenced our results. The results could be different with invasive electrophysiological evaluation. However, the major limitation of electrophysiologic method is that such a procedure may not be approved by the local ethics committee. In addition to these, the electrophysiologic modalities cannot be reached easily, are more expensive, require more advanced expertise and reside a complication risks. Conducting more frequent blood pressure measurements and serial ECGs to identify the timing of the greatest change in blood pressure and each electrocardiographic parameter may provide additional insights. Volunteers included in the study did not receive a standard diet program before the study. Different diets may have an impact on the results. We have concluded that even a single can of Red Bull can acutely increase atrial electromechanical conduction time in healthy young adults. These findings may be the cause of EDassociated AF. However, randomized controlled studies are needed to confirm the current hypothesis. Disclosures The authors have no conflicts of interest to disclose. Acknowledgements None 8
1. Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T, Barber-Heidal K. A survey of energy drink consumption patterns among college students. Nutr J 2007; 6:35. 2. Red Bull company figures. https://energydrink.redbull.com/company. Accessed April 5, 2019. 3. Lattouf A, Vukovic D (2017) Energy drinks could be deadly for young people with heart conditions, study finds. ABC (16 February 2017), Sydney. https://www.abc.net.au/news/2017-0216/energy-drinks-dangers-for-young-unaware-of-heart-problems/8275484 Accessed 30 Dec 2018 4. Higgins JP, Tuttle TD, Higgins CL. Energy beverages: content and safety. Mayo Clin Proc 2010; 85: 1033-1041. 5. Goldfarb M, Tellier C, Thanassoulis G. Review of published cases of adverse cardiovascular events after ingestion of energy drinks. Am J Cardiol 2014; 113: 168-172. 6. Thyagarajan B, Alagusundaramoorthy SS, Agrawal A. Atrial fibrillation due to over the counter stimulant drugs in a young adult. J Clin Diagn Res 2015; 8: 5-7. 7. Di Rocco JR, During A, Morelli PJ, Heyden M, Biancaniello TA. Atrial fibrillation in healthy adolescents after highly caffeinated beverage consumption: two case reports. J Med Case Rep 2011; 5:18. 8. Sattari M, Sattari A, Kazory A. Energy drink consumption and cardiac complications: a case for caution. J Addict Med 2016; 10: 280-282. 9. Mattioli AV, Pennella S, Farinetti A, Manenti A. Energy drinks and atrial fibrillation in young adults. Clin Nutr 2018; 37: 1073-1074. 10. Izquierdo Fos I, Vázquez Gomis RM, Vázquez Gomis C, Piernas R, Climent Forner E, Llaguno Salvador MD, Vargas Torcal F. Atrial fibrillation after ingestion of a high energy drink. An Pediatr 2012; 77: 417-419. 9
11. Rein AJ, O’Donnell CP, Colan SD, Marx GR. Tissue velocity Doppler assessment of atrial and ventricular electromechanical coupling and atrioventricular time intervals in normal subjects. Am J Cardiol 2003; 92: 1347-1350 12. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440-1463. 13. Omi W, Nagai H, Takamura M, Okura S, Okajima M, Furusho H, Maruyama M, Sakagami S, Takata S, Kaneko S. Doppler tissue analysis of atrialel ectromechanical coupling in paroxysmal atrial fibrillation. J Am Soc Echocardiogr 2005; 18: 39–44. 14. Seifert SM, Schaechter JL, Hershorin ER, Lipshultz SE. Health effects of energy drinks on children, adolescents, and young adults. Pediatrics 2011; 127: 511-528. 15. Cannon ME, Cooke CT, McCarthy JS. Caffeine-induced cardiac arrhythmia: an unrecognized danger of health food products. Med J Aust 2001; 174: 520-521. 16. Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, Oates JA. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978; 298: 181186. 17. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks--a growing problem. Drug Alcohol Depend 2009; 99:1-10. 18. Satoh H. Cardiac actions of taurine as a modulator of the ion channels. Adv Exp Med Biol 1998; 442: 121-128. 19. Read WO, Byrne JE. Effect of taurine on the refractory period of heart muscle. Physiologist 1966; 9: 273. 10
20. Platonov PG, Yuan S, Hertervig E, Kongstad O, Roijer A, Vygovsky AB, Chireikin LV, Olsson SB. Further evidence of localized posterior interatrial conduction delay in lone paroxysmal atrial fibrillation. Europace 2001; 3: 100-107. 21. Daubert JC, Pavin D, Jauvert G, Mabo P. Intra- and interatrial conduction delay: implications for cardiac pacing. Pacing Clin Electrophysiol 2004; 27: 507-525. 22. Cui QQ, Zhang W, Wang H, Sun X, Wang R, Yang HY, Meng XQ, Zhang Y, Wang H. Assessment of atrial electromechanical coupling and influential factors in nonrheumatic paroxysmal atrial fibrillation. Clin Cardiol 2008; 31: 74-78. 23. Atienza F, Almendral J, Moreno J, Vaidyanathan R, Talkachou A, Kalifa J, Arenal A, Villacastín JP, Torrecilla EG, Sánchez A, Ploutz-Snyder R, Jalife J, Berenfeld O. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation 2006; 114: 2434-2442. 24. Martínez-Sellés M, Martínez-Sellés M, Massó-van Roessel A, Álvarez-García J, García de la Villa B, Cruz-Jentoft AJ, Vidán MT, López Díaz J, Felix Redondo FJ, Durán Guerrero JM, Bayes-Genis A, Bayes de Luna A; Investigators of the Cardiac and Clinical Characterization of Centenarians (4C) registry. Interatrial block and atrial arrhythmias in centenarians: prevalence, associations, and clinical implications. Heart Rhythm 2016; 13: 645-651. 25. Bayés De Luna A, Cladellas M, Oter R, Torner P, Guindo J, Martí V, Rivera I, Iturralde P. Interatrial conduction block and retrograde activation of the left atrium and paroxysmal supraventricular tachyarrhythmia. Eur Heart J 1988; 9: 1112-1118. 26. Johner N, Namdar M, Shah DC. Intra- and interatrial conduction abnormalities: hemodynamic and arrhythmic significance. J Interv Card Electrophysiol 2018; 52: 293-302.
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Figure 1. Atrial electromechanical coupling time.
Figure 2. Atrial electromechanical conduction times before and after Red Bull. Table 1. Demographic Characteristics and Laboratory Findings of the Subjects (n=54)
Age (year) Male Female Body mass index (kg/m2) Smoke (-) (+) Fasting blood glucose (mg/dl) Creatinine (mg/dl) Blood urea nitrogen Thyroid-stimulating hormone (mIU/L) Aspartate transaminase (U/L) Hemoglobin (g/dl)
Mean value ± standard deviation (n=54) 23.3 ± 4.2 34 (63.0%) 20 (37.0%) 24.3 ± 4.5 26 (48.1%) 28 (51.9%) 83.6 ± 8.0 0.7 ± 0.1 12.8 ± 2.1 1.4 ± 1.3 22.1 ± 3.7 13.7 ± 1.2
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Table 2. Blood pressure and heart rate findings Before Red Bull (n=54) Systolic blood pressure (mmHg) 109.9 ± 4.0 Diastolic blood pressure (mmHg) 73.1 ± 3.0 Mean blood pressure (mmHg) 85.5 ± 4.0 Heart Rate (beat per minute) 74.7 ± 10.8
After Red Bull (n=54) 113.1 ± 2.6 72.2 ± 4.8 86.4 ± 5.5 80.7 ± 11.9
p value <0.001 0.8 0.1 <0.001
Table 3. Basic Echocardiographic Characteristics
Left atrial diameter (mm) Trans-mitral flow velocity during early ventricular filling (E) (cm/s) Trans-mitral flow velocity during atrial contraction (A) (cm/s) Mitral deceleration time (ms) Mitral E/A ratio Tissue Doppler velocity at the mitral annulus during early ventricular filling (E’) Tissue Doppler velocity at the mitral annulus during atrial contraction (A’) (cm/s) Mitral lateral E’/A’ ratio (cm/s) Mitral lateral isovolumetric relaxation time (ms) Right atrial diameter Systolic pulmonary artery pressure (mmHg) Left ventricle interventricular septum thickness (mm) Left ventricle posterior wall thickness (mm) Left ventricle end-diastolic diameter (mm) Left ventricle end-systolic diameter (mm) Left ventricle ejection fraction (%)
Before Red Bull (n =54) 29.5 ± 1.1 0.8 ± 0.1 0.6 ± 0.0
After Red Bull (n = 54) 29.4 ± 1.2 0.84 ± 0.1 0.6 ± 0.2
p value
163.1 ± 4.7 1.2 ± 0.1 18.3 ± 0.4
161 ± 4.0 1.22 ± 0.0 18.8 ± 0.1
0.1 0.6 0.07
11.8 ± 0.8
12.0 ± 0.1
0.1
1.6 ± 0.1 58.4 ± 2.7 28.4 ± 0.8 20.2 ± 4.2
1.6 ± 0.4 58.5 ± 2.1 28.5 ± 0.2 21.1 ± 5.8
0.9 0.1 0.8 0.09
7.7 ± 0.7 6.8 ± 0.5 42.2 ± 1.6 27.4 ± 1.2 66.1 ± 1.7
7.7 ± 0.7 6.8 ± 0.4 41.7 ± 2.4 27.8 ± 5.6 67.2 ± 3.8
1.0 0.9 0.6 0.8 0.06
0.5 0.5 0.8
Table 4. Atrial electromechanical functions
Lateral-atrial electromechanical coupling (ms) Septal-atrial electromechanical coupling (ms) Tricuspidal-atrial electromechanical coupling (ms) Inter-atrial electromechanical delay (ms) Left intra- atrial electromechanical delay (ms) Right intra- atrial electromechanical delay (ms)
Before Red Bull (n = 54) 49.7 ± 11.2 40.8 ± 9.1 34.7 ± 7.9 14.4 ± 10.6 8.1 ± 7.6 6.1 ± 6.8
After Red Bull (n = 54) 54.1 ± 11.0 43.7 ± 10.5 35.7 ± 9.9 18.1 ± 8.5 8.2 ± 6.6 7.9 ± 7.2
p value 0.001 0.032 0.4 0.01 0.9 0.1
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