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Caffeine delays autonomic recovery following acute exercise Kanokwan Bunsawat, Daniel W White, Rebecca M Kappus and Tracy Baynard European Journal of Preventive Cardiology published online 8 October 2014 DOI: 10.1177/2047487314554867 The online version of this article can be found at: http://cpr.sagepub.com/content/early/2014/10/08/2047487314554867
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EURO PEAN SO CIETY O F CARDIOLOGY ®
Original scientific paper
Caffeine delays autonomic recovery following acute exercise Kanokwan Bunsawat, Daniel W White, Rebecca M Kappus and Tracy Baynard
European Journal of Preventive Cardiology 0(00) 1–7 ! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487314554867 ejpc.sagepub.com
Abstract Background: Impaired autonomic recovery of heart rate (HR) following exercise is associated with an increased risk of sudden death. Caffeine, a potent stimulator of catecholamine release, has been shown to augment blood pressure (BP) and sympathetic nerve activity; however, whether caffeine alters autonomic function after a bout of exercise bout remains unclear. Methods: In a randomized, crossover study, 18 healthy individuals (26 1 years; 23.9 0.8 kgm2) ingested caffeine (400 mg) or placebo pills, followed by a maximal treadmill test to exhaustion. Autonomic function and ventricular depolarization/repolarization were determined using heart rate variability (HRV) and corrected QT interval (QTc), respectively, at baseline, 5, 15, and 30 minutes post-exercise. Results: Maximal HR (HRmax) was greater with caffeine (192 2 vs. 190 2 beatmin1, p < 0.05). During recovery, HR, mean arterial pressure (MAP), and diastolic blood pressure (DBP) remained elevated with caffeine (p < 0.05). Natural log transformation of low-to-high frequency ratio (LnLF/LnHF) of HRV was increased compared with baseline at all time points in both trials (p < 0.05), with less of an increase during 5 and 15 minutes post-exercise in the caffeine trial (p < 0.05). QTc increased from baseline at all time points in both trials, with greater increases in the caffeine trial (p < 0.05). Conclusions: Caffeine ingestion disrupts post-exercise autonomic recovery because of increased sympathetic nerve activity. The prolonged sympathetic recovery time could subsequently hinder baroreflex function during recovery and disrupt the stability of autonomic function, potentiating a pro-arrhythmogenic state in young adults.
Keywords Caffeine, autonomic function, exercise recovery Received 18 July 2014; accepted 19 September 2014
Introduction The dynamic balance between the sympathetic and parasympathetic nervous systems is used to modulate steady-state control of cardiovascular function.1 Although a parasympathetic dominance influences resting heart rate (HR), dynamic exercise is associated with a shift towards sympathetic dominance during the exercise and after its cessation,2 potentially leading to an increase in susceptibility to sudden cardiovascular events.3,4 In particular, post-exercise recovery is a critical phase for sudden cardiovascular events, predominantly in the 30 minutes immediately following vigorous exercise,5 which is attributable to increased sympathetic and decreased parasympathetic nerve activity.6 Complete autonomic recovery may take even longer
after relatively greater exercise bouts, depending on the intensity, duration, and fitness of the individual, hence greater risk of sudden cardiovascular events.7 It is important to assess autonomic function during exercise recovery, as it provides prognostic information, as well as allows for a greater understanding in autonomic alterations in response to physiological stress.
Department of Kinesiology and Nutrition, The University of Illinois at Chicago, IL, USA Corresponding author: Kanokwan Bunsawat, Integrative Physiology Laboratory (IPL), Department of Kinesiology and Nutrition, The University of Illinois at Chicago, 1919 W. Taylor St, Rm 650, Chicago, IL 60612, USA. Email: [email protected]
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Heart rate variability (HRV) and heart rate recovery (HRR) are non-invasive methods that provide information regarding the cardiac sympathetic and parasympathetic modulations of HR during and after exercise.8,9 Low HRV, attributed to depressed parasympathetic modulation, has been shown to predict cardiovascular mortality with vulnerability to sudden cardiac arrest and cardiac arrhythmias after acute myocardial infarction.5 Delayed HRR after exercise is associated with autonomic dysfunction and increased mortality, in which parasympathetic reactivation is impaired.8 Furthermore, changes in autonomic tone can directly influence the QT interval, prolongation of which disrupts the electrophysiolocal environment.10 Caffeine, present in many beverages and foods including tea, coffee, energy drinks, and chocolate, is a popular performance enhancer.11 In addition, caffeine is a potent stimulator of sympathetic nerve activity,12 which exerts various effects on cardiovascular function including increased catecholamine release,13 elevated blood pressure (BP),14,15 inhibited baroreflex function,16 prolonged QT interval,17 and depressed HRV.14 Caffeine consumption also transiently increases the risk of acute cardiovascular events,18 and several deaths caused by sudden cardiac arrest have been reported after caffeine overdose.19 Whether caffeine attenuates autonomic recovery following exercise is unclear, but is important because caffeine may inhibit sympathetic withdrawal and hinder parasympathetic reactivation, which may potentiate the risk of sudden cardiovascular events.20 The purpose of this study was to investigate the effects of pre-exercise caffeine ingestion on autonomic recovery using analyses of HRV and QT interval following an acute bout of dynamic exercise. We hypothesized that acute caffeine ingestion would attenuate autonomic recovery and prolong the QT interval compared with the control condition.
Methods Participants Eighteen young and healthy volunteers (10 males and 8 females; age 26 1 years; BMI 23.9 0.8 kgm2; waist circumference 78.4 2.1 cm) participated in this randomized, double-blind, crossover study. All participants were recruited from the general population of the University of Illinois at Chicago. Exclusion criteria included cardiovascular diseases, hypertension, metabolic disorders, orthopedic conditions, tobacco use, caffeinated beverage consumption of greater than the equivalent of three cups of coffee per day (285 mg), and use of multi-vitamins and medications of any kind (including over-the-counter NSAIDS). All participants
abstained from caffeinated and alcoholic beverages, food, and strenuous exercise for at least 12 hours before each testing session, separated by at least 48 hours. Female participants were tested during the first 7 days of their menstrual cycle to control for the effects of sex hormones on HRV. Prior to the start of the study, all participants gave written informed consent and completed physical activity and health history questionnaires. The study was approved by the institutional review board at the University of Illinois at Chicago.
Experimental design All testing sessions were conducted at the same time of day (between 07:00 and 10:00 h) to reduce diurnal variations. After 15 minutes rest in the supine position, baseline measurements of HR, BP, QTc, and HRV were taken, followed by an ingestion of either 400 mg of caffeine or placebo (similar looking pills) before the testing protocol. This amount of caffeine has been used in a previous study21 and represents the upper quartile of caffeine ingestion in the general population.22 Fortyfive minutes after ingestion,23 the participants underwent a treadmill exercise test to assess maximum oxygen consumption (VO2max), followed by 2 minutes active recovery at a speed of 3.5 kmh1 and grade of 0%.24 Participants were then moved to a supine position, and recovery data were collected at 5, 15, and 30 minutes after the max test. HRV data were collected 5 minutes post-exercise to allow for steady HRs.25 Beatto-beat arterial BP was recorded for 5 minutes (Finometer Pro, Amsterdam, The Netherlands). The second visit followed the same protocol as the first visit, but with the opposite treatment.
Maximum oxygen uptake test VO2max was determined by means of a continuous incremental treadmill exercise until volitional exhaustion. Specific details are in the supplemental data. Rating of perceived exertion (RPE) was collected every 2 minutes using Borg’s 6–20 scale.
Heart rate variability A continuous 5-minute recording of ECG was obtained in the supine position at a sampling rate of 1000 Hz (Biopac Systems, Santa Barbara, CA, USA). Respiration was paced with a metronome at 12 breathsmin1. The ECG data were automatically peak detected, visually inspected for accuracy and the occurrence of ectopic beats, and subsequently used to generate a tachogram of the R-R interval time event series. HRV was analyzed in the frequency domain (WinCPRS, Turku, Finland).
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3 Table 1. Comparison of heart rate and performance variables between placebo and caffeine trials (n ¼ 18).
Heart rate recovery Heart rate recovery (HRR) is an index of autonomic function and cardiovascular fitness.26 HR data were collected at 1 (HR-1) and 2 minutes (HR-2) postexercise during active recovery. The percentage difference (%HRR) from HRmax and HR-1 and HR-2 after exercise termination was calculated using the formula: %HRR-1 or 2 ¼ ðHRmax HR-1 or 2Þ=HRmax 100
Corrected QT intervals Analysis of the QT intervals, from the continuously recorded ECG data mentioned above, was performed as previously described.27 QT interval analysis was carried out in 5-minute ectopy/noise free epochs (WinCPRS, Turku, Finland). The QT interval was defined as the time difference between the start of the Q-wave and the end of the T-wave. The QT interval was rate corrected using the Bazett’s correction (c) formula: QTc ¼ QT/RR½.28
Statistical analysis Power spectral densities were not normally distributed, so natural logarithmic transformation (Ln) was performed on HRV measures. Student’s paired t-tests were used to compare baseline differences between the placebo and caffeine trials. A 2 3 ANOVA with repeated measures [trial by time] was conducted on HR. A 2 4 ANOVA with repeated measures [trial by time] was conducted on all HRV, BP, and QTc variables. Appropriate post-hoc tests were conducted where a significant interaction was detected. All data analysis was carried out using Statistical Package for the Social Sciences (SPSS, v 19.0, IBM SPSS, Inc., Armonk, NY, USA).
Results HR and performance data are shown in Table 1. HRmax, HR-2, VO2max, and time to exhaustion were higher with the caffeine trial (p < 0.05, Table 1), with no trial differences found in resting HR, HR-1, %HRR-1, %HRR-2, RERmax and RPEmax. During recovery, HR declined similarly in both trials but absolute HR was higher in the caffeine trial at all time points (p < 0.05). HR was 97 2, 92 2, and 85 2 beatmin1 in the control trial, whereas HR was 102 3, 99 2, and 92 3 beatmin1 in the caffeine trial at 5, 15, and 30 minutes post-exercise,
Resting HR (beats min1) HRmax (beats min1) HR-1 (beats min1) HR-2 (beats min1) %HRR-1 %HRR-2 VO2max (mL kg1 min1) RERmax RPEmax Time to exhaustion (min)
Placebo
Caffeine
60 3 189 2 161 4 140 4 14.3 1.6 25.4 2.1 45.2 2.3 1.10 0.01 19 0 12.8 0.7
59 3 192 2a 162 4 144 4a 14.7 1.6 24.6 1.7 46.5 2.4a 1.10 0.01 19 0 13.3 0.7a
Values are mean SE. HR: heart rate; HRmax: maximum heart rate; HR-1 and 2: heart rates at min 1 and 2 during active recovery; %HRR-1 and 2: percentage difference from peak heart rate and at min 1 and 2 in active recovery; VO2max: maximum oxygen consumption; RERmax: maximum respiratory exchange ratio; RPEmax: maximum ratings of perceived exertion. a p < 0.05, different from placebo. Resting HR is HR pre-caffeine ingestion.
respectively. No baseline differences were observed for any BP variable (Figure 1). Compared with baseline, MAP and DBP increased in the caffeine trial at all recovery time points (p < 0.05, Figure 1). Figure 2 shows that LnTP, LnLF, and LnHF declined similarly from baseline in both trials (p < 0.05). LnLF/LnHF increased from baseline at all time points in both trials, with greater increases during 5 and 15 minutes post-exercise in the placebo trial (p < 0.05). A significant interaction was detected for QTc (p < 0.05, Figure 3). QTc increased from baseline at all time points in both trials, with greater increases in the caffeine trial (p < 0.05).
Discussion The main findings of this study are: (a) caffeine increased VO2max and time to exhaustion, (b) caffeine elevated HR, MAP, and DBP, (c) LnLF/LnHF ratio increased from baseline in both trials, but was lower in the caffeine trial than in the placebo trial during 5 and 15 minutes post-exercise, and (d) QTc interval became elongated during exercise recovery in the caffeine trial. To the best of our knowledge, this is the first study to examine the prolonged effects of caffeine on autonomic recovery following acute dynamic exercise.
Caffeine and performance Caffeine has previously been shown to prolong time to exhaustion and increase oxygen consumption during endurance exercise.29,30 Similarly, we report that
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110
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100
90
MAP - Placebo MAP - Caffeine 80
DBP - Placebo DBP - Caffeine
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Baseline
Post-5
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Figure 1. Comparison of blood pressure at baseline, 5, 15, and 30 minutes post-exercise during both the placebo (solid line) and caffeine (dash line) trials. Values are mean SE. SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure. *p < 0.05, different from baseline only in the caffeine trial.
caffeine supplementation enhanced VO2max and time to exhaustion during graded treadmill exercise. The enhanced endurance performance was suggested to be the combined effects of caffeine on lipolysis and its positive influence on sympathetic nerve transduction,31 as caffeine is a potent stimulator of the release of catecholamines, particularly norepinephrine.30
Caffeine effects on hemodynamics during post-exercise recovery We observed higher HRmax with caffeine compared with placebo, which is consistent with previous findings.29 The higher HRmax may be explained by the increased work capacity caused by caffeine. Following maximal exercise, HR decreased similarly in both groups during active recovery at min 1, but remained elevated in the caffeine trial thereafter. Additionally, during recovery, both MAP and DBP were significantly increased from baseline in the caffeine trial. The caffeine-induced elevated BP has been suggested to be partly mediated by increased peripheral resistance,32 which may result in a reduction in regional blood
flow and conductance and an attenuation of postexercise hypotension.33 Although caffeine enhanced work capacity in healthy adults, it prolonged the recovery of HR and BP following exercise, suggesting a caffeine-induced increase in sympathetic nerve activity,12 which perturbed cardiovascular homeostasis.34
Caffeine effects on autonomic function during post-exercise recovery The effects of caffeine on autonomic function have been studied at rest and during exercise;14,35 however, the influence of caffeine on post-exercise autonomic recovery remains unclear. During exercise recovery, HR decreases in a mono-exponential manner, dependent on exercise intensity.25 The first minute of HR recovery is largely attributable to parasympathetic reactivation, whereas further HR reduction depends on the gradual decrease in sympathetic nerve activity.25,26 In the current study, HRmax was higher during the caffeine trial, but there were similar HR reductions at min 1 in both trials, which became differentiated (4 beat min1 higher in the caffeine trial) during the second min of active
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# 2.4
#
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Figure 2. Natural log transformation (Ln) of frequency domain heart rate variability (HRV) variables at baseline, 5, 15, and 30 minutes post-exercise during placebo (solid line) and caffeine (dash line) trials. Values are mean SE. *p < 0.05, different from baseline for both the placebo and caffeine trials; #p < 0.05, different from the caffeine trial within the same time point.
* 440
#
QTc (ms)
420
#
400
Placebo Caffeine
#
380 360 340 320
Baseline
Post-5
Post-15
Post-30
Figure 3. Corrected QT (QTc) intervals at baseline, 5, 15, and 30 minutes post-exercise during placebo (solid line) and caffeine (dash line) trials. Values are mean SE. *p < 0.05, different from baseline for both the placebo and caffeine trials; #p < 0.05, different from the caffeine trial within the same time point.
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recovery. As our participants performed maximal exercise, the combination of caffeine-induced sympathetic activation along with the higher work capacity may have led to higher HR at min 2 and beyond.25 Analysis of HRV detected that the LnLF/LnHF ratio increased from baseline in both trials, but the increase was lower in the caffeine trial than in the placebo trial during 5 and 15 minutes post-exercise. The lower LnLF/LnHF ratio in the caffeine trial was caused by a reduced LnLF without a change in LnHF. LnLF is said to reflect the actions of the sympathetic nerve system through baroreflex-mediated changes in HR,36,37 but it is conceivable that steady sympathetic outflow caused by caffeine would reduce oscillatory modulation of the HR at frequencies normally associated with sympathetic modulation.12,16 Therefore, the increase in sympathetic nerve activity would actually present as a reduction in LnLF, such as seen in our results. Increased sympathetic nerve activity would be consistent with the higher HR, MAP, and DBP during post-exercise recovery with caffeine. Furthermore, caffeine-induced increase in sympathetic nerve activity would predispose an individual to a pro-arrhythmogenic condition.19 In addition, prolongation of the QT interval can disrupt the electrophysiolocal environment, leading to ventricular instability and the risk of cardiac arrhythmias/cardiac death.10 In the present study, we did not detect any arrhythmia in the ECG recordings, possibly because the dosage was not high enough to produce arrhythmias, as seen in several case studies of caffeine overdose.19 However, we observed greater prolongation of the QTc at all recovery time points in the caffeine trial, suggesting that caffeine may predispose an individual to a pro-arrhythmogenic state during recovery, given that a higher dosage is associated with sudden cardiac death.38
Limitations This study was conducted in young, healthy individuals; therefore, the results cannot be applied to patients with cardiovascular disease. We did not directly measure catecholamine or caffeine concentrations in the blood, but these effects have been shown in a previous study.32 We did not measure sympathetic nerve activity, and although its increase is speculative in the present study, caffeine has previously been shown to increase sympathetic nerve activity.12 HRV following caffeine ingestion prior to exercise was not examined; the focus of the study was recovery and resting effects of caffeine ingestion have been previously described. Finally, we used HRV to assess autonomic function, which is an indirect method; however, this method has been widely used in clinical research and is, in
humans, the best method of estimating sympathetic and parasympathetic interactions.39
Conclusions Given the prevalence of caffeine usage growing among athletes as a performance enhancer,40 the cardiovascular impacts need to be reassessed. Although it is not unusual that caffeine ingestion improved time to exhaustion and work capacity as shown by the higher HRmax and VO2max, the increased catecholamine load within the recovering cardiovascular system may be detrimental as it may disrupt autonomic recovery because of increased sympathetic nerve activity. An increased HR and BP and a longer QTc interval with caffeine ingestion, suggesting a prolonged sympathetic recovery time, could subsequently attenuate baroreflex function recovery, which is consistent with the higher HR and BP during post-exercise recovery with caffeine. This is clinically important because caffeine could disrupt the stability in autonomic function particularly following exercise termination, which could predispose young and healthy adults to a pro-arrhythmogenic state. Acknowledgement We thank Dr. Bo Fernhall for his intellectual contribution to this manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
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Caffeine delays autonomic recovery following acute exercise Kanokwan Bunsawat, Daniel W White, Rebecca M Kappus and Tracy Baynard European Journal of Preventive Cardiology published online 8 October 2014 DOI: 10.1177/2047487314554867 The online version of this article can be found at: http://cpr.sagepub.com/content/early/2014/10/08/2047487314554867
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Caffeine delays autonomic recovery following acute exercise Kanokwan Bunsawat, Daniel W White, Rebecca M Kappus and Tracy Baynard
European Journal of Preventive Cardiology 0(00) 1–7 ! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487314554867 ejpc.sagepub.com
Abstract Background: Impaired autonomic recovery of heart rate (HR) following exercise is associated with an increased risk of sudden death. Caffeine, a potent stimulator of catecholamine release, has been shown to augment blood pressure (BP) and sympathetic nerve activity; however, whether caffeine alters autonomic function after a bout of exercise bout remains unclear. Methods: In a randomized, crossover study, 18 healthy individuals (26 1 years; 23.9 0.8 kgm2) ingested caffeine (400 mg) or placebo pills, followed by a maximal treadmill test to exhaustion. Autonomic function and ventricular depolarization/repolarization were determined using heart rate variability (HRV) and corrected QT interval (QTc), respectively, at baseline, 5, 15, and 30 minutes post-exercise. Results: Maximal HR (HRmax) was greater with caffeine (192 2 vs. 190 2 beatmin1, p < 0.05). During recovery, HR, mean arterial pressure (MAP), and diastolic blood pressure (DBP) remained elevated with caffeine (p < 0.05). Natural log transformation of low-to-high frequency ratio (LnLF/LnHF) of HRV was increased compared with baseline at all time points in both trials (p < 0.05), with less of an increase during 5 and 15 minutes post-exercise in the caffeine trial (p < 0.05). QTc increased from baseline at all time points in both trials, with greater increases in the caffeine trial (p < 0.05). Conclusions: Caffeine ingestion disrupts post-exercise autonomic recovery because of increased sympathetic nerve activity. The prolonged sympathetic recovery time could subsequently hinder baroreflex function during recovery and disrupt the stability of autonomic function, potentiating a pro-arrhythmogenic state in young adults.
Keywords Caffeine, autonomic function, exercise recovery Received 18 July 2014; accepted 19 September 2014
Introduction The dynamic balance between the sympathetic and parasympathetic nervous systems is used to modulate steady-state control of cardiovascular function.1 Although a parasympathetic dominance influences resting heart rate (HR), dynamic exercise is associated with a shift towards sympathetic dominance during the exercise and after its cessation,2 potentially leading to an increase in susceptibility to sudden cardiovascular events.3,4 In particular, post-exercise recovery is a critical phase for sudden cardiovascular events, predominantly in the 30 minutes immediately following vigorous exercise,5 which is attributable to increased sympathetic and decreased parasympathetic nerve activity.6 Complete autonomic recovery may take even longer
after relatively greater exercise bouts, depending on the intensity, duration, and fitness of the individual, hence greater risk of sudden cardiovascular events.7 It is important to assess autonomic function during exercise recovery, as it provides prognostic information, as well as allows for a greater understanding in autonomic alterations in response to physiological stress.
Department of Kinesiology and Nutrition, The University of Illinois at Chicago, IL, USA Corresponding author: Kanokwan Bunsawat, Integrative Physiology Laboratory (IPL), Department of Kinesiology and Nutrition, The University of Illinois at Chicago, 1919 W. Taylor St, Rm 650, Chicago, IL 60612, USA. Email: [email protected]
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Heart rate variability (HRV) and heart rate recovery (HRR) are non-invasive methods that provide information regarding the cardiac sympathetic and parasympathetic modulations of HR during and after exercise.8,9 Low HRV, attributed to depressed parasympathetic modulation, has been shown to predict cardiovascular mortality with vulnerability to sudden cardiac arrest and cardiac arrhythmias after acute myocardial infarction.5 Delayed HRR after exercise is associated with autonomic dysfunction and increased mortality, in which parasympathetic reactivation is impaired.8 Furthermore, changes in autonomic tone can directly influence the QT interval, prolongation of which disrupts the electrophysiolocal environment.10 Caffeine, present in many beverages and foods including tea, coffee, energy drinks, and chocolate, is a popular performance enhancer.11 In addition, caffeine is a potent stimulator of sympathetic nerve activity,12 which exerts various effects on cardiovascular function including increased catecholamine release,13 elevated blood pressure (BP),14,15 inhibited baroreflex function,16 prolonged QT interval,17 and depressed HRV.14 Caffeine consumption also transiently increases the risk of acute cardiovascular events,18 and several deaths caused by sudden cardiac arrest have been reported after caffeine overdose.19 Whether caffeine attenuates autonomic recovery following exercise is unclear, but is important because caffeine may inhibit sympathetic withdrawal and hinder parasympathetic reactivation, which may potentiate the risk of sudden cardiovascular events.20 The purpose of this study was to investigate the effects of pre-exercise caffeine ingestion on autonomic recovery using analyses of HRV and QT interval following an acute bout of dynamic exercise. We hypothesized that acute caffeine ingestion would attenuate autonomic recovery and prolong the QT interval compared with the control condition.
Methods Participants Eighteen young and healthy volunteers (10 males and 8 females; age 26 1 years; BMI 23.9 0.8 kgm2; waist circumference 78.4 2.1 cm) participated in this randomized, double-blind, crossover study. All participants were recruited from the general population of the University of Illinois at Chicago. Exclusion criteria included cardiovascular diseases, hypertension, metabolic disorders, orthopedic conditions, tobacco use, caffeinated beverage consumption of greater than the equivalent of three cups of coffee per day (285 mg), and use of multi-vitamins and medications of any kind (including over-the-counter NSAIDS). All participants
abstained from caffeinated and alcoholic beverages, food, and strenuous exercise for at least 12 hours before each testing session, separated by at least 48 hours. Female participants were tested during the first 7 days of their menstrual cycle to control for the effects of sex hormones on HRV. Prior to the start of the study, all participants gave written informed consent and completed physical activity and health history questionnaires. The study was approved by the institutional review board at the University of Illinois at Chicago.
Experimental design All testing sessions were conducted at the same time of day (between 07:00 and 10:00 h) to reduce diurnal variations. After 15 minutes rest in the supine position, baseline measurements of HR, BP, QTc, and HRV were taken, followed by an ingestion of either 400 mg of caffeine or placebo (similar looking pills) before the testing protocol. This amount of caffeine has been used in a previous study21 and represents the upper quartile of caffeine ingestion in the general population.22 Fortyfive minutes after ingestion,23 the participants underwent a treadmill exercise test to assess maximum oxygen consumption (VO2max), followed by 2 minutes active recovery at a speed of 3.5 kmh1 and grade of 0%.24 Participants were then moved to a supine position, and recovery data were collected at 5, 15, and 30 minutes after the max test. HRV data were collected 5 minutes post-exercise to allow for steady HRs.25 Beatto-beat arterial BP was recorded for 5 minutes (Finometer Pro, Amsterdam, The Netherlands). The second visit followed the same protocol as the first visit, but with the opposite treatment.
Maximum oxygen uptake test VO2max was determined by means of a continuous incremental treadmill exercise until volitional exhaustion. Specific details are in the supplemental data. Rating of perceived exertion (RPE) was collected every 2 minutes using Borg’s 6–20 scale.
Heart rate variability A continuous 5-minute recording of ECG was obtained in the supine position at a sampling rate of 1000 Hz (Biopac Systems, Santa Barbara, CA, USA). Respiration was paced with a metronome at 12 breathsmin1. The ECG data were automatically peak detected, visually inspected for accuracy and the occurrence of ectopic beats, and subsequently used to generate a tachogram of the R-R interval time event series. HRV was analyzed in the frequency domain (WinCPRS, Turku, Finland).
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3 Table 1. Comparison of heart rate and performance variables between placebo and caffeine trials (n ¼ 18).
Heart rate recovery Heart rate recovery (HRR) is an index of autonomic function and cardiovascular fitness.26 HR data were collected at 1 (HR-1) and 2 minutes (HR-2) postexercise during active recovery. The percentage difference (%HRR) from HRmax and HR-1 and HR-2 after exercise termination was calculated using the formula: %HRR-1 or 2 ¼ ðHRmax HR-1 or 2Þ=HRmax 100
Corrected QT intervals Analysis of the QT intervals, from the continuously recorded ECG data mentioned above, was performed as previously described.27 QT interval analysis was carried out in 5-minute ectopy/noise free epochs (WinCPRS, Turku, Finland). The QT interval was defined as the time difference between the start of the Q-wave and the end of the T-wave. The QT interval was rate corrected using the Bazett’s correction (c) formula: QTc ¼ QT/RR½.28
Statistical analysis Power spectral densities were not normally distributed, so natural logarithmic transformation (Ln) was performed on HRV measures. Student’s paired t-tests were used to compare baseline differences between the placebo and caffeine trials. A 2 3 ANOVA with repeated measures [trial by time] was conducted on HR. A 2 4 ANOVA with repeated measures [trial by time] was conducted on all HRV, BP, and QTc variables. Appropriate post-hoc tests were conducted where a significant interaction was detected. All data analysis was carried out using Statistical Package for the Social Sciences (SPSS, v 19.0, IBM SPSS, Inc., Armonk, NY, USA).
Results HR and performance data are shown in Table 1. HRmax, HR-2, VO2max, and time to exhaustion were higher with the caffeine trial (p < 0.05, Table 1), with no trial differences found in resting HR, HR-1, %HRR-1, %HRR-2, RERmax and RPEmax. During recovery, HR declined similarly in both trials but absolute HR was higher in the caffeine trial at all time points (p < 0.05). HR was 97 2, 92 2, and 85 2 beatmin1 in the control trial, whereas HR was 102 3, 99 2, and 92 3 beatmin1 in the caffeine trial at 5, 15, and 30 minutes post-exercise,
Resting HR (beats min1) HRmax (beats min1) HR-1 (beats min1) HR-2 (beats min1) %HRR-1 %HRR-2 VO2max (mL kg1 min1) RERmax RPEmax Time to exhaustion (min)
Placebo
Caffeine
60 3 189 2 161 4 140 4 14.3 1.6 25.4 2.1 45.2 2.3 1.10 0.01 19 0 12.8 0.7
59 3 192 2a 162 4 144 4a 14.7 1.6 24.6 1.7 46.5 2.4a 1.10 0.01 19 0 13.3 0.7a
Values are mean SE. HR: heart rate; HRmax: maximum heart rate; HR-1 and 2: heart rates at min 1 and 2 during active recovery; %HRR-1 and 2: percentage difference from peak heart rate and at min 1 and 2 in active recovery; VO2max: maximum oxygen consumption; RERmax: maximum respiratory exchange ratio; RPEmax: maximum ratings of perceived exertion. a p < 0.05, different from placebo. Resting HR is HR pre-caffeine ingestion.
respectively. No baseline differences were observed for any BP variable (Figure 1). Compared with baseline, MAP and DBP increased in the caffeine trial at all recovery time points (p < 0.05, Figure 1). Figure 2 shows that LnTP, LnLF, and LnHF declined similarly from baseline in both trials (p < 0.05). LnLF/LnHF increased from baseline at all time points in both trials, with greater increases during 5 and 15 minutes post-exercise in the placebo trial (p < 0.05). A significant interaction was detected for QTc (p < 0.05, Figure 3). QTc increased from baseline at all time points in both trials, with greater increases in the caffeine trial (p < 0.05).
Discussion The main findings of this study are: (a) caffeine increased VO2max and time to exhaustion, (b) caffeine elevated HR, MAP, and DBP, (c) LnLF/LnHF ratio increased from baseline in both trials, but was lower in the caffeine trial than in the placebo trial during 5 and 15 minutes post-exercise, and (d) QTc interval became elongated during exercise recovery in the caffeine trial. To the best of our knowledge, this is the first study to examine the prolonged effects of caffeine on autonomic recovery following acute dynamic exercise.
Caffeine and performance Caffeine has previously been shown to prolong time to exhaustion and increase oxygen consumption during endurance exercise.29,30 Similarly, we report that
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110
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100
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MAP - Placebo MAP - Caffeine 80
DBP - Placebo DBP - Caffeine
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Figure 1. Comparison of blood pressure at baseline, 5, 15, and 30 minutes post-exercise during both the placebo (solid line) and caffeine (dash line) trials. Values are mean SE. SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure. *p < 0.05, different from baseline only in the caffeine trial.
caffeine supplementation enhanced VO2max and time to exhaustion during graded treadmill exercise. The enhanced endurance performance was suggested to be the combined effects of caffeine on lipolysis and its positive influence on sympathetic nerve transduction,31 as caffeine is a potent stimulator of the release of catecholamines, particularly norepinephrine.30
Caffeine effects on hemodynamics during post-exercise recovery We observed higher HRmax with caffeine compared with placebo, which is consistent with previous findings.29 The higher HRmax may be explained by the increased work capacity caused by caffeine. Following maximal exercise, HR decreased similarly in both groups during active recovery at min 1, but remained elevated in the caffeine trial thereafter. Additionally, during recovery, both MAP and DBP were significantly increased from baseline in the caffeine trial. The caffeine-induced elevated BP has been suggested to be partly mediated by increased peripheral resistance,32 which may result in a reduction in regional blood
flow and conductance and an attenuation of postexercise hypotension.33 Although caffeine enhanced work capacity in healthy adults, it prolonged the recovery of HR and BP following exercise, suggesting a caffeine-induced increase in sympathetic nerve activity,12 which perturbed cardiovascular homeostasis.34
Caffeine effects on autonomic function during post-exercise recovery The effects of caffeine on autonomic function have been studied at rest and during exercise;14,35 however, the influence of caffeine on post-exercise autonomic recovery remains unclear. During exercise recovery, HR decreases in a mono-exponential manner, dependent on exercise intensity.25 The first minute of HR recovery is largely attributable to parasympathetic reactivation, whereas further HR reduction depends on the gradual decrease in sympathetic nerve activity.25,26 In the current study, HRmax was higher during the caffeine trial, but there were similar HR reductions at min 1 in both trials, which became differentiated (4 beat min1 higher in the caffeine trial) during the second min of active
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Figure 2. Natural log transformation (Ln) of frequency domain heart rate variability (HRV) variables at baseline, 5, 15, and 30 minutes post-exercise during placebo (solid line) and caffeine (dash line) trials. Values are mean SE. *p < 0.05, different from baseline for both the placebo and caffeine trials; #p < 0.05, different from the caffeine trial within the same time point.
* 440
#
QTc (ms)
420
#
400
Placebo Caffeine
#
380 360 340 320
Baseline
Post-5
Post-15
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Figure 3. Corrected QT (QTc) intervals at baseline, 5, 15, and 30 minutes post-exercise during placebo (solid line) and caffeine (dash line) trials. Values are mean SE. *p < 0.05, different from baseline for both the placebo and caffeine trials; #p < 0.05, different from the caffeine trial within the same time point.
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recovery. As our participants performed maximal exercise, the combination of caffeine-induced sympathetic activation along with the higher work capacity may have led to higher HR at min 2 and beyond.25 Analysis of HRV detected that the LnLF/LnHF ratio increased from baseline in both trials, but the increase was lower in the caffeine trial than in the placebo trial during 5 and 15 minutes post-exercise. The lower LnLF/LnHF ratio in the caffeine trial was caused by a reduced LnLF without a change in LnHF. LnLF is said to reflect the actions of the sympathetic nerve system through baroreflex-mediated changes in HR,36,37 but it is conceivable that steady sympathetic outflow caused by caffeine would reduce oscillatory modulation of the HR at frequencies normally associated with sympathetic modulation.12,16 Therefore, the increase in sympathetic nerve activity would actually present as a reduction in LnLF, such as seen in our results. Increased sympathetic nerve activity would be consistent with the higher HR, MAP, and DBP during post-exercise recovery with caffeine. Furthermore, caffeine-induced increase in sympathetic nerve activity would predispose an individual to a pro-arrhythmogenic condition.19 In addition, prolongation of the QT interval can disrupt the electrophysiolocal environment, leading to ventricular instability and the risk of cardiac arrhythmias/cardiac death.10 In the present study, we did not detect any arrhythmia in the ECG recordings, possibly because the dosage was not high enough to produce arrhythmias, as seen in several case studies of caffeine overdose.19 However, we observed greater prolongation of the QTc at all recovery time points in the caffeine trial, suggesting that caffeine may predispose an individual to a pro-arrhythmogenic state during recovery, given that a higher dosage is associated with sudden cardiac death.38
Limitations This study was conducted in young, healthy individuals; therefore, the results cannot be applied to patients with cardiovascular disease. We did not directly measure catecholamine or caffeine concentrations in the blood, but these effects have been shown in a previous study.32 We did not measure sympathetic nerve activity, and although its increase is speculative in the present study, caffeine has previously been shown to increase sympathetic nerve activity.12 HRV following caffeine ingestion prior to exercise was not examined; the focus of the study was recovery and resting effects of caffeine ingestion have been previously described. Finally, we used HRV to assess autonomic function, which is an indirect method; however, this method has been widely used in clinical research and is, in
humans, the best method of estimating sympathetic and parasympathetic interactions.39
Conclusions Given the prevalence of caffeine usage growing among athletes as a performance enhancer,40 the cardiovascular impacts need to be reassessed. Although it is not unusual that caffeine ingestion improved time to exhaustion and work capacity as shown by the higher HRmax and VO2max, the increased catecholamine load within the recovering cardiovascular system may be detrimental as it may disrupt autonomic recovery because of increased sympathetic nerve activity. An increased HR and BP and a longer QTc interval with caffeine ingestion, suggesting a prolonged sympathetic recovery time, could subsequently attenuate baroreflex function recovery, which is consistent with the higher HR and BP during post-exercise recovery with caffeine. This is clinically important because caffeine could disrupt the stability in autonomic function particularly following exercise termination, which could predispose young and healthy adults to a pro-arrhythmogenic state. Acknowledgement We thank Dr. Bo Fernhall for his intellectual contribution to this manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
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