Evaluation of the Effects of Different Energy Drinks and Coffee on Endothelial Function

Accepted Manuscript Evaluation of the Effects of Different Energy Drinks and Coffee on Endothelial Function Janos Molnar, MD, John C. Somberg, MD PII:

S0002-9149(15)01778-6

DOI:

10.1016/j.amjcard.2015.07.073

Reference:

AJC 21350

To appear in:

The American Journal of Cardiology

Received Date: 15 January 2015 Revised Date:

29 July 2015

Accepted Date: 30 July 2015

Please cite this article as: Molnar J, Somberg JC, Evaluation of the Effects of Different Energy Drinks and Coffee on Endothelial Function, The American Journal of Cardiology (2015), doi: 10.1016/ j.amjcard.2015.07.073. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

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Evaluation of the Effects of Different Energy Drinks and Coffee on Endothelial Function

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Authors: Authors: Janos Molnar, MDa*, John C. Somberg, MDa.

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Affiliations: a). American Institute of Therapeutics, Lake Bluff, IL

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Running Head: Energy drinks and endothelial function

*Corresponding author: John C. Somberg, MD

American Institute of Therapeutics

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21 N. Skokie Hwy, G-3 Lake Bluff, IL 60044

Telephone number: (847) 735-1170

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Fax number: (847) 735-1173

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Email address: [email protected]

Conflict of Interest: None Source of Funding: None

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Abstract Endothelial function plays an important role in circulatory physiology. There has been differing reports on the effect of energy drink on endothelial function. We set out to

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evaluate the effect of three energy drinks as well as coffee on endothelial function.

Endothelial function was evaluated in healthy volunteers employing a device that utilizes digital peripheral arterial tonometry measuring endothelial function as the Reactive

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Hyperemia Index (RHI). Six volunteers (25±7 years) received energy drink in a random order at least 2 days apart. Drinks studied were 250 mL “Red Bull” containing 80 mg

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caffeine, 57 mL “5-hour Energy” containing 230 mg caffeine, a can of 355 mL “NOS” energy drink containing 120 mg caffeine. Sixteen volunteers (25±5 years) received a cup of 473 mL coffee containing 240 mg caffeine. Studies were performed before drink (baseline) at 1.5 and 4 hours post drink. Two of the energy drinks (Red Bull and 5-hour

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Energy) significantly improved endothelial function at 4 hours post drink, while one (NOS) as well as coffee did not change endothelial function significantly. RHI increased by 82±129% (p=0.028) and 63±37% (p=0.027) following 5-hour Energy and Red Bull

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respectively. The RHI change following NOS by 2±30% (p=1.000) and by 7±30% (p=1.000) following coffee. In conclusion, some energy drinks appear to significantly

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improve endothelial function. Caffeine does not appear to be the component responsible for these differences.

Keywords: Energy drink; Coffee; Endothelial function.

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INTRODUCTION Energy drinks are consumed by millions (1,2) and consumption has been anecdotally linked to the development of adverse cardiovascular events, although clinical trials to

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support this association are lacking (3). Some studies report an increase in heart rate (4,5,6), while a number of studies did not report an increase in heart rate (7,8,9). Some report an increase in blood pressure (4,6,10), while others did not (5,8,9,11). Limited

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number of studies evaluated the effect of energy drinks on endothelial function

(12,13,14). Noninvasive measurements of endothelial function may be considered a

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surrogate for the measurement of coronary blood flow (15,16,17).

The aim of this study was to evaluate the effect of 3 commonly consumed energy drinks on endothelial function using a standard consistently applied methodology. As the main active ingredient of energy drinks is caffeine, to place the observed changes in

METHODS

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context, comparison was made to coffee, a drink with a substantial caffeine content.

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The study was performed in the Clinical Testing Center of the American Institute of Therapeutics (Laker Bluff, IL). The study received IRB approval and each participant

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gave written informed consent. A total of 19 healthy volunteers were recruited (8 females, 11 males); 11 Caucasian, 4 Hispanic, 4 Asian and 1 Native American. Mean age was 24±5 years, weight: 72±12 kg, height: 168±12 cm, systolic blood pressure: 116±11 mmHg, and diastolic blood pressure: 74±10 mmHg. None of the volunteers were smokers. To be eligible for the study, participants had to be between 18 and 35 years of age with no clinically important findings on medical history, 12-lead

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electrocardiogram (EKG), and physical examination, having body weight between 54 and 79 kg (120-175 pounds) for women and between 64 and 90 kg (140-200 pounds) for men, heart rate between 60 and 88 bpm and blood pressure between 95-130 mmHg

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systolic and 55-88 mmHg diastolic after sitting for 5 minutes. Pregnancy, taking birth control pills, being on prescription medications, use of illegal drugs, having allergy to coffee, or any known components of the energy drinks were reasons for exclusion from

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the study.

This study was a single center, open label trial. The effects of energy drinks were

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evaluated in 6 volunteers (3 males, 3 females, age: 25±7 years, weight: 71±16 kg, height: 168±12 cm). Four of the 6 volunteers were energy drink naïve. Three consumed 1 cup coffee and 1 consumed 2 cups of coffee a day. Two volunteers did not consume any other caffeinated products while 4 did occasionally. The following energy drinks

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were evaluated: a) a can of 250 mL (8.4 oz.) Red Bull Energy Drink containing 80 mg caffeine, b) 57 mL (1.93 oz.) “5-hour Energy”, extra strength, sugar free drink containing 230 mg caffeine, c) a can of 355 mL (12 oz.) “NOS” high performance energy

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drink containing 120 mg caffeine. Participants were randomized to the sequence of drinks to be consumed. The shortest time between study days was at least 2 days.

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The effect of coffee on endothelial function was evaluated in 16 volunteers (3 of

them also participated in the energy drink evaluations). The volunteers consumed a cup of 473 ml (16 oz.) Starbuck’s K-cup Breakfast Bland coffee (2 K-cups in 16 oz. water) containing 240 mg caffeine. The mean age of these 16 participants was 25±5 years, gender: 7 females, 9 male , body weight ; 72±11 kg, height: 169±10 cm. Energy drink naïve were 13 of the 16 volunteers, 10 consumed coffee on a daily basis and 6

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were not coffee drinkers. Other source of caffeine intake (i.e. tea, Coca or Pepsi Cola, etc.) were more common in 12 of the 16 volunteers. On each study day, the effect of the study drink on endothelial function was

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evaluated by digital peripheral arterial tonometry (PAT) employing the EndoPAT™

device (Itamar Medical, Caesarea, Israel) (18). The method is based on a 5-minute occlusion of the brachial artery using a standard blood pressure cuff and quantifying the

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endothelium-mediated changes in vascular tone by comparing pre-occlusion and postocclusion measurements via changes in finger arterial pulse wave amplitude from pre-

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occlusion to post occlusion using digital peripheral arterial tonometry signals (PAT signals). The PAT signals were collected from both index fingers by the EndoPAT™ device, which automatically calculates a single measurement of the endothelial function, the Reactive Hyperemia Index (RHI). The RHI is the post-to-pre occlusion PAT signal

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ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone (18) This method will be referred to as PAT, and the measurement as RHI in this study. This technique has been extensively used to

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evaluate endothelial function (13,15,16, 18,19,20), has been validated (15,18,21), and the subject of a supporting editorial comment (22)

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Participants had to be fasting from midnight the night before the study day and

no water consumption was allowed 2 hours before entering the study. Smoking was not allowed. No “soft drinks”, no coffee or tea, no hot chocolate, or other caffeinated products were permitted 24 hours prior and during a study day. On the study day, a physical and brief history was taken which included discussing any clinically significant events since the pre-study screening, as well as determining compliance with study

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restrictions. The evaluations were undertaken in a closely monitored quiet test environment. Care was taken to maintain an ambient room temperature of 21-24 Celsius (70-

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75°Farenheit) with dimmed lighting during the proce dure. Blood pressure was measured from the leg as measurement in either arm could effect the result of endothelial function. PAT probes measuring digital pulse amplitude were placed on both index fingers. After

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a 6 minute baseline measurement, a 5 minute occlusion of the brachial artery of the non-dominant arm was employed at 220 mmHg pressure. Following the 5 minute

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occlusion, the cuff was deflated and PAT signals were measured for an additional 6 minutes. At the end of the measurements, EndoPAT™ automatically calculated the RHI.

The RHI was determined in each individual after 30 minutes of rest at baseline.

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Following energy drink (over 15-30 minutes) the RHI was determined at 1.5 hours and 4 hours. The endpoints of 1.5 and 4 hours were selected based on our previous experience. Additional time points were not measured because of the limited number of

response.

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artery occlusions that can be performed without modifying endothelial hyperemic

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Statistical analysis was performed by IBM SPSS Statistical program (version 22).

Statistical analysis consisted of computation of means and standard deviations for continuous variables and frequencies for categorical variables. Changes from baseline in continuous variables (i.e. RHI) following a study drink were analyzed by repeated measures of ANOVA. For post hoc pairwise multiple comparisons, the Bonferroni test was used. Each variable was tested for normal distribution using the Kolmogorov-

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Smirnov and Shapiro-Wilk tests of normality. When data did not show normal distribution, nonparametric test was performed (Wilcoxon Signed Ranks Test). To increase the sensitivity of the testing, percent changes from baseline measurements

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were analyzed. Differences in continuous variables between the study drinks were

analyzed by repeated measures of ANOVA. A two-sided alpha error of p<0.05 was

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considered statistically significant

RESULTS

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The RHI was obtained at baseline (prior study drink) and at 1.5 and 4 hours with the results are shown in Table 1. There were significant differences between the study drink effects on endothelial function. The effects of 5-hour Energy and Red Bull were similar. Compared to baseline, endothelial function significantly improved following 5-

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hour Energy at 1.5 hours (RHI increased from 1.58±0.54 to 2.37±0.50, p=0.008). Following Red Bull, endothelial function significantly improved at 4 hours (RHI increased from 1.47±0.35 to 2.31±0.45, p=0.009). Compared to baseline, NOS showed no

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significant change in RHI at 1.5 hours (p=0.981) or at 4 hours (p=1.000). Similarly, compared to baseline, coffee resulted in no significant change in RHI either at 1.5 hours

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(p=1.000) or at 4 hours (p=1.000), Table 1. To account for individual differences in baseline measurements and the

magnitude of changes in RHI, percent change from baseline were calculated at 1.5 and 4 hours in each individual following study drink (Table 2).Compared to baseline, the greatest improvement in endothelial function was seen at 4 hours following 5-hour Energy and Red Bull (Figure 1). Following 5-hour Energy, RHI increased by 82±129%,

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(p=0.028). Following Red Bull, RHI increased by 63±37% (p=0.027). NOS resulted in no significant changes in RHI either at 1.5 hours (p=1.000) or at 4 hours (p=1.000). Similarly, coffee resulted in no significant changes in RHI at 1.5 hours (p=0.935) or at 4

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hours (p=1.000). Multiple pairwise comparisons of the drinks showed no difference between 5-hour Energy and Red Bull (p=0.491), as well as between NOS and coffee (p=0.943). However, both the 5-hour Energy and Red Bull significantly differed from

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NOS and coffee. (5-hour Energy versus NOS: p=0.016, 5-hour Energy versus coffee:

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p=0.004, Red Bull versus NOS: p=0.028, Red Bull versus coffee: p=0.028).

DISCUSSION

Previous reports have found conflicting results for the effect of energy drinks on endothelial function (12,13,14). We found that 5-hour Energy and Red Bull significantly

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increased endothelial function as measured by RHI. NOS and coffee had essentially no effect on endothelial function.

There are two well recognized and well accepted distinct noninvasive methods

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for the measurement of endothelial function (18,23). One method, the PAT and the other employs vascular ultrasound and measures the endothelium-dependent flow

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mediated vasodilatation (FMD) (23). Both are based on a 5-minute occlusion of the brachial artery using a blood pressure cuff. Both quantify the endothelium-mediated changes in vascular tone by comparing pre-occlusion and post- occlusion measurements. The vascular ultrasound method measures the changes in the brachial artery diameter (23). When the cuff is released, the increased blood flow is associated with flow mediated dilatation and an increase in brachial artery diameter. The PAT

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method (18) measures the endothelium-mediated changes in vascular tone via changes in arterial pulse wave amplitude from pre-occlusion to post occlusion in the distal fingers using digital peripheral arterial tonometry. The EndoPAT device automatically

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calculates the RHI. Since analysis is performed by the software, the EndoPAT test is both operator and interpreter independent (18). The EndoPAT test provides a good correlation when compared to coronary artery endothelial function (15). For these

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reasons the PAT method was selected to evaluate acute changes in endothelial function in this study.

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A case report found endothelial function worsening 90 minutes following energy drink in a single volunteer (12). That study used the brachial ultrasonography method to measure FMD. Given the technical difficulties of the method, as well as studying a single individual poses limitations. The second study employed the PAT method,

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evaluating the effect of an unnamed sugar free energy drink (250 mL) in 15 healthy young subjects. They reported a worsening endothelial function 60 minutes after drink (13). The third study was a randomized crossover trial evaluating the effect of 355 mL

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Red Bull energy drink on endothelial function in 25 healthy subjects. Measurements were made prior to drink and at 2 hours after drink. The authors report an improvement

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in endothelial function (14).

The effect of caffeine on endothelial function has been reported in several

studies with conflicting results. Some reported a favorable effect (24,25,26), while others found an unfavorable effect (27,28), or no effect (29,30). The conflicting observations may be due to different methodologies employed, the timing of the measurements, and that some studies might have included habitual coffee drinkers

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while others caffeine naïve individuals, groups that may respond differently. The results we report exclude caffeine as the ingredient that improves endothelial function in energy drinks. Coffee and 5-hour Energy have approximately the same

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caffeine content. Coffee did not improve endothelial function while 5-hour Energy

significantly improved it. Red Bull has the smallest caffeine content of the drinks studied with a significant positive effect on endothelial function. NOS has approximately half the

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caffeine content as coffee (used in our study) and showed no improvement in

endothelial function. Given the lack of improvement in endothelial function with coffee,

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the effect of 5-hour Energy and Red Bull is probably due to ingredient(s) other than caffeine which include taurine, glucuronolactone, niacine, ginseng and guarana. Future studies may elucidate the effects of these component(s).

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Disclosures: The authors have no conflicts of interest to disclose.

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endothelial function in healthy individuals.

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Figure Legends

Energy Drinks and Coffee

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Figure 1. Percent Changes in Reactive Hyperemia Index (RHI) Following Three

Percent changes in RHI at 1.5 and 4 hours. Compared to baseline, RHI increased by 82±129% following 5-hour Energy (p=0.028) and 63±37% (p=0.027) following Red Bull.

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RHI did not change significantly following NOS and coffee.

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Table 1. Effect of Three Energy Drinks and Coffee on Endothelial Function as Measured by the Reactive

Time

Mean ± SD p

Mean ± SD p

Baseline

1.58 ± 0.54

1.47 ± 0.35

1.5 hour

2.37 ± 0.50

0.008

2.12 ± 0.76

4 hours

2.48 ± 0.80

0.228

2.31 ± 0.45

NOS

Coffee

Mean ± SD p

Mean ± SD p

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Red Bull

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5-Hour Energy

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Hyperemia Index (RHI)

1.60 ± 0.45

1.82 ± 0.48

0.104

1.78 ± 0.40 0.981

1.91 ± 0.51 1.000

0.009

1.57 ± 0.41 1.000

1.88 ± 0.36

1.000

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p value indicates the significance of difference at each time point compared to baseline (prior drink) measurement. Compared to baseline, endothelial function significantly improved following 5-Hour Energy at 1.5 hours (p=0.008), as well

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as following Red Bull at 4 hours (p=0.009) and a non significant changes were seen in RHI following NOS and coffee.

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Table 2. Effect of Three Energy Drinks and Coffee on Endothelial Function as Measured by the Percent Changes

Red Bull

Time

Mean ± SD p*

Mean ± SD p

Baseline

0 ± 0%

0. ± 0%

1.5 hour

58 ± 36%

0.028

44 ± 31%

0.052

4 hours

82 ± 129%

0.028

63 ± 37%

0.027

NOS

Coffee

Mean ± SD p

Mean ± SD p

0 ± 0%

0 ± 0%

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5-hour Energy

16 ± 38%

1.000

8 ± 29%

0.935

2 ± 30%

1.000

7 ± 30%

1.000

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A.

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in Reactive Hyperemia Index (RHI)

p value indicates the significance of difference at each time point compared to baseline (prior drink) measurement.

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Compared to baseline, endothelial function significantly improved following 5-Hour Energy at 1.5 and 4 hours (p=0.028), as well as following Red Bull at 4 hours (0.027), and a non significant changes were seen following NOS and coffee. Multiple pairwise comparisons of the drinks showed no difference between 5-Hour Energy and Red Bull (p=0.491), as well

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as between NOS and coffee (p=0.943). However, both the 5-Hour Energy and Red Bull significantly differed from NOS

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and coffee. (5-Hour Energy versus NOS: p=0.016, 5-Hour Energy versus coffee: p=0.004, Red Bull versus NOS: p=0.028, Red Bull versus coffee: p=0.028).

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90

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82±129*

70 60

63±37* 58±36*

50

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44±31

40

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30 20 10 0

0±0

BL 1.5hr 4hr

16±38 8±29

0±0

5-hour Energy *p<0.05

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80

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Percent Change in RHI From Baseline (%)

Figure 1

0±0

BL 1.5hr 4hr

Red Bull

2±30

0±0

7±30

BL 1.5hr 4hr

BL 1.5hr 4hr

NOS

Coffee