|Year : 2012 | Volume
| Issue : 3 | Page : 243-250
Study of cardiovascular effects of caffeine in healthy human subjects, with special reference to pulse wave velocity using photoplethysmography
Raveendranadh Pilli, MUR Naidu, Usha Rani Pingali, Ramesh Kumar Rao Takallapally
ICMR Advanced Centre for Clinical Pharmacodynamics, Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, India
|Date of Web Publication||8-Aug-2012|
ICMR Advanced Centre for Clinical Pharmacodynamics, Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Caffeine is one of the most widely used pharmacologically active substances. It increases blood pressure and peripheral vascular resistance by stimulation of the sympathetic nervous system. Studies on the cardiovascular effects of caffeine have often produced contradictory results. Arterial stiffness and pulse wave reflections are important determinants of the efficient performance of the cardiovascular system, with prognostic value for cardiovascular risk. Materials and Methods: This is a randomized, double-blind, placebo-controlled, parallel-design study, comparing the effects of a single oral dose of 250 mg or 500 mg caffeine and placebo on arterial stiffness and pulse wave reflections in 36 healthy male subjects by measuring arterial pulse wave velocity by recording fingertip second derivative of photoplethysmogram (SDPTG) and ECG simultaneously. Blood pressure, heart rate, pulse wave velocity, and b/a ratio (SDPTG index) were measured at baseline and at 30 and 60 minutes after administration of caffeine. Results: Compared to baseline, systolic and diastolic blood pressures were increased significantly at 30 minutes and 60 minutes with caffeine, while heart rate decreased significantly at 30 minutes (P<0.05 for 250mg and P<0.01 for 500mg caffeine) but showed no significant change at 60 minutes. Pulse wave velocity increased significantly with both the doses of caffeine at 30 minutes (P<0.05) and 60 minutes (P<0.001). Similarly, the b/a ratio also increased significantly at 30 minutes (P<0.01) and 60 minutes (P<0.01) with 250 mg, but the change was insignificant with 500 mg. No significant changes were observed after administration of placebo. Conclusion: Acute administration of caffeine produced rise in blood pressure, arterial stiffness, and change in wave reflections in healthy subjects as indicated by pulse wave velocity and b/a ratio.
Keywords: Arterial stiffness, caffeine, pulse wave velocity, pulse transit time, second derivative of photoplethysmogram
|How to cite this article:|
Pilli R, Naidu M, Pingali UR, Takallapally RR. Study of cardiovascular effects of caffeine in healthy human subjects, with special reference to pulse wave velocity using photoplethysmography. Int J Nutr Pharmacol Neurol Dis 2012;2:243-50
|How to cite this URL:|
Pilli R, Naidu M, Pingali UR, Takallapally RR. Study of cardiovascular effects of caffeine in healthy human subjects, with special reference to pulse wave velocity using photoplethysmography. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 May 26];2:243-50. Available from: http://www.ijnpnd.com/text.asp?2012/2/3/243/99478
| Introduction|| |
Many epidemiological studies suggest that regular consumption of caffeine is associated with adverse cardiovascular outcomes, ,, but this is not a consistent finding. , Caffeine has a strong and persistent acute pressor effect, which could increase cardiovascular disease risk through its known effects on blood pressure (BP). It appears to affect BP through adenosine receptor inhibition and an increased release of select neurotransmitters.  Several studies suggest that habitual use of caffeine leads to the development of tolerance to its physiological effects on BP and hormonal reactivity. ,, Caffeine has been demonstrated to increase the aortic stiffness as well as aortic pressure in healthy adults as well as in adults with hypertension. ,,,,
Large-artery stiffness and wave reflections are important independent prognosticators of cardiovascular disease risk because they affect left ventricular function, coronary blood flow, and the mechanical integrity of arteries. ,, The measurement of pulse wave velocity (PWV) is one of the representative methods for assessing arterial stiffness. ,, Another method for evaluating arterial properties uses the finger photoplethysmogram (PTG). ,,
The PWV provides information on the time period within which a pressure or flow wave travels a known distance. PWV is the speed of a pressure pulse propagating along the arterial wall and can easily be calculated from the pulse transit time (PTT) (the time between two pulse waves propagating on the same cardiac cycle from two separate sites). PTT, measured as the interval from the R wave of the ECG to the pulse plethysmograph upstroke obtained from finger PTG, was used recently to assess cardiovascular responses to anesthesia and intubation. ,,
The second derivative of PTG-known as SDPTG-is a simple, noninvasive, and convenient technique for measuring arterial stiffness. ,, Previous studies have reported the effect of caffeine on arterial stiffness and aortic blood pressures measured from radial and carotid-femoral artery waveform using applanation tonometry. ,,,, PWV measured between the carotid-femoral regions provides an indicator of arterial stiffness, whereas PWV measured by digital volume pulse (DVP) shows stiffness of the global arterial system, since PWV measured by this technique is the wave velocity traveling through the aorta as well as the arteries of limbs. The digital pulse plethysmography (DPG) technique in the evaluation of the effect of caffeine on PWV has not been reported. To the best of our knowledge there is no data on the use of SDPTG to examine the effects of acute caffeine administration in humans. Hence, in the present study, we have attempted to find out the effect of caffeine on PWV and the b/a ratio (SDPTG index) using SDPTG by the DPG technique.
| Materials and Methods|| |
Thirty-six healthy male participants aged between 20-40 years took part in the study. All participants were nonobese, nonsmokers, and relatively non-habitual caffeine consumers (i.e., no consumption of coffee or tea or not more than one caffeinated beverage per day). Detailed history was taken and clinical examination was done, with particular emphasis on the examination of the cardiovascular system. Written informed consent was obtained from those who agreed to participate after a full explanation had been given of the aims, procedures, and risks of the study. The study was approved by the Institutional Ethics Committee of Nizam's Institute of Medical Sciences, Hyderabad, India.
Study design and procedure
This study used a double-blind, placebo-controlled, parallel design. The participants were randomized into three groups of 12 each; they received either a single oral dose of 250 mg or 500 mg of caffeine or matching placebo capsule. Subjects arrived at the experimental laboratory in the department of clinical pharmacology and therapeutics following an overnight fast and abstinence from caffeine-containing beverages or alcohol for 24 hours (confirmed by a questionnaire administered at the beginning of the session). Subjects rested in a sitting position for 20 minutes in a quiet, temperature-controlled (26°±1°C) room before the recordings. They were asked to breathe normally and to remain still during the measurements. They were permitted to listen to music or to read, except during the periods of cardiovascular measurements.
First, all the cardiovascular tests were performed at baseline. This was followed by administration of a single oral dose of 250 mg or 500 mg caffeine or placebo, as per the pre-randomization schedule, along with 200 ml of water. The cardiovascular tests were then repeated at 30 minutes and 60 minutes post drug administration.
Brachial BP and heart rate (HR) were measured with an automated digital BP monitor (OMRON, SEM-1), and the mean of three readings was calculated. All readings were taken with the cuff wrapped around the subject's nondominant arm, with the forearm resting on the table so that the cuff was at the level of the heart.
After BP determination, the electrocardiogram (ECG) and DPG measurements were recorded using Biopac MP-30 data acquisition system (MP30BCE, Biopac Systems INC, Santa Barbara, CA, USA), which allows online simultaneous recording of all the above parameters and calculation of the PTT offline.
The subjects were examined in the sitting position, with the ECG electrodes placed on the thorax (lead II ECG). The digital pulse transducer was fixed to the distal phalanx of the left index finger, with the wrist resting on a padded support. The DPG signals were recorded for 60 seconds and timed against a simultaneous ECG recording. During the experiment, ECG and DPG signals were amplified (×2000), low-pass filtered (66.50-0.50 Hz), and digitalized at 250 samples per second. The recorded signals were saved on the computer for offline analysis using BSL Pro® software. The BSL Pro® software program was used to calculate the time delay between the R wave of the ECG and the second derivative of the upstroke of the digital arterial pulse wave of the same cardiac cycle. The PTT was calculated as the interval between the ECG R wave and the point at which the pulse wave reached 100% amplitude [Figure 1]. The PWV is defined as the length of arterial segment divided by the transit time of the pulse wave. The PWV was measured by dividing the externally measured distance between suprasternal notch and the cuticle of the index finger of the left forearm by the recorded PTT. The SDPTG waveform consists of four waves in systole (a-d) and one in diastole (e), as shown in [Figure 1]. We measured the height of the 'a' and 'b' waves from the baseline, with the values above the baseline being considered positive and those under it negative. The parameter that is related to distensibility of large arteries (b/a ratio) was defined as the ratio of the height of the 'b' wave to that of the 'a' wave. Average PTTs and the b/a ratio were calculated from 20 consecutive good-quality waves. All the measurements were performed by the same operator.
|Figure 1: ECG and measured SDPTG pulse. PTT is calculated as the time interval between each R wave of the ECG and 100% of the pulse wave rise. The waveform of SDPTG consists of four systolic waves (a, b, c, and d waves) and one diastolic wave (e wave)|
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Statistical analysis was performed using Microsoft® Excel (2003) and GraphPad® software (version 4.03). The values are reported as mean± SEM. Demographic details were summarized for all randomized subjects using descriptive statistics. ANOVA for repeated measures was performed in order to detect significant changes in variables over time within the three groups separately. Student's paired 't' test was used for comparisons of intersubject variability, and the unpaired 't' test was used to find the difference between the groups. Statistical significance was at P<.05.
| Results|| |
The effects of caffeine on cardiovascular parameters are shown in [Table 1].
|Table 1: Cardiovascular parameters before and after oral intake of different doses of caffeine and placebo|
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Thirty-six male subjects were enrolled into the study. They were randomized into three treatment groups, with 12 subjects in each group. The mean age, height, and weight in the three groups were as follows: 27.70±2.12 years (range: 20-40 years), 168.6±1.41 cm, and 65.35±2.32 kg in group A; 27.71±2.07 years (range: 20-40 years), 165.2±1.1 cm, and 55.64±5.3 kg in group B; and 28.33±2.04 years, (range: 20-40 years), 164.9±1.0 cm, 61.60±2.7 kg in group C. All subjects completed the study.
There were no statistically significant differences in the baseline values of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), PWV, and b/a ratio between the groups [Table 1].
Effect of caffeine on blood pressure
Effect of caffeine on systolic blood pressure
Caffeine 250 mg increased the mean SBP from 112.4±2.13 mmHg to 119.0±2.79 mmHg at 30 minutes and to 119.3±2.37 mmHg at 60 minutes. The increase in SBP with 250 mg of caffeine was found to be significant at both the time points (P<.01). Similarly, 500 mg of caffeine also produced an increase in SBP from 114±2.10 mmHg to 123.30±3.04 mmHg at 30 minutes and to 122.7±3.33 mmHg at 60 minutes. The increase in SBP with 500 mg of caffeine was found to be highly significant at both the time points (P<.001). SBP remained virtually unchanged after placebo administration at both the time points. The effects of the two doses of caffeine differed significantly from those of placebo.
However, no significant difference was seen between the doses of 250 mg and 500 mg of caffeine with regard to effect on SBP [Table 1] and [Figure 2].
|Figure 2: Systolic and diastolic BP before and after oral intake of different doses of caffeine and placebo. Figures are mean values (±SEM) of 12 subjects in each group. *P<.05, **P<.01, and ***P<.001, as compared to baseline.^ P<.05, ^^P<.01, and ^^^P<.001, as compared to placebo|
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Effect of caffeine on diastolic blood pressure
Both doses of caffeine increased the DBP significantly at 60 minutes (P<.05), with caffeine 500 mg producing a significant increase in DBP at 30 minutes also (P<.05). There was minimal variation in DBP in the placebo group. Caffeine 250 mg and 500 mg produced a significant increase in DBP as compared to placebo at 30 minutes (P<.05 and P<.01, respectively) and 60 minutes (P<.01, P<.05, respectively).
There was no statistically significant difference between the two doses of caffeine with regard to the effect on DBP [Table 1] and [Figure 2].
Effect of caffeine on heart rate
HR decreased markedly after the administration of caffeine 250 and 500 mg at 30 minutes only (P<.05 and P<.01, respectively). In comparison, the HR remained unchanged after placebo at both 30 minutes and 60 minutes. Compared to placebo, caffeine 500 mg was significantly more potent than 250 mg caffeine in reducing HR at 30 minutes (P<.05). The effects of the two doses of caffeine on HR differed only minimally (P>.05) [Table 1].
Effect of caffeine on PWV and b/a ratio
Effect of caffeine on PWV
As shown in [Table 1] and [Figure 3], PWV increased markedly (compared to baseline) after administration of caffeine 250 mg and 500 mg at 30 minutes (P<.05) and 60 minutes (P<.001). The PWV remained virtually unchanged at both the time points after placebo. As compared to the placebo group, a significant increase in PWV was seen with caffeine 500 mg only at 60 minutes (P<.001). No significant difference was observed between caffeine 250 mg and 500 mg with regard to effect on the PWV.
|Figure 3: Pulse wave velocity before and after oral intake of different doses of caffeine and placebo. Figures are mean values (±SEM) of 12 subjects in each group. *P<.05 and ***P<.001, as compared to baseline, ^^^P<.001, as compared to placebo|
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Effect of caffeine on b/a ratio
Caffeine 250 mg significantly increased b/a ratio at 30 minutes (P<.01) and 60 minutes (P<.001), but no demonstrable effect on b/a ratio was seen with caffeine 500 mg as compared to baseline. A slight, nonsignificant, increase in b/a ratio was observed with placebo (P>.05). The effect of 250 mg caffeine on the b/a ratio (as compared to placebo) was significant at 30 minutes only (P<.01). No significant change in b/a ratio was observed with caffeine 500 mg. No significant difference was observed between the two doses of caffeine with regard to effect on the b/a ratio [Table 1].
Caffeine (250 mg and 500 mg) was well tolerated. However, three subjects reported gastric irritation 60 minutes after drug administration with the dose of 500 mg.
| Discussion|| |
The present study demonstrates the acute effects of caffeine on vascular function. The results of our study add to the growing evidence that caffeine has deleterious effects on the cardiovascular system. ,, In this study we used fingertip SDPTG to evaluate cardiovascular responses to two doses of caffeine in healthy male participants. We measured the time interval between the ECG R wave and the upsweep of the SDPTG to calculate the PWV; the b/a ratio of SDPTG was used to evaluate the distensibility of the vascular wall. This measured time interval incorporates two principal components, the time between electrical activation of the ventricle and cardiac ejection, and the time taken for the resultant pressure wave to be transmitted along the artery to generate the plethysmograph upstroke. The time from ventricular activation to cardiac ejection depends upon a number of factors related to preload, heart rate, and contractility. To the best of our knowledge, the present study is the first to demonstrate that the SDPTG is capable of detecting vascular changes induced by caffeine in healthy subjects. SDPTG is one of the alternative methods for assessment of arterial stiffness. It was originally proposed as an assessment tool for 'vascular aging' and a number of previous studies have shown considerable association between SDPTG indices and age,  BP, ,, coronary heart disease,  and presence of atherosclerotic disorders.  Although the measurements are obtained from the periphery of the circulation, SDPTG provides information about both central and peripheral arterial properties. It has been shown that SDPTG indices closely correlate with the augmentation index of the ascending aorta  and distensibility of the carotid artery, suggesting that SDPTG indices may be a good surrogate measure of arterial stiffness. It is a noninvasive procedure and it is easy for patients to undergo the measurement. We believe that the SDPTG is a good parameter of arterial stiffness. We chose to study this scenario because caffeine acutely increases BP and peripheral vascular resistance. Pincomb et al.  reported that caffeine produced no increase in cardiac output or contractility but did cause a progressive increase in vascular resistance.
According to our results, caffeine at both doses (250 mg and 500 mg) increased wave reflections, as shown by the increase in b/a ratio and PWV. Results of studies on the impact of caffeine consumption on cardiovascular risk are conflicting, with some studies showing a strong positive association and even a 'J' shaped one. , Previous studies have shown that caffeine results in an acute and chronic deterioration of arterial function, with increased PWV and wave reflections. ,,,,
The b/a ratio has been considered a marker of the distensibility of large arteries that is little affected by the reflection wave.  Imanaga et al.  reported that the b/a ratio is correlated with the distensibility of the carotid artery, a surrogate measure of large arterial stiffness. An increased b/a ratio and a decreased d/a ratio have been thought to represent increased arterial stiffness and are associated with aging. In our study, the group receiving caffeine 250 mg showed a tendency toward increase in b/a ratio (P<.01, compared with the baseline), which indicated change in distensibility of large arteries following caffeine administration. On the other hand, 500 mg caffeine did not show any significant effect on the b/a ratio. Although it is not possible to clearly explain this discrepancy, it may be due to the difference in the change of HR with the two doses. Caffeine in high doses is also known to cause irregular heart rhythm, including premature contractions of the heart ventricle.
Increased PWV is considered to reflect an increase in aortic stiffness, whereas the effect on arterial wave reflection may be due to in part to both increased PWV and increased vascular smooth muscle tone of the peripheral muscular arteries. Several studies have shown that arterial stiffness depends on variations in BP (stiffness becomes higher at high BP and lower at low BP) as well as sympathetic stimulation.  Our study shows an increase in PWV and wave reflections, as evidenced by the increase in BP with both doses of caffeine.
Epidemiological studies , have produced conflicting results regarding the association between caffeine consumption and BP. Studies , have shown that 200-300 mg of caffeine will cause a modest increase in BP of about 8-12 mmHg systolic and 5-7 mmHg diastolic, but this is only in subjects who have recently abstained from caffeine-containing beverages or foods. Robertson et al.  reported a significant increase in SBP and DBP after oral administration of 250 mg caffeine, while Bruce et al.  showed that both 250 mg and 500 mg doses of caffeine did not affect BP. In the present study we found an increase in BP of about 4-10 mmHg systolic and 2-5 mmHg diastolic with 250 and 500 mg doses of caffeine. The effect of caffeine on BP appears to be mediated through an increase in systemic vascular resistance brought about by the ability of caffeine to block adenosine receptors in blood vessels, enhancing the action of norepinephrine.
The effect of caffeine on HR is more controversial, with variable and opposite observations reported. ,, For instance, several studies found that moderate  or even high doses  of caffeine did not significantly affect cardiac rhythm or rate. Others, in contrast, reported a small decline in resting HR. , These latter findings were thought to be caused by a baroreceptor-mediated effect  compensating for the raised BP, but the precise timing of the changes in HR was not addressed. Also, the decrease in HR was probably due to either direct vagal stimulation  or an effect on the sinoatrial node.  In our study the effect of caffeine on the HR is consistent with the results of some earlier research studies, ,, with HR showing decrease with both doses of caffeine.
This study has some limitations. Firstly, the study population consisted of only middle-aged Indian men and thus the results cannot be extrapolated to other populations, including women, the elderly, or other ethnic groups. Secondly, the number of subjects in each group is small and more studies on larger populations may be required to adequately clarify the effects of caffeine on hemodynamic parameters. Thirdly, blood chemical evaluations of risk factors affecting cardiovascular parameters have not been performed. In addition, the DPG signal has certain limitations. The amount of reflected light depends on several factors, including degree of skin pigmentation, individual tissue characteristics, and initial blood volume in the measured area. Another fact to be kept in mind, is that our study is confined to asymptomatic subjects with normal sinus rhythm.
| Conclusions|| |
In conclusion, our results suggest that acute caffeine consumption increases aortic stiffness and wave reflections as assessed using SDPTG. Aortic stiffness and wave reflections are prognosticators of cardiovascular risk as they are important determinants of left ventricular function, coronary perfusion, and arterial wall integrity. These findings suggest that SDPTG measurement may be useful in evaluating arterial properties such as arterial stiffness induced by vasoactive agents. The application of SDPTG in epidemiological settings is possible because of the simplicity of the procedure and its easy accessibility. The present results may therefore indicate the usefulness of the SDPTG in the field of cardiovascular preventive medicine.
| Acknowledgments|| |
The authors are grateful to the Indian Council of Medical Research, New Delhi, India, for the financial support and facilities to carry out this study. We extend our thanks to Suraksha Pharmaceuticals Ltd., Roorkee, India, for providing the medication used in the study.
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[Figure 1], [Figure 2], [Figure 3]