More than 80% of the world population consumes

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1 AJH 2005; 18: Acute Effects of Caffeine on Arterial Stiffness, Wave Reflections, and Central Aortic Pressures Theodoros G. Papaioannou, Kalliopi Karatzi, Emmanouil Karatzis, Christos Papamichael, and John P. Lekakis Caffeine is considered to be the most widely consumed pharmacologic substance in the world. Several recent sources of evidence suggest that caffeine, besides its wellestablished pressor effects, provokes further alterations in arterial stiffness, wave reflections, and especially aortic blood pressures, which are often overlooked. The increasing evidence regarding the prognostic value of the latter cardiovascular factors prompted us to seek additional information concerning the relationship of aortic blood pressures to caffeine consumption. The main purpose of the present review was to evaluate the acute influence of caffeine on arterial stiffness, wave reflections, and central systolic pressures, which are involved in the pathogenesis and prognosis of cardiovascular diseases. Current evidence supports the hypothesis that caffeine influences the More than 80% of the world population consumes caffeine daily, making this substance the most widely consumed drug in history. 1 Coffee, tea, and caffeinated drinks are some beverages in which caffeine is the common constituent in various concentrations, rendering both short- and long-term cardiovascular effects of caffeine an intriguing issue of research. A thorough investigation has been conducted concerning the shortand long-term pressor effects of caffeine; however, the findings have been controversial. 2 The role of caffeine consumption on the mechanical properties of arteries has been recently investigated, providing data obtained mainly in short-term studies in normal and hypertensive subjects. We attempted to review briefly the current information concerning the vascular effects of caffeine, such as the increase in arterial stiffness, wave reflections, and aortic blood pressure (BP), focusing mainly on the acute response. Analysis of Published Data cardiovascular system at least acutely, not only through a peripheral blood pressure elevation but also through an increase in arterial stiffness and an enhancement of arterial wave reflections. Moreover, it seems that peripheral pressure measurements might have underestimated caffeine pressor effects, as a significantly greater response is observed in aortic pressures. The mechanisms explaining these effects of caffeine are not always clear, and neither is the role of caffeine in cardiovascular risk. However, it is concluded that strategies aiming at the control of dietary caffeine consumption merit serious consideration. Am J Hypertens 2005;18: American Journal of Hypertension, Ltd. Key Words: Caffeine, coffee, arterial stiffness, wave reflections, central aortic blood pressures, distensibility. To provide an overview of the available literature concerning the acute effects of caffeine on arterial stiffness, wave reflections, and aortic systolic pressure, we reanalyzed and compared the already published data by means of net response. Published curves describing the shortterm variation of these variables after caffeine consumption were digitized (WinDig 2.5, for Windows [WinDig 2.5 for Windows, University of Geneva, Switzerland]) to calculate the net absolute changes induced by caffeine as follows. The net absolute response of each variable was determined as the caffeine induced change (at each time point) from baseline minus the respective change after placebo administration, as depicted in Figs. 1 to 3. Arterial Stiffness Various longitudinal studies demonstrated that arterial stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with end-stage renal disease 3 and essential hypertension. 4 Additionally, arterial stiffness has been characterized as an independent predictor of cardiovascular events, 5 and it has been associated with various factors such as aging, exercise, gender, body size, 6 8 hypertension, 6 coronary artery disease, 9 end-stage renal failure, 10 diabetes, 11 hyperlipidemia, 12 and mechanical assistance in cardiogenic shock. 13 The association of Received May 29, First decision August 11, Accepted August 12, From the Vascular Laboratory, Department of Clinical Therapeutics, Alexandra University Hospital, National and Kapodistrian University of Athens, Greece. Address correspondence and reprint requests to Dr. Theodoros G. Papaioannou, I. Patatsou 13, N. Kipseli, Athens, Greece; theopap@mail.ntua.gr 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc /05/$30.00 doi: /j.amjhyper

2 130 CAFFEINE AND ARTERIAL STIFFNESS AJH January 2005 VOL. 18, NO. 1 FIG. 1 Net effect of caffeine on arterial stiffness estimated by the pulse wave velocity. arterial compliance with left ventricular functional properties and structure should also be underscored Various methods exist for the estimation of arterial stiffness. 17 Pulse wave velocity (PWV) is an established indicator of arterial stiffness, and its assessment has been proposed in patients with hypertension and in those at risk for cardiovascular disease. 18 This method is based on principles related to pressure waves. Pressure waves are generated during every cardiac systole and propagate throughout the arterial system. The velocity of pressure wave propagation is predominantly determined by arterial stiffness. Greater arterial stiffness is accompanied by a greater velocity of forward and backward traveling pressure waves. Thus, PWV measurement between two locations in the arterial system (ie, the carotid to femoral arteries) provides valuable information regarding regional arterial stiffness. Effects of Caffeine on Arterial Stiffness During the last decade, researchers have started to examine the acute effects of caffeine on arterial stiffness. How- FIG. 2 Net effect of caffeine on wave reflections estimated by the augmentation index.

3 AJH January 2005 VOL. 18, NO. 1 CAFFEINE AND ARTERIAL STIFFNESS 131 FIG. 3 Net effect of caffeine on aortic systolic blood pressure. ever, the topic is disproportionately unexplored compared with the extensive use of this substance. In 2001, an unfavorable acute effect of caffeine on arterial stiffness was reported in a double-blind crossover study with a very small sample (n 7) of young ( years of age) healthy volunteers. 19 Quantities (250 ml) of regular and decaffeinated coffee containing 150 mg and 2 mg caffeine, respectively, were given to the study subjects. Arterial stiffness was estimated by the carotid femoral artery PWV at baseline and 30, 60, and 90 min after ingestion of regular or decaffeinated coffee. A significant maximal increase of PWV from m/sec to m/sec after caffeine ingestion was reported. 19 Two years later, the acute effects of caffeine were investigated in 20 healthy middle-aged subjects (50 16 years old), following a placebo-controlled, double-blind, cross-over design. 20 The study population consisted of 17 men and three women. All subjects were regular caffeine consumers ( 100 mg caffeine per day). In this study, 250 mg quantities of caffeine were administered orally in capsule form. It was found that caffeine acutely increased arterial stiffness as estimated by the enhancement of carotid femoral artery PWV, which remained augmented even 3 h after caffeine consumption. Both studies 19,20 indicated a peak increase in PWV 30 min after caffeine intake. Finally, very recently, 16 healthy subjects (eight men and eight women, years of age) were investigated according to a randomized, double-blind, crossover design, in which each subject consumed either a cup of coffee ( 80 mg caffeine) or a cup of decaffeinated coffee ( 2 mg caffeine). 21 In this study, timing of reflected waves was used as an estimate of PWV. The decrease in the arrival time of reflected waves at the aorta, induced by caffeine consumption, was significantly greater compared with the respective changes after consumption of decaffeinated coffee, verifying the enhancement of PWV previously reported. 19,20 The influence of caffeine on arterial stiffness was also investigated in 12 middle-aged (60 3 years), treated hypertensive patients. 22 A significant increase in PWV was observed after caffeine consumption and lasted at least 3 h. Caffeine was again administered in capsules containing 250 mg caffeine. Surprisingly, no other data exist either in hypertensive or in other patient groups. In summary, caffeine was found to affect arterial stiffness acutely in normal and hypertensive subjects The increase in PWV after caffeine consumption reported in previous studies is illustrated at Fig. 1. All three studies 19,20,22 used carotid-to-femoral artery PWV, rendering the results comparable to each other. A similar maximal PWV increase by almost 0.5 m/sec has been reported in both normal 20 and hypertensive subjects, 22 although a somewhat greater increase up to 0.7 m/sec has been also found, 19 despite the fact that lower caffeine dose was administered (150 mg compared with the 250 mg). Another important observation is that PWV increase in hypertensive patients persisted for 3 h after caffeine consumption ( 0.4 m/sec), whereas in normal subjects it returned almost to baseline values 3 h after consumption. Consequently, the unfavorable acute effect of caffeine on arterial stiffness could be considered similar between normal and hypertensive subjects. However, these effects last longer in hypertensive compared with normotensive individuals, which renders caffeine an additional burdensome factor that might increase the pre-existing risk in the hypertensive population.

4 132 CAFFEINE AND ARTERIAL STIFFNESS AJH January 2005 VOL. 18, NO. 1 Table 1. pressures Studies investigating the acute effect of caffeine on arterial stiffness, wave reflections, and central Authors Ref. (Year) Wave reflections express the pulsatile component of left ventricular afterload and depend primarily on arterial stiffness and peripheral resistance. The discontinuity in the mechanical and geometrical properties of the arterial tree results in reflection of pressure waves, which plays a major role in modulating the aortic pressure waveform. The pattern of aortic pressure waves is directly modulated by both timing and magnitude of reflected waves. Recently developed, commercially available techniques allow noninvasive estimation of aortic pressure waves based on the use of applanation tonometry and generalized transfer functions. Thus, pulse wave analysis provides valuable information and indices reflecting both the intensity of wave reflections and PWV, such as the aortic augmentation index (AI), and the arrival time of reflected waves at the aorta, respectively. Briefly, augmentation index (AI% 100 AP/PP) represents the pressure boost that is induced by the return of the reflected waves at the aorta (augmentation pressure [AP]) as a percentage of central pulse pressure (PP) and indicates the intensity of wave reflections. (Readers can refer to other studies for a more extensive discussion of pulse wave analysis and the pathophysiologic significance of wave reflections ) It should be underscored that intensity and velocity of pressure waves are associated not only with arterial compliance but with stroke volume, peripheral resistance, heart rate, and body height. 23,26 Wave reflections have been related to left ventricular (LV) relaxation, coronary flow, 27 LV hypertrophy, 28 LV mechanics, 29 and mechanical assistance of the failing heart. 30,31 Caffeine Effects on Wave Reflections Caffeine dose (mg) Administration Subjects Measurement Normal Arterial stiffness, wave reflections, (n 7) aortic pressures Hypertensive (n 10) Wave reflections, aortic pressures Hypertensive Mahmud and Feely 19 (2001) 150 Beverage Vlachopoulos et al, 43 (2001) 250 Capsule Vlachopoulos et al, 22 (2003) 250 Capsule Vlachopoulos et al, 20 (2003) 250 Capsule Waring et al, 33 (2003) 300 Capsule Karatzis et al, 21 (in press) 80 Beverage Caffeine was found to increase wave reflections, mainly as a result of the induced changes in arterial stiffness and peripheral resistance. 32 A total increase in AI from 5.1% 7.6% to 5.28% 5.6% after caffeine intake has been reported. 19 Peak AI (n 12) Arterial stiffness Normal Arterial stiffness, wave reflections, (n 20) central pressures Normal (n 20) Wave reflections, aortic pressures Normal (n 16) Wave reflections, aortic pressures increase was observed at 30 min and remained significant 60 and 90 min after caffeine consumption. 19 These results were confirmed by Vlachopoulos et al, 20 who showed a significant rise in AI 30 min after caffeine consumption ( 7% net effect), which remained increased 3 h later. A significant increase in AI (from 14% 4% to 6% 4%) 45 min after administration of a capsule containing 300 mg caffeine was also reported in 20 healthy subjects in a randomized cross-over study. 33 Recent results by Karatzis et al 21 showed that AI significantly increased (from 12.4% 8% to 18.4% 7.9%) after the consumption of only one cup of coffee containing 80 mg caffeine; the peak AI increase was observed at 90 min and remained significant 120 min after coffee consumption. The enhancement of wave reflections after caffeine consumption was evidenced also in hypertensive patients with a peak AI increase 5% at 30 min. 33 The reported net effects of caffeine on wave reflections are presented in Fig. 2. The effect of caffeine on AI observed in normal subjects by Mahmud and Feely 19 was almost two times greater than the effect reported by other investigators (Fig. 2). The administered dose of caffeine does not seem to explain the variation in AI response among these studies. The lower caffeine dose (80 mg) was administered by Karatzis et al, 21 compared with 150, 250, and 300 mg used by the other investigators (Table 1). However, the results reported by Karatzis et al concerning AI were similar to those obtained in the other studies 21,33 (Fig. 2). The lower AI response was observed at hypertensive subjects, probably due to the already increased baseline AI value. The observed caffeine effects on wave reflections could be attributed predominantly to its action on the resistance vessels and arterial stiffness rather than to an increase in cardiac output and contractility, which seem not to be influenced. 32,34 However, it should be taken into account that aortic AI is inversely related to heart rate. 35 Thus, AI increase after caffeine consumption might be confounded to some extent by the decrease in heart rate, which has

5 AJH January 2005 VOL. 18, NO. 1 CAFFEINE AND ARTERIAL STIFFNESS been reported after caffeine consumption ,33 There is no generally accepted mechanism for this caffeine effect on heart rate except a possible interaction with the autonomic nerve system. Augmentation index corrected for heart rate, as proposed previously, 35 might eliminate this confounding effect of heart rate changes on AI and should be taken into account, at least, in future studies. Finally, it is likely that the extent of AI change after caffeine consumption is dependent on baseline values, which vary among the previous studies from 14% to 27% 19 22,33 ; however, such a hypothesis could hardly be documented by the available data. Aortic BP affects cardiac as well as central arterial characteristics to a greater extent than does peripheral pressure. Intima-media thickness of the carotid arteries has been related to central and not to peripheral pulse pressure. 36 Furthermore, the increase in aortic BP has been related to an increase in left ventricular systolic pressure, LV metabolic demands and hypertrophy, and increase in aortic diameter (especially in disease states), and to mortality in patients with end-stage renal disease. Peripheral pressures are often an inaccurate estimate of central (eg, aortic) pressures; brachial pulse pressure (PP) may not reflect aortic PP, which influences left ventricular afterload and coronary perfusion. This is due to the physiologic PP amplification between central and peripheral arteries. Aortic pressures can be accurately measured invasively by catheterization or noninvasively by mathematical transformation of applanated and calibrated radial artery pressure waveforms. 23,40 Criticism that has been made regarding the accuracy of the derived aortic pressures and the use of brachial arterial pressure for calibration purposes should be taken into account in the assessment of drug effects on central pressures when these are calculated by noninvasive means. Details regarding strengths and weaknesses of this technique are provided 23,24,40 42 elsewhere. Effects of Caffeine on Aortic Pressures Caffeine pressor effects have been extensively examined in both the short and long term. 2 However, little evidence exists concerning the acute effects of caffeine on aortic BP. Vlachopoulos et al highlighted for the first time the disparate caffeine effects between central and peripheral pressures in hypertensive patients; central systolic pressure was found to be increased 30 min after caffeine ingestion to a greater degree ( 25%) than peripheral systolic pressure. 43 In young normal subjects it was also found that a significant increase in aortic systolic pressure occurs ( 8 mm Hg) after caffeine consumption (30 to 60 min). Again, this pressure change was more pronounce in central than in peripheral arteries. 33 Karatzis et al 21 confirmed a greater increase ( 5 mm Hg) in aortic systolic pressure 30 to 60 min after caffeine intake as compared with a nonsignificant increase in peripheral systolic pressure. In contrast, in middle-aged healthy subjects, it was demonstrated that caffeine consumption led to significant changes in both central and peripheral systolic pressure by almost 10 to 12 mm Hg. 20 The majority of previous studies indicate an augmentation in peripheral systolic pressure after acute consumption of caffeine. Specifically, an average consumption of 150 to 400 mg caffeine has been reported to increase systolic and diastolic BP by 5% to 15% Peripheral BP are measured 15 min after ingestion 47 and the pressor effect of caffeine is present for 1 h after consumption. 34,48,49 Moreover, it is intriguing that these results are observed in healthy as well as in hypertensive subjects. 34,49 The acute pressor effect of coffee could be attributed to ingredients other than caffeine, as decaffeinated coffee was also found to increase peripheral BP, possibly via stimulation of sympathetic nerve activity. 50 Brachial systolic pressures were also found to remain unaltered after caffeine consumption in healthy subjects, 19,21,32 although a few studies reported even a decrease in peripheral systolic pressure. 51 Nonetheless, the significant augmentation of aortic systolic pressure after caffeine intake has been confirmed without controversy ,33,43 Moreover, the increase in aortic systolic pressure was more evident compared with the respective increase in peripheral systolic pressure. 21,33,43 The discrepancy between the acute response of central and peripheral pressures could primarily be explained on the basis of wave reflections, which play a major role in modulation of aortic pressure waveforms and a minor role in peripheral pressures. Another possible explanation might be the difference in caffeine dose and the method of administration (ie, pills or beverage) used in the various studies. Blocking of adenosine receptors seems to be a possible mechanism that might explain these cardiovascular effects of caffeine. 2 Caffeine is an antagonist of adenosine receptors and many of its actions are attributed to this capacity. Adenosine, bound to its receptors, leads to vasodilation; caffeine, as an adenosine receptor antagonist, prevents this binding and subsequent vasodilation with a direct impact on BP and wave reflections. It should also be highlighted that most individuals are reported to develop a tolerance to the observed pressor effects of coffee and its impact on either central or peripheral BP. 52 Regular coffee users seem to tolerate coffee better than nonusers; that is, they present a milder response or no significant response to the pressor effects of caffeine. Nonetheless, it has been demonstrated that tolerance to coffee disappears after 12 h of abstinence, which means that the restriction of coffee consumption for 12 or 24 h in most studies diminishes the possibility of coffee tolerance to confound the results. 53 On the other hand, recent studies have documented the likelihood of incomplete tolerance after short-term regular consumption. 54 Because changes in arterial stiffness and wave reflections are partly due to BP changes, we could speculate that in addition to a pressor response to caffeine, tolerance may influence wave

6 134 CAFFEINE AND ARTERIAL STIFFNESS AJH January 2005 VOL. 18, NO. 1 reflections or even arterial stiffness, a hypothesis that remains unsubstantiated. Various possible confounding factors due to different study designs need to be taken into serious consideration. At first, there may be considerable interindividual variability in the rate of absorption. 46,55,56 It has been demonstrated that coffee consumption stimulates the sympathetic nerve system, 50 decreases the release of nitric oxide, and enhances the production of endothelin leading to vasoconstriction. 57,58 Finally, caffeine, as an adenosine antagonist, opposes to the relaxing effects of adenosine. 59 It seems that as far as stimulation of sympathetic activity is concerned, the route of caffeine administration should be remarkable. More specifically, even the taste and odor of coffee, as well as the visual contact of a subject with a cup of coffee, may stimulate the sympathetic nervous system Hence, the route of caffeine consumption is extremely important; intravenous caffeine administration or use of caffeine pills 19,20,22,34 attenuates such stimuli. Methods such as pill administration may well be used when the aim is to investigate the pharmacologic effects of caffeine. Studies investigating the effects of coffee consumption need to have caffeine administered through a well-controlled beverage; otherwise, the results might be confounded. Finally, plasma caffeine levels could likely explain various differences in the observations of previous studies and clarify the mechanisms related to these findings. Unfortunately, in only one study 33 were plasma caffeine levels (via capsule) measured, which does not allow comparison of the previously mentioned studies in terms of caffeine levels, route of administration, and observed results. Conclusion Conclusions considering all of the acute effects reported in this article should be oriented toward the possible cardiovascular risk induced by caffeine consumption. The association between coffee use and risk of coronary artery disease has been debated for decades. The existing epidemiologic literature is rather well balanced between no effect 63,64 and a weak, positive relationship of caffeine with cardiovascular risk. 65 However, many methodologic shortcomings have been reported, such as poor measurement of caffeine consumption and confounders such as smoking, alcohol intake, age, gender, and tolerance. 1 On the other hand, case-control studies showed a significant relationship of caffeine with cardiovascular disease. 66 Moreover, a number of quantitative meta-analyses and critical reviews implicate caffeine use as a preventable cardiovascular risk factor, 1,67,68 especially at intakes of five or more cups of coffee per day ( 500 mg caffeine per day). 66 Possible risk factors predisposing consumers of caffeine to cardiovascular morbidity could be the elevated BP and cholesterol levels after coffee consumption. 2 Another factor that could likely aggravate the unfavorable effects of caffeine is cigarette smoking, which is common in a great number of coffee consumers. The clinical value of the observed effects of caffeine on central pressures and stiffness remain uncertain, but there may be a significant clinical burden imposed by caffeine use, if these effects sustain in long term. Further studies in larger numbers of patients are required to clarify the potential mechanisms through which caffeine influences central BP and large artery function, in both short- and long-term study designs. Considering the existing knowledge about caffeine, some additional points become noteworthy. What advice should the physician give to a patient with hypertension, diabetes mellitus, or convalescence from an acute coronary syndrome regarding the use of caffeine? The unfavorable impact of caffeine on central hemodynamics and arterial stiffness may be of greater importance in individuals with higher cardiovascular risk, including those with hypertension, diabetes mellitus, advanced age, or coronary artery disease. The reported data show that the response of central pressures, AI, and PWV to caffeine consumption is similar in hypertensive and normotensive individuals despite the fact that these variables are usually increased in hypertension. This could lead to the hypothesis that caffeine effects are additive to other potential mechanisms involved in hypertension. Specific recommendations regarding caffeine use could hardly be made until large-scale, randomized, placebocontrolled studies have been performed in healthy individuals and in those with risk factors to investigating the long-term effects of caffeine on cardiovascular morbidity and mortality. However, such a study seems unlikely to be performed, from both a feasibility and a resourcing perspective. Although there is serious evidence about the increase of cardiovascular risk arising from chronic caffeine use, we are not able to estimate it. The existing evidence, however, provides the basis for future studies examining the cardiovascular effects of caffeine and its role in cardiovascular risk. References 1. James JE: Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously. Psychosom Med 2004;66: Nurminen ML, Niittynen L, Korpela R, Vapaatalo H: Coffee, caffeine and blood pressure: a critical review. Eur J Clin Nutr 1999; 53: Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99: Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux X, Guize L, Ducimetière P, Benetos A: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37: Boutouyrie P, Tropeano A, Asmar R, Gautier I, Benetos A, Lacolley P, Laurent S: Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;9:10 15.

7 AJH January 2005 VOL. 18, NO. 1 CAFFEINE AND ARTERIAL STIFFNESS Pearson A, Guo R, Orsinelli D, Binkley P, Pasierski T: Transesophageal echocardiographic assessment of the effects of age, gender and hypertension on thoracic aortic wall size, thickness and stiffness. Am Heart J 1994;128: Tanaka H, Dinenno F, Monahan K, Clevenger C, DeSouza C, Seals D: Aging, habitual exercise and dynamic arterial compliance. Circulation 2000;102: Soma J, Aakhus S, Angelsen BA, Skjaerpe T: Influence of body size and left ventricular ejection dynamics on total arterial compliance determined using Doppler echocardiography and subclavian artery pulse tracing in healthy humans. Blood Press 1998;7: Stefanadis C, Wooley C, Bush C, Boudoulas H, et al: Aortic distensibility abnormalities in coronary artery disease. Am J Cardiol 1987;59: Blacher J, London GM, Safar ME, Mourad A: Influence of age and end-renal disease on the stiffness of carotid wall material in hypertension. Hypertension 1999;17: Salooma V, Riley W, Klark JD, Nardo C, Folsom AR: Non-insulindependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes: the ARIC study. Circulation 1995;91: Pitsavos C, Toutouzas K, Dernellis J, Skoumbourdis E, Stefanadis C, Toutouzas P: Aortic stiffness in young patients with heterozygous familial hypercholesterolemia. Am Heart J 1998;135: Papaioannou TG, Mathioulakis D, Nanas J, Tsangaris S, Stamatelopoulos S, Moulopoulos S: Arterial compliance is a main variable determining the effectiveness of intra-aortic balloon counterpulsation: quantitative data from an in-vitro study. Med Eng Physics 2002;24: Kelly RP, Tunin R, Kass DA: Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ Res 1985;56: Roman M, Ganau A, Saba P-S, Pini R, Pickering T, Devereux R: Impact of arterial stiffening on left ventricular structure. Hypertension 2000;36: Papaioannou TG, Mathioulakis DS, Tsangaris SG: Simulation of systolic and diastolic left ventricular dysfunction in a mock circulation: the effect of arterial compliance. J Med Eng Technol 2003; 27: O Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE: Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertens 2002;15: Lehman ED: Clinical value of aortic pulse wave velocity measurement. Lancet 1999;354: Mahmud A, Feely J: Acute effect of caffeine on arterial stiffness and aortic pressure waveform. Hypertension 2001;38: Vlachopoulos C, Hirata K, O Rourke MF: Effect of caffeine on aortic elastic properties and wave reflection. J Hypertens 2003;21: Karatzis E, Papaioannou TG, Aznaouridis K, Karatzi K, Stamatelopoulos K, Zampelas A, Papamichael C, Lekakis J, Mavrikakis M: Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure? Int J Cardiol (in press). 22. Vlachopoulos C, Hirata K, Stefanadis C, Toutouzas P, O Rourke M: Caffeine increases aortic stiffness in hypertensive patients. Am J Hypertens 2003;16: O Rourke M, Gallagher D: Pulse wave analysis. J Hypertens 1996; 4(Suppl l5):s147 S Vlachopoulos C, O Rourke M: Genesis of the normal and abnormal arterial pulse. Curr Probl Cardiol 2000;25: Van Bortel LM, Duprez P, Starmans-Kool MJ, Safar ME, Giannattasio C, Cockcroft J, Kaiser DR, Thuillez C: Clinical applications of arterial stiffness, Task Force III: Recommendations for user procedures. Am J Hypertens 2002;15: O Rourke M, Kelly R: Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens 1993;11: Yano M, Kohno M, Kobayashi S, Obayashi M, Seki K, Ohkusa T, Miura T, Fujii T, Matsuzaki M: Influence of timing and magnitude of arterial wave reflection on left ventricular relaxation. Am J Physiol Heart Circ Physiol 2001;280:H1846 H London GM, Guerin AP: Influence of arterial pulse and reflected waves on blood pressure and cardiac function. Am Heart J 1999; 138:S220 S Zannoli R, Schiereck P, Celleti F, Branzi A, Magnani B: Effects of wave reflection timing on left ventricular mechanics. J Biomech 1999;32: Vlachopoulos C, McDonald P, Spratt P, O Rourke M: Pulse wave analysis in the assessment of patients with left ventricular assist device. J Heart Lung Transplant 2001;20: Papaioannou TG, Lekakis J, Dagre A, Stamatelopoulos K, Terrovitis J, Gialafos E, Kanakakis J, Nanas J, Stamatelopoulos S, Moulopoulos S: Arterial compliance is an independent factor that predicts acute hemodynamic performance of intra-aortic balloon counterpulsation. Int J Artif Organs 2001;24: Bender A, Donnerstein R, Samson R, Zhu D, Goldberg S: Hemodynamic effects of acute caffeine ingestion in young adults. Am J Cardiol 1997;79: Waring WS, Goudsmit J, Marwick J, Webb D, Maxwell S: Acute caffeine intake influences central more than peripheral blood pressure in young adults. Am J Hypertens 2003;16: Pincomb GA, Lovallo WR, Passey RB, Whitsett TL, Silverstein SM, Wilson MF: Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men. Am J Cardiol 1985;56: Wilkinson I, MacCallum H, Flint L, Cockcroft J, Newby D, Webb D: The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 2000;525: Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S: Association between local pulse pressure, mean blood pressure, and large artery remodeling. Circulation 1999;100: Lekakis J, Zakopoulos N, Protogerou A, Kotsis V, Papaioannou TG, Stamatelopoulos K, Tsitsiricos M, Pitiriga V, Papamichael C, Toumanides S, Mavrikakis M: Cardiac hypertrophy in hypertension: relation to 24-hour blood pressure profile and arterial stiffness. Int J Cardiol 2004;97: Stefanadis C, Dernellis J, Vlachopoulos C, Tsioufis C, Tsiamis E, Toutouzas K, Pitsavos C, Toutouzas P: Aortic function in arterial hypertension determined by pressure diameter relation: effects of diltiazem. Circulation 1997;96: Kelly R, Hayward C, Ganis J, Daley J, Avolio A, O Rourke M: Non-invasive registration of the arterial pressure pulse waveform using high-fidelity applanation tonometry. J Vasc Med Biol 1989; 3: Karamanoglu M, O Rourke MK, Avolio AP, Kelly RP: An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 1993;14: Davies JI, Band MM, Pringle S, Ogston S, Struthers AD: Peripheral blood pressure measurement is as good as applanation tonometry at predicting ascending aortic blood pressure. J Hypertens 2003;21: Hoeks APG, Meinders JM, Dammers R: Applicability and benefit of arterial transfer functions. J Hypertens 2003;21: Vlachopoulos C, Hirata K, O Rourke MF: Pressure-altering agents affect central aortic pressures more than is apparent from upper limb measurements in hypertensive patients: the role of arterial wave reflections. Hypertension 2001;38: Whitsett T, Manion C, Christensen D: Cardiovascular effects of coffee and caffeine. Am J Cardiol 1984;53: Casiglia E, Bongioni S, Paleari C, Petucco S, Boni M, Colangeli G, Penzo M, Pessina A: Haemodynamic effects of coffee and caffeine in normal volunteers: a placebo-controlled clinical study. J Intern Med 1991;229:

8 136 CAFFEINE AND ARTERIAL STIFFNESS AJH January 2005 VOL. 18, NO Smits P, Thien T, van t Laar A: Circulatory effects of coffee in relation to the pharmacokinetics of caffeine. Am J Cardiol 1985;56: Rachima-Maoz C, Peleg E, Rosenthal T: The effect of caffeine on ambulatory blood pressure in hypertensive patients. Am J Hypertens 1998;11: Pincomb G, Lovallo W, McKey B, Sung B, Passey R, Everson S, Wilson M: Acute blood pressure elevations with caffeine in men with borderline systemic hypertension. Am J Cardiol 1996;77: Hartley T, Sung B, Pincomb G, Whitsett T, Wilson M, Lovallo W: Hypertension risk status and effect of caffeine on blood pressure. Hypertension 2000;36: Corti R, Binggeli C, Sudano I. Spieker L, Hanseler E, Ruschitzka F, Chaplin W, Luscher T, Noll G: Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content. Role of habitual versus non habitual drinking. Circulation 2002;106: Salvaggio A, Periti M, Miano L, Zambelli C: Association between habitual coffee consumption and blood pressure. J Hypertens 1990; 8: Mandel H: Update on caffeine consumption, disposition and action. Food Chem Toxicol 2002;40: Watson J, Deary I, Kerr D: Central and peripheral effects of sustained caffeine use: tolerance is incomplete. J Clin Pharmacol 2002; 54: Lovallo WR, Wilson MF, Vincent AS, Sung B-H, McKey BS, Whitsett TL: Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension 2004; 43: Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, Oates JA: Effects of caffeine on plasma rennin activety, catecholamines and blood pressure. N Engl J Med 1978;298: Smits P, Pieters G, Thien T: The role of epinephrine in the circulatory effects of coffee. Clin Pharmacol Ther 1986;40: Bruce C, Yates D, Thomas P: Caffeine decreases exhaled nitric oxide. Thorax 2002;57: Lee W, Wright S: Production of endothelin by cultured human endothelial cells following exposure to nicotine or caffeine. Metabolism 1999;48: Svenningsson P, Moine C, Fisone G, Fredholm B: Distribution, biochemistry and functions of striatal adenosine A2A receptors. Progr Neurobiol 1999;59: Siegel S, Sokolowska M, Kim J: Caffeine and coffee tolerance. Circulation 2003;108: Lovallo W, Whitsett T, Wilson M: Caffeine and coffee tolerance. Circulation 2003;108: Schmitt J, Schmitt J: Caffeine and coffee tolerance. Circulation 2003;108: Grobbee DE, Giovannucci E, Colditz G, Stampfer M, Willet W: Coffee, caffeine, and cardiovascular disease in men. N Engl J Med 1990;323: Klattsky AL, Friedman GD, Armstrong MA: The relationship between alcoholic beverage use and other traits to blood pressure: a new Kaiser Permenante study. Circulation 1986;73: LaCroix AZ, Liang KY, Thomas CB, Pearson TA: Coffee consumption and incidence of coronary heart disease. N Engl J Med 1986; 15: Nawrot P, Jordan S, Eastwood J, Rotstein J, Hugenholtz A, Feeley M: Effects of caffeine on human health. Food Addit Contam 2003; 20: Greenland S: A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology 1993;4: James JE: Is habitual caffeine use a preventable cardiovascular risk factor? Lancet 1997;349: