- Email: [email protected]
Cardiovascular effects of caffeine in men and women
Cardiovascular Effects of Caffeine in Men and Women Terry R. Hartley,
PhD,
William R. Lovallo,
PhD,
and Thomas L. Whitsett,
MD
Caffeine increases blood pressure (BP). In men, acute BP elevations after caffeine intake are due to an increase in vascular resistance, with no change in cardiac output. The hemodynamic effects of caffeine have not been studied in women. Accordingly, BP and hemodynamic responses to caffeine were measured in a double-blind trial comparing age-matched men and women at rest and during mental stress. Caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of brewed coffee) or placebo was given to separate groups of women (n ⴝ 21 and 21) and men (n ⴝ 16 and 19) (mean ages 29 and 27 years, respectively). BP, cardiac output, and vascular resistance were observed at rest, during a stressful public-speaking simulation, reading aloud, and recovery. Caffeine caused nearly identical systolic and diastolic BP elevations in women (4.5 and 3.3 mm Hg, respectively) and
men (4.1 and 3.8 mm Hg, respectively). Men given caffeine versus placebo showed the expected elevation in vascular resistance throughout the remainder of the protocol (p <0.001), with no difference in cardiac output. In contrast, women responded to caffeine with increases in stroke volume (p <0.001) and cardiac output (p <0.001), with no difference in vascular resistance from women taking placebo. Men and women have similar BP responses to caffeine, but the BP responses may arise from different hemodynamic mechanisms. Women who consume a dietary dose of caffeine showed an increase in cardiac output, whereas men showed increased vascular resistance. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1022–1026)
affeine is the world’s most commonly used pharmacologic substance. The United States imports C almost 30% of the world’s coffee, and daily con-
vascular versus cardiac effects of caffeine in women at rest and during mental stress.
sumption is equivalent 2 to 3 cups.2 Caffeine causes mental stimulation and increases blood pressure (BP).3,4 Caffeine corresponding to 1 to 4 cups of coffee can increase BP by up to 14/13 mm Hg in caffeine-withdrawn subjects5 at rest or during mental or exercise stress.6,7 Its pressor effect is greater in subjects with hypertension.8 In men, caffeine increases BP by increasing vascular resistance,9 with no effect on cardiac output.10 The vascular resistance increase is consistent with the blockade of vascular adenosine receptors in caffeine,11 which enhances the action of norepinephrine.12 Interactions between caffeine and adenosine raise the possibility that women may have a vascular response different from that in men. Women before menopause have a lower risk of hypertension and coronary artery disease than do men of the same age.13 This finding has been attributed in part to actions of estrogen, which can increase vascular compliance and decrease resistance to blood flow.14,15 These considerations raise the question of whether caffeine raises BP by the same mechanism in women as in men. Accordingly, we investigated the
METHODS
1
From the Departments of Psychiatry and Behavioral Sciences, and Medicine, Veteran’s Affairs Medical Center, Oklahoma City, Oklahoma. This study was supported by the Medical Research Service of the Department of Veterans Affairs and by grants HL 32050, HL 32050-S2, and HL 07640 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received September 24, 2003; revised manuscript received and accepted December 24, 2003. Address for reprints: William R. Lovallo, PhD, VA Medical Center (151A), 921 NE 13th Street, Oklahoma City, Oklahoma 73104. E-mail: [email protected].
1022
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004
Premenopausal women (n ⫽ 42) were compared with age-matched men (n ⫽ 35). All were nonobese, in good health by physical examination, normotensive (BPs ⬍135/85 mm Hg), regularly consumed caffeine (50 to 700 mg/day), smoked ⬍6 cigarettes/day, and used no medications with cardiovascular or metabolic effects. Women were not taking oral contraceptives and not pregnant according to pregnancy test (One Step, Inverness Medical Ltd., Beachwood Park, Scotland). All signed a consent form approved by the institutional review board of the University of Oklahoma Health Sciences Center and the Veterans Affairs Medical Center and were paid for participating. Subjects were randomly assigned to receive caffeine (n ⫽ 21 women and n ⫽ 16 men) or placebo (n ⫽ 21 women and n ⫽ 19 men) in a double-blind trial. Caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of coffee; USP, Amend Drug and Chemical Co., Irvington, New Jersey) was taken mixed with 6 oz of grapefruit juice (Texsun, Weslaco, Texas). The dose was based on a previous study.4 Placebo consisted of grapefruit juice alone, which does not interfere with the metabolism of caffeine.16 Subjects abstained from caffeine starting at 6:00 P.M. the night before testing. To verify compliance, saliva was collected at the end of baseline by using a commercial device (Salivette, Sarstedt, Hanover, New Jersey) and assayed by highperformance liquid chromatography. All values were near the low detection limit of the assay, indicating compliance. Subjects consumed a light breakfast on the morning of testing. Sessions began at about 8:00 A.M. and 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.057
(Waveshell, Center for Biomedical Engineering, Research Triangle Institute, Research Triangle Park, Variables Women (n ⫽ 42) Men (n ⫽ 35) North Carolina). Cardiovascular variables were systolic BP, diaAge (yrs) 29 (0.98) 27 (0.79) stolic BP, mean arterial pressure, and pulse pressure Height (cm) 167 (4.8) 181 (9.0)† Weight (kg) 64 (1.7) 80 (1.7)† (systolic BP ⫺ diastolic BP) in millimeters of mer2.44 (0.042) 2.28 (0.054)‡ Quetelet index (g/cm2) cury; heart rate in beats per minute; stroke volume in Caffeine intake (mg/d) 154 (10.6) 167 (9.9) milliliters; cardiac output (stroke volume ⫻ heart rate) *Entries show mean (SEM); †p ⬍0.001; ‡p ⬍0.05. in liters per minute; total peripheral resistance (mean arterial pressure ⫻ 80/cardiac output) in dynes per second per centimeters to the fifth TABLE 2 Baseline Cardiovascular Values* power and a vascular compliance inCaffeine Placebo Gender Caffeine dex (stroke volume/pulse pressure) Heart rate (beats/min) in milliliters per millimeter of merWomen 66 (1.6) 67 (1.7) NS NS cury. Men 67 (2.6) 62 (1.9) BP was measured every 2 minSystolic BP (mm Hg) utes throughout the study. ImpedWomen 104 (1.3) 107 (1.6) .001 NS Men 114 (2.0) 116 (1.6) ance data were recorded continuDiastolic BP (mm Hg) ously and then averaged for 12 time Women 62 (1.9) 66 (1.6) NS NS periods: baseline (10 minutes), cafMen 64 (1.4) 65 (1.7) feine or placebo response (15, 30, Stroke volume (ml) and 45 minutes after taking the Women 69 (4.3) 71 (5.0) NS NS Men 68 (5.8) 80 (7.7) drug), task I (preparation and task) Cardiac output (L/min) and recovery periods 1 and 2 (15 Women 4.6 (1.1) 4.8 (1.5) NS NS minutes each), and task II (preparaMen 4.6 (1.5) 5.1 (2.4) tion and task) and recovery periods 1 Peripheral resistance (dyne · s⫺1 · cm⫺5) Women 1,424 (84) 1,518 (161) NS NS and 2 (15 minutes each). Responses Men 1,637 (143) 1,612 (187) to caffeine and the tasks were tested as changes from baseline in the sub*Entries show means (SE); n ⫽ 42 women, 21 in caffeine and 21 in placebo groups, and n ⫽ 35 men, 16 in caffeine and 19 in placebo groups. Comparisons are based on gender ⫻ drug group ANOVAs. sequent 11 periods. Baseline activity during the predrug period was tested using 2 genlasted 3 hours. The protocol included instrumentation der ⫻ 2 drug groups analyses of variance (ANOVAs). (20 minutes), adaptation (30 minutes), baseline (10 To characterize gender differences in response to cafminutes), caffeine or placebo drink (5 minutes), drug feine versus placebo, we performed a multivariate absorption (45 minutes), task I (reading or speaking, 6 ANOVA on each dependent variable comparing 2 minutes), recovery (30 minutes), task II (alternate gender ⫻ 2 drug groups ⫻ 11 periods after taking the task, 6 minutes), and recovery (30 minutes). drug. Significant main effects or interactions were Tasks included reading aloud versus public speak- followed by univariate ANOVAs and specific coning, and task order was counterbalanced across sub- trasts as indicated. jects. Public speaking causes anxiety and increases BP, heart rate, and stress hormones.17 The subject was given a topic and spent 3 minutes preparing and 3 RESULTS Table 1 presents anthropometric and screening minutes delivering a speech to a video camera in front of 2 experimenters wearing white coats. The control data. Men weighed more and had a higher Quetelet task consisted of 3 minutes studying and 3 minutes index than women (F [1,75] ⫽ 41.35 and 5.86, rereading aloud a neutral passage from Readers’ Digest spectively; p ⬍0.02). Table 2 provides cardiovascular data before drug administration. Men had higher syswhile alone. All cardiovascular measurements were made as the tolic BP at rest than women (F [1,73] ⫽ 29.20, p subject sat semirecumbent in a recliner chair. BP was ⬍0.0001). The primary gender ⫻ drug ⫻ periods multivariate measured with a Dinamap monitor (Critikon, Tampa, Florida). Stroke volume and systolic time intervals ANOVAs showed that the caffeine group had higher were recorded by an impedance cardiograph (model systolic and diastolic BPs than the placebo group 304B, Minnesota Impedance Cardiograph, Minneap- (main effects of drug, F [11,59] ⫽ 2.30 and 3.28 and olis, Minnesota) according to previously described p ⬍0.02 and 0.001, respectively). Women had higher methods.18 Impedance cardiography is a noninvasive levels of stroke volume and cardiac output than men technique appropriate for behavioral research, and it is (main effects of gender, F [11,59] ⫽ 2.04 and 2.16 and reliable for within-day and between-day measure- p ⬍0.05 and 0.03, respectively). Men in the caffeine ments if electrode placement is consistent.9,19 Imped- group had the highest levels of total peripheral resisance signals and electrocardiograms were ensemble tance (F [11,56] ⫽ 2.03, p ⬍0.05). These analyses averaged20 and analyzed by proprietary software were followed by separate univariate ANOVAs on TABLE 1 Subject Characteristics*
CARDIOVASCULAR PHARMACOLOGY/CAFFEINE EFFECTS IN MEN AND WOMEN
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FIGURE 1. BP and hemodynamic responses of men and women exposed to placebo and caffeine. Entries show mean (SEM) of change scores from baseline before caffeine or placebo. *Points of significant difference (p <0.05) between men and women.
FIGURE 2. Vascular compliance indexes in men and women exposed to placebo and caffeine. Entries show absolute mean (SEM) values for men and women exposed to caffeine. *Points of significant difference (p <0.05) between men and women.
gender ⫻ periods effects for the placebo and caffeine groups. Figure 1 shows that after placebo, men and women had similar changes from baseline in cardiovascular activity over all time periods; gender and gender ⫻ periods effects were nonsignificant for all variables (F ⬍1.71, p ⬎0.13). In the caffeine group, women and men had comparable heart rate and systolic BP changes to caffeine and the tasks, as demonstrated by 1024 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
nonsignificant gender and gender ⫻ periods interactions (F ⬍2.0, p ⬎0.10). Men had greater diastolic BP responses than women (F [11,23] ⫽ 2.86, p ⬍0.02), and comparisons at each time point showed that the groups differed significantly only during the recovery period after public speaking (F [1,32] ⫽ 5.04 to 5.72, p ⬍0.04), as indicated in Figure 1. We then compared men and women in the caffeine group with regard to stroke volume, cardiac output, and peripheral resistance changes to caffeine. Women who consumed caffeine had greater increases in stroke volume than men (F [11,23] ⫽ 2.67, p ⬍0.03) and a trend toward a greater cardiac output response (F [11,23] ⫽ 1.98, p ⬍0.08). Men had greater increases in total peripheral resistance (F [11,23] ⫽ 2.27, p ⬍0.04). Comparisons of men with women at each time point showed that women had greater stroke volumes and cardiac outputs than men at the times indicated in Figure 1 (F [1,32] ⫽ 4.9 to 15.3, p ⬍0.03). In contrast, the men had greater peripheral resistance at the indicated times after caffeine admininstration (F [1,32] ⫽ 4.37 to 14.77, p ⬍0.05). Because women showed no increase in total peripheral resistance levels after taking caffeine, we compared them with men on an index of arterial compliance. Men and women taking placebo had no differences in the compliance index at any period, including baseline. In the caffeine group, women had significantly higher arterial compliance values than men at most time points (F [1,35] ⫽ 6.3 to 11.1, all p ⬍0.01), as shown in Figure 2. Women who took APRIL 15, 2004
placebo instead of caffeine had similar compliance index values. Among men, arterial compliance was lower in the caffeine group than in the placebo group at most times (all p ⬍0.05), as shown in Figure 2.
DISCUSSION In the present study, women and men who were habitual users of caffeine had similar increases in BP after taking caffeine (equivalent to 2 to 3 cups of coffee), as reported by another study.21 However, the mechanisms facilitating the BP increase in women were different from those in men. Men responded to caffeine with increases in peripheral resistance and no change in cardiac output, as seen in a previous study.9 In contrast, women responded with increases in cardiac output and little or no change in peripheral resistance. Their cardiac output response was accompanied by greater stroke volume. In the absence of caffeine, changes in cardiovascular activity were strikingly similar in men and women across the protocol. The effect of caffeine on BP was similar at rest and during stress. The caffeine-induced increase in cardiac output in the women was unanticipated given the previous results in men. Men and women had lower heart rates after caffeine consumption, but the women also had lower vascular resistance and greater vascular compliance. These 3 factors acting in concert in the women would favor greater return of blood to the heart, increased left ventricular filling, and, hence, increased stroke volume. In keeping with the present findings, it is noteworthy that premenopausal women have greater heart rate responses to mental stress, whereas men have greater increases in vascular resistance22 and that women have a predominance of vagal cardiac regulation, whereas men have a predominant sympathetic vascular tone.23 These new findings of caffeine use in women will require replication and further study. In this study, caffeine and placebo were tested in separate groups of women, raising the question of whether the same findings would apply in a crossover design. Caffeine antagonizes adenosine A-1 and A-2 receptors.11,24 Adenosine is a potent vasodilator that decreases norepinephrine release at sympathetic nerve terminals.25 In men, caffeine attenuates the vasodilator effect of adenosine24 by increasing total peripheral resistance by 12%.9 Caffeine exerts progressively greater BP effects in men who are at increasingly greater risk for hypertension.8 Conversely, in these women, the vascular effects of caffeine appeared to be greatly decreased. We speculate that caffeine may lack an effect on vascular resistance in premenopausal women due to the actions of estrogen. In postmenopausal women, the lack of estrogen leads to greater venous constriction to norepinephrine infusion,26 reduced vascular nitric oxide production,27 and greater BP responses to mental stress, differences that are abolished by estrogen replacement.26,28 The contribution of estrogen to these gender differences in caffeine response requires further testing, including comparisons in women before and after menopause and receiving and not receiving estrogen. In addition, we are not able to rule out differences between men and
women with respect to caffeine effects on neural discharge at the heart muscle or its effects on central cardiovascular control centers.29,30 In the present study, men and women who were regular caffeine consumers had comparable increases in BP after modest doses of caffeine. However, the women sustained their BP response by greater cardiac output, whereas men showed an increase in vascular resistance. This gender difference in the cardiovascular effects of caffeine may have implications for the long-term effects of caffeine on BP regulation in men versus women in relation to their degree of hypertension risk. The present results suggest that the BP effects of caffeine should be tested in women at increased risk of hypertension and in regard to their menopausal status and estrogen use. 1. Lundsberg L. Caffeine consumption. In: Spiller GA, ed. Caffeine. Boca Raton, FL: CRC Press, 1998:199 –224. 2. Barone JJ, Roberts HR. Caffeine consumption. Food Chem Toxicol 1996;34: 119 –129. 3. Rainnie DG, Grunze HC, McCarley RW, Greene RW. Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Science 1994; 263:689 –692. 4. Whitsett TL, Manion CV, Christensen HD. Cardiovascular effects of coffee and caffeine. Am J Cardiol 1984;53:918 –922. 5. Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, Oates JA. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978;298:181–186. 6. Lane JD. Caffeine and cardiovascular responses to stress. Psychosom Med 1983;45:447–451. 7. Sung BH, Lovallo WR, Pincomb GA, Wilson MF. Effects of caffeine on blood pressure response during exercise in normotensive healthy young men. Am J Cardiol 1990;65:909 –913. 8. Hartley TR, Sung BH, Pincomb GA, Whitsett TL, Wilson MF, Lovallo WR. Hypertension risk status and effect of caffeine on blood pressure. Hypertension 2000;36:137–141. 9. 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;56:119 –122. 10. Pincomb GA, Wilson MF, Sung BH, Passey RB, Lovallo WR. Effects of caffeine on pressor regulation during rest and exercise in men at risk for hypertension. Am Heart J 1991;122:1107–1115. 11. Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1980;1:129 –132. 12. Evoniuk G, von Borstel RW, Wurtman RJ. Antagonism of the cardiovascular effects of adenosine by caffeine or 8-(p-sulfophenyl)theophylline. J Pharmacol Exp Ther 1987;240:428 –432. 13. Hayes SN, Taler SJ. Hypertension in women: current understanding of gender differences. Mayo Clin Proc 1998;73:157–165. 14. Rajkumar C, Kingwell BA, Cameron JD, Waddell T, Mehra R, Christophidis N, Komesaroff PA, McGrath B, Jennings GL, Sudhir K, Dart AM. Hormonal therapy increases arterial compliance in postmenopausal women. J Am Coll Cardiol 1997;30:350 –356. 15. West SG, Hinderliter AL, Wells EC, Girdler SS, Light KC. Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women. Am J Obstet Gynecol 2001;184:926 –933. 16. Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WR. Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics. Pharmacotherapy 1996;16:1046 –1052. 17. al’Absi M, Bongard S, Buchanan T, Pincomb GA, Licinio J, Lovallo WR. Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors. Psychophysiology 1997;34:266 –275. 18. Sherwood A, Allen MT, Fahrenberg J, Kelsey RM, Lovallo WR, van Doornen LJ. Methodological guidelines for impedance cardiography. Psychophysiology 1990;27:1–23. 19. Lovallo WR, al’Absi M. Hemodynamics during rest and behavioral stress in normotensive men at high risk for hypertension. Psychophysiology 1998;35:47– 53. 20. Everson SA, Lovallo WR, Pincomb GA, Kizakevich P, Wilson MF. Validation of an ensemble-averaged impedance cardiogram for estimation of stroke volume. In: Proceedings of the Thirteenth Annual International Conference of the IEEE Engineering in Medicine and Biology Society. New York, NY: IEEE, 1991;13:801– 802.
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21. James JE. Chronic effects of habitual caffeine consumption on laboratory and
ambulatory blood pressure levels. J Cardiovasc Risk 1994;1:159 –164. 22. Allen MT, Stoney CM, Owens JF, Matthews KA. Hemodynamic adjustments to laboratory stress: the influence of gender and personality. Psychosom Med 1993;55:505–517. 23. Evans JM, Ziegler MG, Patwardhan AR, Ott JB, Kim CS, Leonelli FM, Knapp CF. Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes. J Appl Physiol 2001;91:2611–2618. 24. Smits P, Lenders JW, Thien T. Caffeine and theophylline attenuate adenosine-induced vasodilation in humans. Clin Pharmacol Ther 1990;48:410 –418. 25. Hoyle CHV. Transmission: purines. In: Burnstock G. Hoyle CHV, eds. Autonomic Neuroeffector Mechanisms. Reading, UK: Harwood Academic Publishers, 1992:367–407. 26. Sung BH, Ching M, Izzo JL Jr, Dandona P, Wilson MF. Estrogen improves
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abnormal norepinephrine-induced vasoconstriction in postmenopausal women. J Hypertens 1999;17:523–528. 27. Virdis A, Ghiadoni L, Sudano I, Buralli S, Salvetti G, Taddei S, Salvetti A. Endothelial function in hypertension: role of gender. J Hypertens 2002;20(suppl 2):S11–S16. 28. Nekooeian AA, Pang CC. Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure. Am J Physiol 1998; 274:H2094 –H2099. 29. Manhem K, Brandin L, Ghanoum B, Rosengren A, Gustafsson H. Acute effects of transdermal estrogen on hemodynamic and vascular reactivity in elderly postmenopausal healthy women. J Hypertens 2003;21:387–394. 30. Hunt BE, Taylor JA, Hamner JW, Gagnon M, Lipsitz LA. Estrogen replacement therapy improves baroreflex regulation of vascular sympathetic outflow in postmenopausal women. Circulation 2001;103:2909 –2914.
APRIL 15, 2004
PhD,
William R. Lovallo,
PhD,
and Thomas L. Whitsett,
MD
Caffeine increases blood pressure (BP). In men, acute BP elevations after caffeine intake are due to an increase in vascular resistance, with no change in cardiac output. The hemodynamic effects of caffeine have not been studied in women. Accordingly, BP and hemodynamic responses to caffeine were measured in a double-blind trial comparing age-matched men and women at rest and during mental stress. Caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of brewed coffee) or placebo was given to separate groups of women (n ⴝ 21 and 21) and men (n ⴝ 16 and 19) (mean ages 29 and 27 years, respectively). BP, cardiac output, and vascular resistance were observed at rest, during a stressful public-speaking simulation, reading aloud, and recovery. Caffeine caused nearly identical systolic and diastolic BP elevations in women (4.5 and 3.3 mm Hg, respectively) and
men (4.1 and 3.8 mm Hg, respectively). Men given caffeine versus placebo showed the expected elevation in vascular resistance throughout the remainder of the protocol (p <0.001), with no difference in cardiac output. In contrast, women responded to caffeine with increases in stroke volume (p <0.001) and cardiac output (p <0.001), with no difference in vascular resistance from women taking placebo. Men and women have similar BP responses to caffeine, but the BP responses may arise from different hemodynamic mechanisms. Women who consume a dietary dose of caffeine showed an increase in cardiac output, whereas men showed increased vascular resistance. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1022–1026)
affeine is the world’s most commonly used pharmacologic substance. The United States imports C almost 30% of the world’s coffee, and daily con-
vascular versus cardiac effects of caffeine in women at rest and during mental stress.
sumption is equivalent 2 to 3 cups.2 Caffeine causes mental stimulation and increases blood pressure (BP).3,4 Caffeine corresponding to 1 to 4 cups of coffee can increase BP by up to 14/13 mm Hg in caffeine-withdrawn subjects5 at rest or during mental or exercise stress.6,7 Its pressor effect is greater in subjects with hypertension.8 In men, caffeine increases BP by increasing vascular resistance,9 with no effect on cardiac output.10 The vascular resistance increase is consistent with the blockade of vascular adenosine receptors in caffeine,11 which enhances the action of norepinephrine.12 Interactions between caffeine and adenosine raise the possibility that women may have a vascular response different from that in men. Women before menopause have a lower risk of hypertension and coronary artery disease than do men of the same age.13 This finding has been attributed in part to actions of estrogen, which can increase vascular compliance and decrease resistance to blood flow.14,15 These considerations raise the question of whether caffeine raises BP by the same mechanism in women as in men. Accordingly, we investigated the
METHODS
1
From the Departments of Psychiatry and Behavioral Sciences, and Medicine, Veteran’s Affairs Medical Center, Oklahoma City, Oklahoma. This study was supported by the Medical Research Service of the Department of Veterans Affairs and by grants HL 32050, HL 32050-S2, and HL 07640 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received September 24, 2003; revised manuscript received and accepted December 24, 2003. Address for reprints: William R. Lovallo, PhD, VA Medical Center (151A), 921 NE 13th Street, Oklahoma City, Oklahoma 73104. E-mail: [email protected].
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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004
Premenopausal women (n ⫽ 42) were compared with age-matched men (n ⫽ 35). All were nonobese, in good health by physical examination, normotensive (BPs ⬍135/85 mm Hg), regularly consumed caffeine (50 to 700 mg/day), smoked ⬍6 cigarettes/day, and used no medications with cardiovascular or metabolic effects. Women were not taking oral contraceptives and not pregnant according to pregnancy test (One Step, Inverness Medical Ltd., Beachwood Park, Scotland). All signed a consent form approved by the institutional review board of the University of Oklahoma Health Sciences Center and the Veterans Affairs Medical Center and were paid for participating. Subjects were randomly assigned to receive caffeine (n ⫽ 21 women and n ⫽ 16 men) or placebo (n ⫽ 21 women and n ⫽ 19 men) in a double-blind trial. Caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of coffee; USP, Amend Drug and Chemical Co., Irvington, New Jersey) was taken mixed with 6 oz of grapefruit juice (Texsun, Weslaco, Texas). The dose was based on a previous study.4 Placebo consisted of grapefruit juice alone, which does not interfere with the metabolism of caffeine.16 Subjects abstained from caffeine starting at 6:00 P.M. the night before testing. To verify compliance, saliva was collected at the end of baseline by using a commercial device (Salivette, Sarstedt, Hanover, New Jersey) and assayed by highperformance liquid chromatography. All values were near the low detection limit of the assay, indicating compliance. Subjects consumed a light breakfast on the morning of testing. Sessions began at about 8:00 A.M. and 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.057
(Waveshell, Center for Biomedical Engineering, Research Triangle Institute, Research Triangle Park, Variables Women (n ⫽ 42) Men (n ⫽ 35) North Carolina). Cardiovascular variables were systolic BP, diaAge (yrs) 29 (0.98) 27 (0.79) stolic BP, mean arterial pressure, and pulse pressure Height (cm) 167 (4.8) 181 (9.0)† Weight (kg) 64 (1.7) 80 (1.7)† (systolic BP ⫺ diastolic BP) in millimeters of mer2.44 (0.042) 2.28 (0.054)‡ Quetelet index (g/cm2) cury; heart rate in beats per minute; stroke volume in Caffeine intake (mg/d) 154 (10.6) 167 (9.9) milliliters; cardiac output (stroke volume ⫻ heart rate) *Entries show mean (SEM); †p ⬍0.001; ‡p ⬍0.05. in liters per minute; total peripheral resistance (mean arterial pressure ⫻ 80/cardiac output) in dynes per second per centimeters to the fifth TABLE 2 Baseline Cardiovascular Values* power and a vascular compliance inCaffeine Placebo Gender Caffeine dex (stroke volume/pulse pressure) Heart rate (beats/min) in milliliters per millimeter of merWomen 66 (1.6) 67 (1.7) NS NS cury. Men 67 (2.6) 62 (1.9) BP was measured every 2 minSystolic BP (mm Hg) utes throughout the study. ImpedWomen 104 (1.3) 107 (1.6) .001 NS Men 114 (2.0) 116 (1.6) ance data were recorded continuDiastolic BP (mm Hg) ously and then averaged for 12 time Women 62 (1.9) 66 (1.6) NS NS periods: baseline (10 minutes), cafMen 64 (1.4) 65 (1.7) feine or placebo response (15, 30, Stroke volume (ml) and 45 minutes after taking the Women 69 (4.3) 71 (5.0) NS NS Men 68 (5.8) 80 (7.7) drug), task I (preparation and task) Cardiac output (L/min) and recovery periods 1 and 2 (15 Women 4.6 (1.1) 4.8 (1.5) NS NS minutes each), and task II (preparaMen 4.6 (1.5) 5.1 (2.4) tion and task) and recovery periods 1 Peripheral resistance (dyne · s⫺1 · cm⫺5) Women 1,424 (84) 1,518 (161) NS NS and 2 (15 minutes each). Responses Men 1,637 (143) 1,612 (187) to caffeine and the tasks were tested as changes from baseline in the sub*Entries show means (SE); n ⫽ 42 women, 21 in caffeine and 21 in placebo groups, and n ⫽ 35 men, 16 in caffeine and 19 in placebo groups. Comparisons are based on gender ⫻ drug group ANOVAs. sequent 11 periods. Baseline activity during the predrug period was tested using 2 genlasted 3 hours. The protocol included instrumentation der ⫻ 2 drug groups analyses of variance (ANOVAs). (20 minutes), adaptation (30 minutes), baseline (10 To characterize gender differences in response to cafminutes), caffeine or placebo drink (5 minutes), drug feine versus placebo, we performed a multivariate absorption (45 minutes), task I (reading or speaking, 6 ANOVA on each dependent variable comparing 2 minutes), recovery (30 minutes), task II (alternate gender ⫻ 2 drug groups ⫻ 11 periods after taking the task, 6 minutes), and recovery (30 minutes). drug. Significant main effects or interactions were Tasks included reading aloud versus public speak- followed by univariate ANOVAs and specific coning, and task order was counterbalanced across sub- trasts as indicated. jects. Public speaking causes anxiety and increases BP, heart rate, and stress hormones.17 The subject was given a topic and spent 3 minutes preparing and 3 RESULTS Table 1 presents anthropometric and screening minutes delivering a speech to a video camera in front of 2 experimenters wearing white coats. The control data. Men weighed more and had a higher Quetelet task consisted of 3 minutes studying and 3 minutes index than women (F [1,75] ⫽ 41.35 and 5.86, rereading aloud a neutral passage from Readers’ Digest spectively; p ⬍0.02). Table 2 provides cardiovascular data before drug administration. Men had higher syswhile alone. All cardiovascular measurements were made as the tolic BP at rest than women (F [1,73] ⫽ 29.20, p subject sat semirecumbent in a recliner chair. BP was ⬍0.0001). The primary gender ⫻ drug ⫻ periods multivariate measured with a Dinamap monitor (Critikon, Tampa, Florida). Stroke volume and systolic time intervals ANOVAs showed that the caffeine group had higher were recorded by an impedance cardiograph (model systolic and diastolic BPs than the placebo group 304B, Minnesota Impedance Cardiograph, Minneap- (main effects of drug, F [11,59] ⫽ 2.30 and 3.28 and olis, Minnesota) according to previously described p ⬍0.02 and 0.001, respectively). Women had higher methods.18 Impedance cardiography is a noninvasive levels of stroke volume and cardiac output than men technique appropriate for behavioral research, and it is (main effects of gender, F [11,59] ⫽ 2.04 and 2.16 and reliable for within-day and between-day measure- p ⬍0.05 and 0.03, respectively). Men in the caffeine ments if electrode placement is consistent.9,19 Imped- group had the highest levels of total peripheral resisance signals and electrocardiograms were ensemble tance (F [11,56] ⫽ 2.03, p ⬍0.05). These analyses averaged20 and analyzed by proprietary software were followed by separate univariate ANOVAs on TABLE 1 Subject Characteristics*
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FIGURE 1. BP and hemodynamic responses of men and women exposed to placebo and caffeine. Entries show mean (SEM) of change scores from baseline before caffeine or placebo. *Points of significant difference (p <0.05) between men and women.
FIGURE 2. Vascular compliance indexes in men and women exposed to placebo and caffeine. Entries show absolute mean (SEM) values for men and women exposed to caffeine. *Points of significant difference (p <0.05) between men and women.
gender ⫻ periods effects for the placebo and caffeine groups. Figure 1 shows that after placebo, men and women had similar changes from baseline in cardiovascular activity over all time periods; gender and gender ⫻ periods effects were nonsignificant for all variables (F ⬍1.71, p ⬎0.13). In the caffeine group, women and men had comparable heart rate and systolic BP changes to caffeine and the tasks, as demonstrated by 1024 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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nonsignificant gender and gender ⫻ periods interactions (F ⬍2.0, p ⬎0.10). Men had greater diastolic BP responses than women (F [11,23] ⫽ 2.86, p ⬍0.02), and comparisons at each time point showed that the groups differed significantly only during the recovery period after public speaking (F [1,32] ⫽ 5.04 to 5.72, p ⬍0.04), as indicated in Figure 1. We then compared men and women in the caffeine group with regard to stroke volume, cardiac output, and peripheral resistance changes to caffeine. Women who consumed caffeine had greater increases in stroke volume than men (F [11,23] ⫽ 2.67, p ⬍0.03) and a trend toward a greater cardiac output response (F [11,23] ⫽ 1.98, p ⬍0.08). Men had greater increases in total peripheral resistance (F [11,23] ⫽ 2.27, p ⬍0.04). Comparisons of men with women at each time point showed that women had greater stroke volumes and cardiac outputs than men at the times indicated in Figure 1 (F [1,32] ⫽ 4.9 to 15.3, p ⬍0.03). In contrast, the men had greater peripheral resistance at the indicated times after caffeine admininstration (F [1,32] ⫽ 4.37 to 14.77, p ⬍0.05). Because women showed no increase in total peripheral resistance levels after taking caffeine, we compared them with men on an index of arterial compliance. Men and women taking placebo had no differences in the compliance index at any period, including baseline. In the caffeine group, women had significantly higher arterial compliance values than men at most time points (F [1,35] ⫽ 6.3 to 11.1, all p ⬍0.01), as shown in Figure 2. Women who took APRIL 15, 2004
placebo instead of caffeine had similar compliance index values. Among men, arterial compliance was lower in the caffeine group than in the placebo group at most times (all p ⬍0.05), as shown in Figure 2.
DISCUSSION In the present study, women and men who were habitual users of caffeine had similar increases in BP after taking caffeine (equivalent to 2 to 3 cups of coffee), as reported by another study.21 However, the mechanisms facilitating the BP increase in women were different from those in men. Men responded to caffeine with increases in peripheral resistance and no change in cardiac output, as seen in a previous study.9 In contrast, women responded with increases in cardiac output and little or no change in peripheral resistance. Their cardiac output response was accompanied by greater stroke volume. In the absence of caffeine, changes in cardiovascular activity were strikingly similar in men and women across the protocol. The effect of caffeine on BP was similar at rest and during stress. The caffeine-induced increase in cardiac output in the women was unanticipated given the previous results in men. Men and women had lower heart rates after caffeine consumption, but the women also had lower vascular resistance and greater vascular compliance. These 3 factors acting in concert in the women would favor greater return of blood to the heart, increased left ventricular filling, and, hence, increased stroke volume. In keeping with the present findings, it is noteworthy that premenopausal women have greater heart rate responses to mental stress, whereas men have greater increases in vascular resistance22 and that women have a predominance of vagal cardiac regulation, whereas men have a predominant sympathetic vascular tone.23 These new findings of caffeine use in women will require replication and further study. In this study, caffeine and placebo were tested in separate groups of women, raising the question of whether the same findings would apply in a crossover design. Caffeine antagonizes adenosine A-1 and A-2 receptors.11,24 Adenosine is a potent vasodilator that decreases norepinephrine release at sympathetic nerve terminals.25 In men, caffeine attenuates the vasodilator effect of adenosine24 by increasing total peripheral resistance by 12%.9 Caffeine exerts progressively greater BP effects in men who are at increasingly greater risk for hypertension.8 Conversely, in these women, the vascular effects of caffeine appeared to be greatly decreased. We speculate that caffeine may lack an effect on vascular resistance in premenopausal women due to the actions of estrogen. In postmenopausal women, the lack of estrogen leads to greater venous constriction to norepinephrine infusion,26 reduced vascular nitric oxide production,27 and greater BP responses to mental stress, differences that are abolished by estrogen replacement.26,28 The contribution of estrogen to these gender differences in caffeine response requires further testing, including comparisons in women before and after menopause and receiving and not receiving estrogen. In addition, we are not able to rule out differences between men and
women with respect to caffeine effects on neural discharge at the heart muscle or its effects on central cardiovascular control centers.29,30 In the present study, men and women who were regular caffeine consumers had comparable increases in BP after modest doses of caffeine. However, the women sustained their BP response by greater cardiac output, whereas men showed an increase in vascular resistance. This gender difference in the cardiovascular effects of caffeine may have implications for the long-term effects of caffeine on BP regulation in men versus women in relation to their degree of hypertension risk. The present results suggest that the BP effects of caffeine should be tested in women at increased risk of hypertension and in regard to their menopausal status and estrogen use. 1. Lundsberg L. Caffeine consumption. In: Spiller GA, ed. Caffeine. Boca Raton, FL: CRC Press, 1998:199 –224. 2. Barone JJ, Roberts HR. Caffeine consumption. Food Chem Toxicol 1996;34: 119 –129. 3. Rainnie DG, Grunze HC, McCarley RW, Greene RW. Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Science 1994; 263:689 –692. 4. Whitsett TL, Manion CV, Christensen HD. Cardiovascular effects of coffee and caffeine. Am J Cardiol 1984;53:918 –922. 5. Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, Oates JA. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978;298:181–186. 6. Lane JD. Caffeine and cardiovascular responses to stress. Psychosom Med 1983;45:447–451. 7. Sung BH, Lovallo WR, Pincomb GA, Wilson MF. Effects of caffeine on blood pressure response during exercise in normotensive healthy young men. Am J Cardiol 1990;65:909 –913. 8. Hartley TR, Sung BH, Pincomb GA, Whitsett TL, Wilson MF, Lovallo WR. Hypertension risk status and effect of caffeine on blood pressure. Hypertension 2000;36:137–141. 9. 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;56:119 –122. 10. Pincomb GA, Wilson MF, Sung BH, Passey RB, Lovallo WR. Effects of caffeine on pressor regulation during rest and exercise in men at risk for hypertension. Am Heart J 1991;122:1107–1115. 11. Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1980;1:129 –132. 12. Evoniuk G, von Borstel RW, Wurtman RJ. Antagonism of the cardiovascular effects of adenosine by caffeine or 8-(p-sulfophenyl)theophylline. J Pharmacol Exp Ther 1987;240:428 –432. 13. Hayes SN, Taler SJ. Hypertension in women: current understanding of gender differences. Mayo Clin Proc 1998;73:157–165. 14. Rajkumar C, Kingwell BA, Cameron JD, Waddell T, Mehra R, Christophidis N, Komesaroff PA, McGrath B, Jennings GL, Sudhir K, Dart AM. Hormonal therapy increases arterial compliance in postmenopausal women. J Am Coll Cardiol 1997;30:350 –356. 15. West SG, Hinderliter AL, Wells EC, Girdler SS, Light KC. Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women. Am J Obstet Gynecol 2001;184:926 –933. 16. Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WR. Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics. Pharmacotherapy 1996;16:1046 –1052. 17. al’Absi M, Bongard S, Buchanan T, Pincomb GA, Licinio J, Lovallo WR. Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors. Psychophysiology 1997;34:266 –275. 18. Sherwood A, Allen MT, Fahrenberg J, Kelsey RM, Lovallo WR, van Doornen LJ. Methodological guidelines for impedance cardiography. Psychophysiology 1990;27:1–23. 19. Lovallo WR, al’Absi M. Hemodynamics during rest and behavioral stress in normotensive men at high risk for hypertension. Psychophysiology 1998;35:47– 53. 20. Everson SA, Lovallo WR, Pincomb GA, Kizakevich P, Wilson MF. Validation of an ensemble-averaged impedance cardiogram for estimation of stroke volume. In: Proceedings of the Thirteenth Annual International Conference of the IEEE Engineering in Medicine and Biology Society. New York, NY: IEEE, 1991;13:801– 802.
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ambulatory blood pressure levels. J Cardiovasc Risk 1994;1:159 –164. 22. Allen MT, Stoney CM, Owens JF, Matthews KA. Hemodynamic adjustments to laboratory stress: the influence of gender and personality. Psychosom Med 1993;55:505–517. 23. Evans JM, Ziegler MG, Patwardhan AR, Ott JB, Kim CS, Leonelli FM, Knapp CF. Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes. J Appl Physiol 2001;91:2611–2618. 24. Smits P, Lenders JW, Thien T. Caffeine and theophylline attenuate adenosine-induced vasodilation in humans. Clin Pharmacol Ther 1990;48:410 –418. 25. Hoyle CHV. Transmission: purines. In: Burnstock G. Hoyle CHV, eds. Autonomic Neuroeffector Mechanisms. Reading, UK: Harwood Academic Publishers, 1992:367–407. 26. Sung BH, Ching M, Izzo JL Jr, Dandona P, Wilson MF. Estrogen improves
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abnormal norepinephrine-induced vasoconstriction in postmenopausal women. J Hypertens 1999;17:523–528. 27. Virdis A, Ghiadoni L, Sudano I, Buralli S, Salvetti G, Taddei S, Salvetti A. Endothelial function in hypertension: role of gender. J Hypertens 2002;20(suppl 2):S11–S16. 28. Nekooeian AA, Pang CC. Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure. Am J Physiol 1998; 274:H2094 –H2099. 29. Manhem K, Brandin L, Ghanoum B, Rosengren A, Gustafsson H. Acute effects of transdermal estrogen on hemodynamic and vascular reactivity in elderly postmenopausal healthy women. J Hypertens 2003;21:387–394. 30. Hunt BE, Taylor JA, Hamner JW, Gagnon M, Lipsitz LA. Estrogen replacement therapy improves baroreflex regulation of vascular sympathetic outflow in postmenopausal women. Circulation 2001;103:2909 –2914.
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