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 21 and 21) and men (n 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. 2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1022–1026)

affeine is the world’s commonly The States imports C macologicofsubstance. most United and used pharalmost 30% the world’s coffee, daily con1

vascular versus cardiac effects of caffeine in women at rest and during mental stress.

sumption is equivalent 2 to 3 cups. 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pressure (BP).3,4 Caffeine corresponding to 1 to 4 cups of coffee can increase BP by up to 14/13 mm Hg in caffeine-withdrawn subjects5 at rest or during mental or exercise stress.6,7 Its pressor effect is greater in subjects with hypertension.8 In men, caffeine increases BP by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
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: bill@mindbody1.org.

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METHODS
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

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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004

4) tion and task) and recovery periods 1 Peripheral resistance (dyne · s 1 · cm 5) Women 1. Minneap.518 (161) NS NS and 2 (15 minutes each).7)† (systolic BP diastolic BP) in millimeters of mer2.05 and 0. Public speaking causes anxiety and increases BP.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. Minnesota) according to previously described p 0. heart rate.group had the highest levels of total peripheral resis2. (20 minutes).05. Variables Women (n 42) Men (n 35) North Carolina).44 (0.7) feine or placebo response (15. 21 in caffeine and 21 in placebo groups. caffeine or placebo drink (5 minutes).5) 5. Men 67 (2. recovery (30 minutes). Research Triangle Institute.424 (84) 1. n 42 women.042) 2. Men weighed more and had a higher Quetelet 41.8) 80 (7. retask consisted of 3 minutes studying and 3 minutes index than women (F [1. F [11.6) NS NS periods: baseline (10 minutes). Significant main effects or interactions were Tasks included reading aloud versus public speak. respectively). 6 minutes).3) 71 (5. Tampa.054)‡ Quetelet index (g/cm2) cury. sequent 11 periods. These analyses ance signals and electrocardiograms were ensemble tance (F [11. Responses Men 1. Baseline activity during the predrug period was tested using 2 genlasted 3 hours.9) BP was measured every 2 minSystolic BP (mm Hg) utes throughout the study. stroke volume in Caffeine intake (mg/d) 154 (10. we performed a multivariate absorption (45 minutes).03.35 and 5.0) NS NS Men 68 (5.7) 80 (1.5) NS NS minutes each). 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. †p 0. cafMen 64 (1. 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. and recovery (30 minutes).1 (2. ImpedWomen 104 (1.75] reading aloud a neutral passage from Readers’ Digest spectively.56] 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 1023 .86. p All cardiovascular measurements were made as the tolic BP at rest than women (F [1.04 and 2. F [11.73] 0.16 and reliable for within-day and between-day measure.8 (1.98) 27 (0.59] 2. Women had higher methods. in liters per minute.05). Center for Biomedical Engineering.79) stolic BP.6) ance data were recorded continuDiastolic BP (mm Hg) ously and then averaged for 12 time Women 62 (1.6) 62 (1.8) 181 (9. BP was The primary gender drug periods multivariate measured with a Dinamap monitor (Critikon. 30.001 NS Men 114 (2. and pulse pressure Height (cm) 167 (4.(Waveshell.9) 66 (1.001.3) 107 (1. drug feine versus placebo. Men in the caffeine ments if electrode placement is consistent. respectively).1) 4.30 and 3. 16 in caffeine and 19 in placebo groups.001. 29.0)† Weight (kg) 64 (1. adaptation (30 minutes). p 0.(main effects of drug. Stroke volume (ml) and 45 minutes after taking the Women 69 (4.59] 2.28 and olis.7) NS NS cury. 6 ANOVA on each dependent variable comparing 2 minutes).6) 167 (9. drug.4) 65 (1. Men had higher syswhile alone. baseline (10 To characterize gender differences in response to cafminutes). and task II (preparaMen 4.0001). Comparisons are based on gender drug group ANOVAs.6 (1. jects. The control data.19 Imped.28 (0. and stress hormones. The protocol included instrumentation der 2 drug groups analyses of variance (ANOVAs).637 (143) 1.9.18 Impedance cardiography is a noninvasive levels of stroke volume and cardiac output than men technique appropriate for behavioral research.02 and 0. and task order was counterbalanced across sub.p 0.followed by univariate ANOVAs and specific coning. task I (reading or speaking. Minnesota Impedance Cardiograph. cardiac output (stroke volume heart rate) *Entries show mean (SEM). heart rate in beats per minute.6) .7) drug).20.612 (187) to caffeine and the tasks were tested as changes from baseline in the sub*Entries show means (SE). task I (preparation and task) Cardiac output (L/min) and recovery periods 1 and 2 (15 Women 4. Cardiovascular variables were systolic BP.6 (1. task II (alternate gender 2 drug groups 11 periods after taking the task.trasts as indicated. and n 35 men. ‡p 0.03.0) 116 (1. mean arterial pressure. subject sat semirecumbent in a recliner chair. Research Triangle Park. and it is (main effects of gender. p 0. Table 2 provides cardiovascular data before drug administration. diaAge (yrs) 29 (0.6) 67 (1.9) milliliters.02). Florida).

Women who took APRIL 15. In the caffeine group. Because women showed no increase in total peripheral resistance levels after taking caffeine.32] 4.86.9 to 15. p 0.08). women and men had comparable heart rate and systolic BP changes to caffeine and the tasks. as shown in Figure 2.05) between men and women. Entries show mean (SEM) of change scores from baseline before caffeine or placebo.04). In the caffeine group. men and women had similar changes from baseline in cardiovascular activity over all time periods.FIGURE 1.32] 4.03). all p 0.05). In contrast. p 0. 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 [1.77. Men and women taking placebo had no differences in the compliance index at any period.03) and a trend toward a greater cardiac output response (F [11.1. p 0. gender periods effects for the placebo and caffeine groups. p 0. *Points of significant difference (p <0. 93 nonsignificant gender and gender periods interactions (F 2.05) between men and women. p 0.10).23] 2. including baseline. and peripheral resistance changes to caffeine.3 to 11. Vascular compliance indexes in men and women exposed to placebo and caffeine.98. gender and gender periods effects were nonsignificant for all variables (F 1. women had significantly higher arterial compliance values than men at most time points (F [1. cardiac output. Figure 1 shows that after placebo. Women who consumed caffeine had greater increases in stroke volume than men (F [11.13). FIGURE 2. BP and hemodynamic responses of men and women exposed to placebo and caffeine.67. *Points of significant difference (p <0. Entries show absolute mean (SEM) values for men and women exposed to caffeine. we compared them with men on an index of arterial compliance.71.02). and comparisons at each time point showed that the groups differed significantly only during the recovery period after public speaking (F [1. p 0.01).0.04 to 5. p 0.32] 5. as demonstrated by 1024 THE AMERICAN JOURNAL OF CARDIOLOGY VOL. p 0. as indicated in Figure 1.23] 2.23] 2.27.3. Men had greater diastolic BP responses than women (F [11. p 0. We then compared men and women in the caffeine group with regard to stroke volume. 2004 .72. Men had greater increases in total peripheral resistance (F [11.04). the men had greater peripheral resistance at the indicated times after caffeine admininstration (F [1.23] 1.37 to 14.35] 6.

Allen MT.65:909 –913. Oates JA.56:119 –122. Pincomb GA. Lovallo WR. Sung BH. 2. Hollifield JW. Lovallo WR.11.23 These new findings of caffeine use in women will require replication and further study. Sherwood A.27 and greater BP responses to mental stress. Carr RK. 19. Lundsberg L. NY: IEEE. Pincomb GA. Am Heart J 1991. Am J Cardiol 1985. Mayo Clin Proc 1998.34: 119 –129. but the women also had lower vascular resistance and greater vascular compliance. Dart AM. Wilson MF. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1980. In the absence of caffeine. Whitsett TL. N Engl J Med 1978. Psychophysiology 1990. Shepard JD. cardiac output and myocardial contractility in young men. New York. Hormonal therapy increases arterial compliance in postmenopausal women.29. Hayes SN. West SG. Whitsett TL.122:1107–1115. catecholamines and blood pressure. Effects of caffeine on plasma renin activity. whereas men have a predominant sympathetic vascular tone. Effects of caffeine on pressor regulation during rest and exercise in men at risk for hypertension. Pincomb GA.05). In: Proceedings of the Thirteenth Annual International Conference of the IEEE Engineering in Medicine and Biology Society. Rainnie DG. J Am Coll Cardiol 1997. Watson JT. 15. Hemodynamics during rest and behavioral stress in normotensive men at high risk for hypertension. Men and women had lower heart rates after caffeine consumption. Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal.9 Caffeine exerts progressively greater BP effects in men who are at increasingly greater risk for hypertension. Greene RW. differences that are abolished by estrogen replacement. Grunze HC. Pincomb GA. Food Chem Toxicol 1996. In keeping with the present findings.1:129 –132. Lovallo WR. 18.73:157–165. Boca Raton.8 Conversely. Psychophysiology 1998. Robertson D. Men responded to caffeine with increases in peripheral resistance and no change in cardiac output. Cardiovascular effects of coffee and caffeine. DISCUSSION In the present study. Silverstein SM. Caffeine antagonizes adenosine A-1 and A-2 receptors.9 In contrast. The caffeine-induced increase in cardiac output in the women was unanticipated given the previous results in men. 20. We speculate that caffeine may lack an effect on vascular resistance in premenopausal women due to the actions of estrogen. ed. 1998:199 –224. J Pharmacol Exp Ther 1987. men and women who were regular caffeine consumers had comparable increases in BP after modest doses of caffeine. 5. In this study. von Borstel RW. as reported by another study. Barone JJ. 11. Everson SA. and. women responded with increases in cardiac output and little or no change in peripheral resistance.25 In men. al’Absi M. 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