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Cardiovascular effects of caffeine in men and women

Cardiovascular effects of caffeine in men and women

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Cardiovascular Effects of Caffeine in Men and Women

Terry R. Hartley,

William R. Lovallo,


and Thomas L. Whitsett,


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pressure (BP).3,4 Caffeine corresponding to 1 to 4 cups of coffee can increase BP by up to 14/13 mm Hg in caffeine-withdrawn subjects5 at rest or during mental or exercise stress.6,7 Its pressor effect is greater in subjects with hypertension.8 In men, caffeine increases BP by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


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


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

Men had higher syswhile alone. 6 ANOVA on each dependent variable comparing 2 minutes).6) 62 (1.05. jects. p All cardiovascular measurements were made as the tolic BP at rest than women (F [1.44 (0. Variables Women (n 42) Men (n 35) North Carolina).4) 65 (1. Significant main effects or interactions were Tasks included reading aloud versus public speak.042) 2. Research Triangle Institute. Minnesota Impedance Cardiograph.05).59] 2.trasts as indicated.75] reading aloud a neutral passage from Readers’ Digest spectively. and pulse pressure Height (cm) 167 (4.6) 67 (1.1) 4.7)† (systolic BP diastolic BP) in millimeters of mer2.612 (187) to caffeine and the tasks were tested as changes from baseline in the sub*Entries show means (SE).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 .0) 116 (1. These analyses ance signals and electrocardiograms were ensemble tance (F [11.001. 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.28 and olis. Baseline activity during the predrug period was tested using 2 genlasted 3 hours.19 Imped. Men weighed more and had a higher Quetelet 41. Table 2 provides cardiovascular data before drug administration.9) 66 (1. 30.79) stolic BP. and it is (main effects of gender.6) NS NS periods: baseline (10 minutes). heart rate. Minnesota) according to previously described p 0.30 and 3.3) 71 (5. mean arterial pressure. Women had higher methods. drug.20. Florida).8) 80 (7. task II (alternate gender 2 drug groups 11 periods after taking the task. 16 in caffeine and 19 in placebo groups.28 (0.6 (1. 29. heart rate in beats per minute.73] 0.8) 181 (9.7) drug).9.p 0. and recovery (30 minutes). caffeine or placebo drink (5 minutes).5) NS NS minutes each). adaptation (30 minutes). Stroke volume (ml) and 45 minutes after taking the Women 69 (4. 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. Public speaking causes anxiety and increases BP. ImpedWomen 104 (1.6 (1.6) .98) 27 (0. cafMen 64 (1. Research Triangle Park.0)† Weight (kg) 64 (1.35 and 5.054)‡ Quetelet index (g/cm2) cury. 6 minutes). F [11. baseline (10 To characterize gender differences in response to cafminutes). Men 67 (2. †p 0. Cardiovascular variables were systolic 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. Comparisons are based on gender drug group ANOVAs.16 and reliable for within-day and between-day measure.02 and 0. Men in the caffeine ments if electrode placement is consistent. and n 35 men. cardiac output (stroke volume heart rate) *Entries show mean (SEM).18 Impedance cardiography is a noninvasive levels of stroke volume and cardiac output than men technique appropriate for behavioral research. F [11.5) 5.9) BP was measured every 2 minSystolic BP (mm Hg) utes throughout the study. retask consisted of 3 minutes studying and 3 minutes index than women (F [1. (20 minutes). The control data.518 (161) NS NS and 2 (15 minutes each). respectively). Tampa. Responses Men 1. Center for Biomedical Engineering.6) ance data were recorded continuDiastolic BP (mm Hg) ously and then averaged for 12 time Women 62 (1.86.followed by univariate ANOVAs and specific coning.3) 107 (1.(main effects of drug.4) tion and task) and recovery periods 1 Peripheral resistance (dyne · s 1 · cm 5) Women 1.0001).001 NS Men 114 (2.04 and 2.02).59] 2. and task order was counterbalanced across sub.7) feine or placebo response (15.03. p 0.7) NS NS cury. subject sat semirecumbent in a recliner chair. and stress hormones. task I (preparation and task) Cardiac output (L/min) and recovery periods 1 and 2 (15 Women 4. ‡p 0.group had the highest levels of total peripheral resis2. The protocol included instrumentation der 2 drug groups analyses of variance (ANOVAs). stroke volume in Caffeine intake (mg/d) 154 (10.(Waveshell. sequent 11 periods.1 (2.637 (143) 1. p 0. recovery (30 minutes). and task II (preparaMen 4.424 (84) 1. n 42 women. Minneap.03.05 and 0.8 (1. drug feine versus placebo.0) NS NS Men 68 (5. task I (reading or speaking.001. diaAge (yrs) 29 (0.6) 167 (9. 21 in caffeine and 21 in placebo groups. in liters per minute. BP was The primary gender drug periods multivariate measured with a Dinamap monitor (Critikon. we performed a multivariate absorption (45 minutes).7) 80 (1.9) milliliters. respectively).

3.9 to 15. p 0. the men had greater peripheral resistance at the indicated times after caffeine admininstration (F [1.08).37 to 14.03).05).23] 1.05) between men and women.98.05) between men and women. p 0.27. *Points of significant difference (p <0. p 0. Men and women taking placebo had no differences in the compliance index at any period. 93 nonsignificant gender and gender periods interactions (F 2.1. gender periods effects for the placebo and caffeine groups. and comparisons at each time point showed that the groups differed significantly only during the recovery period after public speaking (F [1. cardiac output.04). FIGURE 2. Because women showed no increase in total peripheral resistance levels after taking caffeine. In contrast.0. we compared them with men on an index of arterial compliance.32] 5. Women who took APRIL 15. 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. Entries show mean (SEM) of change scores from baseline before caffeine or placebo. p 0. as demonstrated by 1024 THE AMERICAN JOURNAL OF CARDIOLOGY VOL.35] 6. gender and gender periods effects were nonsignificant for all variables (F 1.03) and a trend toward a greater cardiac output response (F [11. p 0.86. Entries show absolute mean (SEM) values for men and women exposed to caffeine. Men had greater increases in total peripheral resistance (F [11. as shown in Figure 2. Vascular compliance indexes in men and women exposed to placebo and caffeine. Men had greater diastolic BP responses than women (F [11. women had significantly higher arterial compliance values than men at most time points (F [1. men and women had similar changes from baseline in cardiovascular activity over all time periods.67.32] 4. In the caffeine group.FIGURE 1. p 0.72. Figure 1 shows that after placebo. 2004 . We then compared men and women in the caffeine group with regard to stroke volume. all p 0.04). BP and hemodynamic responses of men and women exposed to placebo and caffeine. as indicated in Figure 1. p 0. p 0. *Points of significant difference (p <0. p 0. women and men had comparable heart rate and systolic BP changes to caffeine and the tasks. and peripheral resistance changes to caffeine.23] 2. In the caffeine group.23] 2.32] 4.77.10).13).23] 2.02). including baseline.04 to 5. Women who consumed caffeine had greater increases in stroke volume than men (F [11.71.3 to 11.01).

Lundsberg L. 20. Effects of caffeine on blood pressure response during exercise in normotensive healthy young men. Effects of caffeine on vascular resistance. 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. Food Chem Toxicol 1996.27:1–23. In this study. 19. In the absence of caffeine. Pincomb GA. men and women who were regular caffeine consumers had comparable increases in BP after modest doses of caffeine.placebo instead of caffeine had similar compliance index values. 15. cardiac output and myocardial contractility in young men. Cardiovascular effects of coffee and caffeine. Kelsey RM. the vascular effects of caffeine appeared to be greatly decreased.05). Maish WA. Lovallo WR. Sudhir K. Validation of an ensemble-averaged impedance cardiogram for estimation of stroke volume. Wurtman RJ. Lovallo WR. Hypertension 2000. New York. Caffeine consumption. as seen in a previous study. increased left ventricular filling. NY: IEEE. 1. 10. 7. as shown in Figure 2. in these women. von Borstel RW. 8. However. the lack of estrogen leads to greater venous constriction to norepinephrine infusion. differences that are abolished by estrogen replacement. Fredholm BB. Waddell T.9 Caffeine exerts progressively greater BP effects in men who are at increasingly greater risk for hypertension.34: 119 –129.8 Conversely. Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors. Wilson MF. These 3 factors acting in concert in the women would favor greater return of blood to the heart. Whitsett TL. Frolich JC. Lovallo WR. including comparisons in women before and after menopause and receiving and not receiving estrogen.240:428 –432. Shand DG. Lovallo WR. Light KC. al’Absi M. Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Rajkumar C. Hinderliter AL. Caffeine and cardiovascular responses to stress. Whitsett TL. Mayo Clin Proc 1998. Watson JT. Everson SA. 16. ed.21 However. Whitsett TL. Taler SJ. Methodological guidelines for impedance cardiography. the mechanisms facilitating the BP increase in women were different from those in men. In: Proceedings of the Thirteenth Annual International Conference of the IEEE Engineering in Medicine and Biology Society. 3. the women sustained their BP response by greater cardiac output. Boca Raton. Passey RB. Hypertension risk status and effect of caffeine on blood pressure. increased stroke volume. Passey RB. FL: CRC Press. arterial compliance was lower in the caffeine group than in the placebo group at most times (all p 0. Hollifield JW.34:266 –275.11. Lovallo WR. Lane JD. West SG. Whitsett TL. Rainnie DG. Psychophysiology 1997. Psychophysiology 1990. Carr RK. Am J Cardiol 1984. Caffeine antagonizes adenosine A-1 and A-2 receptors. Lovallo WR. 1998:199 –224. Am J Cardiol 1990. Men and women had lower heart rates after caffeine consumption. Mehra R. Am Heart J 1991. CARDIOVASCULAR PHARMACOLOGY/CAFFEINE EFFECTS IN MEN AND WOMEN 1025 .26 reduced vascular nitric oxide production. whereas men have greater increases in vascular resistance22 and that women have a predominance of vagal cardiac regulation. Hormonal therapy increases arterial compliance in postmenopausal women. 2. Effects of caffeine on pressor regulation during rest and exercise in men at risk for hypertension. Bongard S.298:181–186. Grunze HC. whereas men have a predominant sympathetic vascular tone. Hayes SN. 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). Hypertension in women: current understanding of gender differences. 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. Science 1994. whereas men showed an increase in vascular resistance. Fahrenberg J.24 Adenosine is a potent vasodilator that decreases norepinephrine release at sympathetic nerve terminals. Wells EC. Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women. it is noteworthy that premenopausal women have greater heart rate responses to mental stress. Pincomb GA. 4. Komesaroff PA. Christophidis N. Antagonism of the cardiovascular effects of adenosine by caffeine or 8-(p-sulfophenyl)theophylline. 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Am J Obstet Gynecol 2001. J Pharmacol Exp Ther 1987. Their cardiac output response was accompanied by greater stroke volume.1:129 –132. Cameron JD.13:801– 802. Pharmacotherapy 1996. Sung BH. Pincomb GA. McCarley RW.9 In contrast. Dart AM. 1991.45:447–451. 18. Pincomb GA. as reported by another study. Shepard JD. Hampton EM. 12. Sung BH. Wilson MF. 14. In keeping with the present findings. Kingwell BA. Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics. 9.23 These new findings of caffeine use in women will require replication and further study.27 and greater BP responses to mental stress.56:119 –122.73:157–165.53:918 –922. 17.30 In the present study. Wilson MF. Lovallo WR.26. Buchanan T. Greene RW. Lovallo WR. 11. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1980. Among men. The effect of caffeine on BP was similar at rest and during stress. 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