Cardiovascular Effects of Caffeine in Men
and Women
Terry R. Hartley, PhD, William R. Lovallo,
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, equiva-
lent 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 eleva-
tions in women (4.5 and 3.3 mm Hg, respectively) and
C affeine is the world’s most commonly used phar-
macologic substance. The United States imports
1
almost 30% of the world’s coffee, and daily con-
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caffeine-withdrawn subjects5 at rest or during mental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 in-
creases 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 caf-
feine 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 vascu-
lar 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, Okla-
homa. 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.
1022 ©2004 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 93 April 15, 2004
PhD, and Thomas L. Whitsett, MD
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 out-
put. In contrast, women responded to caffeine with in-
creases 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)
vascular versus cardiac effects of caffeine in women at
rest and during mental stress.
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, Scot-
land). All signed a consent form approved by the
institutional review board of the University of Okla-
homa Health Sciences Center and the Veterans Affairs
Medical Center and were paid for participating.
Subjects were randomly assigned to receive caf-
feine (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., Irving-
ton, New Jersey) was taken mixed with 6 oz of grape-
fruit 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 high-
performance liquid chromatography. All values were
near the low detection limit of the assay, indicating
compliance.
Subjects consumed a light breakfast on the morn-
ing 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, Re-
TABLE 1 Subject Characteristics*
search Triangle Institute, Research Triangle Park,
Variables Women (n ⫽ 42) Men (n ⫽ 35) North Carolina).
Age (yrs) 29 (0.98) 27 (0.79) Cardiovascular variables were systolic BP, dia-
Height (cm) 167 (4.8) 181 (9.0)† stolic BP, mean arterial pressure, and pulse pressure
Weight (kg) 64 (1.7) 80 (1.7)† (systolic BP ⫺ diastolic BP) in millimeters of mer-
Quetelet index (g/cm2) 2.44 (0.042) 2.28 (0.054)‡ 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 sec-
TABLE 2 Baseline Cardiovascular Values* ond per centimeters to the fifth
power and a vascular compliance in-
Caffeine Placebo Gender Caffeine
dex (stroke volume/pulse pressure)
Heart rate (beats/min) in milliliters per millimeter of mer-
Women 66 (1.6) 67 (1.7) NS NS cury.
Men 67 (2.6) 62 (1.9)
Systolic BP (mm Hg) BP was measured every 2 min-
Women 104 (1.3) 107 (1.6) .001 NS utes throughout the study. Imped-
Men 114 (2.0) 116 (1.6) ance data were recorded continu-
Diastolic BP (mm Hg) ously and then averaged for 12 time
Women 62 (1.9) 66 (1.6) NS NS
Men 64 (1.4) 65 (1.7)
periods: baseline (10 minutes), caf-
Stroke volume (ml) feine or placebo response (15, 30,
Women 69 (4.3) 71 (5.0) NS NS and 45 minutes after taking the
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
Men 4.6 (1.5) 5.1 (2.4) minutes each), and task II (prepara-
Peripheral resistance (dyne · s⫺1 · cm⫺5) tion and task) and recovery periods 1
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
*Entries show means (SE); n ⫽ 42 women, 21 in caffeine and 21 in placebo groups, and n ⫽ 35 men, as changes from baseline in the sub-
16 in caffeine and 19 in placebo groups. Comparisons are based on gender ⫻ drug group ANOVAs. sequent 11 periods.
Baseline activity during the pre-
drug period was tested using 2 gen-
lasted 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 caf-
minutes), 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 con-
ing, 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
minutes delivering a speech to a video camera in front Table 1 presents anthropometric and screening
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, re-
reading aloud a neutral passage from Readers’ Digest spectively; p ⬍0.02). Table 2 provides cardiovascular
while alone. data before drug administration. Men had higher sys-
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).
measured with a Dinamap monitor (Critikon, Tampa, The primary gender ⫻ drug ⫻ periods multivariate
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 resis-
ance 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

CARDIOVASCULAR PHARMACOLOGY/CAFFEINE EFFECTS IN MEN AND WOMEN 1023

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 ex-
posed 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 interac-
tions (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 in-
creases 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 pe-
ripheral 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 car-
diac output and little or no change in peripheral resis-
tance. Their cardiac output response was accompanied
by greater stroke volume. In the absence of caffeine,
changes in cardiovascular activity were strikingly sim-
ilar 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 re-
sults in men. Men and women had lower heart rates
after caffeine consumption, but the women also had
lower vascular resistance and greater vascular compli-
ance. These 3 factors acting in concert in the women
would favor greater return of blood to the heart, in-
creased 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 regula-
tion, 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 sepa-
rate 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 re-
ceptors.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 postmeno-
pausal women, the lack of estrogen leads to greater
venous constriction to norepinephrine infusion,26 re-
duced vascular nitric oxide production,27 and greater
BP responses to mental stress, differences that are
abolished by estrogen replacement.26,28 The contribu-
tion of estrogen to these gender differences in caffeine
response requires further testing, including compari-
sons in women before and after menopause and re-
ceiving and not receiving estrogen. In addition, we are
not able to rule out differences between men and
CARDIOVASCULAR PHARMACOLOGY/CAFFEINE EFFECTS IN MEN AND WOMEN
women with respect to caffeine effects on neural dis-
charge 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 car-
diac output, whereas men showed an increase in
vascular resistance. This gender difference in the
cardiovascular effects of caffeine may have impli-
cations 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 estro-
gen use.
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