Curr Hypertens Rep (2014) 16:468
DOI 10.1007/s11906-014-0468-2
BLOOD PRESSURE MONITORING AND MANAGEMENT (G OGEDEGBE AND JA STAESSEN, SECTION EDITORS)
Blood Pressure in Relation to Coffee and Caffeine Consumption
Idris Guessous & Chin B. Eap & Murielle Bochud
# Springer Science+Business Media New York 2014
Abstract The relationship between blood pressure (BP) and
coffee is of major interest given its widespread consumption
and the public health burden of high BP. Yet, there is no
specific recommendation regarding coffee intake in existing
hypertension guidelines. The lack of a definitive understand-
ing of the BP-coffee relationship is partially attributable to
issues that we discuss in this review, issues such as acute vs.
chronic effects, genetic and smoking effect modifications, and
coffee vs. caffeine effects. We also present evidence from
meta-analyses of studies on the association of BP with coffee
intake. The scope of this review is limited to the latest ad-
vances published with a specific focus on caffeine, acknowl-
edging that caffeine is only one among numerous components
in coffee that may influence BP. Finally, considering the state
This article is part of the Topical Collection on Blood Pressure
Monitoring and Management
I. Guessous (*)
Unit of Population Epidemiology, Department of Community
Medicine and Primary Care and Emergency Medicine, University
Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva,
Switzerland
e-mail: Idris.Guessous@hcuge.ch
I. Guessous : M. Bochud
Institute of Social and Preventive Medicine (IUMSP), Lausanne
University Hospital, Lausanne, Switzerland
M. Bochud
e-mail: Murielle.Bochud@chuv.ch
C. B. Eap
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre
for Psychiatric Neurosciences, Department of Psychiatry, Centre
Hospitalier Universitaire Vaudois, University of Lausanne, Hospital
of Cery, Lausanne, Switzerland
e-mail: Chin.Eap@chuv.ch
C. B. Eap
School of Pharmaceutical Sciences, University of Geneva,
University of Lausanne, Lausanne, Switzerland
of the research, we propose a mechanism by which the
CYP1A2 gene and enzyme influence BP via inhibition of the
adenosine receptor differentially in smokers and non-smokers.
Keywords Blood pressure . Hypertension . Coffee .
Caffeine . CYP1A2 . Genetics . Enzyme . Smoking .
Adenosine . Renal sodium reabsorption
Introduction
Like many other diet-related domains in health, disentangling
the relationship of blood pressure (BP) with coffee intake is
complex. Elevated BP and coffee consumption are highly
prevalent in Western societies and several thousands of studies
and reviews have been listed in MEDLINE/PubMed since the
1894 British Medical Journal paper entitled “Tea, coffee, and
cocoa” was indexed [1]. Yet, 120 years after this first index-
ation robust evidence-based recommendations on coffee in-
take in the prevention and/or management of high BP are still
lacking. Coffee, as a beverage, includes thousands of com-
pounds, of which caffeine is one. Although coffee intake
represents the main source of caffeine intake, numerous other
beverages and food items (e.g., tea, chocolate, energy drinks,
etc.) contain caffeine. There is currently no specific recom-
mendation regarding coffee or caffeine intake in hypertension
guidelines [2–5].
Part of the lack of a definitive answer on the BP-coffee
relationship is attributable to four issues that we will discuss in
the second part of this review. The acute and chronic effects of
coffee or caffeine intake on BP are, if not opposite, at least
different. Not distinguishing the two effects may lead to
spurious conclusions (issue 1). The information on genetics
and smoking, both factors that may modify the effect of coffee
or caffeine intake on BP, is generally not considered (issues 2
and 3). The last issue is that the effects on BP are probably
468, Page 2 of 9
different whether intake of coffee or caffeine per se is consid-
ered. A related issue is the frequent use of suboptimal methods
to estimate coffee or caffeine intake in epidemiological studies
(issue 4).
The first part of this review will briefly describe the coffee
components, consumption and the metabolism of caffeine.
Evidence from meta-analyses of observational and experi-
mental studies on the association of BP or high BP with coffee
or caffeine intake will then be presented. Finally, considering
the state of the research, including our own contribution and
the different issues raised, we will propose a possible mecha-
nism by which the CYP1A2 gene and enzyme influence BP
and the risk of hypertension by inhibition of the adenosine
receptor differentially in smokers and non-smokers.
We will limit the scope of this review to the latest advances
in published literature with a specific focus on caffeine in
human studies, acknowledging that caffeine is only one
among the numerous components included in coffee that
may potentially influence BP.
Coffee, Caffeine: Composition, Consumption
and Metabolism
Coffee bean extract is a complex mixture of thousands of
chemicals and includes potentially bioactive components such
as caffeine, polyphenols (e.g., chlorogenic acid) and oil diter-
penes fatty acid esters (e.g., cafestol, kahweol) [6]. Worldwide
coffee is among the most widely consumed beverages and
caffeine is ubiquitous in beverages and foods. The latest 2011
per capita average consumption of coffee in the United States
and in Switzerland (n.b., Nestlé Nespresso SA corporate
headquarters is based in Lausanne, Switzerland) are 4.24 kg/
year and 7.85 kg/year, respectively (www.ico.org/countries.
pdf). In the United States the average consumption of caffeine
is 200-300 mg/day [7]. This average is expected to grow given
the increasing number of products (e.g., gum, energy drinks,
syrup) that are “fortified” with caffeine to such an extent that it
has raised sufficient concerns to motivate the Food and Drug
Administration (FDA) to investigate the safety of caffeine in
food products (http://www.fda.gov/forconsumers/
consumerupdates/ucm350570.htm).
Caffeine (1,3,7-Trimethylxanthine) is a purine alkaloid,
more than 70 % of which is provided by coffee consumption
[8]. Caffeine is metabolized by the liver CYP1A2 enzyme into
paraxanthine (about 80 %), theobromine (about 12 %) and
theophylline (about 4 %). Caffeine and caffeine metabolites
are methylxanthines, a family of non-specific adenosine re-
ceptor antagonists with diuretic and natriuretic properties,
among others, [9, 10], discussed in more detail below.
CYP1A2 is an inducible enzyme whose activity is modi-
fied by various factors [11]. For example, cigarette smoking,
intake of charcoal-grilled meat, omeprazole and
carbamazepine-induced CYP1A2 [12]. On the other hand,
Curr Hypertens Rep (2014) 16:468
fluvoxamine and oral contraceptives inhibit CYP1A2 enzyme
activity [13]. Coffee consumption itself could increase
CYP1A2 activity as well [11].
Coffee, Caffeine: Relationship with Cardiovascular Health
Several components in coffee may affect cardiovascular (CV)
health. For example, chlorogenic acids, the most abundant
polyphenols in coffee, are known to function as antioxidants
and may improve glucose metabolism and inhibit formation of
advanced glycation end products [14]. In fact, coffee may
contribute to approximately 60 % of the total dietary intake
of antioxidants in healthy European populations [15]. The two
major natural diterpenes found in coffee, cafestol and
kahweol, have also been associated with notable CV risk via
an elevation of cholesterol [16, 17]. Although caffeine repre-
sents only 1-2 % of the coffee’s total chemical profile, it is an
important bioactive component of coffee and is often consid-
ered the potential mediator of the effect of coffee on CV risk, if
any. Yet, decaffeinated coffee has also been associated with
CV risk. Very recently, the association of caffeinated and
decaffeinated coffee drinking with total and cause-specific
mortality was examined in a large prospective study conduct-
ed in the United States (229,119 men, 173,141 women,
5,148,760 person-years of follow-up between 1995 and
2008) [18••]. Coffee consumption was self-reported once at
baseline. Coffee consumption was associated with reduced
mortality due to respiratory disease, injuries and accidents,
diabetes, and infections, as well as heart disease and stroke.
Interestingly, 2 or more cups per day of caffeinated, but also
decaffeinated, coffee drinking was associated with reduced
death due to heart disease in men (e.g., hazard ratio [95 %
confidence interval (CI)] of 2 or 3 cups of caffeinated coffee/
day vs. none, 0.86 [0.79-0.94]) and women (0.83 [0.72-0.95]).
Only caffeinated coffee drinking was associated with reduced
stroke mortality and this was restricted to men [18••]. While
heart disease and stroke are outcomes related to high BP, data
on high BP were not specifically reported in this study. Spe-
cific evidence is presented below.
Coffee, Caffeine, and Blood Pressure: Cumulative Evidence
from Observational Studies and Clinical Trials
Cumulative evidence regarding the relationship of BP with
coffee or caffeine intake in non-hypertensive participants has
been summarized in four systematic reviews and meta-
analyses, the main results of which are report in Table 1.
The first two meta-analyses of published randomized con-
trolled trials (RCTs) reported a slight increase in both systolic
and diastolic BP associated with coffee or caffeine intake [19,
20]. A meta-analysis of six prospective cohort studies pub-
lished in 2011 by Zhang et al. found an inverse “J-shaped”
curve with high BP risk increasing with up to 3 cups of coffee
Table 1 Summary of meta-analyses on coffee, caffeine consumption, and blood pressure

PubMed ID Publication Study design Number of Number of participants Intervention (caffeine content range) / Duration Outcome Overall associations (95% CI) Reference
(PMID) year included strata pooled included (% normotensive) Exposure range
Curr Hypertens Rep (2014) 16:468

23032138 2012 RCT 10 913 (97%) Coffee dose (not reported) 6–16 weeks Change in systolic BP Coffee dose vs. no coffee dose: [20]
-0.55 mmHg (-2.46, 1.36)
Change in diastolic BP Coffee dose vs. no coffee dose:
-0.45 mmHg (-1.52, 0.61)
10024321 1999 RCT 11 522 (96%) Coffee dose (504–887 mg) 4–79 days Change in systolic BP Coffee dose vs. no coffee dose: [17]
2.4 mmHg (1.0, 3.7)
Change in diastolic BP Coffee dose vs. no coffee dose:
1.2 mmHg (0.4, 2.1)
15834273 2005 RCT 18 1,010 (NS) Coffee dose (225–798 mg) 9–79 days Change in systolic BP Coffee dose vs. no coffee or [18••]
decaffeinated dose:
1.22 mmHg (0.52, 1.92)
Change in diastolic BP Coffee dose vs. no coffee or
decaffeinated dose:
0.49 mmHg (-0.06, 1.04)
15834273 2005 RCT 7 159 (NS) Caffeine-only dose (295–750 mg) 7–84 days Change in systolic BP Caffeine dose vs. no caffeine dose: [18••]
4.16 mmHg (2.13, 6.2)
Change in diastolic BP Caffeine dose vs. no caffeine dose:
2.41 mmHg (0.98, 3.84)
23032138 2012 Cohort 4 1,467,130 (100%) Self-reported coffee intake 6.4–33 years Risk of HTN Higher intake vs. lower intake: [20]
1.03 (0.98, 1.08)
21450934 2011 Cohort 6 172,567 (100%) Self-reported coffee intake 6.4–33 years Risk of HTN 1–3 cups/day vs. <1 cup/day: [19]
1.09 (1.01, 1.18)
3–5 cups /day vs. <1 cup/day:
1.07 (0.96, 1.20)
>5 cups /day vs. <1 cup/day:
1.08 (0.96, 1.21)

BP: blood pressure; HTN: hypertension; NS: not specified; PMID: PubMed identifier (unique identifier assigned to each article as it is added to PubMed; enter this number in PubMed to find the article)
RCT: randomized controlled trial. Significant associations are reported in bold
Page 3 of 9, 468
468, Page 4 of 9
per day compared with less than 1 cup, and then decreasing
with higher intakes [21]. More recently, a meta-analysis of ten
RCTs and five cohort studies did not show any association of
coffee intake on BP or risk of high BP [22••]. Overall, these
reviews highlight the important heterogeneity across studies
(both RCTs and cohort studies) as well as the unclear ascer-
tainment of coffee consumption and adherence to the quantity
assigned (for RCTs).
With respect to hypertensive individuals a 2011 systematic
review identified RCTs that examined the acute effect of
caffeine (five RCTs) and the effect of habitual coffee intake
on BP (three RCTs). Caffeine intake increased both systolic
and diastolic BP up to 3 hours after administration (i.e., acute
effect) while no increase was observed in studies with a two
week intervention (i.e., habitual coffee intake) [23].
Issue 1: Acute Versus Chronic Effects of Coffee and Caffeine
on Blood Pressure
The previous section highlights that the acute and chronic
effects of coffee and caffeine intake on BP differ. Generally,
regular coffee or caffeine intake increases BP in the short term
(i.e., less than 3 months) [20]. Also, acute consumption of
caffeine at dietary levels appears to raise BP [24]. Yet, a
tolerance to the acute CV effects of caffeine has been de-
scribed [25] and there is no clear evidence that regular caffeine
intake over long periods of time increases the incidence of
hypertension, as reflected by an absence of significant positive
association in large scale prospective studies [26–28] and
inconsistent results in cross-sectional studies [29–31]. Thus,
like measuring BP in habitual joggers while they are running
would lead to erroneous conclusions about the effect of reg-
ular physical activity on BP, assessing BP in habitual coffee
drinker while they consume it leads to erroneous conclusions
about the effect of regular coffee intake on BP. Interestingly,
this is similar, yet inverse,- to the relationship of alcohol with
BP; the response of BP to ethanol ingestion is biphasic with a
decrease in BP (attributable to acute vasodilatation) 4-hours
post-ingestion followed by an increase in BP (attributable to a
nonendothelium-based mechanism) at 13 hours [32]. Similar
to what is found for alcohol, one should carefully consider the
timing of BP measurements with respect to coffee/caffeine
intake when interpreting the effect of coffee/caffeineon BP.
Issue 2: The Genetics of Coffee and Caffeine Consumption
The associations of caffeinated beverages (i.e., coffee intake)
with CV outcomes (i.e., myocardial infarction) or risk factors
(i.e., hypertension) seem to be modified by selected geno-
types, including by a few CYP1A2 genotypes [33, 34••].
Caffeine intake itself was found to be heritable [35], and this
heritability appears to be quite specific to caffeine [36], but
few genetic variants have been associated with caffeine intake
Curr Hypertens Rep (2014) 16:468
so far [37, 38•]. We found three CYP1A2 variants, not highly
correlated with each other, to be strongly associated with
reported caffeine intake [34••]. Similarly, genetic polymor-
phisms of CYP2A6, the major enzyme involved in nicotine
metabolism, have been shown to be associated with the num-
bers of cigarettes smoked; poor metabolizers smoke less while
rapid metabolizers smoke more in order to reach a sufficient
amount of nicotine in the organism [39]. Interestingly, recent
meta-analyses of genome-wide association studies (GWAS)
have identified the CYP1A2 locus, on chromosome 15q24.1,
as being robustly associated with BP and hypertension [40,
41]. In humans the CYP1A2 enzyme, encoded by the
CYP1A2 gene, is responsible for about 13 % of the cyto-
chrome P450 activity of the liver [42] and for caffeine metab-
olism. While several CYP1A2 genetic variants have been
identified, their effects on the CYP1A2 enzyme activity are
not clear [43]. Wide inter-individual variability in CYP1A2
activity has been reported [44]. This inter-individual variabil-
ity can be due to both genetic (e.g., variants of CYP1A2 and of
other gene coding for P450 oxydoreductase or for nuclear
receptors controlling CYP1A2 activity) [45, 46] and environ-
mental factors (discussed in more detail below) [47, 48]. For
example, the CYP1A2*1C polymorphism, identified in the 5’-
flanking region of the gene, could lead directly to decreased
CYP1A2 activity [49]. CYP1A2*1 F polymorphism has been
suggested to confer a higher inducibility of CYP1A2 by
smoking [50]. Yet, in a study with sequencing data on the
entire CYP1A1/CYP1A2 locus no single polymorphism or
haplotype could unequivocally predict CYP1A2 activity
[51]. While the currently identified polymorphisms of
CYP1A2 and of other genes controlling CYP1A2 activity
seems to explain only a part of the large inter-individual
variability in CYP1A2 activity [45, 46, 52], the identification
of CYP1A2 genetic markers associated with caffeine intake
are in line with both the activity of the CYP1A2 enzyme and
the significant heritability for caffeine use, toxicity, tolerance
and withdrawal symptoms [35]. Other loci and variants have
been associated with coffee or caffeine intake including the
ADORA2a variants [38•, 53] that have been previously asso-
ciated with caffeine-induced anxiety [54].
Previous studies suggest that genetic markers should be
considered when examining the relationships of BP with
coffee and caffeine intake as genetic factors might modify
these relationships. Furthermore, genetic information can
help in exploring the causal effect of coffee and caffeine
intake on BP by using a Mendelian randomization ap-
proach in which genetic markers are used as instrumental
variables [55, 56]. By using this approach we provided
some evidence that caffeine mediates the effect of
CYP1A2 on BP and high BP [34••]. Care is needed,
however, when interpreting the results of a Mendelian
randomization when one does not explore the direct prod-
uct of a given gene, as several conditions are needed for
Curr Hypertens Rep (2014) 16:468
Mendelian randomization to provide causal inference in
observational epidemiology [57].
Issue 3: The Potential Modifying Effect of Smoking on Coffee
and Caffeine-Related Outcomes
Smoking is a well known inducer of CYP1A2 activity [58]
and quitting smoking decreases CYP1A2 activity. Dobrinas
et al. reported that after smoking cessation the individual
change in CYP1A2 activity ranged from a 1.0-fold (no
change) to 7.3-fold decrease in activity; smokers had 1.55-
fold higher CYP1A2 activity than nonsmokers [52]. This
suggests that not taking into account the induction effect of
smoking has on CYP1A2 activity could mask the influence of
caffeine on CYP1A2 activity, and therefore the influence of
caffeine on BP, if any. Failure to account for the modifying
effect of smoking may also explain why no clear association
of regular caffeine intake with the incidence of hypertension
has been found. In the Nurse’s Health Study that included
83,076 women followed-up for 24 years [59] the protective
effect of long-term coffee consumption on stroke was stronger
among non-smokers and past smokers (Relative risk [95 %
CI] for≥4 cups a day versus<1 cup a month=0.57 [0.39-
0.84]) compared to current smokers (Relative risk=0.97
[0.63-1.48]). The results of this latter study suggest that caf-
feine intake might protect against high BP-related CV out-
comes in the absence of smoking. Our recent observations
[34••] are in line with this observation. Using data from
observational studies including European adults we found that
only in non-smokers the CYP1A2 variants were associated
with higher reported caffeine intake, which in turn was asso-
ciated with lower odds of high BP. CYP1A2 variants were
associated with high BP in non-smokers, but not in smokers
(CYP1A2-smoking interaction, P value=0.01). We observed
no association between CYP1A2 genotypes and high BP
among smokers. Smoking blunted the association of caffeine
intake with hypertension and not considering smoking status
may therefore lead to misleading conclusions.
Issue 4: Challenge in Measuring Coffee and Caffeine Intakes
The fourth and last issue we will discuss is related to whether
coffee or caffeine per se is considered in relation to BP. As
mentioned previously, coffee is a mixture of thousands of
chemicals, several of which might influence BP. In addition,
these chemicals are affected by the brewing methods [60] and
the caffeine content of coffee is highly variable [61].
Reviewing the relationship of each potential chemical with
BP as well as the different effects of all brewing methods on
these relationships is beyond the scope of this report. It is,
however, very clear that the relationship of BP with coffee
intake and with caffeine or caffeinated-beverages should be
compared cautiously. Disentagling the effect of caffeine from
Page 5 of 9, 468
one of the other coffee components is very challenging in
observational studies that generally rely on self-reported in-
take information. One approach that overcomes this limitation
typically observed in non-experimental studies is to measure
caffeine and its main metabolites instead of (or in addition to)
using reported caffeine intake. The urinary excretion of caf-
feine is a valid measure of caffeine intake [62]. Caffeine and
metabolites can be measured by hyphenated methods such as
gas chromatography (GC), high performance liquid chroma-
tography (HPLC) or ultra-high performance liquid chroma-
tography (UPLC) coupled to mass spectrometry (MS) or
tandem mass spectrometry (MS/MS). While urinary collec-
tion and use of such determination methods is not easy in large
sample (i.e., several thousand subjects) we believe that it can
meaningfully contribute to further our understanding on the
relationship of BP with caffeine.
A Likely Mechanism by Which Caffeine Influences Blood
Pressure
There are several mechanisms by which coffee and caffeine
intake can influence BP. However, considering the state of the
research, including our own contribution, we will briefly
discuss a specific mechanism that involves caffeine, the
CYP1A2 gene and enzyme, urinary sodium (Na+) reabsorp-
tion mediated by the inhibition of the adenosine receptor
differentially in smokers and non-smokers. Figure 1 illustrates
this hypothetical mechanism.
Evidence 1: CYP1A2 Activity and Blood Pressure
The paraxanthine/caffeine ratio is a valid marker of
CYP1A2 activity when following a standard protocol
[63, 64] that is usually as follows: individuals are asked
to refrain from caffeine-containing beverages and foods
on the night before the day of the scheduled test. Blood
is generally collected 6 hours after the intake of a 200 mg
caffeine capsule. Before caffeine intake (hour 0) and
again before blood sampling (at 6 hours) compliance
regarding caffeine restriction should usually be assessed
by self-declaration. The paraxanthine and caffeine plasma
levels are then measured and the paraxanthine/caffeine
ratio calculated.
Using data from the GenSmoke study we found that higher
CYP1A2 activity was linearly associated with lower BP after
quitting smoking but not while smoking [34••]. Individuals
with high CYP1A2 activity are rapid caffeine metabolizers.
Caffeine and its metabolites have known diuretic and natri-
uretic effects [65, 66] and belong to the group of methylxan-
thines that are nonselective adenosine receptor antagonists [9].
Caffeine and its metabolites exert their natriuretic action via
the adenosine A1 receptors blockade [10, 67–70] leading to
decreased proximal tubular sodium reabsorption [10, 68, 70];
468, Page 6 of 9
Fig. 1 Hypothetical mechanism linking coffee and blood pressure
this might explain why high coffee consumption is associated
with lower BP.
Evidence 2: CYP1A2 Variants and Renal Segmental Tubular
Sodium Handling
As mentioned previously, the CYP1A2 gene has been
associated with BP but the mechanisms involved are still
unclear. We explored a possible action of a CYP1A2
variant on BP via renal sodium handling (unpublished
data). We used data on measured ambulatory BP monitor-
ing, 24-hour urinary creatinine clearance, 24 h fractional
excretion of endogenous lithium (FELi), and a CYP1A2
variant (rs762551) collected within the population-based
Hercules study [71]. Fractional proximal sodium (Na+)
reabsorption (RNaprox) was defined as (1-FELi). Three
hundred and four participants were included in the anal-
yses. Overall 24-hours RNaprox were similar among non-
smokers and smokers, respectively, 87.7 % and 87.3 %
(P=0.072). In non-smokers RNaprox was lower in subjects
with CYP1A2 AA or AC genotypes than CC genotypes
(86.7 [85.5-87.9] vs 90.7 [87.2-94.2], P value <0.05). In
Curr Hypertens Rep (2014) 16:468
smokers no such association was reported. In this small
sample CYP1A2 genotypes were not associated with am-
bulatory BP but smoking modified significantly the effect
of CYP1A2 on RNa prox and ambulatory diastolic BP
(both P values for interaction were <0.10). This finding
suggests that one of the mechanisms by which CYP1A2,
and thus CYP1A2 activity, could influence BP is via an
increased reabsorption of Na+ in the proximal segments of
the nephron. It also seems that this mechanism is modi-
fied by smoking.
We postulate that people with high CYP1A2 activity
(i.e., rapid caffeine metabolizers) have low BP because
they consume large amounts of caffeine and have in the
body large amounts of caffeine plus paraxanthine (the
caffeine metabolite produced in vivo by CYP1A2), both
being potent adenosine receptor antagonists with natri-
uretic and diuretic effects [72]. Adenosine is an adenine
nucleoside that is produced from the hydrolysis of ATP.
The paracrine actions of adenosine are mediated by re-
ceptors that activate second messenger systems resulting
in hemodynamic effects in the vascular beds of the kid-
ney, brain and heart. Four subtypes of adenosine receptors
have been identified: A1, A2a, A2b and A3. A1 and A3
were presented in [73]. In the kidney, adenosine receptors
A1 have been localized in the afferent arteriole, glomeru-
lus, proximal tubule and collecting ducts. Activation of
adenosine A1-receptors (A1-Rs) in the afferent arteriole
of the kidney results in vasoconstriction that reduces the
glomerular filtration rate and renal blood flow [73]. Infu-
sion of selective adenosine receptor A1 antagonists into
the renal vasculature causes diuresis and natriuresis,
which highlights the important role of adenosine A1 re-
ceptors in sodium and water reabsorption [10, 74]. Inter-
estingly, the adenosine receptor A1 is encoded by the
ADORA1 gene and recent studies have shown significant
effects of ADORA1 polymorphisms on left ventricular
function, left ventricular dimensions and myocardial in-
farct size [75]. These results suggest that genetic variants
in the adenosine receptor genes might influence an indi-
vidual's response to adenosine and adenosine antagonism.
Of note, Cornelis et al. reported in 2011 an association of
ADORA2a variants with caffeine intake [38•]. To explore
this hypothetical mechanism, further studies should ideal-
ly measure proximal tubular sodium reabsorption and
determine its role in the caffeine-BP relation while taking
into account the modification effect of genetic variants
and smoking.
While we suggest that the relationship of caffeine on BP
is mediated by renal segmental tubular Na+ handling we
acknowledge that other mechanisms including sympatho-
mimetic effects, smooth muscle relaxation, arterial stiff-
ness and phosphodiesterase inhibition may also mediate
this relationship [76–79].
Curr Hypertens Rep (2014) 16:468
Conclusions
The relation of BP with coffee and caffeine is of major interest
given their widespread consumption in foods and beverages
and the public health burden of high BP. In this report we
discussed four issues that future studies should ideally con-
sider when exploring the relationship of BP with coffee. While
waiting for new evidence it is worth noting that - outside the
specific case of BP measurements - there is no specific rec-
ommendation regarding coffee or caffeine intake in current
hypertension guidelines [2–5]. In our view, there is currently
no evidence to suggest that people with high BP should refrain
from consuming caffeinated beverages when taken in reason-
able amounts. On the contrary, coffee intake seems to be
associated with decreased mortality in general and
caffeinated-beverages seem to be associated with lower risk
of high BP in non-smokers. We proposed a hypothetical
mechanism linking coffee, caffeine, CYP1A2 enzyme activity
andrenal sodium reabsorption that could be modified by
CYP1A2 genotypes and smoking. This hypothesis is mostly
based on observational studies and should be tested
experimentally.
Acknowledgments This work was supported by the Swiss National
Science Foundation FN 33CM30-124087and FN 33CM30-140331.
Compliance with Ethics Guidelines
Conflict of Interest Idris Guessous has received a grant from the Swiss
National Science Foundation.
Chin B. Eap has received a grant from Roche Organ Transplantation
Research Foundation and Takeda and payment for development of edu-
cational presentations from Advisis, Astra Zeneca, Essex Chemie,
Lundbeck, Merck Sharp & Dohme, Sandoz, Servier, and Vifor-Pharma.
Murielle Bochud has received a grant from the Swiss National Science
Foundation.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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