Caffeine and cardiovascular diseases: Critical review of current research

Abstract

Caffeine is a most widely consumed physiological stimulant worldwide, which is consumed via natural sources, such as coffee and tea, and now marketed sources such as energy drinks and other dietary supplements. This wide use has led to concerns regarding the safety of caffeine and its proposed beneficial role in alertness, performance and energy expenditure and side effects in the cardiovascular system. The question remains “Which dose is safe?”, as the population does not appear to adhere to the strict guidelines listed on caffeine consumption. Studies in humans and animal models yield controversial results, which can be explained by population, type and dose of caffeine and low statistical power. This review will focus on comprehensive and critical review of the current literature and provide an avenue for further study.

Full text

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Eur J Nutr
DOI 10.1007/s00394-016-1179-z
REVIEW
Caffeine and cardiovascular diseases: critical review of current
research
Anthony Zulli1 · Renee M. Smith1 · Peter Kubatka2 · Jan Novak3,4 · Yoshio Uehara5 ·
Hayley Loftus1 · Tawar Qaradakhi1 · Miroslav Pohanka6 · Nazarii Kobyliak7 ·
Angela Zagatina8 · Jan Klimas9 · Alan Hayes1 · Giampiero La Rocca10,11 ·
Miroslav Soucek3 · Peter Kruzliak12
Received: 29 August 2015 / Accepted: 6 February 2016
© Springer-Verlag Berlin Heidelberg 2016
Keywords Cardiovascular diseases · Caffeine ·
Cardioprotective effects · Pathogenesis · Clinical studies ·
Experimental studies
Introduction
Cardiovascular disease (CVD) is an indiscriminate lead-
ing cause of death worldwide. Given the potential burden
on the health system, there has been much effort put into
uncovering methods of decreasing risk and improving dis-
ease management.
Caffeine is one of the most commonly consumed phar-
macologically active substances worldwide and is read-
ily available from several sources including coffee, tea
and soft drinks. For decades, the association between caf-
feine consumption and CVD has been widely researched
Abstract Caffeine is a most widely consumed physiolog-
ical stimulant worldwide, which is consumed via natural
sources, such as coffee and tea, and now marketed sources
such as energy drinks and other dietary supplements. This
wide use has led to concerns regarding the safety of caf-
feine and its proposed beneficial role in alertness, perfor-
mance and energy expenditure and side effects in the car-
diovascular system. The question remains “Which dose is
safe?”, as the population does not appear to adhere to the
strict guidelines listed on caffeine consumption. Studies
in humans and animal models yield controversial results,
which can be explained by population, type and dose of
caffeine and low statistical power. This review will focus
on comprehensive and critical review of the current litera-
ture and provide an avenue for further study.
* Peter Kruzliak
kruzliakpeter@gmail.com
1 Centre for Chronic Disease (CCD), College of Health
and Biomedicine, Victoria University, Melbourne, VIC,
Australia
2 Department of Medical Biology, Jessenius Faculty
of Medicine, Comenius University in Bratislava, Martin,
Slovakia
3 2nd Department of Internal Medicine, St. Anne’s University
Hospital and Masaryk University, Brno, Czech Republic
4 Department of Physiology, Masaryk University, Brno, Czech
Republic
5 Division of Clinical Nutrition, Faculty of Home Economics,
Kyoritsu Women’s University, Tokyo, Japan
6 Faculty of Military Health Sciences, University of Defence,
Hradec Kralove, Czech Republic
7 Bogomolets National Medical University, Kiev, Ukraine
8 Cardiology Center Medika, St. Petersburg, Russia
9 Department of Pharmacology and Toxicology, Faculty
of Pharmacy, Comenius University, Odborarov 10,
832 32 Bratislava, Slovak Republic
10 Human Anatomy Section, Department of Experimental
Biomedicine and Clinical Neurosciences, University
of Palermo, Palermo, Italy
11 Euro-Mediterranean Institute of Science and Technology
(IEMEST), Palermo, Italy
12 Laboratory of Structural Biology and Proteomics, Faculty
of Pharmacy, University of Veterinary and Pharmaceutical
Sciences, Palackeho tr 1/1946, Brno 612 42, Czech Republic

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with conflicting results. In older studies, habitual caffeine
intake has been frequently reported to be associated with an
increased risk of CVD; however, these results have not been
reproducible in more recent studies. In fact, the opposite
holds true for recent studies which tend to report a neutral or
inverse relationship between habitual caffeine consumption
and CVD morbidity and mortality. Caffeine and its role in
CVD are yet to be fully understood. Caffeine acts via 3 dis-
tinct pathways, but it is the inhibition of the adenosine recep-
tor that appears to be the most important for typical human
consumption and its perceived cardioprotective properties.
Although there has been some disagreement as to the
efficacy of the proposed caffeine protective effect, recent
animal studies generally suggest that it may be protective,
at least for certain CVD parameters. Animal studies which
confer a protective role for caffeine have shown attenuation
of endothelial dysfunction, hypertension, inflammation and
increased apoptosis.
This review summarizes the effects of caffeine on the
risk of cardiovascular diseases based on available preclini-
cal and clinical studies. However, in worldwide population,
caffeine is consumed within natural or marketed sources.
Natural sources of caffeine, e.g. coffee or tea, are defined
as plant functional foods rich on the mixture of phytochem-
icals with a plethora of biological activities on the cell. It
is important to mention that coffee is a complex beverage
containing >1000 compounds—except of caffeine it con-
tains myriad bioactive substances with either health-pro-
moting effects (e.g. chlorogenic acid, phenolic compounds
and derived antioxidants, melanoidins, trigonelline-derived
niacin) or potentially negative health effects (diterpene
alcohols, acrylamide, 5-hydroxymethylfurfural metabo-
lized into potentially harmful 5-sulfooxymethylfurfural)
[1]. The presence of these substances depends among oth-
ers on industrial processing (e.g. natural, blend, torrefacto,
soluble coffee) as well as culinary preparation of coffee
(boiled, filtered, presso, etc.).
Caffeine: physical, chemical properties
Caffeine (1,3,7-trimethylpurine-2,6-dione in chemical
words) is a purine alkaloid produced by Coffea plants, such
as Coffea arabica and Coffea canephora [2], and tea plants
such as Camellia sinensis [3]. Harvesting of tea originated
in the mid of 3rd millennium BC, and Coffea plants have
been cultivated since fifteenth century [4]. Physiologically,
caffeine is excitatory, and it is able to ameliorate transient
cognitive impairments and fatigue [5]. Currently, many
countries do not ban the sale of products with caffeine
and do not impose taxes on its sale (such as alcohol). This
makes caffeine cost-efficient and accessible for the broad
population.
Solvents including water and ethanol can be used to make
solutions of caffeine. However, caffeine is only moderately
soluble in water and ethanol at room temperature [6]. Thus,
heated water is to be used for coffee or tea preparation to max-
imize caffeine concentration. Caffeine is dissolvable in flu-
idic carbon dioxide, and this is utilized in industrial processes
when decaffeinated coffee or tea is manufactured [7, 8].
Caffeine is a purine alkaloid. The biologically active
purine alkaloids are members of the main caffeine biosyn-
thetic pathway and hence present in products which con-
tain caffeine. These include xanthosine, 7-methylxantho-
sine and theobromine [9]. Caffeine is metabolized by liver
microsomal cytochrome P450. Two of the cP450 isoen-
zymes, 1A2 and 2C9, are important to demethylate caffeine
giving rise to paraxanthine, theobromine and theophylline
[10, 11]. The metabolism of caffeine should be taken into
consideration when the effect of caffeine is evaluated, as
the overall impact on homoeostasis is the sum of caffeine,
paraxanthine, theobromine and theophylline. The demeth-
ylation to other purine alkaloids by P450s in the liver is
depicted in Fig. 1. Caffeine reaches peak concentration in
plasma after 30–120 min, and half-life of caffeine in blood
is 3–6 h [12]. Pharmacokinetics of caffeine can be altered
by physical condition, gender, consumption of other active
compounds, which could explain why the extended half-
life of caffeine is 2.5–10 h [13]. Thus, the half-life of caf-
feine should be taken into consideration whenever results
from caffeine relating clinical studies discussed.
The nervous system is sensitive to caffeine as caffeine
can interact with several regulatory pathways. The major
effect of caffeine is mediated via adenosine receptors.
Adenosine is a simple compound interacting with G-pro-
tein-coupled adenosine receptors having broad physiologi-
cal importance. Currently, types A1, A2A, A2B and A3 of the
receptors are known and caffeine is able to act as an antag-
onist which prevents adenosine stimulation of the receptors
[14, 15]. Stimulation of the receptors can initiate disparate
effects including bronchospasm, inhibition of neutrophils
degranulation, smooth muscle contraction, vasodilatation
and regulation of heart rate [16–18]. Caffeine can interfere
in these pathways. For example, tachycardia due to caffeine
agonism on receptor A1, mental excitation due to agonism
on A2A receptor, bronchodilatation due to A2B receptor ago-
nism, protection from neutrophil degranulation due to ago-
nism on A3 receptor can be observed (Fig. 2) [19–23].
Though antagonism of caffeine on adenosine receptors
is suggested to be the major effect in the body, caffeine can
mediate its effect via other pathways. Impact of caffeine on
homoeostasis by these other pathways is underestimated. As
caffeine is a reversible inhibitor of enzyme monoamine oxi-
dase, exposure to caffeine can cause higher accessibility of
dopamine, epinephrine, norepinephrine and serotonin [24,
25]. Apart from monoamine oxidase, acetylcholinesterase

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is also inhibited by caffeine; thus, high dose of caffeine can
cause increased accessibility of the neurotransmitter, acetyl-
choline [26, 27]. Involvement of caffeine in neurotransmission
is followed by targeting of some intracellular signalling path-
ways. Phosphodiesterase, poly(ADP-ribose)polymerase-1
and ryanodine receptors interact with caffeine. Caffeine is an
inhibitor of phosphodiesterase; hence, intracellular messen-
gers, cAMP and cGMP, have protracted signal in the presence
of caffeine [28, 29]. Inhibition of poly(ADP-ribose)polymer-
ase-1 provides link between caffeine and control of cell cycle
[30, 31] and thus could also be implicated in the pathogenesis
of atherosclerosis [32] and oncogenesis [33], yet these are not
well supported by clinical trials. Lastly, caffeine is an agonist
of ryanodine receptors serving as a Ca2+-specific channel
on sarcoplasmic reticulum [34–36]. Stimulation of ryano-
dine receptors is an essential step in muscle contraction and
thus has been used by sportsmen for increased performance,
although the benefits are probably overestimated [37, 38].
Effects of caffeine on heart and vessels: critical
review of results obtained from experimental
studies
Experimental studies using caffeine are focusing either
directly on the effects of caffeine on cells, heart and
Fig. 1 The demethylation of the caffeine to other purine alkaloids by
P450s in the liver
Fig. 2 Scheme on the caffeine
effects imposed by interaction
with different adenosine recep-
tors (A1, A2A, A2B, A3—differ-
ent adenosine receptors; Gi,
Gs—inhibitory or stimulatory
G-protein)

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vessels, or caffeine is used within these studies as a stimu-
lant to induce arrhythmias via ryanodine receptors and its
mutated forms [38]. By binding to ryanodine receptor, caf-
feine stimulates calcium fluxes that can result in arrhyth-
mias [e.g. in RyR2(R420W/R420W)] rats [38] which are
connected to the positive inotropic effect of caffeine [39,
40]; however, these effects can be observed only at high
caffeine concentrations that are usually not reached in clin-
ical studies or after drinking a moderate amount of coffee
[39, 40]. While past studies have focused mainly on direct
effects of caffeine on the cardiovascular system, studies
performed within the last few years are focusing on poten-
tial adverse effects of caffeine consumption in pregnancy
and on molecular mechanisms.
Cardiometabolic effects of caffeine
Using isolated vessels or cells (in vitro), usually vaso-
dilatory response is observed after caffeine application
[41–43], and results from our laboratory on phenylephrine
precontracted rabbit aortic rings confirm a vasodilatory role
for caffeine. At the doses used within experimental stud-
ies—that are much higher than doses used in human stud-
ies—caffeine seems to inhibit phosphodiesterase, which
further results in increase in cAMP and cGMP (that are
under normal circumstances both degraded by phosphodi-
esterase), both resulting in vasodilation. Another important
aspect of in vitro models is the fact that usage of isolated
cells or denervated organs prevents action of contraregu-
latory mechanisms, which may be partly responsible for
opposite results observed in human studies, i.e. in vasocon-
striction and increase in blood pressure.
Interestingly, caffeine was shown to diminish NOS
expression in rat myocardium [44] and increased mean
arterial pressure [44] as well as with increase in heart rate,
systolic and diastolic blood pressures [45]. As well, meta-
bolic effects of caffeine were described—increase in LDL
cholesterol and decrease in HDL cholesterol were observed
after caffeine ingestion [45], and in animal model of meta-
bolic syndrome, decrease in total body fat (with adequate
increase in plasma lipid concentrations) was observed
together with improvement of insulin tolerance and lipid
resistance [46]. These results may partly explain the
decreased prevalence of type 2 diabetes (T2DM) in indi-
viduals drinking coffee in epidemiological studies [47, 48].
Insulin resistance and caffeine in CVD
Defects in hepatic fructose metabolism in certain groups,
such as T2DM and the metabolic syndrome (MS), could
affect the physiological effect of caffeine. The high-fruc-
tose-fed animal model is well established to study meta-
bolic syndrome, insulin resistance and T2DM [49–51]. Yeh
et al. [51] showed that rats fed fructose (10 % of diet) sig-
nificantly increased BP, fasting serum glucose, insulin, IR
and plasma norepinephrine levels, while the HDL-C levels
decreased, compared to controls. Adding caffeine (equiva-
lent to 3–4 cups per day) to the fructose-fed group resulted
in a significant reduction of those parameters (compared to
fructose-only group) and was comparable to control. The
authors concluded that caffeine ameliorated a fructose-
induced defect in the insulin–PI3K–Akt signalling pathway
possibly via a reduction in superoxide production and also
an increase in NO production, which attenuated hyperten-
sion [51].
Interestingly, the autophagy–lysosomal pathway in
hepatic lipid metabolism has been described in a related
study [52]. Using both in vivo and in vitro techniques,
they found that caffeine-induced autophagy and lipoly-
sis was partly influenced by caffeine (moderate to heavy
intake; 2–3 cups of coffee per day). The authors suggest
that caffeine can inhibit the mammalian target of rapa-
mycin (mTOR), which is an important step for autophagy.
These are all potentially important, particularly for those
diagnosed with erratic liver fat oxidation, as reduced liver
lipid oxidation can lead to non-alcoholic fatty liver dis-
ease (NAFLD) which is a risk factor for T2DM [52, 53].
In another study looking at the effects of MS in male rats,
subjects were fed high fat and high carbohydrate plus caf-
feine [46]. The authors found that caffeine supplementation
reduced obesity, hypertension, heart remodelling, NAFLD
and improved metabolic markers such as insulin sensitiv-
ity but worsened dyslipidaemia. The authors also addressed
the role of A1 receptors, where caffeine acted as an antago-
nist, which increased lipolysis in abdominal adipocytes.
Interestingly, these results differ from Sacramento et al.
[54], who showed that agonism of A1 receptors in skeletal
muscle increases glucose uptake, but caffeine acted as an
antagonist to A1 which ultimately reduced insulin sensitiv-
ity. Thus, the caffeine/A1 receptor interaction requires fur-
ther research to understand its role in CVD.
Ischaemia, A2A adenosine receptor and caffeine
Ischaemic stroke is a leading cause of death worldwide,
and the risk is increased in those with impaired blood flow,
involving both an oxidative stress and inflammatory path-
way [55, 56]. Interestingly, Fronz et al. [55] report that
antagonism of the A2A receptor has potentially protective
properties if given immediately following ischaemia as
this receptor mediates NO release and vasodilation [57].
Caffeine is a non-selective adenosine receptor antago-
nist [58] resulting in different outcomes dependent on the
pathway inhibited. For example, Nishida et al. [59] used
caffeine to induce calcium (Ca2+) release from the myo-
cardial sarcoplasmic reticulum and found that this created

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an environment favourable to atrial fibrillation (AF) and
could be important to understanding AF pathophysiology
in coronary artery disease (CAD). Momoi et al. [57] also
assessed the role of caffeine in hypoxia. Levels of adeno-
sine could be protective as they showed that administration
of caffeine (10 mg/kg/dose) and hypoxia (100 % nitrogen
for 45 s) in pregnant mice resulted in negative effects on
foetal CV function and development, attributed to the inhi-
bition of the A2A adenosine receptor by caffeine. It should
be noted that foetal levels of adenosine are higher than in
adults; thus, they are probably required to protect the devel-
oping foetal organ system. Fronz et al. [55] also assessed
the role that caffeine might play in ischaemia, focusing on
cerebral artery occlusion. As they report, the A2A recep-
tor can be inhibited to reduce severity of stroke. They also
report, however, that the underlying mechanism is yet to be
fully elucidated, although an inflammatory link has been
proposed. Despite other laboratories providing evidence
that antagonism of the A2A receptor is neuroprotective, the
authors were unable to treat acute ischaemia in spontane-
ously hypertensive rats, possibly due to metabolism of the
compound. However, as Sun et al. [56] report, there is also
a suggestion that targeting inflammatory processes may be
a better option, as cerebral ischaemia–reperfusion injury
is accompanied by a changed local inflammatory environ-
ment. Using a tea compound, theanine, that has reactive
oxygen species (ROS)-scavenging properties, the authors
were able to reduce both infarct size and water content in
rats with a combined treatment of theanine and caffeine
(1 mg/kg body mass and 10 mg/kg, respectively), but not
caffeine alone, suggesting a role for ROS. Similarly, a
study assessing the combination of caffeine and ethanol
(caffeinol; caffeine 10 mg/kg + ethanol 0.32 g/kg) found
that the combination of the drugs, but not either drug on its
own, was able to ameliorate the effects of damage induced
by ischaemia via the N-methyl-d-aspartate (NMDA) recep-
tor in male rats [60].
Caffeine in foetal programming
Interesting studies using caffeine suggest that its use dur-
ing pregnancy results in adverse cardiac remodelling and
aberrant vessel formation. In pregnant dams treated chroni-
cally with caffeine, aberrant activation of local renin–angi-
otensin–aldosterone system was observed both in kidneys
and in hearts of the offspring rats. This was connected to
adverse cardiac remodelling (e.g. increased left ventricu-
lar wall thickness) and increase in blood pressure, which
further resulted in increased energy expenditure and heart
rate and reduction in body mass gain [61] and in decrease
in cardiac output [62]. Usage of caffeine also resulted in
intrauterine growth restriction, probably due to adenosine
2A receptor-mediated vasoconstriction and concomitant
flow reduction in umbilical arteries [63]. Generally, adeno-
sine 2A receptor seems to be more involved in foetal pro-
gramming compared to adenosine 1 receptor (A1R). Caf-
feine can affect A2A receptor at lower doses compared to
A1 receptor [64], and expression of A2A receptor was also
shown to be altered in maternal hearts exposed to caffeine
[65]. On the other hand, involvement of A1R in the hypoxic
response of neonatal myocardium was also shown [66].
Moreover, caffeine also inhibits angiogenesis, as shown
in mice [61] or zebrafish [67, 68]. Zebrafish is an accepted
model to study angiogenesis and treatment of zebrafish
embryos with caffeine resulted in defects in new vessels
formation [68] that are probably caused by decrease in
VEGF expression [67].
Molecular mechanisms leading to above-described
effects seem to be connected with DNA methylation [62]
or oxidative stress [69]. In ApoE−/− mice, caffeine use
was shown to inhibit DNA damage [70] and it was shown
to inhibit formation or reactive oxygen species, partly by
restoring cytochrome oxidase activity in the animal model
of sepsis [71]. Recently, Fang et al. [72] showed that caf-
feine treatment affects expression of crucial cardiac genes
(e.g. myosin heavy chains or cardiac troponins) and it gen-
erally causes decrease in DNA methylation.
Effects of caffeine on heart and vessels: critical
review of results obtained from clinical studies
Cardiovascular effects of caffeine in studies involving
human subjects are generally mediated via its antagonism
of adenosine receptors, since binding to other receptors
occurs only at much higher doses than those reached after
drinking a moderate amount of coffee or tea [73]. Adeno-
sine receptors are distributed thorough the body, and caf-
feine thus has potential to directly affect the myocardium
(where it affects contractility and conduction), the vessel
wall (where it affects vascular tone) and also the auto-
nomic nervous system [73]. As results from human studies
are often different from the results obtained in preclinical
studies, this could be explained by other regulatory mecha-
nisms which are initiated after caffeine ingestion (involv-
ing, e.g. baroreflex, renin–angiotensin–aldosterone system
and others).
Caffeine, blood pressure and vessel wall
Caffeine ingestion in the form of caffeine pills, coffee,
tea or various energy drinks usually leads to increase in
blood pressure in human subjects [74–78]. This is a result
of increase in total peripheral resistance [40, 79], which
occurs without any concomitant increase in stroke vol-
ume or cardiac output, although heart rate is reported to

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decrease, probably due to feedback mechanisms [40, 79].
Direct vasoconstriction of several intracranial arteries, e.g.
ophthalmic, central retinal and short nasal ciliary artery
[80, 81], was also described, which seems to be connected
with decreased cerebral blood flow and increased intracer-
ebral pressure [82].
Except of direct or indirect effects on vasoconstriction or
vasodilation, caffeine also affects endothelial function and
arterial stiffness. Endothelial function can be assessed either
by using flow-mediated dilation of brachial artery, which is
a parameter reflecting endothelial function and its values
also correlate with the number of cardiovascular events [83,
84], or by assessing post-occlusive reactive hyperaemia in
finger arteries [74]. Acute caffeine, but not nitroglycerine,
application in both healthy volunteers and patients with
coronary artery disease resulted in significant increase in
flow-mediated dilation and decrease in hs-CRP level, sug-
gesting positive effects of caffeine on endothelial function
and inflammation [83]. This result was not observed in
healthy subjects after coffee ingestion—flow-mediated dila-
tion was decreased in these individuals, and this decrease
was the most prominent within the first hour after coffee
ingestion [85]. Differences between these two studies may
be explained by different caffeine dosages (caffeine pills vs.
coffee drinking) and by differences between study groups
(the latter study involving regular non-heavy coffee drinkers
and the first study restricting individuals from any caffeine
intake prior study). Studying reactive hyperaemia of finger
arteries, Noguchi et al. [74] showed that caffeine ingestion
increased microvascular endothelial function. Whether the
impact of caffeine on endothelial function is positive or neg-
ative still needs to be determined by larger studies.
Arterial stiffness, another parameter reflecting cardio-
vascular system function, was also shown to be affected by
caffeine both positively and negatively. Arterial stiffness
may be assessed by various methods, using renal resistive
index (RRI) or pulse wave velocity (PWV). Coffee drink-
ing was shown to increase both pulse wave velocity [86,
87] and augmentation index [86, 88, 89], parameter reflect-
ing increase in pulse wave reflections. On the other hand,
RRI was shown to be inversely correlated with caffeine
intake, which suggests protective effect of coffee drink-
ing—higher RRI associates, e.g. with insulin resistance or
presence of renal insufficiency [90].
Also, studies were performed on preterm infants, where
caffeine application was associated with improved hemo-
dynamics [91] and increased cerebral cortical activity and
resulted in shorter stay at ICU [92]. This was accompa-
nied by increase in heart rate, mean arterial blood pressure
and oxygen saturation [92]. On the other hand, study by
Ulanovsky et al. [93] did not observe these effects. Thus,
caffeine use in this specific group of patients needs to be
validated to reveal whether its use is beneficial.
Caffeine and autonomic nervous system function
Autonomic nervous system function may be assessed using
various methods, mostly using either variability of blood
pressure, baroreflex sensitivity or heart rate variability
(HRV) [94, 95]. Already in 1990, it was shown that caffeine
decreases baroreflex sensitivity [96], which may partly
blunt cardiovascular response to caffeine administration.
Later studies then repeatedly showed that caffeine intake
increases high-frequency part of the HRV spectra that is
known to be connected with parasympathetic (or vagal)
activity [95, 97]; however, similar effect was observed after
ingestion of decaffeinated coffee or hot water. Although the
effects of caffeine on parasympathetic system activation
are present in young healthy individuals, its effects were
not shown in patients with heart failure, where diminished
HRV predicts poor prognosis [98].
Caffeine and sports performance
Numerous studies have emerged during the past few years
focusing on the potential ergogenic effect of caffeine. Most
are small in size enrolling from 6 to 20 individuals per-
forming various sporting activities, which could explain the
variability of results.
Considering the short-term performance activities, in
young adults during exercise (n = 14) [99], in soccer play-
ers during regular match [37, 100] or in judo fitness test
(n = 6) [101], caffeine did not increase their physical abil-
ity. Its usage was connected to reduction in perceived exer-
tion, reduced perception of muscle pain and with increase
in plasma lactate [101, 102]. It was also shown that inges-
tion of caffeine prior to exercise may result in increase
in post-exercise energy expenditure in young athletes
(n = 12) [103], which may be connected to increase in
post-exercise systolic blood pressure, preventing patients
from the development of post-exercise hypotension [77].
On the other hand, in the post-exercise period also blunted
autonomic system function recovery was observed—after
maximal treadmill test, heart rate, mean arterial pressure
and diastolic blood pressure remained elevated in individu-
als that received caffeine prior to exercise, which is known
to be connected to the development of various arrhythmias
[104].
Concerning endurance performance, caffeine chew-
ing gum was shown to improve mean and sprint perfor-
mance power in the cyclist in the last third of the 30-km
trail (n = 20) [105]; similarly, caffeine increased power and
speed only during the last 2 km of the 20-km trial [106]. In
2-km rowing competition, caffeine also showed beneficial
effects on rowing time (n = 13) [107], and in 8-km cross-
country skiing, caffeine also enhanced endurance perfor-
mance [108].

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In summary, caffeine does not seem to increase sig-
nificantly the power or strength of sportsmen; however,
it affects endurance, either by increasing the resistance to
fatigue or by increasing the activity of the nervous system.
Considering described effects of caffeine in post-exercise
period, drinking caffeine prior to sporting activities should
be carefully considered taking in mind all advantages and
disadvantages and individual characteristics of the person.
Caffeine and risk of cardiometabolic diseases
A wide variety of studies, both large and small, have been
carried out on both healthy participants and patients who
already suffer from cardiovascular affliction (cardiovascu-
lar disease, hypertension, stroke) or one of its risk factors.
Overall, there is no evidence to suggest a negative effect
of moderate coffee/caffeine consumption on cardiovascular
health [109–111]. Previously, coffee intake was considered
a traditional risk factor for cardiovascular diseases. How-
ever, results from large epidemiological studies do not seem
to support this idea and it even appears that coffee drinking
may exert protective effect against some CV diseases. Cof-
fee drinking was associated with lower prevalence of sub-
clinical atherosclerosis (determined by CT coronary artery
calcium) [112], and there was no association between cof-
fee intake and markers of coronary or carotid atherosclero-
sis [113]. Coffee consumption neither associated with the
long-term risk of coronary heart disease development [114]
nor associated with stroke [115]. It thus seems that caffeine
intake does not promote atherosclerosis process and its use
even associates with lower cardiovascular mortality [116,
117].
The connection between caffeine and atrial fibrilla-
tion (AF) was also unconfirmed, and low doses of caffeine
were shown to have protective effects against atrial fibril-
lation development [118, 119]. Moreover, Cheng et al.
[120] conducted a meta-analysis to investigate the associa-
tion between chronic exposure of caffeine and the risk of
AF and to evaluate the potential dose–response relation.
They concluded that it is unlikely that caffeine consump-
tion causes or contributes to AF. Habitual caffeine con-
sumption might reduce AF risk. In another study, Larsson
et al. [121] investigated the association between coffee con-
sumption and incidence of AF in two prospective cohorts
and summarized available evidence using a meta-analysis.
They found no evidence that coffee consumption is associ-
ated with increased risk of AF. In a large population-based
cohort study (the Danish Diet, Cancer and Health Study),
higher levels of coffee consumption were associated with
a lower rate of incident AF [122]. If caffeine was applied
to patients prior to supraventricular tachyarrhythmias abla-
tion, no effects on cardiac conduction or refractoriness
were observed [75]. It thus seems that there is no need to
abstain patients with atrial fibrillation and even those after
myocardial infarction from drinking coffee [123].
The relationship between caffeine consumption and the
occurrence of arrhythmias remains controversial. Despite
the lack of scientific evidence, counselling to reduce caf-
feine consumption is still widely advised in clinical prac-
tice. Zuchinali et al. [124] conducted a systematical review
and meta-analysis of interventional studies of the coffee
and caffeine effects on ventricular arrhythmias. Their meta-
analysis demonstrates that data from human interventional
studies do not show a significant effect of coffee and caf-
feine consumption on the occurrence of ventricular prema-
ture beats. The harmful effects of caffeine on arrhythmias
observed in animal studies are most probably the result of
very high caffeine doses that are not regularly consumed in
a daily basis by humans.
Ding et al. [110] examined the associations of consump-
tion of total, caffeinated and decaffeinated coffee with risk
of subsequent total and cause-specific mortality among
74,890 women in the Nurses’ Health Study, 93,054 women
in the Nurses’ Health Study II and 40,557 men in the Health
Professionals Follow-up Study. Significant inverse associa-
tions were observed for decaffeinated coffee. Significant
inverse associations were observed between coffee con-
sumption and deaths attributed to cardiovascular disease,
neurologic diseases and suicide. No significant association
between coffee consumption and total cancer mortality was
found. A growing body of data suggests that habitual coffee
consumption is neutral to beneficial regarding the risks of a
variety of adverse CV outcomes including coronary heart
disease, congestive heart failure, arrhythmias and stroke.
Moreover, large epidemiological studies suggest that regu-
lar coffee drinkers have reduced risks of mortality, both CV
and all-cause [48, 125, 126].
In case of heart failure, association of caffeine intake
seems to be dose-dependent and it represents with J-shape
curve so only where high doses of coffee seems to increase
the risk of congestive heart failure development [47, 127].
In metabolic diseases, coffee intake was associated
with lower risk of obesity and T2DM [48, 127]. In a Bra-
zil study, daily drinking two to three cups of coffee were
inversely associated with metabolic syndrome in both
patients and healthy subjects [128]. The association
between coffee consumption, T2DM and impaired glu-
cose tolerance was examined in Swedish study [129]. In
subjects with T2DM and impaired glucose tolerance, high
coffee consumption (greater than or equal to 5 cups per
day) was inversely associated with insulin resistance. In
addition, in those with T2DM and in women (not in men)
with impaired glucose tolerance, high coffee consumption
was inversely associated with low beta-cell function. In
women, but not obviously in men, with normal glucose tol-
erance, coffee consumption was associated with a reduced

Eur J Nutr
1 3
risk of insulin resistance. The long-term use of coffee/caf-
feine was shown to decrease HbA1c and to increase levels
of adiponectin both in healthy individuals and in patients
with T2DM [130], and in patients with T2DM, it was also
shown to promote reduction in blood sugar levels during
exercise [131]. On the other hand, it negatively affects lipid
profiles if coffee is boiled or unfiltered [48]. Coffee intake
even seems to modestly participate on weight loss [132,
133].
Adverse effects of caffeine in overdosed individuals
The effects of “safe” caffeine doses reached either by caf-
feine pills or by coffee ingestion have been described.
However, as shown in experimental studies, higher doses
of caffeine activate or inhibit other signalling pathway
and since coffee is one of the most commonly used drugs,
effects of its overdosing have already been described in
various case reports.
Although usual intake of caffeine in coffee bever-
age is not associated with arrhythmias and atrial fibrilla-
tion, overdosing with caffeine may induce atrial fibrilla-
tion [134, 135] or other supraventricular tachyarrhythmias
[136]. In one case report, 27-year-old woman in an suicidal
attempt used 50 g of caffeine powder which resulted ini-
tially in simplex supraventricular tachycardia followed
by broad complex tachycardia and ventricular fibrillation
[137]. Higher doses of caffeine moreover seem to decrease
potassium levels, which is known to be proarrhythmogenic
[138]. This seems to be result of skeletal-muscle Na/K-
pump stimulation [139]. This may also be an underlying
mechanism for unmasking the congenital type 1 long QT
syndrome, as described in patients after usage of energy
drink with high caffeine content [140].
Toxic doses of caffeine thus seem to affect conductance
and refractoriness on the heart, which results in the devel-
opment of various arrhythmias. Moderate and rational cof-
fee intake thus should be recommended to all patients in
order to avoid these adverse effects.
Future perspectives and challenges
Studies in humans hold conflicting results due to the vari-
ability of population, dose and techniques, yet solid results
from animal studies studying the safe and toxic cardiovas-
cular effects of caffeine/coffee have not yet been reported.
As noted, there have been inconsistent reports regarding
the efficaciousness of caffeine as a protective agent. In a
study assessing the intake of green tea and the develop-
ment of atherosclerotic lesions, Cai et al. [141] suggests
that an active catechin, epigallocatechin-3-gallate (EGCG)
reduces markers associated with atherosclerosis in mice,
thus making it unlikely that caffeine in green tea is pro-
tective. In addition to this, Loopstra-Masters et al. [50]
reported that decaffeinated coffee was also significantly
associated with improved insulin biomarkers in non-dia-
betics, further supporting the important role that those
other compounds probably play in the protection against
CVD. Also, coffee fatty acids have been isolated and range
between 14 and 22 carbon chains [142], further complicat-
ing the identification of possible single beneficial factors.
It is therefore essential to make the appropriate distinc-
tions between the supposed protective effect of caffeine
and any other compounds that may be present and not
draw conclusions from one to the other. It will be a dif-
ficult and costly task to undertake a clinical study to deter-
mine which compounds of coffee are beneficial or detri-
mental to human health. Thus, further studies in animal
models are warranted to determine which factor and dose
are safe to prevent and protect against CVD, including ath-
erosclerosis and myocardial function. Regarding the effect
of industrial processing on the content of plethora biologi-
cally active chemicals in natural sources of caffeine (e.g.
coffee, tea) and thus their effect on CVD risk, available
clinical data are insufficient for relevant conclusions. As
for the culinary preparation, boiled and unfiltered coffee
appears to increase plasma cholesterol and triglycerides,
but for the overall metabolic syndrome, there appears to
be benefiting [143]. It seems that caffeine/coffee is neutral
in relation to atrial fibrillation and ventricular arrhythmias;
moreover, several large epidemiological studies demon-
strated that regular coffee drinkers have reduced risks of
mortality, both CV and all-cause.
Compliance with ethical standards
Conflict of interest Authors declare no conflict of interest.
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