Effects of Aspirin on Endothelial Function and Hypertension
Curr Hypertens Rep
Effects of Aspirin on Endothelial Function and Hypertension
Mikhail S. Dzeshka 0 1 2
Alena Shantsila 0 1 2
Gregory Y. H. Lip 0 1 2
0 Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University , Aalborg , Denmark
1 Grodno State Medical University , Grodno , Belarus
2 University of Birmingham Institute of Cardiovascular Sciences, City Hospital , Dudley Road, Birmingham B18 7QH , UK
Purpose of review Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. Recent findings Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. Summary Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations.
Aspirin; Endothelial function; Arterial hypertension; Cyclooxygenase; Platelets; Inflammation
Published online: 27 October 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
Endothelium is of paramount importance for maintaining
homeostasis of cardiovascular system [
]. Healthy endothelium,
both in vasculature and heart chambers, is continuously
releasing plethora of bioactive substances. Acting in autocrine,
paracrine and systemic fashion and participating in regulation
of smooth muscle contractions, vascular wall permeability,
platelet aggregation, activation of coagulation and fibrinolytic
activity, cellular proliferation, as well as in prevention of
inflammatory cells adhesion and vascular inflammation.
Imbalance between any of above functions is broadly defined
as endothelial dysfunction. To the different extent, most
cardiovascular diseases are classically attributed to endothelial
dysfunction (from atherosclerotic heart disease to rhythm
disturbances, e.g. atrial fibrillation) [
Given that endothelium takes part in regulation of vascular
tone, arterial hypertension and endothelial function are
reciprocally and intimately associated with each other. However,
this association is far beyond simple imbalance between
vasodilator and vasoconstrictor release in favour of the latter.
Multiple mechanisms are involved in regulation of blood
pressure, including the endothelium, kidneys and central
Of note, the endothelium does not only provide short-term
effects on vascular tone. Endothelial dysfunction also has
chronic long-term consequences, which, in indirect way,
eventually have major impact on vascular remodelling and
blood pressure regulation. Oxidative stress, i.e. production of
free radicals outweighing their scavenging, is one of the
systemic pathological processes, related to endothelium.
Inflammation in the vascular wall is another example,
synthesis of pro-inflammatory cytokines and recruitment of
inflammatory cells, with hypertension being considered even as
inflammatory disease now [
Endothelial function has been extensively used as putative
target for pharmacological correction with drugs inhibiting
renin-angiotensin-aldosterone system, statins, antioxidants
and so on, but less attention was paid to vascular effects of
aspirin (i.e. acetylsalicylic acid) given its primary
antiaggregatory mechanism of action. However, with the
emerging evidence on role of platelets in inflammatory reactions and
immunomodulation, platelet inhibition with aspirin has been
found to also elicit also anti-inflammatory effects [
7, 8, 9 , 10
Moreover, aspirin was found to work as acetylating agent with
a range of beneficial effects on vascular endothelium beyond
With regard to the possible effects of aspirin on blood
pressure and management of arterial hypertension, these will be
discussed in this review article.
Brief Overview of Aspirin Pharmacology: Inhibition
Aspirin has been used for years as analgesic, antipyretic and
anti-inflammatory drug due to non-selective cyclooxygenase
(COX)-1 and COX-2 inhibition (historically at high doses).
Later, the major indication for aspirin shift to prevention of
thrombotic cardiovascular complications as anti-platelet drug
via predominant COX-1 inhibition within platelets,
achievable at low doses.
Cyclooxygenases are present in the endothelial cells and
tissues in two isoforms: COX-1 is considered to be a
constitutively expressed enzyme, assuring physiological functions
while COX-2 isoform is thought to carry potential for
inducibility, but it is expressed constitutively at lower levels too.
Cyclooxygenases are also defined as prostaglandin
endoperoxide synthases or prostaglandin (Pg) G/H synthases since
first PgG2 is synthesised from the arachidonic acid by
incorporation of oxygen molecules, then PgH2 is formed by
reduction of PgG2. PgH2 is a substrate for enzymes, which via
isomerisation, reduction or other transformations produce
range of prostanoids. For example, thromboxane A2 (TxA2)
is synthesised by TxA2 synthase (TXAS) and prostacyclin
(PgI2) is synthesised by prostacyclin synthase (PGIS) [
These inhibitory effects of aspirin are determined by
presence of acetyl group that leads to acetylation of serine
hydroxyl group at position 529 in COX-1 with eventual irreversible
inhibition of the enzyme activity due to its inability to bind to
substrate, arachidonic acid. Inhibition of platelet-dependent
synthesis of TxA2 is accompanied by diminished release of
platelets granules, numerous chemokines, growth factors and
coagulation factors (Fig. 1) [
Many other ‘pleiotropic’ favourable effects of aspirin,
which are not directly related to inhibition of TxA2 synthesis,
are attributed to acetylation of target proteins. Their total
number is far beyond half a thousand molecular targets, including
transcription factors, enzymes, genes, metabolites and so on
12, 13 , 14
The maximal plasma concentration of aspirin reaches
1 mg/L within half an hour for aspirin 100 mg taken orally
and 3 mg/L for aspirin 300 mg taken orally. These doses do
not inhibition of COX-2 with COX-1 inhibition being the net
pharmacological effect [
]. Because of irreversible action
of aspirin (i.e. acetylation), duration of its effects is determined
by target protein resynthesis, that in case of mature platelets
lacking nuclei is equal to their lifetime (approximately
1 week). New platelets are needed in circulation to recover
TxA2 synthesis. The endothelial effects of aspirin are more
short lived as only few hours are required for endothelial cells
to restore their capacity for COX-1 regeneration .
Thromboxane A2 and Prostacyclin in Platelets
Thromboxane A2 is synthesised via common pathway with
other prostanoids and is largely deposited in platelets,
although the non-platelet sources (e.g. leukocytes, endothelial
cells) exist (Fig. 1). Effects of TxA2 are mainly local and
realised in autocrine (i.e. platelet activation) and paracrine
(e.g. on endothelial cells, leukocytes and so on) manner rather
than systemic [
8, 10, 11, 16, 17
]. Multiple biological effects of
TxA2 are due to binding of TxA2 prostanoid (TP) receptors,
which are widely expressed in human body, including
platelets, endothelium and smooth muscle cells in vasculature and
]. Genetic polymorphism of TP receptors
may result in their hypo- or hyperreactivity [
of TP receptors on the cellular surface is enhanced in various
cardiovascular diseases. For example, in vessels affected by
atherosclerosis, there is a 3-fold increase of TP receptors
density observed [
Activation of TP receptors on platelets leads to platelet
activation and further amplification of TxA2 synthesis and
release. Moreover, platelets α-granule content is released to
the blood flow that is represented by a multitude of
biologically active molecules including coagulation,
proinflammatory and growth factors, adhesive receptors and so on (Fig. 1).
Following their release, these factors induce leukocytes
recruitment, formation of heterotypic aggregates
(platelets–leukocytes), promote inflammation, oxidative stress and
remodelling of the vascular wall [
7, 9 , 20–22
Oxidative stress is prominent in cardiovascular diseases
including hypertension, and it typically leads to reduced NO
bioavailability and NO-dependent relaxation (Fig. 1) [
Oxidative stress stimulates TxA2 pathway by TXAS
upregulation and reduced degradation of the immature form of TP
Pselectin, integrins (αIIb,
α6, β3), fibrinogen, vWf,
FV, XI, XIII, GPVI,
CXCL1, 4, 5, 7, 8, 12,
VEGF, PDGF, FGF,
EGF, IGF, MMP-1, 2, 9,
TIMP-1, 4, TGF-β1
receptors, thus stabilising them; vice versa, continuous
signalling via TP receptors leads to downstream generation of more
reactive oxygen species (ROS) [
]. Angiotensin II, the
major effector of the renin-angiotensin system not only
promotes hypertension, myocardial and vascular remodelling, but
it also contributes to activation of TxA2 synthesis and
increased expression of TP receptors either directly or through
nicotinamide adenine dinucleotide phosphate oxidase (NOX)
Endothelial nitric oxide synthase (eNOS) uncoupling (via
oxidation of eNOS cofactor tetrahydrobiopterin) and
diminished NO bioavailability are other well-recognised
consequences of oxidative stress in endothelium (Fig. 1).
Essentially, these processes lead to reduction of its
vasodilation, anti-aggregatory and anti-inflammatory effects and
monocyte chemoattractant protein 1; MIP-1α, macrophage inflammatory
protein 1α; MMP-1, 2, 9, matrix metalloproteinase 1, 2 and 9,
respectively; mRNA, matrix ribonucleic acid; NO, nitric oxide; NOX, nicotinamide
adenine dinucleotide phosphate-oxidase; PDGF, platelet-derived growth
factor; PgG2/H2, prostaglandin G2/H2; PgI2, prostacyclin; PGIS,
prostacyclin synthase; PSGL-1, P-selectin glycoprotein ligand 1;
RANTES, regulated on activation, normal T Cell expressed and secreted;
S1P, phingosine-1-phosphate; S1P2, S1P receptor 2; sGC, soluble
guanylate cyclase; SMC, smooth muscle cell; TGF-β1, transforming
growth factor beta 1; TIMP-1, 4, tissue inhibitor of MMP 1 and 4,
respectively; TNF-α, tumour necrosis factor α; TP, thromboxane
prostanoid receptor; TSP-1, thrombospondin 1; TxA2, thromboxane A2;
TXAS, thromboxane A2 synthase; VEGF, vascular endothelial growth
factor; vWF, von Willebrand factor
exaggeration of above described changes [
]. Instead of
counterbalancing of vasoconstriction, platelet activation and
other pathological effects of TxA2, NO when exposed to ROS,
results in peroxynitrite formation. This was found to
upregulate TxA2 synthesis and nitration of PGIS and promote platelet
]. Platelet activation is also associated with a
release of thrombospondin-1 from α-granules that was shown
to diminish NO-dependent vasodilation in arteries via
induction of ROS .
Thromboxane A2-triggered NOX also upregulates
phosphodiesterase type 4, which leads to hydrolysis of a
downstream mediator of prostacyclin, cyclic adenosine
monophosphate (cAMP), reducing its favourable
vasoprotective and vasodilatory effects [
]. At a background of
oxidative stress 8-isoprostane (PgF2α) is synthesised in
increased amount and may serve as TP receptor ligand,
causing similar to TxA2 downstream effects [
blockade of NOX, on the contrary, is associated with decrease in
TxA2, and it improves vasodilatory response in arteries [
Apart from ROS-mediated decrease in NO, stimulation of
TP receptors also inhibits endothelial NO production via
direct suppression of eNOS phosphorylation [
relationship appears to be reciprocal, as inhibition of NO production,
e.g. with L-NAME (NG-methyl-L-arginine acetate ester),
activates aggregation of platelets [
]. Consequently, NO within
platelets is involved in regulation of platelet activation and
aggregation (Fig. 1). The mechanisms involved are not
entirely clear, and they are at least partly mediated by a
NOdependent release of calcium from the platelet dense granules.
Reduction in NO levels causes accumulation of calcium in
platelets cytoplasm. This triggers TxA2 synthesis from the
arachidonic acid located within the platelet membrane
phospholipids. Interestingly, Banerjee et al. showed that decreased
NO synthesis in platelets was a convergent point in platelet
activation pathway irrespectively of an activating agent via
various platelet receptors (i.e. adenosine diphosphate,
collagen, thrombin or epinephrine) [
Endothelium-dependent hyperpolarisation, another
important mechanism of vasodilation and regulation of the blood
flow, is also interfered with TxA2 due to its involvement in
modulation of Ca2+-activated potassium channels [
Moreover, it impairs signal propagation through gap junctions
within endothelial layer and smooth muscle cells that affects
endothelium dependent hyperpolarisation and vasodilation
(Fig. 1) [
In line with NO-dependent mechanisms and
endotheliumdependent hyperpolarisation, prostacyclin counteracts the
vasocontracting factors, like as TxA2 and other prostanoids,
endothelin I, angiotensin II, etc. Prostacyclin can be
synthesised both in endothelial cells and vascular smooth muscle
cells, and it is the most abundant prostaglandin among other
prostanoids. Similarly to TxA2, prostacyclin works locally,
and then metabolised to 6-keto-PgF1α. Prostacyclin effects
are realised via prostacyclin receptors (IP), which are also
have widely distributed in tissues (Fig. 1) [
11, 40, 41
There are also two competing points of view whether
COX-1 or COX-2 is the main isotype contributing to
prostacyclin synthesis [
11, 40, 42, 43
]. This question has been
extensively discussed, since a decrease in prostacyclin levels has
long been considered as the main cause of adverse
cardiovascular events associated with COX-2 selective inhibitors .
Indeed, selective COX-2 depletion in vascular smooth muscle
cells and endothelial cell in mice decreased prostacyclin
levels, which was associated with blood pressure elevation
and accelerated atherogenesis [
]. However, recent data
favour COX-1, as the source of prostacyclin synthesis in
vasculature both under basal conditions and stimulation with
shear stress or pharmacologically [
43, 46, 47
These data may provide some insights into the mechanisms
of hypertension. Simplistically, hypertension occurs when
endothelium-dependent vasoconstriction outweighs
vasorelaxation, due to either decreased production of
endotheliumderived relaxing factors or increased production of
endothelium-derived contractile factors, or both [
Obviously, pathogenesis of hypertension is complex and this
is only one of the multiple pathways involved.
Interplay between mediators, receptors and cellular
environment is also complex. This can be illustrated by the
prostacyclin effects on vasculature. COX-1 is likely to be the main
source of prostacyclin synthesis; however, COX-2 is likely to
input towards the prostacyclin pool, particularly in various
conditions known to be associated with endothelial
dysfunction, e.g. arterial hypertension, atherosclerosis, diabetes
mellitus and aging [
43, 48, 49
]. Also patterns of enzymes
and receptors expression may vary, depending on setting.
In terms of signalling via TxA2 receptors and intermediate
metabolite in prostanoi synthesis, PgH2 were considered as
major drivers of endothelium-dependent contraction, while
NO and prostacyclin as potent relaxing factors. However,
prostacyclin was yielded to serve as a contracting agent as
well, when binding to TP receptors rather than to IP receptors
(Fig. 1) [
]. This appears to happen when IP receptors are
getting dysfunctional, e.g. in cardiovascular diseases
associated with endothelial dysfunction. Compensatory increase in
prostacyclin synthesis in these settings (previously considered
as protective mechanism)  results in more prostacyclin
bound to TP receptors [
]. For example, Liu et al.
observed contraction of mice aorta, the effect that was eliminated
either at a receptor level (via inhibition of TP receptors) or by
reduction of prostacyclin synthesis via COX-1 knockout at a
background of low TxA2 synthesised .
Reduced NO release further exaggerates the imbalance
]. Under physiological conditions, when sufficient NO is
available, prostacyclin produces IP receptors-mediated
vasodilation. In contrast, when NO availability is low, signalling
via TP receptors is triggered by prostacyclin [
40, 41, 43
Given that expression of eNOS in hypertension in
endothelium is reduced, prostacyclin is prone to trigger signalling via
TP receptors [
Thromboxane A2 Inhibition: Cyclooxygenase-1 Versus
Platelet aggregation is part of maintenance of haemostasis and
homeostasis. Nonetheless, in cardiovascular diseases, linked to
endothelial damage, platelet functioning exceeds physiological
range and risk of thrombotic complications increases [
clinical practice, aspirin is the most commonly used antiplatelet
agent for prevention of adverse events in patients with
cardiovascular or cerebrovascular disease [
]. Preventive effect is
achieved via inhibition of platelet activation and aggregation
due to inhibition of TxA2 synthesis. Apparently, one can also
anticipate breaking the vicious cycle of TxA2-mediated platelet
activation, oxidative stress, vascular inflammation, eNOS
uncoupling and reduced NO bioavailability with TxA2
inhibition. Resulting effects are essentially beneficial for vascular
function irrespectively of the nature of disease, e.g. coronary
artery disease, hypertension, or arrhythmia.
Indeed, taking into account consequences of activations of
TP receptors, their inhibition could be clinically beneficial.
Several drugs were developed to avoid side effects associated
with COX-1 inhibition, but to retain beneficial effects of TP
signalling interruption [
]. A selective inhibitor of TXAS
synthase and TP receptor antagonist (BM-573) was tested in
apolipoprotein E knockout mice, a model of atherosclerosis
associated with reduced endothelium-derived relaxation and
NO bioavailability, enhanced oxidative stress and blood
pressure elevation. The treatment led to improvement in all of the
above parameters . Reduction in blood pressure and
abolished atherosclerosis progression were also observed in
other experimental studies of TP antagonists [
28, 58, 59
Terutroban (S18886) is perhaps the best known TP receptor
antagonist. In animal studies, terutroban showed ability to
reduce NOX upregulation and ROS production [
endothelial function [
] and attenuate renal damage in
]. In spontaneously hypertensive stroke-prone rats,
the use of terutroban prevented cell proliferation in the vessel
media, abolished accumulation of collagen and fibronectin in
the vascular wall and inhibited expression of heat shock
protein-47, MCP-1 and transforming growth factor 1β [
Although in some experiments effects of terutroban on
inflammation and endothelial function even outweighed effects
of aspirin [
], positive effects of TP receptors blockade
obtained in animal models did not translate into better outcomes
in humans [
]. In the PERFORM trial (Prevention of
cerebrovascular and cardiovascular Events of ischaemic origin
with teRutroban in patients with a history oF ischaemic
strOke or tRansient ischaeMic attack), there was a similar rate
of primary end-point of fatal or non-fatal ischaemic stroke,
fatal or non-fatal myocardial infarction, or other vascular
death observed in terutroban and aspirin groups (11 vs.
11 %, hazard ratio (HR) 1.02, 95 % confidence interval (CI)
0.94–1.12) and increased risk of minor bleeding in terutroban
arm (12 vs. 11 %, HR 1.11, 95 % CI 1.02–1.21) [
]. The trial
was stopped prematurely. There was also no difference in
carotid atherosclerosis progression, assessed by carotid
intima-media thickness measurements and carotid plaques
between the two treatment groups . Nonetheless, despite the
lack of clinical success so far, selective inhibition of TxA2,
either by synthesis or TP receptors or both, remains one of
attractive pharmacological targets in cardiology [
Aspirin and Endothelial Function: Beyond Thromboxane
What makes the difference between aspirin and selective
TxA2 inhibition given controversies between animal and
bedside data? One explanation is that dual inhibition, TXAS and
TP receptors is required because the latter can be activated by
other substances, e.g. isoprostanes . Obviously, the more
pathways of platelets activation are blocked, the higher
effectiveness of treatment is expected in relation to both clinical
outcomes and endothelial function [66, 67]. Also, aspirin has a
plethora of favourable vascular effects in addition to
modulation of the COX-1-dependent TxA2 synthesis and platelet
activation, which will be discussed below. Noteworthy, decrease
in prostacyclin synthesis in endothelium, due to COX-1
inhibition, was thought to be an unfavourable effect of aspirin,
now in light of emerging role of prostacyclin in TP receptor
signalling is considered to be advantageous [
]. It was also
discovered that IP and TP receptors were capable of formation
of heterodimeric receptor complex. Within such complex
biological downstream effects of TP receptors can shift towards
those realised via IP receptors stimulation .
Endothelial Nitric Oxide Synthase Acetylation
Aspirin was found to acetylate lysine of eNOS, which evokes
activation of its enzymatic activity, i.e. NO synthesis, release
and bioavailability of NO not only in endothelial cells, but
also in platelets (Fig. 1). Moreover, this effect appeared to be
independent of COX-1 inhibition and TxA2 production
[69–72]. Obviously, in platelets pre-treated with aspirin,
TxA2 level is reduced; thus, their activation is prevented by
modulation of both pathways, and downstream decrease in
platelet-mediated inflammation in vascular wall can be
Two small clinical trials assessed the effect of various doses
of aspirin, ranging 81 to 1300 mg, on NO production in
patients with metabolic syndrome and coronary artery disease.
NO production was indirectly assessed based on levels of
heme-oxygenase-1 (HO-1), which is known to be upregulated
w i t h i n c r e a s e d N O p r o d u c t i o n , a n d a s y m m e t r i c a l
dimethylarginine (ADMA), that serves as eNOS inhibitor.
These biomarkers were measured at baseline and after
12 weeks of the treatment. In both primary and secondary
prevention cohorts, aspirin increase in HO-1 and decrease in
ADMA indicate its ability to increase NO production [74, 75].
Aspirin-Triggered Lipoxins and Resolvins
Lipoxins are a type of lipid mediators generated from
arachidonic acid. Following aspirin intake, COX-2 is acetylated that
switches its enzymatic activity from a prostaglandin
endoperoxide synthase to a lipoxygenase pathway (Fig. 1). First,
intermediate 15(R)-hydroxyeicosatetraenoic acid is synthesised,
then it is converted to ATL by 5-, 12-, or 15-lipoxygenases in
various cell types (e.g. endothelial cells, platelets and
leukocytes) to 15R-epimers of intrinsic lipoxin A4 and B4, defined
as 15-epi-lipoxins or aspirin-triggered lipoxins (ATL) [76, 77].
Aspirin-triggered lipoxins are considered to be more potent
than intrinsic lipoxins with effects mediated via appropriate
receptor lipoxin A4 receptor (ALX) / formyl peptide receptor
(FPR2) with high affinity to it [76, 77]. Aspirin-triggered
lipoxins are capable of reduction of NOX-mediated
endothelial production of ROS via suppression of redox-sensitive
activation of the transcriptional factor nuclear factor-kappa B,
induced by either angiotensin II, tumour necrosis factor-α, or
thrombin . Aspirin-triggered lipoxins also block
plateletderived growth factor-stimulated proliferation and migration
of smooth muscle cells in vasculature . ATL were shown
to reduce adhesion of human leukocytes to endothelial cells,
reducing inflammation within the vascular wall [80, 81].
Given the role platelets play in regulation of leukocytes
adhesion to vascular endothelium, lipoxins released by platelet–
leukocyte aggregates control leukocyte activation and
adhesion and reduce damage to the vascular wall . Noteworthy,
ATL levels were found to be reduced in patients with
atherosclerotic lesions, particularly in patients with advanced
Resolvins (resolution phase interaction products) represent
another group of substances with potent anti-inflammatory
properties. Resolvins are synthesised from docosohexaenoic
and eicosopentaenoic omega-3 polyunsaturated fatty acids
(PUFA); hence, PUFA supplementation was found to restore
resolvins level if decreased in cardiovascular disease .
For example, resolvin E1 (RvE1) is generated by the
transformation of 18R-hydro (peroxy)-eicosapentaenoic acid,
which in turn is synthesised by the aspirin-acetylated COX-2
in endothelium. Resolvin E1 inhibits transmigration and
infiltration of polymorphonuclear leukocytes in vascular wall as
well as formation of platelet aggregates . Significant
decrease of expression of pro-inflammatory cytokines and
adhesion molecules, increase in RvE1 level and, interestingly,
decrease in blood pressure were observed in mice treated with
fish oil (as source of PUFA) and aspirin .
Lysosphingolipid sphingosine-1 phosphate (S1P) is another
mediator released from platelets in large quantities upon
activation, during thrombus formation and inflammation. Given
that the S1P release is promoted by TxA2, aspirin indirectly
inhibits S1P signalling (Fig. 1). Sphingosine-1 phosphate is
produced via two isoforms of sphingosine kinase (SphK), of
which SphK2 is predominant in platelets, and then binds to
S1P receptors on endothelial cells and smooth muscle cells
Circulating S1P may confer protective signalling for
vasculature by taking part in maintenance of endothelial layer
integrity, reduction in expression of adhesion molecules in
endothelium and inhibition of leukocyte adhesion to the
endothelium, and increase NO production (mostly via S1P1
receptor). On the contrary, opposing effects are triggered by
high levels of S1P released locally from the activated platelets
(via S1P2 receptor) .
Clinical Implications of Aspirin Use in Hypertension
Impact of Aspirin on Vasculature and Blood Pressure:
Few studies addressed impact of aspirin on vascular function
and blood pressure in patients with arterial hypertension.
Moreover, the studies were generally small and heterogeneous
in term of the studies population, concomitant drugs use,
aspirin dose, duration of treatment and generally had small
numbers. For example, Pietri et al. assessed effect of 160 mg of
aspirin administered for 2 weeks, on blood pressure and
parameters of arterial stiffness in a small group, of untreated
patients with mild hypertension. They observed 0.5 m/s
reduction in pulse wave velocity in the aspirin arm of the study
(which they reasonably attributed to endothelial function and
vascular tone), and there were no changes found in placebo
arm. There was no significant decrease in blood pressure as
well . Another study, with similar aspirin dosing and
duration of treatment, showed improvement in flow-mediated
dilation and decrease in C-reactive protein and intercellular
adhesion molecules level with aspirin. However, due to the
study design, it was impossible to reliably separate effects of
aspirin from effects of concomitant treatments . In another
study, aspirin therapy resulted in improvement of
flowmediated dilation and blood pressure reduction, when
combined with statins, while no significant dynamics was
observed on aspirin monotherapy .
The impact of aspirin on blood pressure was found to
depend on the time of administration and also to differ in males
and females. Hermida et al. performed a series of studies that
addressed time-dependent effect of low-dose aspirin (100 mg)
administration. Interestingly, a 3-month course of treatment
resulted in a minor but significant reduction of ambulatory
blood pressure when patients received aspirin at bedtime
rather than at awakening, both in mild hypertension and
prehypertension states [91–94]. The effect was consistent across
patients subgroups, but particularly pronounced in females
and non-dippers [93, 94].
Overall, robust clinical data on effects of aspirin on
vascular function and blood pressure control are scarce, which
prevents reliable conclusion on clinical significance of these
Prevention of Cardiovascular and Cerebrovascular Events
Despite high blood pressure values being the major cause of
vascular complications per se, duration of hypertension,
particularly when poorly controlled, is associated with ‘silent’
endothelial damage that in turn hastens atherosclerosis
]. Thus, patients with no clinically apparent
coronary artery disease may have their first manifestation of
CAD as acute one, e.g. acute coronary syndrome .
Despite multiple effects of aspirin that in theory can reduce
blood pressure, it is not clinically used for blood pressure
lowering. However, given that in management of patients with
arterial hypertension, prevention of adverse cardiovascular
events is crucial, many hypertensive patients use the agent.
Aspirin has a large body of evidence favouring its use for
the secondary prevention, but use of aspirin for primary
prevention remains controversial. Recent European guidelines on
cardiovascular disease prevention did not support
prophylactic use of aspirin in individuals without established
cardiovascular disease because the risk of major bleeding outweighs the
minor decrease in rate of major adverse cardiac events [
However, European guidelines for the management of arterial
hypertension suggested consideration of aspirin use for
primary prevention in patient with high cardiovascular risk or
reduced kidney function based on more balanced risk-benefit
profile in these categories of patients .
The US Preventive Services Task Force has also recently
updated recommendations on the use of aspirin for the
primary prevention of cardiovascular disease and colorectal cancer.
Low-dose aspirin is now supported in men and women aged
50 to 59 years who have a predicted risk for myocardial
infarction or stroke of at least 10 % over 10 years, with no
elevated bleeding risk, and willing to take aspirin within
10 years or longer. In patients aged 60 to 69 years, a decision
has to be made on an individual basis. Other age groups were
omitted in the document because of the lack of evidence .
Broadly, similar principles were incorporated in the
recommendations for antiplatelet treatment for primary prevention
of cardiovascular disease in the UK. Age over 50 years with a
high cardiovascular risk, defined as 10 years risk of greater
than 20 %, or reduced renal function (e.g. estimated
glomerular filtration rate less than 45 mL/min/1.73 m2) are the
clinical scenarios, when aspirin treatment in patients with
hypertension can be recommended .
There is also controversy in relation to aspirin use in primary
prevention settings in patients with diabetes, which is closely
linked to other cardiovascular risk factors and cardiovascular
morbidity, including hypertension and coronary artery disease.
Diabetes is known to be associated with persistent
TxA2-dependent platelet activation . In diabetic patients, aspirin use
showed a significant 10 % reduction of risk of major adverse
cardiovascular events, with no effect on myocardial infarction,
stroke, cardiovascular or all-cause mortality, and a trend
towards higher rate of gastrointestinal bleeds .
Despite relation between hazards and benefits of aspirin for
primary prevention remained broadly stable with adding new
clinical trials to meta-analyses (Table 1), update for evidence
is still needed at least because of the following reasons.
Widespread use of statins for primary prevention needs to be
accounted for as well improving control of cardiovascular risk
factors, e.g. hypertension itself, smoking and obesity. These
factors can modulate the overall net benefits of aspirin for
primary prevention, and they need to be accounted for future
There are several on-going trials on the utility of aspirin in
primary prevention settings. The ARRIVE (Aspirin to Reduce
Risk of Initial Vascular Events) study aims to evaluate the
efficacy and tolerability of 100 mg enteric-coated aspirin
compared to placebo in patients with no history of established
cardiovascular disease and moderate risk of major coronary
heart disease events for the prevention of cardiovascular
disease events, including myocardial infarction, unstable angina,
stroke or transient ischaemic attack, as well as cardiovascular
death . In the ASPREE (Aspirin in Reducing Events in
the Elderly) trial effects of 100 mg enteric-coated aspirin on
the composite primary endpoint, defined as ‘disability-free
life’, including onset of dementia, all-cause mortality, or
persistent disability in at least one of the Katz Activities are
assessed in individuals free of dementia, disability and
cardiovascular disease .
There are also two ongoing trials, addressing aspirin for
primary prevention in diabetic patients, who are known to be
particularly prone to develop atherosclerosis and coronary
artery disease, but based on current guidelines should not take
aspirin for primary prevention [
]. The ACCEPT-D (Aspirin
and Simvastatin Combination for Cardiovascular Events
Prevention Trial in Diabetes) assesses efficacy of aspirin,
added to simvastatin in patients with either type I or type II
diabetes mellitus on development of the primary combined
end-point of cardiovascular death, non-fatal myocardial
infarction, non-fatal stroke and hospital admission for
cardiovascular causes, including acute coronary syndrome, transient
ischemic attack, not planned revascularization procedures,
peripheral vascular disease . In the ASCEND (A Study of
Cardiovascular Events iN Diabetes), patients are randomised
to aspirin and/or omega-3 fatty acid for the primary prevention
of cardiovascular events . Finally, the TIPS-3
(International Polycap Study 3) trial will assess effect of
combination of enteric-coated aspirin and cholecalciferol versus
placebo on the composite end point of major cardiovascular
disease (cardiac death, non-fatal stroke, non-fatal myocardial
infarction), plus heart failure, resuscitated cardiac arrest, or
revascularization with evidence of ischemia; aspirin versus
placebo on composite of cardiovascular events (cardiac death,
myocardial infarction or stroke) and cancer as well as risk of
fractures against a cholecalciferol therapy . These new
studies would hopefully optimise utilisation of aspirin for
primary prevention and identify patients groups who are likely to
benefit from such treatment.
High On-treatment Platelet Reactivity
High-on-treatment platelet reactivity (or less appropriately
termed as aspirin resistance) refers to failure of aspirin to
prevent cardiovascular events . It is less related to use of
aspirin in hypertension because of limited indications in this
group of patients, but representing an important phenomenon
of aspirin, platelets and endothelial dysfunction interplay. Such
patients were found to have approximately four time higher risk
of cardiovascular events, compared to patients with low
residual platelet reactivity [113, 114]. It is often explained by
insufficient inhibition of TxA2 synthesis in platelets; however,
precise mechanisms have not been fully elucidated, yet .
First, platelets are activated via multiple pathways and
receptors, among which aspirin targets only one. Multiple studies
showed substantial decrease in TxB2 level, reflecting
diminished TxA2 synthesis; however, applying COX-1 functional
testing, as a reliable measure for residual platelet reactivity
and prognostication of cardiovascular outcomes, remained
17, 112, 116–119
]. Second, non-platelet sources of
TxA2 generation should be considered, specifically,
endothelium and monocytes/macrophages [
8, 10, 120
]. Therefore, usual
once a day dosing regimen may be less effective to assure
continuous inhibition of TxA2 synthesis [121, 122]. Third,
environment in vasculature seems to play important role, e.g.
oxidative stress, inflammation, NO synthesis as well as patient
characteristics which are causative of the former like as
smoking, obesity and diabetes mellitus [9 , 123, 124 , 125 ].
For example, brachial flow-mediated dilation was found to be
inversely associated with platelet adhesion and aggregation
[124 ]. Also, immature reticulated platelets were found to be
less suppressed by antiplatelet drugs .
Aspirin has been introduced into clinical practice more than a
century ago, and its use is supported by large body of
evidence, e.g. for secondary prevention of cardiovascular events.
Despite this, it is increasingly acknowledged that the
multitude of actions of aspirin is not fully elucidated yet. Ongoing
trials may spread current use of aspirin to new areas, which are
now considered largely controversial. Notwithstanding
pleiotropic effects of aspirin on endothelial function, it is unlikely
that we will start using aspirin as an antihypertensive agent;
however, this may bring additional clinical benefits in selected
patients with hypertension, for primary prevention of adverse
Compliance with Ethical Standards
Conflict of Interest Drs. Dzeshka, Shantsila, and Lip declare no
conflicts of interest relevant to this manuscript.
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.
Open Access This article is distributed under the terms of the Creative
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distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
ischaemic events (PERFORM): a randomised, double-blind,
parallel-group trial. Lancet (London, England). 2011;377(9782):
Bots ML, Ford I, Lloyd SM, Laurent S, Touboul PJ, Hennerici
MG. Thromboxane prostaglandin receptor antagonist and carotid
atherosclerosis progression in patients with cerebrovascular
disease of ischemic origin: a randomized controlled trial. Stroke; J
Cerebral Circ. 2014;45(8):2348–53.
Chan MV, Knowles RBM, Lundberg MH, Tucker AT, Mohamed
NA, Kirkby NS, et al. P2Y12 receptor blockade synergizes
strongly with nitric oxide and prostacyclin to inhibit platelet activation.
Br J Clin Pharmacol. 2016;81(4):621–33.
Thomas MR, Storey RF. Effect of P2Y12 inhibitors on
inflammation and immunity. Thromb Haemost. 2015;114(9):490–7.
Frey AJ, Ibrahim S, Gleim S, Hwa J, Smyth EM. Biased
suppression of TP homodimerization and signaling through disruption of
a TM GxxxGxxxL helical interaction motif. J Lipid Res.
Heiss EH, Dirsch VM. Regulation of eNOS enzyme activity by
posttranslational modification. Curr Pharm Des. 2014;20(22):
Jung SB, Kim CS, Naqvi A, Yamamori T, Mattagajasingh I,
Hoffman TA, et al. Histone deacetylase 3 antagonizes
aspirinstimulated endothelial nitric oxide production by reversing
aspirin-induced lysine acetylation of endothelial nitric oxide
synthase. Circ Res. 2010;107(7):877–87.
Kabirian F, Amoabediny G, Haghighipour N, Salehi-Nik N,
Zandieh-Doulabi B. Nitric oxide secretion by endothelial cells in
response to fluid shear stress, aspirin, and temperature. J Biomed
Mater Res A. 2015;103(3):1231–7.
Ghosh R, Bank S, Maji UK, Bhattacharya R, Guha S, Khan NN,
et al. The effect of acetyl salicylic acid induced nitric oxide
synthesis in the normalization of hypertension through the stimulation
of renal cortexin synthesis and by the inhibition of dermcidin
isoform 2, a hypertensive protein production. Int J Biomed Sci:
Karmohapatra SK, Chakraborty K, Kahn NN, Sinha AK. The role
of nitric oxide in aspirin induced thrombolysis in vitro and the
purification of aspirin activated nitric oxide synthase from human
blood platelets. Am J Hematol. 2007;82(11):986–95.
Hennekens CH, Schneider WR, Pokov A, Hetzel S, Demets D,
Serebruany V, et al. A randomized trial of aspirin at clinically
relevant doses and nitric oxide formation in humans. J
Cardiovasc Pharmacol Ther. 2010;15(4):344–8.
Hetzel S, DeMets D, Schneider R, Borzak S, Schneider W,
Serebruany V, et al. Aspirin increases nitric oxide formation in
chronic stable coronary disease. J Cardiovasc Pharmacol Ther.
Schror K, Rauch BH. Aspirin and lipid mediators in the
cardiovascular system. Prostaglandins Lipid Mediators. 2015;121(Pt A):17–23.
Romano M, Cianci E, Simiele F, Recchiuti A. Lipoxins and
aspirin-triggered lipoxins in resolution of inflammation. Eur J
Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Fierro IM.
Aspirin-triggered lipoxin A4 blocks reactive oxygen species
generation in endothelial cells: a novel antioxidative mechanism.
Thromb Haemost. 2007;97(1):88–98.
Ho KJ, Spite M, Owens CD, Lancero H, Kroemer AH, Pande R,
et al. Aspirin-triggered lipoxin and resolvin E1 modulate vascular
smooth muscle phenotype and correlate with peripheral
atherosclerosis. Am J Pathol. 2010;177(4):2116–23.
Vital SA, Becker F, Holloway PM, Russell J, Perretti M, Granger
DN, et al. Formyl-peptide receptor 2/3/Lipoxin a4 receptor
regulates neutrophil-platelet aggregation and attenuates cerebral
inflammation: impact for therapy in cardiovascular disease.
1. Cahill PA , Redmond EM . Vascular endothelium-gatekeeper of vessel health . Atherosclerosis . 2016 ; 248 : 97 - 109 .
2. Deshko MS , Snezhitsky VA , Dolgoshey TS , Madekina GA , Stempen TP . Flow-mediated dilation in patients with paroxysmal atrial fibrillation: initial evaluation, treatment results, pathophysiological correlates . Europace : Eur , Arrhythmias, Cardiac Electrophysiol: J Working Groups Cardiac Pacing , Arrhythmias, Cardiac Cell Electrophysiol Eur Soc Cardiol . 2011 ; 13 ( suppl 3 ).
3. Kornej J , Apostolakis S , Bollmann A , Lip GY . The emerging role of biomarkers in atrial fibrillation . Can J Cardiol . 2013 ; 29 ( 10 ): 1181 - 93 .
4. Lehoux S , Jones EA . Shear stress, arterial identity and atherosclerosis . Thromb Haemost . 2016 ; 115 ( 3 ): 467 - 73 .
5. Brandes RP . Endothelial dysfunction and hypertension . Hypertension . 2014 ; 64 ( 5 ): 924 - 8 .
6. De Miguel C , Rudemiller NP , Abais JM , Mattson DL . Inflammation and hypertension: new understandings and potential therapeutic targets . Curr Hypertens Rep . 2014 ; 17 ( 1 ): 1 - 10 .
7. Schrottmaier WC , Kral JB , Badrnya S , Assinger A . Aspirin and P2Y12 inhibitors in platelet-mediated activation of neutrophils and monocytes . Thromb Haemost . 2015 ; 114 ( 9 ): 478 - 89 .
8. Muller KA , Chatterjee M , Rath D , Geisler T . Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD . Thromb Haemost . 2015 ; 114 ( 3 ): 498 - 518 .
9. Thomas MR , Storey RF . The role of platelets in inflammation . Thromb Haemost . 2015 ; 114 ( 9 ): 449 - 58 . Comprehensive review of the role of platelets in inflammation.
10. Hohlfeld T , Schrör K. Antiinflammatory effects of aspirin in ACS: relevant to its cardiocoronary actions? Thromb Haemost . 2015 ; 114 ( 9 ): 469 - 77 .
11. Feletou M , Huang Y , Vanhoutte PM . Endothelium-mediated control of vascular tone: COX-1 and COX-2 products . Br J Pharmacol . 2011 ; 164 ( 3 ): 894 - 912 .
12. Alfonso L , Ai G , Spitale RC , Bhat GJ . Molecular targets of aspirin and cancer prevention . Br J Cancer . 2014 ; 111 ( 1 ): 61 - 7 .
13. Dai SX , Li WX , Li GH , Huang JF . Proteome-wide prediction of targets for aspirin: new insight into the molecular mechanism of aspirin . Peer J . 2016 ; 4 : e1791 . An analysis showing multiple targets for aspirin.
14. Serebruany VL , Cherepanov V , Cabrera-Fuentes HA , Kim MH . Solid cancers after antiplatelet therapy: confirmations, controversies, and challenges . Thromb Haemost . 2015 ; 114 ( 12 ): 1104 - 12 .
15. Nagelschmitz J , Blunck M , Kraetzschmar J , Ludwig M , Wensing G , Hohlfeld T. Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers . Clin Pharmacol: Adv Appl . 2014 ; 6 : 51 - 9 .
16. Smyth EM . Thromboxane and the thromboxane receptor in cardiovascular disease . Clin Lipidol . 2010 ; 5 ( 2 ): 209 - 19 .
17. Petrucci G , Rizzi A , Cavalca V , Habib A , Pitocco D , Veglia F , et al. Patient-independent variables affecting the assessment of aspirin responsiveness by serum thromboxane measurement . Thrombosis Haemostasis . 2016(2016-07-21 00 :00: 00 ).
18. Gleim S , Stitham J , Tang WH , Li H , Douville K , Chelikani P , et al. Human thromboxane A2 receptor genetic variants: in silico, in vitro and "in platelet" analysis . PLoS ONE . 2013 ; 8 ( 6 ), e67314 .
19. Katugampola SD , Davenport AP . Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT(1) receptor antagonist losartan . Br J Pharmacol . 2001 ; 134 ( 7 ): 1385 - 92 .
20. Blair P , Flaumenhaft R . Platelet α-granules: basic biology and clinical correlates . Blood Rev . 2009 ; 23 ( 4 ): 177 - 89 .
21. Koenen RR . The prowess of platelets in immunity and inflammation . Thrombosis Haemostasis . 2016(2016-07-07 00 :00: 00 ).
22. Soon ASC , Chua JW , Becker DL . Connexins in endothelial barrier function - novel therapeutic targets countering vascular hyperpermeability . Thrombosis Haemostasis . 2016(2016-08-04 00 :00: 00 ).
23. Pierini D , Bryan NS . Nitric oxide availability as a marker of oxidative stress . Methods Mol Biol (Clifton , NJ). 2015 ; 1208 : 63 - 71 .
24. Higashi Y , Maruhashi T , Noma K , Kihara Y. Oxidative stress and endothelial dysfunction: clinical evidence and therapeutic implications . Trends Cardiovasc Med . 2014 ; 24 ( 4 ): 165 - 9 .
25. Ball SK , Field MC , Tippins JR . Regulation of thromboxane receptor signaling at multiple levels by oxidative stress-induced stabilization, relocation and enhanced responsiveness . PLoS ONE . 2010 ; 5 ( 9 ), e12798 .
26. Muzaffar S , Shukla N , Massey Y , Angelini GD , Jeremy JY . NADPH oxidase 1 mediates upregulation of thromboxane A2 synthase in human vascular smooth muscle cells: inhibition with iloprost . Eur J Pharmacol . 2011 ; 658 ( 2-3 ): 187 - 92 .
27. Zhang M , Song P , Xu J , Zou MH . Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase . Arterioscler Thromb Vasc Biol . 2011 ; 31 ( 1 ): 125 - 32 .
28. Francois H , Athirakul K , Mao L , Rockman H , Coffman TM . Role for thromboxane receptors in angiotensin-II-induced hypertension . Hypertension . 2004 ; 43 ( 2 ): 364 - 9 .
29. Sparks MA , Makhanova NA , Griffiths RC , Snouwaert JN , Koller BH , Coffman TM . Thromboxane receptors in smooth muscle promote hypertension, vascular remodeling, and sudden death . Hypertension . 2013 ; 61 ( 1 ): 166 - 73 .
30. Schildknecht S , van der Loo B , Weber K , Tiefenthaler K , Daiber A , Bachschmid MM . Endogenous peroxynitrite modulates PGHS-1-dependent thromboxane A2 formation and aggregation in human platelets . Free Radic Biol Med . 2008 ; 45 ( 4 ): 512 - 20 .
31. Zou MH . Peroxynitrite and protein tyrosine nitration of prostacyclin synthase . Prostaglandins Lipid Mediators . 2007 ; 82 ( 1-4 ): 119 - 27 .
32. Nevitt C , McKenzie G , Christian K , Austin J , Hencke S , Hoying J , et al. Physiological levels of thrombospondin-1 decrease NOdependent vasodilation in coronary microvessels from aged rats . Am J Physiol Heart Circ Physiol . 2016 ; 310 ( 11 ): H1842 - H50 .
33. Muzaffar S , Jeremy JY , Angelini GD , Shukla N. NADPH oxidase 4 mediates upregulation of type 4 phosphodiesterases in human endothelial cells . J Cell Physiol . 2012 ; 227 ( 5 ): 1941 - 50 .
34. Lassegue B , San Martin A , Griendling KK . Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system . Circ Res . 2012 ; 110 ( 10 ): 1364 - 90 .
35. Gamez-Mendez AM , Vargas-Robles H , Rios A , Escalante B . Oxidative stress-dependent coronary endothelial dysfunction in obese mice . PLoS ONE . 2015 ; 10 ( 9 ), e0138609 .
36. Liu CQ , Leung FP , Wong SL , Wong WT , Lau CW , Lu L , et al. Thromboxane prostanoid receptor activation impairs endothelial nitric oxide-dependent vasorelaxations: the role of Rho kinase . Biochem Pharmacol . 2009 ; 78 ( 4 ): 374 - 81 .
37. Banerjee D , Mazumder S , Sinha AK . The role of inhibition of nitric oxide synthesis in the aggregation of platelets due to the stimulated production of thromboxane A2 . Blood Coagul Fibrinolysis: Int J Haemostasis Thrombosis . 2014 ; 25 ( 6 ): 585 - 91 .
38. Banerjee D , Mazumder S , Kumar Sinha A. Involvement of nitric oxide on calcium mobilization and arachidonic acid pathway activation during platelet aggregation with different aggregating agonists . Int J Biomed Sci: IJBS . 2016 ; 12 ( 1 ): 25 - 35 .
39. Ellinsworth DC , Shukla N , Fleming I , Jeremy JY . Interactions between thromboxane A(2), thromboxane/prostaglandin (TP) receptors, and endothelium-derived hyperpolarization . Cardiovasc Res . 2014 ; 102 ( 1 ): 9 - 16 .
40. Vanhoutte PM . Endothelium-dependent contractions in hypertension: when prostacyclin becomes ugly . Hypertension . 2011 ; 57 ( 3 ): 526 - 31 .
41. Luo W , Liu B , Zhou Y. The endothelial cyclooxygenase pathway: insights from mouse arteries . Eur J Pharmacol . 2016 ; 780 : 148 - 58 .
42. Kirkby NS , Lundberg MH , Harrington LS , Leadbeater PD , Milne GL , Potter CM , et al. Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the c a r d i o v a s c u l a r s y s t e m . P r o c N a t l A c a d S c i U S A . 2012 ; 109 ( 43 ): 17597 - 602 .
43. Zhou Y , Luo W , Zhang Y , Li H , Huang D , Liu B . Cyclooxygenase-1 or −2-mediated metabolism of arachidonic acid in endothelium-dependent contraction of mouse arteries . Exp Physiol . 2013 ; 98 ( 7 ): 1225 - 34 .
44. Patrono C . Cardiovascular effects of nonsteroidal antiinflammatory drugs . Curr Cardiol Rep . 2016 ; 18 ( 3 ): 1 - 8 .
45. Tang SY , Monslow J , Todd L , Lawson J , Pure E , FitzGerald GA . Cyclooxygenase-2 in endothelial and vascular smooth muscle cells restrains atherogenesis in hyperlipidemic mice . Circulation . 2014 ; 129 ( 17 ): 1761 - 9 .
46. Kirkby NS , Zaiss AK , Urquhart P , Jiao J , Austin PJ , Al-Yamani M , et al. LC-MS/MS confirms that COX-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of COX-2 expression . PLoS ONE . 2013 ; 8 ( 7 ), e69524 .
47. Liu B , Li Z , Zhang Y , Luo W , Zhang J , Li H , et al. Vasomotor reaction to cyclooxygenase-1-mediated prostacyclin synthesis in carotid arteries from two-kidney-one-clip hypertensive mice . PLoS ONE . 2015 ; 10 ( 8 ), e0136738 .
48. Li S , Liu B , Luo W , Zhang Y , Li H , Huang D , et al. Role of cyclooxygenase-1 and −2 in endothelium-dependent contraction of atherosclerotic mouse abdominal aortas . Clin Exp Pharmacol Physiol . 2016 ; 43 ( 1 ): 67 - 74 .
49. Tang EH , Vanhoutte PM . Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension . Physiol Genomics . 2008 ; 32 ( 3 ): 409 - 18 .
50. Pratico D , Tillmann C , Zhang ZB , Li H , FitzGerald GA . Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice . Proc Natl Acad Sci U S A . 2001 ; 98 ( 6 ): 3358 - 63 .
51. Feletou M , Verbeuren TJ , Vanhoutte PM . Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors . Br J Pharmacol . 2009 ; 156 ( 4 ): 563 - 74 .
52. Liu B , Luo W , Zhang Y , Li H , Zhu N , Huang D , et al. Involvement of cyclo-oxygenase-1-mediated prostacyclin synthesis in the vasoconstrictor activity evoked by ACh in mouse arteries . Exp Physiol . 2012 ; 97 ( 2 ): 277 - 89 .
53. Liu D , Liu B , Luo W , Li H , Zhang Y , Zhou Y. A vasoconstrictor response to COX-1-mediated prostacyclin synthesis in young rat renal arteries that increases in prehypertensive conditions . Am J Physiol Heart Circ Physiol . 2015 ; 309 ( 5 ): H804 - 11 .
54. White SJ , Newby AC , Johnson TW . Endothelial erosion of plaques as a substrate for coronary thrombosis . Thromb Haemost . 2016 ; 115 ( 3 ): 509 - 19 .
55. Piepoli MF , Hoes AW , Agewall S , Albus C , Brotons C , Catapano AL , et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice . Eur Heart J . 2016 .
56. Romero M , Leon-Gomez E , Lobysheva I , Rath G , Dogne JM , Feron O , et al. Effects of BM-573 on endothelial dependent relaxation and increased blood pressure at early stages of atherosclerosis . PLoS ONE . 2016 ; 11 ( 3 ), e0152579 .
57. Huang SW , Kuo HL , Hsu MT , Tseng YJ , Lin SW , Kuo SC , et al. A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models . Thrombosis Haemostasis . 2016 ; 116 ( 2 ).
58. Francois H , Makhanova N , Ruiz P , Ellison J , Mao L , Rockman HA , et al. A role for the thromboxane receptor in L-NAME hypertension . Am J Physiol Renal Physiol . 2008 ; 295 ( 4 ): F1096 - 102 .
59. Cayatte AJ , Du Y , Oliver-Krasinski J , Lavielle G , Verbeuren TJ , Cohen RA . The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis . Arterioscler Thromb Vasc Biol . 2000 ; 20 ( 7 ): 1724 - 8 .
60. Del Turco S , Basta G , Lazzerini G , Chancharme L , Lerond L , De Caterina R . Involvement of the TP receptor in TNF-alpha-induced endothelial tissue factor expression . Vasc Pharmacol . 2014 ; 62 ( 2 ): 49 - 56 .
61. Sebekova K , Ramuscak A , Boor P , Heidland A , Amann K. The selective TP receptor antagonist, S18886 (terutroban), attenuates renal damage in the double transgenic rat model of hypertension . Am J Nephrol . 2008 ; 28 ( 1 ): 47 - 53 .
62. Gelosa P , Sevin G , Pignieri A , Budelli S , Castiglioni L , BlancGuillemaud V , et al. Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis . Am J Physiol Heart Circ Physiol . 2011 ; 300 ( 3 ): H762 - 8 .
63. Gelosa P , Ballerio R , Banfi C , Nobili E , Gianella A , Pignieri A , et al. Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, increases survival in stroke-prone rats by preventing systemic inflammation and endothelial dysfunction: comparison with aspirin and rosuvastatin . J Pharmacol Exp Ther . 2010 ; 334 ( 1 ): 199 - 205 .
64. Bousser MG , Amarenco P , Chamorro A , Fisher M , Ford I , Fox KM , et al. Terutroban versus aspirin in patients with cerebral Gil- Villa AM , Norling LV , Serhan CN , Cordero D , Rojas M , Cadavid A . Aspirin triggered-lipoxin A4 reduces the adhesion of human polymorphonuclear neutrophils to endothelial cells initiated by preeclamptic plasma . Prostaglandins Leukot Essent Fat Acids . 2012 ; 87 ( 4-5 ): 127 - 34 .
Ed Rainger G , Chimen M , Harrison MJ , Yates CM , Harrison P , Watson SP , et al. The role of platelets in the recruitment of leukocytes during vascular disease . Platelets . 2015 ; 26 ( 6 ): 507 - 20 .
Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling . FASEB J : Off Publ Fed Am Soc Exp Biol . 2016 .
Dona M , Fredman G , Schwab JM , Chiang N , Arita M , Goodarzi A , et al. Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets . Blood.
Sphingosine-1-phosphate and its receptors: a mutual link between blood coagulation and inflammation . Mediat Inflamm.
Vito CD , Hadi LA , Navone SE , Marfia G , Campanella R , Mancuso ME , et al. Platelet-derived sphingosine-1-phosphate and inflammation: from basic mechanisms to clinical implications . Platelets . 2016 ; 27 ( 5 ): 393 - 401 .
Soloviev MA , Kulakova NV , Semiglazova TA , Borodulina EV , Udut VV . Correction of endothelial dysfunction in patients with arterial hypertension . Bull Exp Biol Med . 2011 ; 151 ( 2 ): 183 - 5 .
J Hum Hypertens . 2005 ; 19 ( 9 ): 667 - 73 .
Hermida RC , Ayala DE , Mojon A , Fernandez JR . Ambulatory blood pressure control with bedtime aspirin administration in subjects with prehypertension . Am J Hypertens . 2009 ; 22 ( 8 ): 896 - 903 .
Ayala DE , Hermida RC . Sex differences in the administrationtime-dependent effects of low-dose aspirin on ambulatory blood pressure in hypertensive subjects . Chronobiol Int . 2010 ; 27 ( 2 ): 345 - 62 .
Hypertension . 2005 ; 46 ( 4 ): 1060 - 8 .
Mancia G , Fagard R , Narkiewicz K , Redon J , Zanchetti A , Böhm M , et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension . Eur Heart J . 2013 ; 34 ( 28 ): 2159 - 219 .
National Institute for Health and Care Excellence. Clinical Knowledge Summaries . Antiplatelet treatment (Last revised in October 2015 ). Scenario: Antiplatelet treatment for primary prevention of cardiovascular disease (CVD) . Available from Page 12 of 12 110.
http://cks.nice.org.uk/antiplatelet-treatment#!scenario. Accessed August 10 , 2016 .
Santilli F , Pignatelli P , Violi F , Davì G . Aspirin for primary prevention in diabetes mellitus: from the calculation of cardiovascular risk and risk/benefit profile to personalised treatment . Thromb Haemost . 2015 ; 114 ( 11 ): 876 - 82 .
Kunutsor SK , Seidu S , Khunti K. Aspirin for primary prevention of cardiovascular and all-cause mortality events in diabetes: updated meta-analysis of randomized controlled trials . Diabetic Med: J British Diabetic Assoc . 2016 .
Am J Cardiol . 2006 ; 98 ( 6 ): 746 - 50 .
Am J Cardiol . 2011 ; 107 ( 12 ): 1796 - 801 .
Effect of aspirin on mortality in the primary prevention of cardiovascular disease . Am J Med . 2011 ; 124 ( 7 ): 621 - 9 .
Raju N , Sobieraj-Teague M , Bosch J , Eikelboom JW . Updated meta-analysis of aspirin in primary prevention of cardiovascular disease . Am J Med . 2016 ; 129 ( 5 ): e35 - 6 .
2016 ; 164 ( 12 ): 804 - 13 . A systematic review of effectiveness of aspirin for primary prevention of cardiovascular events .
2016 ; 164 ( 12 ): 826 - 35 . A systematic review of safety of aspirin for primary prevention of cardiovascular events .
Bayer . A Study to Assess the Efficacy and Safety of EntericCoated Acetylsalicylic Acid in Patients at Moderate Risk of Cardiovascular Disease (ARRIVE) . July 12 , 2007 . Updated: July 1 , 2016 . NLM Identifier: NCT00501059 Available from: https://clinicaltrials.gov/ct2/show/NCT00501059. Accessed July 30 , 2016 .
ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial . Contemp Clin Trials . 2013 ; 36 ( 2 ): 555 - 64 .
De Berardis G , Sacco M , Evangelista V , Filippi A , Giorda CB , Tognoni G , et al. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPTD): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins . Trials . 2007 ; 8 : 21 .
Aung T , Haynes R , Barton J , Cox J , Murawska A , Murphy K , et al. Cost-effective recruitment methods for a large randomised trial in people with diabetes: A Study of Cardiovascular Events iN Diabetes (ASCEND) . Trials . 2016 ; 17 ( 1 ): 286 .
Population Health Research Institute. The International Polycap Study 3 (TIPS-3) . July 10 , 2012 . Updated: May 22, 2015 .
Available from: https://clinicaltrials.gov/ct2/show/NCT01646437.
Accessed July 28 , 2016 .
Le Quellec S , Bordet JC , Negrier C , Dargaud Y. Comparison of current platelet functional tests for the assessment of aspirin and clopidogrel response. A review of the literature . Thrombosis Haemostasis . 2016(2016-07-21 00 :00: 00 ).
Krasopoulos G , Brister SJ , Beattie WS , Buchanan MR . Aspirin Bresistance^ and risk of cardiovascular morbidity: systematic review and meta-analysis . BMJ . 2008 ; 336 ( 7637 ): 195 - 8 .
Snoep JD , Hovens MM , Eikenboom JC , van der Bom JG , Huisman MV . Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis . Arch Intern Med . 2007 ; 167 ( 15 ): 1593 - 9 .
Pettersen AA , Arnesen H , Seljeflot I. A brief review on high onaspirin residual platelet reactivity . Vasc Pharmacol . 2015 ; 67 - 69 : 6 - 9 .
Nagatsuka K , Miyata S , Kada A , Kawamura A , Nakagawara J , Furui E , et al. Cardiovascular events occur independently of high on-aspirin platelet reactivity and residual COX-1 activity in stable cardiovascular patients . Thrombosis Haemostasis . 2016 ; 116 ( 2 ).
Brun C , Daali Y , Combescure C , Zufferey A , Michelson AD , Fontana P , et al. Aspirin response: Differences in serum thromboxane B2 levels between clinical studies . Platelets . 2016 ; 27 ( 3 ): 196 - 202 .
Homorodi N , Kovacs EG , Lee S , Katona E , Shemirani AH , Haramura G , et al. The lack of aspirin resistance in patients with coronary artery disease . J Transl Med . 2016 ; 14 : 74 .
Kakouros N , Nazarian SM , Stadler PB , Kickler TS , Rade JJ . Risk factors for nonplatelet thromboxane generation after coronary artery bypass graft surgery . J Am Heart Assoc . 2016 ; 5 ( 3 ), e002615 .
Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes . Platelets.
Henry P , Vermillet A , Boval B , Guyetand C , Petroni T , Dillinger JG , et al. 24 -hour time-dependent aspirin efficacy in patients with stable coronary artery disease . Thromb Haemost . 2011 ; 105 ( 2 ): 336 - 44 .
2015 ; 10 ( 5 ), e0126767 .
2015 ; 67 - 69 : 30 - 7 . A study showing association between endothelial function and effectivenes of aspirin therapy .
Larsen SB , Grove EL , Wurtz M , Neergaard-Petersen S , Hvas AM , Kristensen SD . The influence of low-grade inflammation on platelets in patients with stable coronary artery disease . Thromb Haemost . 2015 ; 114 ( 3 ): 519 - 29 . A study showing impact of vascular inflammation on platelets aggregation.
Thrombosis Haemostasis . 2016(2016-08-04 00 :00: 00 ).