Commentary :
Current practice in arterial disease is to establish the site of stenosis,to dilate thestenosis with angioplasty or surgical bypass, and to try to maintain the integrity ofthe arterial lumen with stents. There are either bare stents or drug eluting stents whichare more thrombogenic requiring long term dual antiplatelet therapy with its risk of increased bleeding. For coronary disease, this is called Percutaneous Coronary Intervention (PCI). Current practice in arterial disease
is to establish the site of stenosis, to dilate the stenosis with angioplasty or surgical bypass,
and to try to maintain the integrity of the arterial lumen with stents. There
are either bare stents or drug eluting stents which are more thrombogenic
requiring long term dual antiplatelet therapy with its risk of increased
bleeding. For coronary disease, this is called percutaneous coronary
intervention (PCI). A recent a study showed that heart stents for stable angina
show no benefit over placebo [1,2]. It has also been shown that 12% of PCI
patients are readmitted within 30 days [3]. A study of 60 day re-admission
after PCI showed that among 1193 enrolled patients, 71 (6.0%) underwent
unplanned 60-day re-admission for unstable angina (35.3%), chest pain (21.1%),
heart failure (14.1%), and acute
Myocardial infarction (11.3%);
40.8% patients underwent repeated PCI. Drug eluting stents are associated with
lower rates of restenosis but may be associated with later in-stent thrombosis,
and/or bleeding at vascular access sites, intracranially, and in the upper
gastrointestinal tract [4]. This is all very unsatisfactory. Have we have taken
a wrong pathway in the treatment of arterial disease? At an arterial narrowing
(stenosis), the relationship between the pressure drop and the flow is both
proportional and quadratic due to turbulence. A quantitative expression of a
stenosis is the area ratio As/Ao, where As is the cross-sectional area of the
stenosis and Ao is the cross-sectional are of the open, normal artery; this can
be expressed as a percentage as (1- As/Ao)x100. As the same flow has to go
through both the normal section, Ao and the much smaller As of the stenosis,
the blood has to go faster, i.e., velocity of blood flow increases; this is
called convective acceleration. Think of watching a placid full river running
into a gorge. So we envisage a mass of fluid accelerating into a narrowing of
the artery exerting greater force, and just as objects in a river gorge feel
force, so do blood cells in a stenosis. This effect is called shear stress. Shear
stress applied to blood platelets activates them, initiating thrombus growth in
such sites even in the absence of plaque rupture. This explains why coronary
thrombosis occurs in stenosis in contrast to the lack of thrombosis in sites of
endothelial damage but no narrowing. An increase in flow through an
artery, due to an increase in downstream demand, causes the artery to dilate.
This is commonly known as flow mediated dilatation (FMD) [5] and is commonly
used to assess arterial endothelial function. It has been suggested that this
effect of increased shear stress at the arterial wall is beneficial because the dilatation is mediated by
nitric oxide [6], which is thought to be an anti atherothrombosis factor by
Louis Ignarro (see his You-tube presentation), giving a scientific basis for
the supposed beneficial effect of exercise [7]. No-one seems to have queried the
mechanism of predilection of arterial thrombosis to occur in stenosis. Here the
analogy of the river gorge does not hold. Whereas objects in the gorge are
swept downstream, in an arterial stenosis there occurs a platelet rich thrombus
growth. When developing an experimental model of coronary arterial thrombosis,
we all experienced the fact that endothelial damage alone does not producethrombosis. One has to apply a
stenosis to set off thrombus growth [8-12]. Why has this fact been ignored? Why
is current drug therapy based on the results of platelet aggregation only in
response to endothelial damage? Is it not likely that there is something about
the presence of arterial narrowing and the hemodynamics of stenosis that is the
correct target for therapy? Platelets within a stenosis are subjected to force
and turbulence and these factors activate them. The response of platelet
activation is release of serotonin which is packed into their dense granules.
Reduction of secretion of these dense granules is associated with marked
protection from the development of arterial thrombosis, inflammation and
neointimal hyperplasia after vascular injury [13]. The reason for this is that
platelets are also activated by serotonin through the 5HT2A receptor, so that
serotonin released by stenosis shear stress activates more platelets which
release more serotonin, setting up the well-known serotonin (in addition to
other feedback mediators) positive feedback cycle [14]. The importance of
serotonin in this platelet feedback process is its abolition by 5HT2A
receptors, for which at least 20 references are available [11,12]. Modern imaging of internal organs
using magnetic resonance, yields images with much greater detail of the
structure of stenosis, including complex ones at artery bifurcations together
with the accompanying blood velocity patterns [15-17]. This is combined with computational
fluid dynamic measurements and multi-scale modeling [18-20] with which one
perceives the exciting possibility that the force applied to each platelet
might be calculated. Leading to a prediction of which platelets are likely to
be activated by the shear stress and release serotonin to trigger thrombus
growth. Already, these techniques have been useful when applied to the study of
atheromatous lesion growth and post stenting disease. Nevertheless, in
practical cardiology today, it is predicted that the altered hemodynamics of stenosis,
which have a variety of patho-antomical features and abnormal blood flow patterns,
all activate platelets if the increase in shear stress and turbulence are sufficiently
great. Since stenosis thrombus growth is
serotonin dependent, that treatment of arterial disease with 5HT2A receptor
antagonists is urgently required. The additional benefit of this approach is
that, there being no serotonin in wounds, the prediction is that there will be
no bleeding complications, as occurs with dual antiplatelet therapy [4]. There is
at least one of these drugs that has shown no change in bleeding time in
patients [12,21,22]. The proposed treatment for the
future is that patients with symptoms suggestive of arterial disease be
prescribed a 5HT2A antagonist. If the symptoms are acute. i.e., possible acute coronary
syndrome, stroke, leg ischemia, the drug should be given intravenously. If not
acute, the patient would be given a course of oral 5HT2A antagonist. While the
patient is thus protected, the patient undergoes investigation, e.g.,
angiography, MRI imaging [15-17], exploratory surgery, which will induce only normal
operative bleeding. Any stenosis that is shown, resting, or upon stress
testing, may then undergo an appropriate procedure to remove stenosis. Post
intervention treatment will be chronic administration of a 5HT2A antagonist
with no fear of excessive bleeding, only normal bleeding. 1. Al-Lamee
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MIM and Drake-Holland AJ. Preservation of haemostasis with anti-thrombotic
serotonin antagonism (2017) J Hematol Clin Res 1: 19-25. https://dx.doi.org/10.29328/journal.jhcr.1001004 Mark IM Noble, Department of Medicine and Therapeutics, Polwarth Building, Foresterhill, Aberdeen AB25 2ZH, University of Aberdeen, UK, Tel: +44 1224 272000; E-mail: mimnoble@abdn.ac.uk Noble MIM. Initiation of Arterial Stenotic Thrombosis (2018) Clinical Cardiol Cardiovascular Med 1: 9-10.Initiation of Arterial Stenotic Thrombosis
Abstract
Full-Text
Introduction
Arterial Stenosis
cause damaging increases in Shear Stress
Shear stress at
the normal arterial wall may be beneficial
What happens in
a stenosis?
Imaging of
arterial stenosis
Can arterial
stenosis-induced arterial thrombosis be treated specifically?
References
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