Question 4: Atherosclerosis in the coronary circulation causes heart disease; discuss the causes of atherosclerosis and its effect on the cardiovascular system. How are stents used to treat atherosclerosis?
Answer:
Atherosclerosis
is the build-up of plaque formed primarily by white blood cells and cholesterol
within the innermost membrane of an artery wall, called the tunica intima
(Seeley, VanPutte, Regan and Russo, 2011, p. 725). This accumulation of plaque
is a slow process, often taking years or decades to present with any symptoms,
if at all, to the person suffering from it. It is important to note that
oxidised low-density lipoproteins (ox-LDLs) are considered more atherogenic
than native LDLs. This is agreed upon in many works, for example; Samsioe
(1994), Panza, and Cannon, eds. (1999, pp. 89-92), and Kummerow, (2013). Dr. Kummerow,
in particular, gives much weight to the pathological effects of oxidised
cholesterols, known as oxysterols. He believes that the intake of oxysterols
via fried foods, excess vegetable oils (especially partially hydrogenated
vegetable oils) and cigarette smoking play a far greater role than simple
dietary cholesterol. This will be a part of the original thought later on in
this essay.
Schmidt
(2000, p. 38), explains that as cells take in LDL cholesterol to satisfy their
metabolic requirements, they begin to exhibit fewer cell membrane receptor
sites for LDLs. Therefore, if a high concentration of LDL cholesterol exists in
the bloodstream, then cells will take in as much as they need, down-regulate
their receptor sites, and the remaining cholesterol will be free to circulate
the body. This means that more of the cholesterol will be free to travel the
circulatory system and become deposited in walls of blood vessels, leading to
an increased risk of arterial diseases. The use of receptors on cell surface
membranes in order to take in a specific molecule or nutrient is an example of
receptor-mediated endocytosis (Pack, 2001, pp. 26-27). When this occurs, a
vesicle is formed as the cell membrane folds inwards around the substance being
received. Once the substance is safely inside of the cell, the vesicle can
break-down, releasing, in this case, the LDL.
The resultant problems associated with
atherosclerotic lesions are typically due to the narrowing of blood vessels
(stenosis), this decreases the available size of lumen for blood to travel
through, leading to a reduction in blood supply to tissues (ischemia). There
are many causes of atherosclerosis, these include: Hypercholesterolemia or
dyslipidemia (particularly increased LDL [low-density lipoprotein]
concentrations, but decreased levels of HDL [high-density lipoproteins that
appear to offer a protective effect against plaque build-up] are also a risk factor
[Carmena, Duriez and Fruchart, 2004]). Habitual cigarette smoking (Lin, et al,. 1992) has also been found
as a potential factor in disease progression. Mitchell, et al. (2007, p.345)
show that diabetes, elevated C-reactive protein in serum, growing older, male
gender, genetic faults that produce high levels of cholesterol and family
members who have suffered from atherosclerosis and its related cardiovascular
incidences (more detail further on in this essay), were more likely to get the
disease. Concomitant disorders also include obesity and insulin resistance (as
well as type 2 diabetes), as shown by Hotamisligil (2010).
The above
factors will be touched upon briefly, however a lot of this write-up will be
dedicated to biochemical pathways within the body that both decrease and
contribute to atherosclerosis, and how a down-regulation of antiatherogenic
chemicals can lead to this disease.
Some of the
more microscopic changes that occur to bring about atherosclerosis include but
are not limited to the following: Monocyte and macrophage adhesion to
endothelial cells, platelet aggregation, reduced endothelial nitric oxide
levels, high endothelial permeability increasing the migration of lipoproteins
into the walls of arteries, and increased vascular smooth muscle cell
proliferation, this rapid reproduction rate greatly speeds up the aging process
(Panza, and Cannon, eds., 1999, p. 44).
One of the
largest factors in the occurrence and progression of atherosclerosis is the
movement of lipoproteins, primarily LDLs, into the arterial wall, where they
can then deposit cholesterol which can become oxidised. HDL is considered
protective in this situation as it bonds to cholesterol and carries it to the
liver. This is one of the main reasons why proportions of varying types of
lipoproteins is an important study in these diseases, in particular, having low
HDL and high LDL is considered a strong factor in the onset of atherosclerosis
(American Heart Association, 2014a).
Mescher (2013, pp.
234-239) shows that the whole blood consists of approximately 1% leukocytes and
platelets combined (white blood cells) which are usually inactive while
circulating the body. Their activity is apparent however, when they are
signalled to sites of infection, inflammation or general damage. Here they will
migrate into tissues and exert (generally) appropriate action. In the case of
atherosclerosis, the prime white blood cell to be considered is the monocyte,
an agranulocytic blood cell that, among many other functions, modulates the
concentrations of LDLs in the arterial wall, it has this capability because it
is a precursor of the macrophage (an immune cell of the mononuclear [one
nucleus] phagocyte system, that engulfs cellular remnants and infectious
agents, among other substances and living matter). Whenever LDLs and
particularly oxidised LDLs are present in the arterial wall, monocytes (a form
of leukocyte) are coaxed into adherence to the endothelial cells by the
presence of a protein, VCAM-1 (vascular cell adhesion molecule 1 or vascular
cell adhesion protein 1, as shown by the National Center for Biotechnology
Information, 2015). Without this protein, the monocyte would
continue its journey around the body without stopping. Instead, the monocyte
will migrate into the endothelium experiencing LDL-induced inflammation and
will differentiate into a macrophage, in order to phagocytise the offending
molecule and carry it away.
If this
process becomes chronic, i.e. many LDLs are constantly permeating the
endothelium and causing inflammation, then a high concentration of macrophages
will exist within the endothelium in order to try and remove these LDLs. This
accumulation of monocytes is called extravasation (Mescher, 2013, p. 245).
Unfortunately, the presence of so many macrophages and resultant inflammatory
response leads to disproportionate tissue damage within the artery. As the macrophages engulf lipoproteins they begin to change
size and shape, and are termed “foam cells” (Oh, et al., 2012). The change in
appearance is due to the high concentration of lipoproteins within the
macrophages. When this occurs, the atherosclerotic lesion begins to look like a
fatty streak. This point in the progression of atherosclerosis is usually not
severe enough to induce significantly restricted blood flow within the artery
to the point of producing symptoms, but the artery becomes more rigid and
susceptible to damage.
Thus, we can see that endothelial
permeability to low-density lipoproteins is a prime factor in atherosclerosis.
If the endothelium did not allow LDL to move into it, then there would be no
need for macrophages to enter either, possibly preventing atherosclerosis from
even beginning.
As time goes on, macrophages begin to die
and release chemicals that further exacerbate inflammation, leading to a
greater immune response within the area. This causes more monocytes to be
signalled to the vessel wall and differentiate into macrophages, furthering the
progression of plaque formation. This occurs primarily between the tunica
intima and tunica media (American Heart Association, 2014a). Also over time,
calcium deposits build up due to poor clearance of cellular debris from these
deceased cells. This is because the atherosclerotic plaque proves too great a
physical barrier to facilitate their removal. Further to this, if the
atherosclerotic plaque ruptures, possibly due to the high blood pressure in the
artery and weak structural strength of the plaque, then a clot may form. A clot
is the entrapment of blood cells, fluid and platelets by fibrin (a protein that
encourages clotting).
Another name for a blood clot is
coagulation, and the proteins involved in its production are called either coagulation
or clotting factors, which are contained in blood plasma. Under ordinary
conditions, these factors remain inactivated, however, when damage occurs to
tissue, such as a weakened blood vessel in our case of atherosclerosis, the
coagulation factors become more active. The initiation of clotting can occur
via an extrinsic or intrinsic pathway, though both link into a later route of
chemical reactions called the common pathway (Seeley, VanPutte, Regan and Russo, 2011, pp. 660-661).
The extrinsic pathway of clotting starts
due to the presence of chemicals that are not contained within the bloodstream.
This could be from the release of thromboplastin (other names for this chemical
are factor III or tissue factor) as a result of tissue damage. If calcium ions
react with thromboplastin, the result is a compound containing factor VII which
can react to activate another chemical called factor X. This is the point where
the common pathway begins at the end of the extrinsic pathway (Seeley, VanPutte, Regan and Russo,
2011, p. 661).
The
intrinsic pathway starts off differently, with chemicals that are contained
within the blood stream, such as collagen which can be exposed when blood
vessels are injured. Whenever a chemical called plasma factor XII reacts with
this collagen, the factor XII becomes active. Consequently, factor XI is
activated, leading to stimulation of factor IX, which binds with various other
molecules, such as factor VIII, phospholipids contained within platelets, and
positive calcium ions. The result of this is that factor X becomes acitivated,
and this is the point where the common pathway begins, just like at the end of
the extrinsic pathway (Seeley, VanPutte, Regan and Russo,
2011, pp. 661-662).
At the
beginning of the common pathway, prothrombinase is formed by the binding of
factors X and V, along with phospholipids from platelets, and calcium ions.
Prothrombinase is capable of converting a protein dissolved in plasma, called
prothrombin, into thrombin, an enzyme highly important in clot formation. This
enzyme produces a protein called fibrin from fibrinogen (another protein
dissolved in plasma). The fibrin formed is responsible for the entrapment of
platelets, blood cells and fluids that make up a blood clot. Blood clotting is
a relatively rare example of positive feedback in the human body, because its
presence can lead to the production of its own precursors (e.g. factor XI and
prothrombinase). Vitamin K is necessary for clot formation, and its deficiency
can lead to excessive bleeding (Seeley, VanPutte, Regan and Russo,
2011, p. 662).
When a clot is attached to an arterial
wall it is called a thrombus. After a clot has formed and attached itself, it
starts to become denser due to clot retraction. This occurs because platelets,
arranged as extensions to fibrinogen (which are bonded to fibrinogen receptors
on cells of the blood vessel wall), begin to contract through the use of actin
and myosin filaments, effectively pulling on the fibrinogen and drawing the
clot into a more compact structure. This process liberates serum (a fluid
similar to plasma, but which doesn’t contain some clotting factors, as well as
fibrinogen). As a result of this, the injured blood vessel is more tightly
sealed up, allowing it to recover more easily, and reducing the possibility of
infection (Seeley,
VanPutte, Regan and Russo, 2011, p. 663).
Figure 4.1 shows the development of
atherosclerotic plaque and subsequent clot formation. Here we see that the
plaque itself is enough to cause significant narrowing of the blood vessel,
however, due to rupture of plaque, a thrombus has started to form. This
thrombus is further restricting blood flow through the artery and will be
discussed further blow. The diagram also shows that the plaque is developing
between the tunica intima (innermost membrane of the artery, and one that
separates other tissue layers from the lumen) and the tunica media. (Seeley, VanPutte, Regan and Russo,
2011, p. 725).
A
fundamental chemical involved in atherosclerosis is nitric oxide. A reading of
the literature greatly brought up the antiatherogenic importance of this small,
highly-reactive free radical. Its production is decreased in atherosclerosis
(Panza, and Cannon, eds., 1999, p. 20) and this has a strong effect in the
progression of the disease, as will be elaborated on below.
It is
important to note before continuing that the following substances either
inhibit nitric oxide (NO) directly, either in production (which occurs via the
nitric oxide synthase enzyme), release or functional effect:
Endothelin-1,
abbreviated to ET-1. This is a petide composed of 21 amino acids that is
produced in the endothelium, one of its main effects is as a vasoconstrictor.
ET-1 has been shown to be elevated in atherosclerosis and likely contributes to
the disease. Its vasoconstriction effects are roughly a hundred times stronger
than noradrenaline per unit of concentration. Oxidised low-density lipoproteins
increase its release, explaining its increased production during
atherosclerosis. It also attracts monocytes to atherogenic lesions because it
has chemoattractant effects (Panza, and Cannon, eds., 1999, pp. 97-109).
Angiotensin
II or Ang II is also implicated in the development of atherosclerosis and
reduction of nitric oxide. This is a peptide hormone that also has
vasoconstrictive effects. Its administration has been shown to increase the size
of atherosclerotic lesions in mice deficient in apolipoprotein E (this is a
molecule that breaks down lipoproteins, and without it, mice as well as humans,
have a much greater risk of developing atherosclerosis,
Asymmetrical
di-methylarginine (ADMA), this is a circulating amino acid that is similar in
structure to L-arginine. As l-arginine is a precursor to nitric oxide, ADMA is
able to interfere with this metabolic pathway, by interacting with its
components, namely the nitric oxide synthase enzyme (NOS).
NG-monomethyl-L-arginine
(L-NMMA) as well as L-nitroarginine methylester (L-NAME) share a similar
effect, by competing with L-arginine for the active site of the NOS enzyme
(Panza, and Cannon, eds., 1999, p. 165).
This occurs because the production of nitric oxide from L-arginine results from
the oxidation of the terminal containing a guanidine-nitrogen bond, which is
also contained within the inhibitors mentioned above.
Implicated
as well in the down-regulation of various aspects of nitric oxide are many
reactive oxygen species (ROS) including the superoxide anion (O2-)
and hydrogen peroxide (H2O2). This is due to the effect
of these species to rapidly and chemically alter nitric oxide. Panza, and
Cannon, eds. (1999, p. 134) show that the reaction between the superoxide anion
and nitric oxide produces the peroxynitrite anion, a relatively stable ion
compared to the particular radicals in this example of its creation. The
peroxynitrite anion loses many of the qualities of nitric oxide, but retains a
small ability to cause vasodilation, unfortunately it is also damaging to cells
and therefore needs to be detoxified (Panza, and Cannon, eds., 1999, p. 23).
The
following substances in some way enhance the effect, production or release of
NO:
Estrogen,
via its effect of up-regulating the eNOS enzyme (Chambliss, K.L., and Shaul,
P.W. 2013). Interestingly, estrogen has also been shown to alter lipid profile
in humans. Specifically, estrogen has been shown to reduce both total and
LDL-cholesterol levels while raising HDL. Evidence is currently gathering which
points towards an additional antiatherosclerotic effect of estrogen, namely in
the inhibition of lipid oxidation, this is based on an overall review of the
literature by Samsioe, 1994. As mentioned above, oxidised lipids are considered
more important in the onset and progression of atherosclerosis.
L-arginine
is also important (as mentioned above, L-arginine is a precursor for NO).
The
peroxynitrite anion (the actual formation of this anion actually greatly
reduces the effect of NO because it is formed via the reaction of nitric oxide
with the superoxide anion and attenuates the vasodilatory effects of NO,
however, the presence of the peroxynitrite anion itself still contributes to
some of NO’s effects, this information is referenced above in the text about
reactive oxygen species).
The
cysteine-containing NO donor SPM-5185, as demonstrated in (Panza, and Cannon, eds.,
1999, p. 22).
Finally,
antioxidants such as vitamin C (in some trials), and the enzyme superoxide
dismutase (SOD) as shown in (Panza, and Cannon, eds., 1999, p. 135).
When talking
about nitric oxide in relation to atherosclerosis, the endothelium of arteries
is the primary point of interest. Thus, the notation eNO (for endothelial
nitric oxide) and eNOS (short for endothelial nitric oxide synthase) can be
used interchangeably with NO and NOS for this topic.
eNO is
highly important in alleviating and preventing atherosclerosis because it first
of all decreases endothelial permeability. As covered previously, when the
endothelium is highly permeable, more low-density lipoproteins are allowed to
pass through it into the arterial wall, and this is what requires macrophage
activity. In decreasing endothelial permeability, the whole onset of
atherosclerosis could be abated. Much of the information regarding nitric oxide
as shown above is available in the works of Panza, and Cannon, (1999) where it
is backed up by hundreds of in-text citations.
The eNO
radical also reduces monocyte adhesion to cells of the endothelium, seemingly
by inhibiting the expression of VCAM-1. This would prevent the influx of
monocytes and subsequent differentiation into macrophages, thus inhibiting foam
cell occurrence. eNO also attenuates platelet aggregability, as shown by Panza,
and Cannon, eds. (1999, pp. 120-122). The cohesion of platelets at the site of
inflammation of endothelium can lead to a thrombosis (a clot attached to a
blood vessel) that starves cells and tissue further down the vessel of oxygen.
If the cells further downstream of the thrombosis are cardiac muscle cells
(myocardium) then the result can range from angina to a heart attack.
This next
section details the possible adverse effects associated with atherosclerosis.
It is important to note that each issue may occur as both a result of the build
of plaque directly, but also indirectly, as plaque formation can lead to blood
clots that cause and/or exacerbate many cardiovascular incidents. As plaque
builds up between the tunica intima and the lumen there is a possibility of
plaque rupture. This is shown on the atherosclerosis webpage of the American
Heart Association (2014b). The subsequent effect of this is that a stationary
clot (thrombus) in the wall of the affected blood vessel may further reduce the
size of the lumen and ability of blood to through the vessel. This can cause or
contribute to all of the problems shown below, for the same reason as a gradual
build-up of plaque, for it limits the blood flow to areas of the body
downstream from the affected blood vessel.
Alternatively,
the blood clot formed at the rupture site of plaque can dislodge from the
arterial wall and become free-floating. In this case it is called an embolus
and can cause an embolism (a substance that produces obstruction within a blood
vessel). This can cause the same effect as a thrombus, but the embolism can
float around and block a vessel located in the distal systemic circulation (Kumar, Abbas, and Fausto, 2004). This is also briefly pointed
out in the work of Seeley,
VanPutte, Regan and Russo, 2011, p. 663.
Angina
pectoris usually presents as a pain in the chest, though it may also appear in
the lower jaw, neck and possibly also the left arm or shoulder. It is caused by
anaerobic respiration in the heart. It can arise from atherosclerosis due to
narrowing of blood vessels within the coronary circulation. This causes
restricted blood and oxygen flow to the cardiac muscle. Unable to respire
aerobically but still requiring energy, the cardiac muscle cells must survive
on anaerobic respiration due to hypoxic conditions. Unfortunately, this
respiratory pathway causes a build-up of acidic by-products that raise acidity
(and lower pH) in the affected area. This causes a pain response to be
stimulated. This situation is exacerbated by any process demanding additional
cardiac output, for example physical and mental stress. On the other hand,
relaxation would have the opposite effect by reducing cardiac exertion.
Vasodilation via chemical intervention (nitro-glycerine or free radical NO) or
placement of a stent can increase the blood flow through the affected artery
and improve oxygen of the cardiac muscle as well as improving the removal rate
of acidic by-products of respiration. A clot could also cause this issue as a
result of atherosclerotic plaque rupture. The formation of a clot in a blood
vessel in this situation would further restrict blood flow through the vessel,
provided that the clot doesn’t cause severe obstruction. Angina pectoris is a
relatively minor condition, provided that it is only short-lasting. Normally if
the blood flow is restored, there is only mild permanent damage to cardiac
tissue.
Myocardial
infarction (heart attack), is caused by a more lengthened condition of hypoxia
(or even anoxia). In this circumstance, instead of just pain, the cardiac cells
may die in large numbers in affected areas. Atherosclerosis increases the
possibility of myocardial infarction because the resultant lesions can greatly
reduce the size of the lumen of coronary arteries, thus increasing blood
pressure and possible clot formation (thrombus). This thrombus further narrows
the blood vessel and exacerbates cell hypoxia, perhaps leading to total anoxia
in some areas, depending on severity. This leads to cell death in the cardiac
tissue. The above information on angina pectoris and myocardial infarction can
be found in the work of Seeley, VanPutte, Regan and Russo (2011), p. 686.
Stenosis can
also lead to enlargement of certain regions of the heart, such as the left
ventricle. Because the left ventricle is required to pump blood around the
whole body via the aorta, if there is stenosis in the aorta as a result of
atherosclerotic plaque, then there is increased resistance to the contraction
of the left ventricle. This means that the left ventricle must work harder in
order to overcome the resistance, otherwise the whole body will become affected
by hypoxia due to decreased blood supply. This can lead to hypertrophy of the
left ventricle, an increase in size of the muscles located here. The ventricular
hypertrophy allows the left ventricle to have more contractile force and push
more red blood cells through the stenosed aorta and into the systemic
circulation. It was mentioned in question 2 that the arterial stenosis causes
an increase in ventricular afterload which the left ventricle must overcome
(Jardins, 2008, p. 210). The increased force through the aorta increases
systolic pressure. This information was found from Seeley, VanPutte, Regan and
Russo, 2011, Appendix G, A-34 9 a-f.
A stent can
be used to treat atherosclerosis. In this case, the stent is typically made of
metal and is transported into the artery which is clogged with atherosclerotic
plaque. This occurs during a procedure called angioplasty in which an empty
balloon is inserted via catheter into the blood vessel which has narrowed. Once
inside the vessel, the balloon is inflated in order to open it up and reduce
stenosis. This occurs because the pressure of the balloon is both able to
forcibly widen the blood vessel and also in squeezing the atherosclerotic
plaque so that it takes up less space within the lumen of the blood vessel. At
this point, if the catheter also contains a stent, as it would in the case of
atherosclerosis, then this stent can hold the vessel open to the extent that
the balloon did. Thus, even when the inflating balloon has left the blood
vessel, it stays open to the same extent via the stent. Therefore, the stent
provides a more long-term ability to reduce stenosis. This has the same effect
as a vasodilator in holding the blood vessel open. So far, only the mechanical
properties of the stent have been touched upon. However, a stent can also
produce pharmacological effects as well. This is achieved by coating the outer
surface of a stent with medication which slowly releases into the arterial wall
and/or blood stream. Stents that have this capacity are called
drug-eluting-stents (DES). Blood which would ordinarily be forced through a
narrower space in the vessel, possibly leading to a blood clot or greatly
increased blood turbulence, is now free to travel through at the normal speed
and pressure. This can decrease the likelihood of cardiovascular incidences,
such as those covered above. Additional
lifestyle measures must also be taken however, as over time the stent itself
can become clogged if the underlying cause of arterial stenosis is not removed.
This process of repeated narrowing of the blood vessels after a measure has
been taken to reduce it is called restenosis. This information is shown clearly
on the stent webpage of the American Heart Association (2014c). Figure 4.2
shows the placement of a stent in the coronary artery. As can be seen from this
diagram, the stent is made of a metal mesh and is pressing against the
atherosclerotic plaque, thus opening up the lumen of this blood vessel. Once
the stent has been placed via the catheter, both it and the guide wire are
removed, leaving the stent to hold the artery open.
This portion
of the essay is dedicated to thought not seen in work by other sources on
atherosclerosis. Any relation to previous work done by any author on this topic
is purely coincidental.
It is
possible that some of the development of atherosclerosis is due to increased
ventilation and oxidative stress during mental stress. Granted modern society
has many problems when it comes to eating nutrient-depleted, high-fat foods and
breathing indoor air, but with many economic factors causing significant stress
and subsequent increases in respiration occurring as part of the
fight-or-flight reaction, various bodily changes are likely to occur. For
example, it is possible that prolonged mental stress and resultant
over-breathing reduce the bodily carbon dioxide levels and inhibit the Bohr
Effect, leading to an increased need for erythrocytes and a permanent shifting
towards elevated ventilation. This would also increase the level of oxygen
dissolved in blood plasma, as a result of air pressure within the lung during
inspiration. From this, more oxygen would travel through the bloodstream, and
cause oxidative stress throughout the body. This would exacerbate the
peroxidation of lipoproteins and oxysterol production, thus contributing
towards atherosclerosis.
Another
possible related mechanism for atherosclerosis is mouth-breathing. Because
nitric oxide is also produced within the nose, nose-breathing may also allow
significant quantities of nitric oxide to diffuse into the blood stream, which
may perhaps be unlikely given that it is a highly-reactive free radical, but it
could bind to haemoglobin, as opposed to travelling freely, see Seeley,
VanPutte, Regan and Russo, (2011) p. 653. The aforementioned reaction between
the superoxide anion and nitric oxide would readily result, decreasing the
amount of oxygen available for lipid peroxidation and subsequent atherosclerotic
plaque formation in blood vessels.
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