Pathology Aantekeningen Deeltentamen 2
Week 3 Chapter 10 and 11 (The Heart and Artherosclerosis)
Atherosclerosis
In the normal artery, you can see one layer of endothelial cells (intima), a tunica media
(consisting of smooth muscle cells and elastin) and extracellular matrix proteins (add to the
strength of the blood vessel). There is also an adventitia that consists of fat and blood vessels.
In a vessel that suffers from atherosclerosis, there is an increased intima due to ceroids
(lipids) that are causing atherosclerotic lesions.
- In picture 3 you can also see the presence of many macrophages (brown stained cells) that
are phagocytosing the lipids but are not succeeding completely. This eventually results in
a chronic inflammation of lymphocytes, macrophages, neutrophilic granulocytes and to a
lesser extent eosinophilic granulocytes. Mast cells can also be found in these
atherosclerotic lesions.
- Even though all three layers of the blood vessels undergo changes, the intima will
increase and the media will decrease. Smooth muscle cells of the media will migrate to
the intima (the media is therefore inflamed to a lesser extent).
- In the adventitia you also have inflammation, but you can also find fibrosis of the blood
vessels. The fibrosis of the adventitia and the decrease of the media can cause
complications because the structure of the blood vessel is not that comprehensive
anymore.
- In atherosclerosis you have a decrease in the media, loss of elastic fibers and smooth
muscle cells and degeneration of collagen that all results in the strength of the blood
vessel wall is decreased (see slide 5). This results in dilatation that can cause the blood
vessel to rupture (aneurysm). This can be fatal.
Aorta dissection
In this slide, the vessel wall is spliced between the tunica media and adventitia. In this splicing
area a hemorrhage/thrombosis has occurred. This dissection can be caused by:
- A perforation of an atherosclerotic plaque
- Bleeding within the vessel wall, a so-called hematoma (can be independent of
atherosclerosis)
Mucoid media degeneration of the aorta
An important age dependent degeneration of the aorta is the mucoid media degeneration of
the vessel wall.
- In picture 1 the essence of this degeneration is shown: there is a loss of elastic fibers
(therefore a loss in elastic aorta) and mucoid depositions (glycosaminoglycans; causes the
weakening of the tunica media).
- The mucoid depositions can cause an aneurysm and also a dissection of the blood vessel
wall.
- A striking feature of extensive mucoid depositions is that if the patient is above 45 years
old, the cause of these depositions is most probably age dependent. If the patient is under
45 years old, the cause of these depositions is most probably a genetic cause (slide 8).
Slide 8: the left and right picture show a normal elastic fiber that is depicted by
transmission electron microscopy.
Slide 8: people with Marfan disease have thin and fragmented elastin (disease of
fibrillin that causes fragmentation and thinning of the elastic fibers) that can cause
BOMF, aneurysm and dissection.
, Slide 8: people with Ehlers-Danlos have a degeneration of collagen (malformation)
that causes a huge variation in collagen diameter. This can result in an aneurysm and
dissection.
Heart valves
The heart valves can also develop a pathologic degeneration: especially in the mitral valve
and aortic valve.
- Because the pressure in the left ventricle is quite high, this can cause all kinds of
disturbances in the endothelial layer and heart valves.
Two mechanisms of degeneration can occur (non-infectious valve disease):
1. Degeneration in which the valves thicken due to fibrosis and inflammation
2. Degeneration of the heart valves due to ceroid chronic inflammations and calcification.
This is also known as atherosclerosis.
The CRP/sPLA2-IIA and complement are more increased in atherosclerotic valves
than degenerated valves. Clinical studies have shown that increased levels of
CRP/sPLA2-IIa and complement in the blood (vessels) are related to atherosclerotic
changes of the heart valves.
Infectious endocarditis (infectious valve disease)
Infectious endocarditis is defined by an infection of the heart valves that is mainly caused by
a bacterial infection.
- There is a huge increase in neutrophilic granulocytes and high depositions of complement
that cause necrosis and thrombosis of the valves. The result of this is that the valves
cannot function anymore.
- In infectious endocarditis the levels of neutrophilic granulocytes and … proteins are
higher compared to degenerative heart valves (these granulocytes and proteins are present
in a lower amount).
Acute myocardial infarctions
So far we have discussed atherosclerosis in big blood vessels, however this can also occur in
small vessels. This phenomenon is called an acute myocardial infarction (AMI) that occurs
in the coronary arteries.
- Picture 1 shows a heart with healthy coronary arteries.
- An AMI can be caused by diseased coronary arteries. You can more so predict where the
AMI will be caused by looking at which coronary arteries are suffering from
atherosclerosis.
So atherosclerosis (occlusion) in the proximal part of the wall (LCX and LAD) will
most likely cause an AMI in interior wall and the lateral wall of the left ventricle of
the heart.
An occlusion in solely the LAD will result in an infarction in the interior wall.
An occlusion in solely the LCX will cause an infarction in the lateral wall.
An occlusion in solely the RCA will cause an infarction in the posterior and/or the
right ventricle.
Levels of occlusions that can occur (slide 15)
When a patient has a grade 4 stenosis (so more than 75% of the coronary artery is suffering
from stenosis), you can figure that the patient also had this occlusion a week before he had an
infarction. So why did he have the infarction now and not a week ago for example?
- This is related to plaque complications (stable versus unstable) that, on itself, are related
to inflammation.
,Stable versus unstable plaque
There are two types of atherosclerotic plaque:
1. Stable atherosclerotic plaque is a thick fibrous cap without inflammation in the cap
o This stable plaque is more or less protected against shear stress development that
can cause complications of the plaque.
2. Unstable atherosclerotic plaque is a thin OR thick fibrous cap with inflammation in the
cap
o A stenosis causes all kinds of complications regarding the blood flow through the
vessels and there is also increased shear stress. If you also have a thin fibrous cap
in this situation, the atherosclerotic plaque can rupture and cause an AMI.
Causes of an AMI (extramyocardial)
1. Coronary artery thrombus
- Presence of atherosclerotic plaque and its ability to rupture
2. Microscopic thrombus
- There is an inflammation on the luminal side of the coronary artery that causes an
disruption in endothelial cells that will result in an occluding thrombus.
3. Plaque bleeding (increase in intima)
- As mentioned earlier, atherosclerosis results in in an increased intima. In addition to this,
there is a development of small blood vessels that run through this increased intima. These
blood vessels have a malformation (basal lamina is not developed correctly) that causes
them to easily rupture due to the high shear stress. This will result in a bleeding inside of
the atherosclerotic plaque that causes the plaque to increase, eventually causing an AMI.
4. Dissection coronary artery
- The cause of the dissection is unknown. However, it is known that an atherosclerotic
plaque can cause a degeneration of extracellular matrix proteins in the tunica media (this
might be genetically caused but it is not fully known yet). This dissection (just like a
dissection in the aorta) can cause bleeding that leads to a stenosis of lumen of the coronary
artery.
- This phenomenon can also occur independent of an atherosclerotic plaque.
Causes of an AMI: intramyocardial coronary artery
1. Hypertension
- This can cause a stenosis in the intermyocardial coronary arteries that can cause an AMI.
2. Small vessel disease
- Normally the basal membrane has a thickness of between 70 and 80 nanometers.
However, in small vessel disease the basal membrane is increased up to 1000 nanometers
and this causes a decrease in oxygen diffusion.
- The occurrence of small vessel disease can be related to developmental problems (not
genetic problems), diabetes mellitus and people who use cocaine.
3. Myocardial bridging of the coronary artery (rare)
- The large epicardial coronary artery that normally resides on the outside of the heart, is
now inside of the heart (myocardium). Normally, during contraction of the heart (systole)
there is a compression of the lumen of the coronary arteries, while during the dilatation of
the heart (diastole) the heart can be filled with blood. When myocardial bridging is
present, the dilatation in diastole is inhibited because the vessel is surrounded by fibrosis.
This can cause an AMI.
- These patients also have a thickened coronary artery (tunica intima).
, Clinical findings in the heart during an AMI
With an electron microscopy, you can see these black dots that represent calcium related
depositions in the mitochondria. The influx of calcium and reactive oxygen proteins are
increased during an AMI and this results in calcium depositions in the mitochondria. When
you find these, you can conclude that there is cell damage.
On macroscopical level you can use nitrobluetetrazolium (NBT) to stain the LDH (Lactate
DeHydrogenase) that is normally present in cardiomyocytes (cytoplasma). During an AMI,
the cardiomyocytes suffer from ischemia (and therefore cell damage). These cardiomyocytes
will then release LDH.
- The blue arrow points to the place where an infarction has taken place and how many
hours it has been since the AMI.
Acute myocardial infarction: acute and chronic inflammation
During an AMI, there is an acute and chronic inflammation of the heart.
In picture 1 you can see an AMI that is 6-12 hours old:
- The neutrophilic granulocytes (PMN) are accumulated in the blood vessel and will then
penetrate the heart itself. This is due to the fact that the cardiomyocytes become necrotic
and then have high levels of complement that is chemotactic for these granulocytes.
In picture 2 you can see an AMI that is 12 hours – 3 days old:
- There is a huge increase of neutrophilic granulocytes in the heart.
In picture 3 you can see an AMI that is 3-5 days old:
- The neutrophilic granulocytes are disrupted (after huge necrosis of the cardiomyocytes)
In picture 4 you can see an AMI that is 1-2 weeks old:
- There is a development of granulation tissue that consists of lymphocytes, macrophages
and fibroblasts.
Research
The positive loaded phospholipids on the outside of the cell membrane have a strong
electrostatic interaction. During an infarction, the membrane will ‘flip-flop’, meaning that the
negative loaded phospholipids, that usually reside on the inside of the lipid bilayer, are now
flipped towards the outside of the cell membrane. This process can still be reversed and is also
found in apoptosis.
- The flip-flopped negative phospholipids can be detected using a Annexin V stain (binds
to phosphatidylserine).
Cells become apoptotic during an infarction. However, this is a problem because in order for
apoptosis to occur, the cells need ATP. This is not available during an infarction because there
is a decrease of ATP (ischemia). As a result, most of the cardiomyocytes during an infarction
become secondary necrotic in time.
- Research of these cardiomyocytes (where ischemia is induced) show that if there are no
inflammatory mediators, the cell damage is still reversible and the cells become normal
again. In the presence of inflammatory mediators, the cells will become secondarily
necrotic (as previously mentioned).
- sPLA2-IIA (secretory phospholipase A2) will bind to these flip-flop membranes and
then form binding sites for CRP (C-reactive protein). The CRP will bind and activate
complement (C) that will attract neutrophils and cause cell damage.
In case you add an sPLA2-IIA inhibitor called PX-18, the occurrence of secondary
necrosis will be prevented.
Complications AMI
