Dyslipidemia Part 3: Atherosclerosis
Do you know what’s the most common cause of death worldwide?
It’s atherosclerotic cardiovascular diseases, in short, ASCVD.
The most important are, depending on the most commonly affected vessels, coronary heart
disease with myocardial infarction, peripheral arterial occlusive disease, ischemic stroke,
and aortic aneurysm.
Less common ASCVDs include vascular dementia, abdominal angina, mesenteric ischemia, and
renal artery stenosis.
Atherosclerosis is asymptomatic but plays a decisive role as a trigger for these potentially
fatal complications.
So, what exactly is atherosclerosis?
It’s a chronic disease of the vascular intima of large and medium-sized vessels.
The fatty plaques and especially inflammatory processes within the intima lead to the displacement
of the lumen, hardening and blockage of the vessels, as well as aneurysms.
The precise pathophysiological development of atherosclerosis, that is, atherogenesis,
isn’t quite fully understood.
The process begins gradually, continuing over decades.
However, certain known factors contribute to the development of atherosclerosis via
various mechanisms.
We’ll take a closer look at the risk factors at a later stage.
All triggering factors initially lead to chronic stress and, therefore, to endothelial dysfunction.
Depending on the initiating factor, this stress can be of hemodynamic or toxic nature.
Endothelial dysfunction is mainly caused by a lack of nitric oxide, which usually regulates
blood vessel diameter and permeability.
This deficiency is caused by oxidative stress and dysfunctional NO synthase.
As a result, microlesions appear in the endothelium, increasing its permeability for lipoproteins.
LDL accumulates in the intima, which thickens as a result.
Subsequently, the deposited LDL is oxidized.
Today, it’s assumed that this oxidation marks the start of the development of atherosclerosis.
Oxidized lipids have a negative effect in a variety of ways.
They’re cytotoxic and lead to persistent inflammatory and immune reactions in tissue.
They further inhibit formation of the transmitter nitric oxide.
This leads to increased platelet aggregation and adhesion, as well as the adhesion of monocytes
and leukocytes to the endothelium.
Vascular permeability becomes increasingly out of balance.
Also, oxidized lipids stimulate endothelial cells to produce adhesion molecules and chemokines.
As a result, macrophages migrate into the intima.
Here, they absorb unregulated cholesterol and die, undergoing necrosis.
Microscopically, these cells have a foamy appearance due to the numerous lipid droplets.
Accordingly, they’re termed foam cells.
In the vessel, they initially form yellow flat streaks that are the first visible lesions
and are called fatty streaks.
The role of fatty streaks in the development of atherosclerosis hasn’t been conclusively
clarified: Though, it’s certain that they can occur in children and are distributed
throughout the vascular system, that is, not only in sites prone to atherosclerosis.
Also, they’re initially reversible.
As an early sign, fatty streaks aren’t observed in all cases of atherosclerosis.
However, they can develop into atherosclerotic plaques over time as atherogenesis progresses:
The previously mentioned microlesions in the endothelium lead to platelet and leukocyte
adhesion.
Platelets and invading macrophages release cytokines, including growth factors such as
platelet-derived growth factor.
They promote smooth muscle cell migration from the tunica media into the intima, where
they proliferate.
Through this, an extracellular matrix of collagen, elastic fibers, proteoglycans, and calcium
starts to form.
The growing atherosclerotic plaque now consists of a fibrous cap and an underlying necrotic
core with foam cells.
At first, the cap is thick and stable.
Through an increasing number of macrophages and growing lipid core, the stabilizing matrix
may undergo inflammatory degradation.
The cap becomes increasingly thinner, which can eventually lead to plaque rupture.
This exposes the necrotic core.
A thrombus can form at the site of rupture, or an embolism distal to the site.
However, atherosclerotic plaques can have very different compositions and don’t always
lead to rupture.
Let’s take a closer look at the different morphologies.
There are two types of plaques, stable and unstable: In unstable plaques, as we’ve
just seen, a lipid-rich core forms with a strong inflammatory response.
This destabilizes the fibrous cap, increasing the risk of plaque rupture.
Here, plaque growth is usually abluminal, that is, outward growth from the lumen; therefore,
unstable plaques are mainly non-stenosing.
In extreme cases, these lesions occur in large numbers.
If plaque rupture occurs, the result is, as we previously saw, the formation of a thrombus
or embolism, with corresponding acute vascular occlusion and infarction.
However, in stable plaques, only small amounts of lipids are deposited in the vascular wall.
Also, there’s a lower inflammatory response.
The lipid core lies under a thick fibrous calcified cap, so the risk of plaque rupture
is relatively low.
Instead, stable plaques don’t show much outward growth, but rather inward.
This results in a slow progressive stenosis and, ultimately, in occlusion.
The number of stable plaques are lower than that usually observed for unstable plaques.
However, strong calcification leads to arterial stiffening and dysfunctional hemodynamics,
that is, blood flow.
Stenosing lesions frequently lead to ischemia or angina pectoris.
As already indicated, atherosclerosis and potential complications develop rather slowly
and gradually.
So, preventive measures and reducing risk factors are crucial to prevent or, at least,
delay their development.
The most important risk factors of atherosclerosis are smoking, diabetes mellitus, arterial hypertension,
and disorders of fat metabolism, that is, dyslipidemia.
These risk factors are associated with obesity, lack of exercise, and poor nutrition.
Besides smoking, this cluster of risk factors is also termed metabolic syndrome.
Genetic predisposition, sex, and age also play a role.
However, the last three factors can’t be affected by preventive measures.
So, how do the main risk factors mentioned favor the development of atherosclerosis?
The means by which smoking leads to atherosclerosis is still incompletely understood.
Smoking definitely increases oxidative stress in the body, has a toxic effect on epithelial
cells, and, therefore, promotes platelet activation and inflammatory reactions as shown.
Also, lipid metabolism is affected: Smokers have higher plasma cholesterol, triglyceride,
and LDL levels, but lower protective HDL levels.
As a result, smokers show an increased share in harmful oxidized LDL particles.
In diabetes mellitus, the production of pro-inflammatory cytokines is increased in the endothelium.
A diabetic metabolic state also leads to the formation of oxygen radicals, and, consequently,
oxidative stress.
This facilitates the inflammatory reaction and directly damages the endothelial cells.
On top of that, diabetes mellitus also disrupts formation of the transmitter NO, and, thereby,
vascular endothelial function.
As a risk factor, arterial hypertension also acts on several levels.
Most importantly, high blood pressure naturally increases the hemodynamic shear stress on
vascular walls.
Moreover, it facilitates inflammatory processes.
This is due to angiotensin II, which stimulates pro-inflammatory cytokine production in endothelial
cells.
Dyslipidemia with increased LDL and total cholesterol, as well as decreased HDL levels,
lead to increased lipid deposition in the vascular intima.
As we’ve seen, these have a cytotoxic effect, especially in their oxidized form, and they
facilitate inflammatory and immune reactions.
You can also check out the AMBOSS article on atherosclerosis for more information.
In the next Chalk Talk episode in this course, we’ll tackle the treatment of the most controllable
risk factor: dyslipidemia and, especially, hyperlipoproteinemia.
But before we do that, here’s a quiz on atherosclerosis.