Inflammation in arteries

What is triggering inflammation in arteries?
I ask myself the same question since I read the seminal paper of Ross.
1/ in my practice I observed that heavy smokers do have the more extensive and accelerated forms of atheroma. They also present this kind of low grade systemic inflammatory state with a moderate increase of CRP and other inflammatory proteins, fibrinogen and prothrombotic imbalance of platelet activity and coagulation.
2/ but atheroma occur also in non-smokers I agree. Who are those patients? First the diabetic patients and patients with insulin resistance. Interestingly in the two papers, I sent to our group, excessive glycolysis in immune cells ( either because of dietary prédominance of carbs and/or because of genomics ) could contribute locally to an inflammatory metabolic state which builds plaques in areas of shear stress, or of damage to the glycocalyx or of retention of LDL or chylomicrons.
3/ atheroma is not a mandatory ageing process of arteries. I operated on nonagenarian patients for cardiac emboli with normal femoral, iliac or more distal arteries.


Obviously, there are initial damages of the arterial wall, to the glycocalyx and to endothelial cells by flow disturbances ( hypertension), smoke products, hyperglycemia and possible infections (bacteria in the blood).

Those damages occur only in arteries because flow conditions in veins do not damage the glycocalyx nor the endothelial cells despite the circulation of the same chemical molecules or biological weapons.

Those damages occur in transfer arteries and not on branches which penetrate deeply in organs. One possible explanation is the fact that in those arteries no lipid particles are supposed to cross to tissues. So they are stagnating in the wall after entering it, because of the damages to glycocalyx and endothelial cells.

Those damages allow LDL particles to enter the arterial wall at those sites where the endothelial barrier is the more damaged. Plaque formation is the following step because retention and inflammation drive immune cells to try to solve the problem by scavenging and destroy those LDL particles either native or modified by ROS in the subendothelial space or in the media of the artery.
Further steps are well known.

Two final remarks:
-only LC W3 PUFA and a potent anti-inflammatory drug have shown a significant risk reduction of cardiac deaths in clinical trials
-if glycolysis is so important in immune cells involved locally in plaque building, a drastic reduction of carbs should be a potent anti-inflammatory tool even in secondary prevention...

This puzzle is far from complete but it seems to me better shaping the reality.

Number of LDL particles
https://www.biorxiv.org/content/10.1101/691089v1?fbclid=IwAR3ruGfvYNffBiPKfC0cLX6Tv7H3BdcvYbbepyBuDn_lhto2WUsRbL4sfuY

Those with insulin resistance have smaller particles.

Why?

Because of cholesteryl ester transfer protein (CETP) and the transferring CE and triglycerides between the lipoproteins. LDLs become smaller, HDLs become smaller and go out through the kidneys, and you have similar levels of serum cholesterol but more particles. The size may have some influence but it’s possible larger can have their own issues because of aggregation and possibly more readily retained.

More particles increases the likelihood of modification happening. It is also a sign, as we have discussed, that the particles are hanging around longer in serum, depleting their antioxidant potential, which increases the likelihood of modification.
it will correlate with that, yes, as will the total-to-HDL-C ratio, the particle size, and the ApoB, but it is not deterministic of it. Particles getting into the subendothelial space is necessary but not sufficient for them to be atherogenic. Residence time within the subendothelial space is strongly influenced by the proteglycan matrix, the vulnerability to oxidation is strongly influenced by particle composition including antioxidant load, and how oxidizing an environment the subendothelial space is is strongly influenced by inflammation and other factors in the endothelial cells. More non-atherogenic particles in non-atherogenic conditions isn't going to increase the atherogenicity.

A Mendelian randomization tries to look at causality, doesn't it? Rather than biomarkers?