Lipoprotein(a) and macrophages in tandem within a human coronary plaque biopsy:

Here are some pictures of Lp(a) together with macrophages taken from a human coronary atherosclerotic plaque.  Panel C are the macrophage foam cells, Panel D is Lp(a).  They are clearly one on top of the other.

This is taken from: Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation  from all the way back in 1998.  It would be inaccurate to say that there is only 1 person on the planet who recognizes Lp(a) as an atherogenic factor.

The question of causality and time-frame is always to question.  The essential point we're trying to make is that Lp(a) doesn't just swoop in from out of nowhere for no reason all the sudden.  Macrophages which do home into inflammatory cytokine signals emitted by the artery, and do burrow in to receive cholesterol via active receptor exchange to return to the liver, also don't just suddenly go in and start chewing up lipoproteins.  That being said, foam cells and Lp(a) happen together frequently.  In any remodeling process in the body, there is nearly certainly found macrophages.  You can't just ignore the immune system.

What is my position?  It is irrelevant.  It is beyond irrelevant "who is right," but what is germaine is "WHAT is right."  I do not care "who" is right, nor should you.  Those who care intensely about who should be right obviously have something else driving them like a jerk's ego or some frivolous vendetta.  The question should be, how do we make each and every one of the millions of people of Earth right in their application of science.  What we should all care about is "what is right," not "who is right."  Needless to say, that is my concern in science, no extraneous nonsense.

What is true is that macrophages are initially participating in a beneficial remodeling process, and not chewing up ox-LDL in some parasitic process, but attempting to hand back the remodeling waste, the construction site debris back to the liver for recycling via....HDL.  We certainly can't ignore HDL in this repair process either.  It will spin cardiopathology's noodle when they see that the majority of atherosclerotic plaques are rich in ApoE, which if extended the old logic applied to LDL is causing harmful things.  On the contrary, the presence of ApoE we all know to be part of the repair process which may be overwhelmed by a net excess of damage as opposed to a net excess of repair.

Does Lp(a) cause atherosclerosis?  Only if there is a reason for atherosclerosis to take place.  For a many humans who eat just an orange a day but still have the Gulo-/- genetic defect, there is a lot of cumulative damage that does occur which needs patching by Lp(a) and the coagulation system.  Think of it this way, when thinking about preserving arterial integrity: a normal rat makes the equivalent of 5 grams a day in a 70 kilo human when nothing is going on.  In stressful times, a rat makes 300% more vitamin C.  This entry certainly is not encouraging or supporting the fallacy that dietary cholesterol causes heart disease.  It does not, but other dietary factors such as too low vitamin C, B, E, magnesium, K, D, amino acids and too much trans-fatty acids and omega-6 do.  The recent US Federal guidance to stop paying attention to ingested cholesterol is a well-studied one made with decades of clinical evidence that cholesterol consumption has historically had nothing to do with the rate of heart disease.

I think this statement I made a long time ago sums it up nicely about what is going on:

 "A big lump is better than a big hole."

One prevents lethal hemorrhage, the most dramatic example in human biology being the aortic dissection with adventitial failure, the other is lethal hemorrhage.  One of the first priorities of the human physiology is to stop bleeding and hemorrhaging.  It drops everything it is doing and attends to that first, even if it means making a pile of disorganized stuff at the site of leaking that is harmful down the road.  Better than bleeding to death.  Lp(a) is very atherogenic at sites of arterial damage, and sticks more to the glycocalyx with ascending concentrations.  If the endothelium is in tact, there is nothing for Lp(a) to react to, no ligand, no binding site to the ligand.  Lp(a) just floats along harmlessly as it does not encounter plasminogen binding sites, free lysyls, fibrin, exposed subendothelial fibronectin, etc.  You can't just ignore the coagulation system either.  Lp(a) has a direct affinity to fibrin(ogen) which is Clotting Factor 1, and gets cross-linked to fibrin clots via FactorXIII.  Do macrophages foam cells CAUSE atherosclerosis?  No.  They are attempting to prevent it, but the process can and does go wrong if they get overwhelmed.  When they are participating in arterial repair, foam cells are formally defined as early plaques, but that is simply a matter of scientific semantics.  Perhaps one day, they will be relabeled as "reparative cells" distinct from a fibrofatty mass devoid of cells that can rupture and cause thrombosis. Given an equal sized foam cell lesion and fibrofatty mass with thin cap that is  less than 20% occlusive, the unstable fibrofatty mass is the dangerous thing, and the foam cell lesion is unconcerning.

Macrophages and foam cells are not always in human atherosclerotic plaques.  In fact, many times, they are not there at all.  Many pathologist specimens of human diseased atherosclerotic arteries do not have foam cells, which is why some scientists choose to de-emphasize them or diminish their importance.  But they do happen, and we can't just ignore them.  One improvement in the future state-of-the-art may be to put macrophages and foam cell "lesions" in a category all on their own as they are dynamically different from all other component atherosclerotic plaques, and not just different in cellular origin and composition.  They also serve an entirely different purpose altogether than other cells found in human plaques, including remodeling, debris clearance, and returning the artery back to its original state.

You can't just ignore foam cells. Fatty streaks happen, with or without Lp(a). An addendum of "Common Sense."

Given that the guinea pig DOES NOT have Lp(a) but only LDL in a higher ratio to HDL than in wild mice, and that they do incur atherosclerosis upon chronic scurvy, there is no ambiguity that vitamin C deficiency is causal to atherosclerosis WITHOUT invoking apo(a).  Unless a genetically modified variant of guinea pig happens, they will never express apo(a) protein.  The "immunological evidence" proferred by others is obviously a cross-reaction to a different protein, perhaps even apo(a)-like, but certainly it is not lipoprotein(a).  It could not be, rendering any reference to Lp(a) an illogical train of thinking.  However, they do have an ample amount of LDL.  ApoB particles are important to atherogenesis.  We can't just suddenly start ignoring ApoB, not the Lp(a) platform people either.  Without ApoB synthesis, amplified by inflammatory arterial cytokines, there is NO Lp(a).  In mice that can't make vitamin C but also don't have much LDL but a vast majority of HDL, atherosclerosis is limited to a mild physiological hypertrophy, proteoglycan accumulation, and fibrosis, called arteriosclerosis in olden days.  There are some thoracic aortic lesions especially at bifurcations to the digestive system, but little to no atheroma of any visible or clinically significant nature with a majority HDL and few ApoB particles/absolute mass/LDL-cholesterol.  This clearly shows that ApoB containing particles outnumbering ApoA containing particles is a precondition to scurvy induced atherosclerosis, as much as scurvy is a precondition to endothelial dysfunction, the cause and initiation of most atherosclerosis.  This is without getting into the complicated vasa vasorum component which later contributes to erythrocyte evasation into pre-existing plaques where they die and rupture, releasing membrane cholesterol and iron. (It may be in the very near future, the lipid cores and free cholesterol are found to be from intra-plaque hemorrhage from the interdigitating vasa vasorum rather than the vexing (to some people) foam cell plaque "bust.")

That being said, the atherosclerosis that occurs without Lp(a) is much milder than that which occurs with Lp(a).  Atherosclerosis with low Lp(a) and human-esque levels of LDL is much decreased in lesion number, lesion size, and lesion complexity compared to atherosclerosis that occurs with even moderate Lp(a) around.  Lp(a) over 30mg/dL certainly will drive more atherosclerosis, but lower levels of Lp(a) below 20mg/dL also contribute by virtue of its "homing missile" like quality of binding to areas of damage which it finds in the system circulation of 60,000 miles.  It may not matter how much over a certain threshold of Lp(a), but it does potentiate worse and more with ascending blood levels of Lp(a).  There is no question that Lp(a) is atherogenic, but without LDL, how can there be Lp(a)?  It is not an "either-or" or "better or worse" proposition, but where all these facts that the 1000's of highly intelligent global cardiology scientists have seen intersect and what that nexus and conjunction of truth is.

Ox-LDL is a reliable marker of vessel disease and number of vessel involvement

Does this mean that Ox-LDL causes atherosclerosis?  Yes AND No.  It is too low to ever cause atherosclerosis, with circulating levels in multi-vessel CAD being at most 4mg/dL, and normally being 1mg/dL.  However, it is an extremely reliable indicator of CAD, with a level of 3mg/dL Ox-LDL most certainly revealing plaque in the coronaries somewhere.  Its importance is locally in microenvironments where inflammation causes ROS which causes oxidation and acetylation of LDL in the microscopic milieu around the lesion.  If LDL is not oxidized or denatured, it is not "irritating" to the artery, no.  Regular LDL, even in very high concentrations has been proven not to be cytotoxic to the endothelial cell or cause stress fiber contraction.  As I have already said a long time ago, the LDL gets into the artery if and when the endothelial layer (or vasa vasorum) is compromised and has spatially large enough breaches for it to go through.  Vesicular transport would cause LDL to accumulate inside a cell, not outside it, which we'll get to in just a second.

LDL consumption by a cell is highly regulated, and a cell stops internalizing LDL when it has enough, or the cell will turn down its internal synthesis while maintaining internalization.  Extracellular aggregates of native LDL could not be there if they could not reach these subendothelial compartments somehow (increased vascular permeability).  Ox-and Ac-LDL has a special receptor, scavenger receptor, evolutionarily built in humans, the creature with nearly exclusively the majority of fatal heart attacks and strokes, to get rid of apoptotic cells...and denatured LDL.  When scavenger receptor cells encounter ox-LDL, they engulf it without stop.  Call it gobbling, but more accurately, they are the "trash men," the "recycling team," not "police men."  As much as a policeman can clear debris on a highway, and often does for the public benefit, the macrophage can also serve to clean the artery, not "eat it" or "police" it.  The "old concept" people know that fatty streaks, cellular foam cell masses DO NOT burst.  So, the cartoon does call out an inaccuracy - the notion that foam cell lesions form, burst open, and evulse their cholesterol into the artery.  Early on, no.  These are most stable cellular accumulations which would prevent further destabilization of an artery.  Later on, if the condition is unresolved, the damage unmended, and the "artery tumor" becomes hypoxic, like in a tumor, the macrophages would undergo necrosis and form a necrotic core, just like happens in a tumor core.

In human plaques, foam cell formation from the smooth muscle cell component is vastly underestimated because in mice, the majority of foam cells occur from macrophages.  In humans a greater proportion of foam cells happen from the artery cells themselves.  Yet, make no mistake, foam cell "fatty streaks" are found all the time in human atherosclerosis.  They may be there, they may not be, but an astute scientist does not simply ignore foam cells, especially those colocalized upon an Lp(a) deposit.  There are vastly more human plaques that do not have a foam cell component, and these actually are more worrisome because they are less revertible than a foam cell fatty streak.  Why?

The foam cell, like the apo(a) protein, isn't just some random superfluous curiosity, an accident of biology with no purpose.  Foam cells not only contribute to the artery structure temporarily as additional cells with their hydrophobic seal against hemorrhage, cholesterol, but also are participating in transport of excess unused or remaining cholesterol back to the liver, just as LDL delivers useful cholesterol for cell replacement.  Of all cell types, the macrophage is very efficient at this process.  So we see that this too is a useful, purposeful event, that if resolves satisfactorily, signals the macrophages to exit the artery wall, making the fatty streak lump vanish.  Some call it "reverse cholesterol transport," others don't like that name and call it something else.  Once again, you can't just ignore foam cells or dismiss fatty streaks.  Just as Goldstein and Brown didn't just fabricate a mythic fable of LDL homeostasis, despite this encouraging systemic statin poisoning, scientists and pathologists did not 'just make up' a fable of fatty streaks and foam cells being in human arteries.  Truly, these are about repair, rather than a nonsensical auto-attack on the artery wall, although auto-immune arteritis is a real disease too.  It is increasingly important to stay updated with the field to see others' understanding of the issue so that all science and scientists everywhere can eventually come to a real-world consensus.  Or we can rage around ham-fisted and grandstanding, pretending to know everything without the diligence necessary to know everything.

Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?