Statins prescribed to those with elevated cholesterol are among the most prescribed medications. Have you ever wondered how they protect users? (Even a little curious?) A new study on how plaque progresses is an opportunity to fill a gap in our understanding.
Before jumping into the study, we need to understand how elevated cholesterol causes cardiovascular problems. If the truth is told, sharing this information was one of the reasons I chose the study to share.
We’ll begin with the main characters in our story, the wall of the arteries and cholesterol. The arterial wall consists of three layers: the innermost, intima, which helps regulate the interaction between elements in the bloodstream. A middle layer, the media, consists of smooth muscle that constricts or dilates the artery and a tough outer layer, the adventitia, that holds it all together. 
Cholesterol is not always a villain; it is a bit misunderstood. It is the basis for steroid and sex hormones and Vitamin D. It is a significant component of cell walls, and it is either ingested in our diet or synthesized by our liver.
Our story begins at the intima, the surface where LDL cholesterols and triglycerides enter the arterial wall. The prolonged presence of LDL, oxygen and other arterial wall constituents causes the LDL to oxidize and signal for their removal. Cells, called monocytes, migrate to the area beckoned by, among other mediators, cytokines – the same ones involved in cytokine storm of COVID-19. The monocytes, now renamed macrophages, ingest the cholesterol and remove it from the cell wall taking it to the liver to be repurposed.
There is an equilibrium between the LDL in the blood and within the arterial wall, making our LDL levels a valuable biomarker of what is transpiring within the arteries. Besides its concentration, the other factor that drives LDL into arterial walls is the force pushing LDL into the wall – our blood pressure. That is why people with chronically higher blood pressures (hypertension) are more likely to have these fatty plaques.
When more LDL enters the cell wall than the monocytes can effectively remove, the equilibrium is altered. Those signals, meant to be transient, are now more persistent and chronic, bringing other changes.
The macrophages full of cholesterol but with no place to go are rebranded as foam cells because of their appearance. Some of these cells die, leaving behind that rich lipid load. Their death, along with “calls for help” by the remaining macrophage/foam cells, causes the smooth muscle cells of the media to migrate and cover over the area forming a fibrous cap against further lipid intrusion. The covering traps macrophages, smooth muscle, calcium, lipids, and fibrous tissue. It also snares some T cells that have responded to the localized inflammation.
As the plaque begins to enlarge, it begins to encroach on the lumen of the artery reducing the flow of blood. In response, the smooth muscle of the artery relaxes under the influence of nitrous oxide, and the vessel dilates. The formation of nitrous oxide is a stress response governed by an enzyme. It counterbalances the inflammatory response by reducing cytokine signaling and migration of smooth muscle. But ultimately, the enzyme cannot keep up with the need, and the equilibrium again shifts. Without nitrous oxides' “anti-inflammatory” response, more plaque can form. The anti-inflammatory counterbalance is the reason why fruits and vegetables high in flavonoids may improve our cardiovascular health.
These fibrous caps offer some temporary safety, but the signals of arterial wall distress continue. The trapped macrophages try to “bust out” by weakening and matrix they are surrounded by, while the T cells reduce the fibrous tissue formation by the smooth muscles. The end result is a weakening fibrous cap. Most patients think of LDL clogging our arteries like silt reducing the depth of a river. But this is not the case; the loss of the fibrous cap can result in dramatic changes.
At some point, the fibrous cap is so weakened that it is breached, exposing the bloodstream to all of those cellular elements. In some cases, this debris continues to travel downstream, getting stuck in tiny capillaries. A form of transient blindness, amaurosis fugax, is caused by these showers of cholesterol and was first identified in 1961 by an ophthalmologist Dr. Hohllenhorst. Often these tiny atheroembolic events go unnoticed, but they have a cumulative effect resulting in sluggish and stopped blood flow. Think of it like a highway where all of the exits are blocked. Even though the road may be wide open, there is no place for the cars to go.
The loss of the fibrous cap also exposes the blood to cells, smooth muscle, and fibers, all that facilitate clot formation. The clots may be large enough to break away and cause further downstream damage, like a heart attack. Or they can cover the exposed area and subsequently become incorporated, narrowing the artery still more.
As a new study confirms, statins reduce the volume in plaques by lowering the total circulation LDLs, but they also make the plaque less vulnerable to being breached.
Researchers used 2500 serial images of the coronary circulation obtained using CT angiography of 860 patients. The imaging technique is less invasive than cardiac catheterization and more easily characterizes plaque by its density expressed in Hounsfield units. They may be low attenuation (least dense), fibro-fatty, fibrous, low-density calcium, high-density calcium, and 1K (highest density). As a generalization, the less dense the plaque, the more vulnerable it is to being breached and causing atheroembolization, clotting, or dramatic changes in luminal size.
The researchers looked at the changes in the plaque over time, categorizing patients by their use of statins. Those taking statins were slightly older, more frequently male, and with a greater incidence of diabetes and hypertension. Statin use lowers LDL levels by about 17%; among those statin-free, LDL dropped by 2.5%, so we can confirm that statin use effectively lowers serum LDL. By our newfound understanding of plaque formation, we would expect plaque volume to decrease – and that is what the researchers found.
- Statin users had lower volumes of low-attenuation plaque and higher volumes of those calcified forms. The higher density plaques’ volumes were the most increased.
- Without statins, low-attenuation plaque and fibro-fatty plaques increased in volume.
- Those mid-density fibrous plaques were unchanged by statin or non-statin use.
The natural trend in plaque progression is that all forms get bigger; that should be no surprise. Statins reduce the degree of advancement, more so for the less dense, more vulnerable plaques. It also increases the volume of the less vulnerable plaques, increasing their calcification; it does not, however, hasten the conversion of the vulnerable to the less vulnerable.
Once again, the complexity of our biological responses makes generalizations difficult. The fact that statins are not fully protective for outcomes reflects our biological reaction to them. It is this fact that underlies the concept of personalized medicine.
 The smooth muscle is involuntarily controlled by our nervous system and regulates flow by contracting and relaxing that constricts or dilates the vessel's lumen. That outer layer is like that we see around a hydraulic hose. It gives integrity to a high-pressure system.
Sources: Atherosclerosis: Process, Indicators, Risk Factors and New Hopes International Journal of Preventative Medicine PMD 25489440
Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition JAMA Cardiology DOI: 10.1001/jamacardio.2021.3055