Cholesterol lowering + anti-inflammatory: the two cornerstones of atherosclerosis prevention and treatment!

With the deepening of exploration, the prevention and treatment concept of atherosclerosis is constantly updated
.

Cholesterol + inflammation "fusion" theory

The author points out that the phrase "without cholesterol, there is no atherosclerosis" has the second half - "without inflammation of the blood vessel wall, it is difficult to initiate atherosclerosis"
.

This is also the core content of the "fusion" theory talked about by the academic community, that is, cholesterol is the causative factor of atherosclerosis, and inflammation is also indispensable
.

It is worth mentioning that more than 100 years ago, Virchow, the father of modern pathology, pointed out that atherosclerosis is a chronic inflammation
induced by cholesterol.

Why can inflammation be the trigger?

According to the authors, inflammation can not only partially replace (supplant) or demote lipid risk factors, but also activate a series of signaling pathways that "fuse" lipids with other traditional atherosclerosis risk factors, and promote the formation
of atherosclerotic plaques with immunodisorders.

Fig.
1 Inflammation plays an important role in all stages of atherosclerosis

Thought determines behavior, and the concept of "fusion" has also promoted the change
of thinking in clinical management.
Lowering cholesterol and reducing inflammation are considered to be the two basic strategies
for the prevention and treatment of atherosclerotic disease (ASCVD) today.

A series of anti-inflammatory studies of colchicine and kanavimab have also illuminated the way forward of "fusion" theory
.

Rich in triglyceride lipoprotein and its residues: an independent risk factor for ASCVD

In addition to inflammation, triglyceride lipoproteins and their residues are also gradually coming into view
.

It was previously believed that in addition to the cholesterol in LDL particles having atherogenic effects, other lipoprotein particles in the blood including chylomicrons, very low-density lipoproteins and residues and cholesterol in medium-density lipoproteins did not have the ability to
"penetrate" subthelial to induce atherosclerosis because of their large "loaded" lipoprotein particles.

Recent studies, including genetics, population observations, and some interventions, have found that triglyceride rich lipoproteins and their residual cholesterol are also independent risk factors for
ASCVD.

For example, a study of more than 73,000 people, using the LDL-C genotype as a control, found that genetically every 1 mmol/L increase in residual cholesterol increased the risk of ischemic heart disease by 182%.

A study in China with an average follow-up of 5.
1 years in 4871 patients admitted with chest pain with coronary heart disease showed that residual cholesterol could significantly predict cardiovascular events
in patients with coronary heart disease and prediabetes/diabetes.

Clinically the level of residual cholesterol can be reflected indirectly by measuring blood triglyceride levels, or it can be measured
directly or obtained by computational methods.

In treatment, fibrates, high-purity fish oil and other drugs that significantly reduce triglyceride levels are the main interventions, and other cholesterol-lowering drugs including statins and ezetimibe have a certain degree of cholesterol-lowering effect
.

Lp(a) level: higher risk of atherosclerosis than LDL-C

Some scholars speculate that Lp(a) may have stronger atherogenic properties
than LDL-C.

Fig.
2 Schematic diagram of the structure of LP(a).

First, Lp(a) can penetrate into the arterial lining, binding to components of the extracellular matrix and promoting macrophage infiltration and smooth muscle cell proliferation
.

Secondly, Lp(a) has a unique Apo(a) structure, and Apo(a) is one of
the key structures for Lp(a) to exert its unique atherogenic effect.

Finally, among all lipoproteins, Lp(a) is the largest binding carrier of phospholipids oxide, which have important pro-inflammatory and atherosclerotic effects, and trigger inflammatory responses
in arterial walls by inducing pro-inflammatory signal activation from endothelial cells, smooth muscle cells and macrophages.

The recently released "Expert Scientific Recommendations on the Relationship between Lipoprotein (a) and Cardiovascular Disease Risk and Clinical Management" pointed out that elevated Lp(a) is an independent risk factor
for coronary heart disease, ischemic stroke and calcific aortic stenosis.

Serum Lp(a) levels are recommended in the following populations:

(1) Very high-risk groups of atherosclerotic cardiovascular disease;

(2) Family history of early-onset cardiovascular disease (male < 55 years old, female < 65 years old);

(3) Immediate family serum Lp (a) level increased > 90mg/dl (200nmol/L);

(4) Familial hypercholesterolemia or other hereditary dyslipidemia;

(5) Patients with
calcific aortic stenosis.

It is also recommended that Lp(a)
should be measured at least once in the general population of life.

Regarding the cut-off point value of Lp(a) to increase cardiovascular risk, the recommendations in different national guidelines and consensus are not consistent, and 50mg/dl
is used more often.

Based on available research data from Chinese cohorts, this recommendation tends to support 30 mg/dl as a cut-off point
for increased risk.

Plaque erosion: an important pathophysiology of the pathogenesis of acute coronary syndrome

Modern understanding of plaque erosion includes:

(1) Due to the wide application of statins, plaque erosion has replaced plaque rupture as the most common pathophysiological mechanism in the pathogenesis of acute coronary syndrome;

(2) Plaque erosion is a special lesion completely different from plaque rupture, the mechanism may be more complex, the patient population is younger, the lumen area is larger, and the autopsy results show a large area of endothelial cells shedding rather than stenosis;

(3) Most ST-segment elevation myocardial infarction is caused by plaque rupture, and the vast majority of non-ST-segment elevation type ACS is caused by plaque erosion;

(4) From the imaging point of view, plaque erosion is mostly white thrombus, and the thrombus load is small; Most of the ruptured plaques are red thrombus, and the thrombus load is large;

(5) Optical coherence tomography is the best means to identify thrombosis and thrombosis-related lesions in vivo, and has important value in diagnosing eroded plaques in ACS patients;

(6) The individualized treatment of ACS patients is very important, and traditional anti-plaque rupture treatment can be used for plaque erosion, but acute coronary syndrome caused by plaque erosion is more inclined to conservative drug treatment than revascularization, β receptor blockers, statins, ezetimibe and PCSK9 inhibitor therapy have shown better prospects
.