Borén J, et al. Eur Heart J. 2020 Feb 13. pii: ehz962.

Wide ranging data from epidemiologic, genetic, and clinical intervention studies has certainly observed that low-density lipoprotein (LDL) is causal in the process, as summarized in the first Consensus Statement on this topic. This second Consensus Statement on LDL causality examined the standard and current novel biology of atherosclerotic cardiovascular disease (ASCVD) at the molecular, cellular, and tissue levels, with attention on integration of the central pathophysiological mechanisms.

Trancytosis of low-density lipoprotein across the endothelium

Apolipoprotein B-containing lipoproteins of within ~70nm in diameter [i.e. chylomicron remnants, very low-density lipoproteins (VLDL) and VLDL remnants, intermediatedensity lipoproteins (IDL), LDL, and lipoprotein(a) (Lp(a))] can cross the endothelium. Most important features of the influx and retention of LDL in the arterial intima, with following pathways of modification resulting to (i) extracellular cholesterol accumulation and (ii) development of cholesteryl ester dropletengorged macrophage foam cells with conversion to an inflammatory and prothrombotic phenotype. Both of these major pathways support creation of the plaque necrotic core comprising cellular and extracellular debris and LDL-cholesterol-derived cholesterol crystals (Figure 1).

Figure 1: Low-density lipoprotein (LDL) as the primary driver of atherogenesis. CE, cholesteryl ester; DAMPs, damage-associated molecular patterns; ECM, extracellular matrix; FC, free cholesterol; GAG, glycosaminoglycans; PG, proteoglycans; ROS, reactive oxygen species

Factors affecting the low-density lipoprotein subfraction profile

Subjects with plasma triglyceride (TG) within range of 0.85–1.7mmol/L (75– 150mg/dL) deliver VLDL1 and VLDL2 from the liver, which are delipidated quickly to IDL and then essentially to LDL of average size; therefore, the LDL profile is controlled by LDL-II (Figure 2A). Instead, individuals with low plasma TG levels (<0.85 mmoL/L or 75 mg/dL) have extremely active lipolysis and usually low hepatic TG content. Accordingly, hepatic VLDL inclined to be smaller and certainly some IDL/LDL-sized particles are instantly discharged from the liver. The LDL profile exhibits a greater proportion of larger LDL-I (Figure 2B) and is linked with a healthy state (as in young women).

Figure 2: Model of the metabolic interrelationships between low-density lipoprotein (LDL) subfractions and their hepatic precursors

Responses elicited by low-density lipoprotein retained in the artery wall

The enrolment of myeloid cells is also associated by the penetration of both CD4+ and CD8+ T cells that show indication of activation and may engage with other vascular cells offering molecules for antigen demonstration, like major histocompatibility complex II. Examination of the T-cell receptor capabilities of plaque-infiltrating T cells revealed an oligoclonal origin of these T cells and recommend enlargement of antigen-specific clones. Certainly, T cells with specific feature for apoB-derived epitopes have been determined, correlating adaptive immune responses to the vascular retention of LDL (Figure 3).

Figure 3: Cellular and humoral immune responses in atherosclerosis. EC, endothelial cell; Mph, monocyte-derived macrophage

Defective cellular efferocytosis and impaired resolution of inflammation

The potent removal of dying cells by phagocytes, referred efferocytosis, is an essential homeostatic method that certifies outcome of inflammatory responses (Figure 4). Externalized ‘eat me’ signals which includes phosphatidylserine (PS), calreticulin, and oxidized phospholipids (oxPL) are identified by their specific receptors, Mer tyrosine kinase (MerTK), low-density lipoprotein- receptor-related protein 1 (LRP1), as well as integrin avb3 and CD36 on macrophages; that kind of identification is promoted either straightaway or through by bridging molecules like growth arrest-specific 6 for PS, complement protein C1q for calreticulin and milk fat globule-epidermal growth factor 8 (MFG-E8) for oxPL. Calcium-dependent vesicular trafficking events indicated by mitochondrial fission and LC3-linked phagocytosis (LAP) encourage phagolysosomal fusion and the hydrolytic degradation of apoptotic cells. Concurrently, natural immunoglobulin (Ig)M antibodies with reactivity towards oxidation-specific epitopes further increase the potent clearance of dying cells via complement receptors (Figure 4 A).  In highly evolved atherosclerosis, more than one of these mechanisms are dysfunctional and can give rise to faulty efferocytosis, reproducing non-resolving inflammation and plaque necrosis. Further processes assisting to impaired efferocytosis are ADAM-17-mediated cleavage of MerTK along with the inappropriate expression of the ‘don’t eat me’ signal CD47 on apoptotic cell surfaces (Figure 4 B).

Figure 4: Schematic representation of processes involved in lesional efferocytosis. ACs, apoptotic cells

How does plaque composition and architecture relate to plaque stability?

Recommended final operation those precipitate ruptures which involve senescence and death of residual cap smooth muscle cells (SMC), degradation of the fibrous matrix by macrophage-secreted proteolytic enzymes, and cholesterol crystals, which may diffuse cap tissue. These methods reveal the prothrombotic plaque interior and outcome in neutrophil-accelerated thrombosis. Recent assumptions indicate that the combination of disturbed blood flow and endothelial activation by immune activators, such as hyaluronan fragments, may cause neutrophil recruitment with neutrophil extracellular trapsosis, endothelial cell apoptosis/sloughing, and thrombus formation (Figure 5).

Figure 5: Proposed mechanisms of plaque rupture and plaque erosion. ACS, acute coronary syndrome; NETosis, cell death by neutrophil extracellular traps

Can genes influence the susceptibility of the artery wall to coronary disease?

Genome-wide association studies and linked data demonstrate that predisposition to ASCVD is correlated with multiple variants in genes that have impact on plasma LDL concentration (Figure 6). Loci identified by genome-wide association studies (GWAS) can have distinct impact on low-density lipoprotein (LDL). In figure 6, on the left are highlighted selected GWAS loci linked with LDL-cholesterol (LDL-C) levels, numerous of which are correlated with atherosclerosis events and are included in predictive risk scores. On the right are shown loci that do not primarily have impact on LDL-C levels, but rather support qualitative changes as well as in the particle itself or in the vessel wall to locally encourage atherogenesis.

Figure 6: Genomic loci associated with atherosclerosis.

Eventually, this theory has emphasized novel mechanistic traits of atherosclerosis that can effectively result in estimation of novel therapeutic goals integral to arterial wall biology and plaque stability. Important amongst these are endothelial transcytosis of atherogenic lipoproteins, monocyte/macrophage and SMC biology, efferocytosis, inflammation, innate and adaptive immune responses to the intimal retention of apoB-containing lipoproteins and calcification.