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Stanciulescu, L.A.; Scafa-Udriste, A.; Dorobantu, M. Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes. Encyclopedia. Available online: (accessed on 18 June 2024).
Stanciulescu LA, Scafa-Udriste A, Dorobantu M. Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes. Encyclopedia. Available at: Accessed June 18, 2024.
Stanciulescu, Laura Adina, Alexandru Scafa-Udriste, Maria Dorobantu. "Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes" Encyclopedia, (accessed June 18, 2024).
Stanciulescu, L.A., Scafa-Udriste, A., & Dorobantu, M. (2023, April 13). Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes. In Encyclopedia.
Stanciulescu, Laura Adina, et al. "Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes." Encyclopedia. Web. 13 April, 2023.
Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes

Cardiovascular disease (CVD) impacts hundreds of millions of people each year and is the main cause of death worldwide, with atherosclerosis being its most frequent form of manifestation. Low-density lipoproteins (LDL) have already been established as a significant cardiovascular risk factor, but more studies have shown that small, dense LDLs are the ones more frequently associated with a higher overall risk for developing atherosclerotic cardiovascular disease. Ever since atherogenic phenotypes were defined for the first time, LDL subfractions have been continuously analyzed in order to identify those with a higher atherogenic profile that could further become not only high-accuracy, effective prognostic biomarkers, but also treatment targets for novel lipid-lowering molecules. 

lipoproteins LDL subfractions cardiovascular risk atherosclerosis coronary artery disease NMR spectroscopy dyslipidemia cholesterol cardiovascular prevention

1. Role of Low-Density Lipoproteins in Cardiovascular Disease

Lipoproteins in plasma are responsible for the transportation of lipids to tissues, which can be used for energy production, the storage of lipids, the production of steroid hormones, and the formation of bile acids. Lipoproteins consist of cholesterol, triglycerides, phospholipids, and proteins (apolipoproteins), which serve as structural elements, ligands for cellular receptors, and activators/inhibitors of enzymes. The six main lipoproteins in the blood are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, lipoprotein a (Lp(a)), and HDL [1].
Apolipoprotein B (ApoB), containing lipoproteins of less than 70 nanometers in diameter, can traverse the endothelial barrier, particularly when the endothelium is compromised, where they may become ensnared following interactions with extracellular components such as proteoglycans. Subsequently, they are retained within the arterial wall and further begin a very complex process that ultimately leads to an atheromatous plaque.
Those with higher levels of ApoB-containing lipoproteins in their plasma will take in more particles, build up lipids more quickly, and grow more quickly, leading to the advancement of atherosclerotic plaques. Therefore, the overall atherosclerotic burden is likely to be at least partly defined by the serum-circulating levels of LDL-C and other ApoB-based lipoproteins and also by the period of exposure to these particles.
The development of atherosclerotic plaques starts with damage to the endothelial cells, allowing more LDL particles to pass through the walls of the vessels. These lipoproteins, particularly LDL, become caught in the intima by the cellular matrix. The LDL is then modified and taken in by macrophages using special cell-surface pattern recognition receptors (also known as scavenger receptors), leading to the creation of foam cells. As more lipids accumulate, smooth muscle cells move into the lesion, encapsulating the plaque, and forming a fibrous barrier to protect the lipid core from the lumen of the vessel. In some cases, these plaques can lead to a decrease in blood flow, or the plaque can rupture, causing a thrombus to form and block the flow of blood.

2. What We Know So Far

The latest ESC/EAS Good Clinical Practice Guidelines for the Management of Dyslipidaemias (2019) recommend an LDL-C reduction of at least 50% from baseline and an LDL-C goal of less than 55 mg/dL (1.4 mmol/L) for both primary and secondary prevention in very high-risk individuals, as well as for primary prevention in very high-risk individuals with familial hypercholesterolemia. The guidelines also recommend LDL-C goals of less than 40 mg/dL (1 mmol/L) in patients with ASCVD who experienced a second vascular event within 2 years while on a maximally tolerated statin treatment, less than 70 mg/dL (1.8 mmol/L) for overall prevention in high-risk individuals, less than 100 mg/dL (2.6 mmol/L) in moderate risk individuals, and less than 116 mg/dL (3 mmol/L) in those at low risk of developing a major cardiovascular event.
The lipid goals and lipid-lowering therapeutic strategy are part of a larger, more comprehensive cardiovascular (CV) risk reduction management approach and it was previously believed that it was appropriate to reduce the LDL-C serum levels to as low as possible in high- and very high-risk patients.
The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) study compared the effects of two different doses of simvastatin (20 mg and 80 mg) on 12,064 people who had previously suffered a heart attack in a double-blind trial. After two months, the 80 mg group had a 0.51 mmol/L (19.7 mg/dL) lower LDL cholesterol level than the 20 mg group, but this difference was reduced to 0.29 mmol/L (11.2 mg/dL) after five years. There was a nominal reduction in nonfatal myocardial infarctions in the 80 mg group, but the primary endpoint of major vascular events was reduced by only 6% (p = 0.10) [2].
A meta-analysis published later based on similar studies revealed a 15% reduction in risk with a mean decrease in LDL cholesterol of 0.51 mmol/L (19.7 mg/dL) when using high-dose statins (p < 0.0001) [3].
On the other hand, more recent studies propose a different hypothesis. A study published in 2020 by C.D.L. Johannesen et al. prospectively evaluated 108,243 subjects with a median follow-up period of 9.4 years in order to evaluate the correlation between the serum levels of LDL-C and all-cause mortality, and concluded that the association between LDL-C and the risk for all-cause mortality was U-shaped, with both low and high levels associated with an increased risk of mortality (the lowest overall risk being observed at an LDL-C concentration of about 140 mg/dL–3.6 mmol/L) [4].
Another prospective study based on a cohort of 14,035 adults aged 18 years and older, with a median follow-up period of 23.2 years (with a mean age of 41.5 years, 51.9% women), noted that both very low and very high LDL-C levels were associated with increased risk of CVD mortality. In particular, very low LDL-C levels were associated with a higher risk of stroke and all-cause mortality [5].
Another study evaluated the association between low levels of LDL-C and intracerebral hemorrhage (ICH) and concluded that, in patients who present a high risk of developing ICH, a cautious approach and individualized therapy strategy are advised before considering an aggressive LDL-C level reduction approach, as the association still remains uncertain, even after a comprehensive literature review. This particularly relates to the new cholesterol-lowering treatments that have emerged lately, and those that are currently in development, which are created to achieve swift and effective lowering of LDL-C with improved clinical outcomes and less excessive ICH adverse events [6].
Furthermore, a recent study by Yen et al. (2022) [7] focusing on assessing the benefit of LDL-C level lowering treatment and the overall cardiovascular and renal outcomes in patients with stage 3 chronic kidney disease (CKD) evaluated approximately 8500 newly diagnosed CKD patients and divided them into three groups according to their first LDL-C level after the index date: <70 mg/dL, 70 to 100 mg/dL, and >100 mg/dL. Compared with the LDL-C ≥ 100 mg/dL group, the 70 ≤ LDL-C < 100 mg/dL group exhibited significantly lower risks of major adverse cardiac and cerebrovascular events (6.8% versus 8.8%; subdistribution hazard ratio (SHR) 0.76 (95% CI, 0.64–0.91)), intracerebral hemorrhage (0.23% versus 0.51%; SHR 0.44 (95% CI 0.25–0.77)), and new-onset end-stage renal disease requiring chronic dialysis (7.6% versus 9.1%; SHR 0.82 (95% CI 0.73–0.91)). On the other hand, the LDL-C < 70 mg/dL category exhibited a slightly lower risk of major adverse cardiac and cerebrovascular events (7.3% versus 8.8%; SHR 0.82 (95% CI 0.65–1.02)) and a remarkably lower risk of new-onset end-stage renal disease requiring chronic dialysis (7.1% versus 9.1%; SHR 0.76 (95% CI 0.67–0.85)). Although considerable progress is being made at the moment regarding novel lipid-lowering agents and therapeutic strategies, it is still uncertain whether an aggressive targeted approach to lipid management still remains the optimal choice for all patients, regardless of their overall CV risk, and the discussion becomes all the more nuanced as the patients associate other comorbidities.

3. Genetics

Genetic influences on serum lipoprotein levels have been studied for many years now, and a reference study from as early as 1990 demonstrated that the proposed genetic locus accountable for LDL subfraction phenotypes eventually results in an atherogenic lipoprotein phenotype. Thus, two distinct phenotypes (namely, A and B) were presented, which were identified through the non-denaturing gradient gel electrophoretic analysis of LDL subclasses. While phenotype A was defined by large, floating LDL particles, phenotype B was characterized by a predominance of small, dense particles, and the latter was further associated with a higher risk of myocardial infarction [8].
Recent advances in technology have enabled the identification of a variety of genetic variants, from extremely rare to more common, that have substantial impacts, from major to minor, on the dissimilarities in the plasma lipid and lipoprotein levels among individuals.
Monogenic dyslipidemias are mainly defined by the primary lipid or lipoprotein disrupture: higher or lower concentrations of LDL-C or HDL-C, or elevated triglycerides (TG) [9]. At the moment, there are 27 clearly identified monogenic dyslipidemias, characterized by unusually high or low levels of plasma lipids or lipoproteins, with distinct clinical manifestations due to numerous genetic mutations impacting a total of 25 genes [10].
Familial hypercholesterolemia (FH), probably the most common monogenic dyslipidemia, is regulated by three primary genes (LDL-R, APOB, and PCSK9) and can cause premature atherosclerosis and cardiovascular complications. However, in some individuals, the FH symptoms are linked to variants of other genes. It was previously believed that it occurs in about 1 in 500 people, but more recent studies have shown that the real prevalence of 1 in 127 individuals is actually established by the LDL receptor gene pathogenic variant carrier status. There are currently nine genes that underlie FH and FH-like phenotypes; in addition to the before-mentioned well-known causative genes for co-dominant forms of FH and LDLRAP1 or ARH involved in the purely recessive FH.
New potential FH loci have recently been studied using exome sequencing, with promising results. PNPLA5 carriers, especially those with a rare or low-frequency variant, have a higher risk of developing extreme serum levels of LDL-C, although vertical transmission in families or mechanistic impairment was not demonstrated [11]. Other newly identified genes with a potential implication in the disrupting mechanisms involved in FH phenotypes include CH25H and INSIG2, but further studies are needed in order to validate them [12].
More recent studies have clarified the role of polygenic determinants in FH and even proposed a screening score to distinguish between patients with FH from healthy subjects, concluding that in 88% of mutation-free patients, the hypercholesterolemia is most likely to have a polygenic basis [13]. About 40% of clinically diagnosed individuals with heterozygous forms of FH (HeFH) do not have a monogenic mutation, but rather have gained an atherogenic burden of LDL-C-raising single nucleotide polymorphism (SNP) alleles that ultimately raise their LDL-C levels up to the HeFH range. This effect could explain the high FH-like LDL levels in patients without any clearly identified monogenic mutation, despite adequate genetic testing, which is exactly why screening for polygenic factors should be included in all FH molecular cases [14][15].

4. Importance of Dosing LDL Subfractions and How It Impacts Overall Cardiovascular Risk

While it may be true that a complete, standardized lipid panel should be performed for a first-time estimation of the overall ASCVD risk, dosing the plasmatic levels of ApoB and LDL subfractions could allow for a more complex evaluation of the atherogenic burden and could also provide a proper starting point for therapeutic management. Recent studies have shown that dosing the LDL particle subclasses has the potential for the early detection of certain atherogenic lipoprotein patterns that are below the discrimination level of standardized testing and can therefore identify those at a higher risk of major cardiovascular events before they become clinically symptomatic [16][17][18][19][20].
Multiple types of research evaluated the significance of dosing LDL subfractions in estimating the risk of further developing major cardiovascular events. The Quebec Cardiovascular Study showed that small LDL subfraction levels were independently correlated with coronary heart disease (CHD) risk in 2072 men over a 13-year follow-up period. Contrariwise, large LDL particles were proven to have no predictive value in this matter [21]. Two other prospective studies, namely, the Atherosclerosis Risk in Communities (ARIC) and the Multi-Ethnic Study of Atherosclerosis (MESA), proved a directly proportional relationship between small, dense LDL-C levels and the risk for ischemic heart disease. As previously shown by the Quebec Cardiovascular Study, no relationship with large LDL particles was found [22][23]. The Stanford Five Cities Project [24] and the Physician’s Health Study [25] also proved that a small LDL-C diameter is an important univariate predictor for coronary artery disease (CAD). The same findings were also confirmed by many other subsequent research projects and ultimately reviewed by the European Panel of Experts while discussing the pathophysiology, atherogenic potential, and clinical importance of LDL-C subfractions [26][27].
Given their size and diameter, small, dense LDL (sdLDL) particles have a higher chance of entering arterial tissue than larger subspecies, indicating greater permeability through the endothelium. Additionally, these particles have a significantly lower receptor-mediated uptake, a higher binding to proteoglycans, and are more prone to oxidation, which eventually leads to a modified surface lipid layer caused by decreased free cholesterol, fewer antioxidants, and higher amounts of polyunsaturated fatty acids [28][29].
SdLDL-C subfractions are highly susceptible to oxidation, and this could be due to their configuration, as they carry fewer antioxidative vitamins. The plasmatic oxidative process ultimately leads to various specific epitopes on the surface of LDL particles that generate an increased immune and inflammatory response.
There is a known correlation between elevated levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) in LDL particles and cardiovascular disease. Higher PLA2 levels have been found in electronegative LDL as well as in more progressed atherosclerotic plaques. Inside the lipoprotein particle, this enzyme cuts apart oxidized phospholipids, liberating proinflammatory substances and further raising its atherogenic potential [30][31].
An additional atherogenic alteration of LDL particles is desialylation, a process performed by trans-sialidase, a glycosylphosphatidylinositol (GPI)-anchored surface enzyme that plays an important part in the metabolism of glycoconjugates. Long-term contact with blood plasma leads to a progressive desialylation of the particles, which already have a decreased sialic acid content in comparison to large buoyant LDL (lbLDL) in subjects with an atherogenic phenotype B. As the desialylation process creates a higher affinity between the sdLDL particles and proteoglycans, the final products (desialylated sdLDL molecules) can resist within the subendothelial space for a longer period, thus leading to an increased lipid storage and atherosclerosis plaque development [32][33][34].
The various characteristics of sdLDL particles make them highly atherogenic and related to the beginning stages of subclinical atherosclerosis and endothelial dysfunction, which increases the risk of cardiovascular events. Research has revealed that the predominance of sdLDL particles is associated with a higher risk of CAD, as shown in large epidemiological and clinical intervention trials. Consequently, sdLDL is now considered a novel, high-accuracy biomarker for assessing the overall ASCVD risk, as it is a significant lipid abnormality observed in individuals with CAD, peripheral arterial disease (PAD), diabetes, metabolic syndrome, and other cohorts with a global high cardiovascular risk [35][36][37][38][39].


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