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Dr. Konstantinos C. Koskinas ,
Retention of apolipoprotein-B-containing lipoproteins within the arterial wall is the key initiating event in the pathobiology of atherosclerosis. Consistent evidence from genetic studies, epidemiologic observations, and randomised controlled trials has unequivocally shown that elevated plasma concentrations of atherogenic lipid are causally linked to atherosclerotic cardiovascular disease, and that lowering these levels substantially reduces the risk of first or recurrent cardiovascular events. This article will focus on the role of lipids in the development of atherosclerosis and summarise currently recommended targets for lipid-lowering treatment as a means of reducing cardiovascular risk.
Despite substantial progress in currently available diagnostic tools and treatment modalities, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide and a major health and economic burden to society. Atherosclerosis is a multifactorial process regulated by a complex interplay among well-characterised risk factors. Following decades of research in the field, compelling evidence from preclinical investigations, Mendelian randomisation studies, epidemiologic observations, and randomised trials of lipid-modifying medications supports the key causal role of atherogenic lipoproteins, particularly low-density lipoprotein (LDL), in the pathogenesis of ASCVD . Elevated plasma levels of these lipoproteins are strongly associated with the risk of adverse cardiovascular events. Importantly, dyslipidaemia is a modifiable risk factor, and pharmacologic LDL-cholesterol (LDL-C) lowering has been shown to halt the progression of atherosclerosis  and improve clinical outcomes in the context of primary as well as secondary prevention [3,4]. The totality of currently available evidence indicates that the greater the absolute reduction in plasma LDL-C levels, the larger the reduction of ASCVD risk, without offsetting safety issues arising from intensive lipid-lowering strategies [1,4]. This accumulating evidence has solidified “the lower, the better” concept for LDL-C, and redefined the answer to the question “how low should lipid levels be lowered?”.
Because lipids are insoluble in plasma, circulating lipids are bound to lipoproteins and transported to various tissues where they are used for various functions including energy utilisation, synthesis of steroid hormones, and bile acid formation. Lipoproteins consist of lipids (cholesterol, triglycerides, phospholipids) and a protein component known as apolipoprotein. Based on their physicochemical characteristics, lipoproteins are classified into five major subclasses, as summarised in Table 1 below.
Table 1. Composition and physicochemical properties of lipoproteins.
Main lipid component
Other lipid components
Cholesteryl esters, phospholipids, cholesterol
ApoA-I, A-II, A-IV, A-V
Phospholipids, cholesteryl esters, cholesterol
ApoA-I, C-II, C-III, E, A-V
Cholesteryl esters (~35%)
Phospholipids, cholesterol, triglycerides
Cholesteryl esters, triglycerides, cholesterol
ApoA-II, C-III, E, M
Cholesteryl esters (~35-45%)
All apolipoprotein-B (apoB)-containing lipoproteins with a diameter up to approximately 70 nm, including LDL, very low-density lipoprotein (VLDL), smaller triglyceride-rich lipoproteins and their remnant particles, can cross the endothelial barrier into the intimal layer of the arterial vessel wall. According to the “response-to-retention” concept, the key initiating event in atherogenesis is the retention of these cholesterol-rich apoB-containing lipoproteins within the arterial wall, particularly in the presence of endothelial dysfunction [5,6]. The preferential development of atherosclerosis at specific arterial sites (e.g., bifurcations or side branches) relates to the exposure of the endothelium to disturbed blood flow and low local shear stress conditions, signalling an interplay between locally acting factors and systemic risk factors in atherogenesis . Due to interactions with extracellular structures such as negatively charged proteoglycans of the arterial wall, these lipoproteins are bound and retained within the subendothelial space.
Following their retention in the arterial wall, lipoproteins undergo modifications and ultimately trigger a series of maladaptive responses that accelerate further lipoprotein retention and cause further plaque progression. Aggregated lipoproteins are taken up by macrophages (by phagocytic uptake or via scavenger receptors) as well as vascular smooth muscle cells (in advanced lesions), leading to the formation of lipid-laden foam cells. This process is facilitated by modification of the LDL particle by non-oxidative alteration, oxidation, glycosylation, or glycooxidation. In addition to facilitating uptake by macrophages and ultimately foam cell formation, oxidised LDL particles promote atherosclerosis via endothelial dysfunction (due to impaired release of nitric oxide and increased endothelial production of oxygen free radicals), macrophage recruitment, enhanced platelet aggregation and thromboxane release (which contributes to vasoconstriction and intravascular thrombus formation), and increased apoptosis of smooth muscle cells and endothelial cells. Retained LDL particles promote inflammatory and immune changes via cytokine release from macrophages, promoting further recruitment of immuno-inflammatory cells (monocytes/macrophages, neutrophils, lymphocytes, dendritic cells). Proatherogenic factors and enzymes that are released by monocytes/macrophages in the developing atheroma, including lipoprotein lipase and phospholipase-A2, induce the formation of proteoglycans with great affinity to atherogenic lipoproteins, promoting a vicious circle that leads to further lipoprotein retention and progression of atherosclerosis. At later stages of plaque development, proteases secreted by macrophages degrade the overlying fibrous cap rendering the plaque vulnerable to acute rupture, whereas procoagulant factors favour thrombus formation upon disruption of a thin-capped plaque .
Different lipids and lipoproteins vary considerably with respect to their contribution to the process of atherosclerosis, with direct implications regarding their prognostic impact and clinical importance as therapeutic targets. Overall, the atherogenic potential of apoB-containing lipoproteins depends on several factors:
LDL is the most abundant atherogenic lipoprotein in plasma and is the main source of cholesterol accumulated within the arterial wall. Plasma levels of LDL-C are a metric of the cholesterol mass carried by LDL particles. Consistent evidence from a broad spectrum of clinical and genetic studies has shown a log-linear relation between the absolute changes in plasma LDL-C levels and the risk of clinical atherosclerotic disease [1,5,9]. This evidence is supported by experimental preclinical evidence, overall providing proof that LDL-C is causally associated with the risk of ASCVD. In addition to LDL, other apoB-containing lipoproteins can exacerbate the atherogenic process, including lipoprotein(a) [Lp(a)] and cholesterol-enriched remnants derived from triglyceride-rich particles .
The causal association between elevated plasma levels of triglycerides and cardiovascular risk has been partly controversial, because hypertriglyceridaemia commonly coexists with other lipoprotein disorders (low levels of high-density lipoprotein cholesterol [HDL-C], small, dense LDL particles, atherogenic triglyceride-rich lipoprotein remnants) or other conditions which are linked to an increased cardiovascular risk (e.g., insulin resistance). In the pathogenesis of atherosclerosis, triglyceride-rich lipoproteins augment endothelial dysfunction, facilitate monocyte infiltration into the arterial wall, and increase activation of pro-inflammatory genes; moreover, triglyceride-enriched HDL particles exhibit reduced cholesterol efflux capacity. Although numerous studies have shown an association between hypertriglyceridaemia and ASCVD risk, a causal, independent relationship (i.e., after adjusting for other lipid abnormalities or risk factors) has not been demonstrated. The development of atherosclerosis is probably related to the cholesterol content of the triglyceride-rich lipoproteins and their remnants (intermediate-density lipoprotein [IDL], chylomicron remnants, and VLDL remnants). A recent meta-analysis of randomised trials of triglyceride-lowering medications did show a lower risk of major vascular events even after adjusting for LDL-C reduction; notably, however, the favourable effect was less than that for LDL-C lowering, and the clinical benefits of marine-derived omega-3 fatty acids (particularly high-dose eicosapentaenoic acid) appeared to exceed their triglyceride-lowering effects .
In contrast to LDL and VLDL, HDL particles exert antiatherogenic properties including removal of cholesterol from macrophages (cholesterol efflux), antithrombotic properties, as well as favourable effects on endothelial function and blood viscosity. Cholesterol efflux is a process consisting of removal of excess cholesterol in macrophage cells and transfer to the liver, where it can be used for the formation of bile salts (reverse cholesterol transport). HDL improves endothelial function by increasing the production of endothelial nitric oxide synthase and inhibiting cellular adhesion molecule expression. While epidemiological studies have consistently shown an inverse association between plasma HDL-C levels and the risk of ASCVD , genetic studies showed a lack of protection from ASCVD by polymorphisms that raise plasma levels of HDL-C . Moreover, a clinically relevant protective impact of HDL-C has been challenged by randomised trials that failed to show a reduction in clinical events with agents that raise plasma levels of HDL-C .
Lp(a) is an LDL particle composed of an apo(a) component linked to apoB, and mainly carries cholesteryl esters and oxidised phospholipids. Due to its physicochemical properties including its size (diameter <70 nm), Lp(a) can cross the endothelial barrier and enter the subendothelial space of the arterial wall, thus contributing to the development of atheroma. Moreover, Lp(a) exerts pro-coagulant properties as its structure resembles that of plasminogen, and it also has pro-inflammatory effects probably related to the oxidised phospholipid load . Elevated plasma levels of Lp(a) are associated with an increased risk of ASCVD, although it appears to be a weaker risk factor compared with LDL-C. Mendelian randomisation studies have shown a strong causal association between lifelong exposure to high Lp(a) levels and the risk of ASCVD . Randomised trials of PCSK9 inhibitors (which lower Lp(a) by approximately 25-30%) have suggested a potential reduction of cardiovascular (CV) risk in relation to Lp(a) lowering . Overall, and as supported by a recent Mendelian randomisation study, individuals with extremely elevated Lp(a) levels (>180 mg/dL) have an increased risk of ASCVD that is comparable to that of individuals with markedly elevated LDL-C levels in the context of heterozygous familial hypercholesterolaemia (HeFH). Moreover, it appears that large absolute reductions in Lp(a) may be needed to achieve a clinically relevant reduction in ASCVD risk. Importantly, the vast majority (90%) of a person’s Lp(a) levels are inherited, and extremely elevated Lp(a) is a disorder twofold more common than HeFH.
In accordance with the evidence summarised above, LDL-C measurement is recommended (class I recommendation) as the primary lipid analysis method for screening, diagnosis, and management in current European dyslipidaemia guidelines . In addition, in the 2019 ESC/EAS guidelines it is recommended for the first time that Lp(a) measurement should be considered (class IIa recommendation) at least once in each adult person’s lifetime to identify those with very high inherited Lp(a) levels (>180 mg/dL or >430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated with HeFH .
Over the past decades, evidence from large, high-quality randomised trials of lipid-lowering medications have enhanced our understanding of which lipid levels are “too high” and how low lipids should be decreased, particularly among patients with already established ASCVD and thus at very high risk of recurrent cardiovascular events [3,17]. Early statin trials comparing statin treatment (of moderate intensity) versus no treatment were able to show significant reduction in cardiovascular morbidity and mortality . Later studies that compared more intensive versus less intensive statin treatment showed that a more aggressive LDL-lowering approach led to further reduction of major ASCVD events [1,3]. More recently, add-on treatment with non-statin medications (ezetimibe or PCSK9 inhibitors) on the background of statin therapy produced incremental reductions in cardiovascular morbidity as compared with optimised, intensive statin therapy alone [4,10]. In these trials, no level of LDL-C below which benefit ceases was identified, and no offsetting safety concerns emerged. Along the same lines, genetic studies showed that mutations leading to very low lifelong LDL-C levels (such as, for example, loss-of-function mutations of the PCSK9 enzyme) are associated with a very low incidence of ischaemic heart disease . In tandem with this accumulating evidence, our appreciation of excessively elevated, slightly elevated or atheroprotective LDL-C levels has changed over time: recommended treatment goals for LDL-C for patients at very high risk have progressively lowered from <3.0 mmol/L in 1998  to <1.8 mmol/L in the 2011 and 2016 ESC/EAS dyslipidaemia guidelines  to <1.4 mmol/L in the 2019 ESC/EAS dyslipidaemia guidelines .
Overall, current European guidelines recommend the use of treatment goals depending on each individual’s total CV risk level . The latter is determined by the presence or absence of known ASCVD or CV risk factors (e.g., diabetes, hypertension, marked hypercholesterolaemia, chronic kidney disease), and can be quantified with the use of a risk estimation system such as SCORE which incorporates patient age, sex, smoking status, blood pressure and cholesterol levels . The greater the estimated CV risk, the lower the recommended LDL-C goal . The goal-oriented approach advocates a tailored treatment with adjustment of drug dose (or with a combination of lipid-modifying drugs, if applicable), aiming to reach the applicable LDL-C goal in each patient. Advantages of this approach include a more specific, individualised treatment for LDL-C lowering and CV risk reduction (also accounting for substantial inter-individual variability in treatment response to LDL-C lowering drugs), better patient–physician communication, and possibly better adherence to recommended treatment. Treatment goals are defined for each CV risk category, as summarised in Table 2 below.
Table 2. Recommended treatment goals for LDL-C across different categories of total cardiovascular risk according to the 2019 ESC/EAS guidelines for the management of dyslipidaemias.
Very high risk
LDL-C goal <1.8 mmol/L (<70 mg/dL) and a ≥50% reduction
LDL-C goal <2.6 mmol/L (<100 mg/dL)
LDL-C goal <3.0 mmol/L (<116 mg/dL)
1 Defined as microalbuminuria, retinopathy, or neuropathy.
ASCVD: atherosclerotic cardiovascular disease; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; FH: familial hypercholesterolaemia; SCORE: Systematic Coronary Risk Estimation
The recommendations regarding target goals for LDL-C are based upon the principle that decreasing the concentration of apoB-containing lipoproteins in the circulation decreases the probability that they will enter and become retained in the subendothelium. The updated treatment goals  are based on results from large trials and meta-analyses confirming the dose-dependent reduction in ASCVD events in relation to the absolute LDL-C reduction [3,9,20], including evidence that lowering of LDL-C beyond the goals that were set in the previous (2016) EAS/ESC guidelines  is associated with fewer ASCVD events in the context of high and very high CV risk.
Konstantinos C. Koskinas, MD, MSc, FESC
Department of Cardiology, Bern University Hospital, Bern, Switzerland
Address for correspondence:
Dr Konstantinos C. Koskinas, Department of Cardiology, Bern University Hospital – INSELSPITAL, 3010 Bern, Switzerland
The author has received honoraria/lecture fees from Amgen and Sanofi.
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