Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally. Widespread in developed areas of the world and now becoming more common in poorer countries, deaths from ASCVD are projected to increase to more than 2.3 × 107 per year by 2030. It is tempting to think of atherosclerosis as a disease of the modern lifestyle. Yet atherosclerosis has plagued humans for thousands of years and has been detected in 4000-year-old Egyptian mummies.
Today, it is no longer a hypothesis, but an established fact, that increased plasma concentrations of cholesterol-rich apolipoprotein-B (apoB)-containing lipoproteins are causatively linked to ASCVD and that lowering LDL concentrations with statins and nonstatins reduces atherosclerotic cardiovascular events in humans [1,2▪▪–4▪▪,5▪,6▪]. Despite the clarity of the evidence today, the role of LDL was questioned and even ridiculed for many years . During that period, numerous competing hypotheses [8–11] were articulated to explain the initiating events in atherogenesis. After decades of research, however, there is now a large body of evidence to support the ‘response-to-retention hypothesis’ – namely, that the key initiating event in atherogenesis is the retention, or trapping, of cholesterol-rich apoB-containing lipoproteins within the arterial wall. The retained lipoproteins and their byproducts provoke a series of strikingly maladaptive local responses that cause plaque initiation, growth, and evolution (Fig. 1).
Modern research on atherosclerosis began with the insightful and pioneering ‘cholesterol hypothesis’ of Anichkov and Khalatov [12,13]. As a point of clarification, however, we now know that many things that carry cholesterol near arteries – such as normal HDL and erythrocytes (which transport a similar amount of cholesterol in blood as LDL does) – do not cause atherosclerosis. Thus, cholesterol per se is not the cause of this disease. In contrast, cholesterol-rich apoB-lipoproteins possess special properties that render them uniquely pathogenic in ASCVD.
The response-to-retention hypothesis of atherogenesis
The response-to-retention hypothesis drew on work from the 1940s to the 1980s showing that lipoproteins can interact with proteoglycans of the arterial wall [14–17]. Lipids and apoB accumulate at lesion-prone sites before gross morphological changes occur [18–21], and retention of apoB-lipoproteins is seen throughout the progression of atherosclerosis. The consequences of the retention of apoB-lipoproteins include, not only an accumulation of lipid, but also prolonged exposure of these particles to local enzymes and other factors within the vessel wall. The retained and modified apoB-lipoproteins trigger cellular responses within the artery wall that accelerate further lipoprotein retention and lesion development [9,11,22].
Influx of apolipoprotein-B-lipoproteins into the artery wall
Lipoproteins normally flux into and out of the arterial wall [20,23]. The molecular mediators of this transendothelial movement of lipoproteins remain incompletely characterized. Recent evidence has suggested roles for caveolin-1 [24,25] and the scavenger receptor class B type I (SR-BI) , but additional mediators are likely .
ApoB-lipoproteins up to only approximately 70 nm in diameter [i.e., chylomicron remnants, smaller VLDL, IDL, LDL, and lipoprotein(a)] can efficiently cross an intact endothelium, and among these, the smaller ones pass more readily than the larger ones . This size limitation explains why patients with lipoprotein lipase deficiency do not develop atherosclerosis despite very high plasma levels of large apoB-containing chylomicrons.
Studies in-vivo of the influx and egress of LDL particles into and out of the arterial intima have shown that, although the endothelial layer remains intact over most atherosclerotic lesions, its permeability to LDL becomes abnormally high [20,28,29]. The precise stimuli and molecular mechanism(s) responsible for this increased permeability are still not elucidated, and it was not known until recently if the increased endothelial permeability for LDL could be reversed. To examine this issue, Bartels et al.[30▪▪] fed LDL receptor null (Ldlr−/−) mice on a high-cholesterol diet for up to 5 months to increase their plasma concentrations of apoB-lipoproteins, thereby provoking the formation of atherosclerotic plaques. To investigate the effect of an abrupt lowering of plasma apoB-lipoprotein concentrations on aortic endothelial permeability to LDL and the fractional degradation rates of apoB-lipoproteins within the atherosclerotic lesions, these authors used an anti-apoB antisense oligonucleotide (ASO) to reduce hepatic apoB synthesis. Concentrations of apoB-containing lipoproteins in plasma fell sharply to nearly undetectable levels within 3 days after administration of the ASO. The authors then analyzed the aortic plaques after 1 or 4 weeks of ASO treatments. Lowering of plasma apoB-lipoprotein concentrations reduced LDL permeability into the arterial wall within 1 week of ASO treatment, and this effect preceded any detectable changes in the cellular composition or size of the atherosclerotic lesions [30▪▪]. The molecular mechanisms involved still remain unclear, and effects on caveolin-1 and SR-BI were not examined. Bartels et al.[30▪▪] ruled out a nonspecific process by showing that the anti-apoB ASO treatment had no effect on endothelial permeability to Evans blue dye. In addition, correction of the hypercholesterolemia caused the fractional degradation rates of apoB within the plaques to fall sharply. Most importantly, the rapid decreases in permeability to LDL and in the fractional degradation of LDL that enters the plaque may turn out to be crucial for subsequent plaque stabilization and atherosclerosis regression [6▪].
Retention of atherogenic apolipoprotein-B-lipoproteins within the artery wall as the key pathogenic event in atherosclerosis
Because the capacity of transendothelial transport is high even in normal arterial segments, it is unlikely that influx of LDL and other smaller apoB-lipoproteins from the bloodstream is rate limiting in determining their concentrations within the artery wall. Instead, mechanisms for the selective retention of a tiny percentage of the apoB-lipoproteins that enter the artery wall drive their local accumulation and hence atherogenesis. Support for this model came from early work by Schwenke and Carew showing that LDL entry did not differ between normal arterial sites that are susceptible versus resistant to subsequent plaque development. Although the same amount of LDL entered, the susceptible sites, though healthy, already showed greater LDL accumulation . More recent support comes from molecular studies by Tran-Lundmark et al. who crossed glycosaminoglycan (GAG)-deficient perlecan (Hspg2Δ3/Δ3) mice with hypercholesterolemic apolipoprotein-E (apoE)-null (Apoe−/−) mice. Because perlecan participates both as a permeability barrier and as a proretentive molecule within the murine arterial wall, the influx of LDL and other apoB-lipoproteins into the aortic wall in vivo was increased in Hspg2Δ3/Δ3/Apoe−/− mice compared with Apoe−/− controls, whereas subendothelial retention of LDL was paradoxically lower. In other words, this ingenious genetic manipulation of perlecan separated the two processes. Importantly, these authors demonstrated a significant reduction of atherosclerotic lesions in Hspg2Δ3/Δ3/Apoe−/− mice compared with Apoe−/− controls, indicating the key role of decreased apoB-lipoprotein retention regardless of the increase in endothelial permeability to LDL entry. Thus, most apoB-lipoprotein particles that entered the arterial wall left without contributing to the growth of the atherosclerotic lesion .
In earliest atherogenesis, negatively charged proteoglycans in the extracellular matrix of the arterial intima bind and trap apoB-lipoproteins via electrostatic interactions with specific positively charged aminoacyl residues in the full-length hepatic form of apoB, apoB100 (residues 3359–3369) , and in the truncated intestinal form, apoB48 (residues 84–94) . Moreover, apoB48-lipoproteins typically contain numerous molecules of apoE, an apoprotein that has a proteoglycan-binding domain almost identical to the proteoglycan-binding sequence in apoB100. Proteoglycans are negatively charged due to the sulfate and carboxylic acid groups in their GAG side-chains. In experimental studies, several arterial-wall proteoglycans have been shown to be important for apoB-lipoprotein retention and atherosclerosis, most notably the matrix-associated proteoglycans biglycan, perlecan, and versican [9,34,35].
Consistent with the response-to-retention model, numerous other interventions have been performed that do not change plasma concentrations of apoB-lipoproteins in hypercholesterolemic animals but specifically decrease or increase the retention of these particles within the arterial wall. These interventions correspondingly decrease or increase atherogenesis. Such interventions include mutagenesis of the proteoglycan/GAG-binding domain of apoB100, thereby slowing LDL retention and atherogenesis , manipulations of arterial matrix to alter its affinity for apoB [31,37–39,40▪▪,41▪], and knockouts of arterial-wall enzymes specifically implicated in apoB-lipoprotein retention and aggregation [42–45].
The first of these studies, which used mutagenesis of apoB100 to block its direct adherence to arterial matrix, emphasizes the importance of LDL quality, as opposed to simply focusing on its concentrations in plasma. Other variations in LDL quality may also affect its atherogenicity, such as surface lipid composition  and core lipid composition (which influences the conformation of apoB and hence its interactions with proteoglycans) [47,48▪▪,49]. In addition, the protein composition of apoB-lipoproteins influences their interactions with proteoglycans. As discussed above, apoE mediates binding of lipoproteins to arterial GAGs, although apoE also facilitates hepatic disposal of atherogenic lipoproteins. In contrast, the small exchangeable apolipoprotein, apolipoprotein-C (apoC)-III, increases the affinity of LDL for arterial-wall proteoglycans, whereas decreasing hepatic uptake of apoB-lipoproteins , thereby increasing the accumulation of atherogenic lipoproteins within the vessel wall [51,52]. The mechanism has been unclear because apoC-III by itself lacks positively charged domains to bind arterial-wall proteoglycans . Hiukka et al. demonstrated that an increased apoCIII : apoB molar ratio in LDL isolated from patients with type 2 diabetes correlated with lower contents of unesterified cholesterol, sphingomyelin, ceramide, and GM1. Importantly, this combination of compositional changes was associated with increased proteoglycan binding . The mechanism remains unclear but one possibility is that a more fluid monolayer on the LDL particle surface may facilitate the insertion of more molecules of apoC-III and permit conformational changes in apoB100 that increase its proteoglycan-binding affinity. In contrast, however, the apoCIII : apoB ratio in LDL from nondiabetic control patients showed no correlations with the content of these lipids, indicating less global changes in LDL composition .
Regarding the subendothelial arterial matrix, recent work has implicated proteases  and other factors [55,56▪] in the regulation of the arterial-wall content of LDL-binding proteoglycans and hence atherosclerosis. She et al.[40▪▪,41▪] recently focused on a less well known proteoglycan in the vasculature, the neural/glia antigen 2 (NG2) proteoglycan. Although NG2 is undetectable in the intima of normal murine arteries, early atheromata in Apoe−/− mice contain immature synthetic smooth muscle cells (s-SMCs) that express NG2 [40▪▪]. Thus, the atherogenic effects of NG2 seem to emerge with accumulation of s-SMCs [21,57]. She et al. also demonstrated a remarkable role for NG2-positive s-SMCs in trapping LDL and then presenting it to macrophages. It is a novel mechanism for the presentation of undesirable material to macrophages that, we speculate, may have evolved to facilitate the disposal of certain infectious agents or cellular debris [58,59]. In the context of retained apoB-lipoproteins, however, the process becomes maladaptive. Thus, NG2-positive s-SMCs dramatically increase the uptake of LDL by macrophages within the arterial wall, promoting foam-cell formation, whereas NG2-deficient s-SMCs reduce LDL uptake. Despite worse obesity and worse hyperlipidemia, double knockout mice (Ng2−/−/Apoe−/−) developed less atherosclerosis than did Apoe−/− controls. Surprisingly, the NG2 GAG chains were not required for the binding of LDL to NG2 [40▪▪]. Furthermore, NG2 also bound acetylated LDL, indicating that NG2 has the capacity to bind LDL through hydrophobic interactions. These features make NG2 unique amongst LDL-binding proteoglycans [40▪▪] and may be related to its normal biologic functions.
Why does atherosclerosis preferentially develop at specific sites in the arterial tree? These sites are often associated with branches and bifurcations, which expose the endothelium to disturbed laminar blood flow and shear stress . Most conventional explanations for increased atherosclerosis susceptibility at these sites have focused on biomechanical alterations of endothelial cells, such as increased permeability and elaboration of cytokines , but none of these proposed mechanisms has been definitely demonstrated. In a recent advance, Steffensen et al. showed that induction of disturbed laminar flow in the straight segment of the otherwise atherosclerosis-resistant common carotid artery of mice provokes matrix proliferation in the nearby arterial wall, transforming it into a lipoprotein-retaining site – but without altering LDL influx. This provides experimental evidence for a causal chain linking disturbed laminar flow patterns to increased arterial matrix deposition, apoB-lipoprotein retention, and atherosclerosis [62▪▪]. Like the prior work cited above [20,31], this study contradicts the notion of a key role for disturbed endothelial permeability to LDL in early phases of atherogenesis. Unraveling the molecular mechanisms from disturbed flow to matrix proliferation and increased lipoprotein retention will be a fruitful area for future research.
New work has focused on apoB-lipoprotein retention as a potential therapeutic target. One strategy is the creation of mAbs that block apoB-binding sites on GAG chains within the arterial matrix [63,64▪]. Interestingly, the antigen-binding site (the CDR3 of the heavy chain) of one of these antibodies contains an arginine motif that resembles the major GAG-binding sequence in apoB100[33,36,64▪]. The antibodies decrease intra-arterial lipoprotein retention and hence the progression of atherosclerosis in hypercholesterolemic Apoe−/− mice [63,64▪].
Cholesterol-rich and triglyceride-rich apolipoprotein-B-containing remnant lipoproteins, which are metabolically distinct from LDL, have emerged as a major driver of human atherosclerosis
Lipid and lipoprotein concentrations are often assessed in fasting plasma, but the idea that particles originating in the postprandial state may contribute to atherosclerosis appeared in the literature at least as far back as the 1940s [65,66]. In that era, however, the overwhelming driver of human atherosclerosis was LDL, which is not primarily a postprandial particle.
The situation has changed dramatically since then. With the rise of overnutrition, obesity, and the atherometabolic syndrome, harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoproteins (C-TRLs) have emerged as a major driver of human ASCVD worldwide [67▪]. The characteristic dyslipoproteinemia of the atherometabolic syndrome increases plasma concentrations of C-TRL remnants, not LDL. The major defect is impaired hepatic removal of C-TRLs from plasma [68▪]. Like LDL , C-TRL remnants become retained within the arterial wall [6▪,11,33,69]. Mendelian randomization studies have clearly demonstrated their causal role in human ASCVD events . Of note, each C-TRL particle contains up to 40 times more cholesterol compared with an LDL particle. Unfortunately, patients treated with optimal statin therapy  and even PCSK9 inhibitors [3▪▪,4▪▪] exhibit considerable residual risk for ASCVD events, which may occur, in large part, because these agents lower fasting or postprandial C-TRL levels by only 4–25% [72–74]. There is therefore a need to find new therapeutic approaches to restore normal, rapid hepatic removal of C-TRLs from plasma, to lower residual ASCVD risk in obesity, the atherometabolic syndrome, and type 2 diabetes.
Aggregation and modifications of retained apolipoprotein-B-lipoproteins within the artery wall
Following retention of cholesterol-rich apoB-lipoproteins within the artery wall, the lipoproteins have been shown to undergo several modifications with important biological consequences. For example, proteoglycan-bound LDL in vitro forms aggregates that resemble material seen in vivo, and retained lipoproteins are more susceptible to further modifications. Key enzymes implicated in apoB-lipoprotein retention, aggregation, and atherogenesis include the secretory sphingomyelinase (S-SMase), lipoprotein lipase, and the nonpancreatic secretory group V phospholipase-A2 (PLA2-V) [9,42–45,75] (Fig. 1). These enzymes, particularly lipoprotein lipase, bridge between LDL and proteoglycans independently of the physical state of apoB and thereby cause a shift in the retentive mechanism from a low-affinity process (apoB-GAG binding) in the pristine arterial wall to a high-affinity process (lipoprotein-GAG binding) in an established atheroma. This shift in retentive mechanism has direct clinical consequences: a lifetime plasma LDL cholesterol concentration of 80 mg/dl almost always protects from atherosclerosis  but pre-existing plaques grow if the LDL-cholesterol is ∼80 mg/dl .
Acidity in deeper parts of normal intima and within atherosclerotic plaques enhances lipolytic, proteolytic, and other modifications of apoB-containing lipoproteins that strongly increase their affinity for proteoglycans and may therefore accelerate their retention and the ensuing maladaptive cellular responses in the arterial intima [78▪]. In a fascinating advance, Sneck et al. elucidated the mechanism for SMase-induced aggregation of LDL. The enzyme induces a massive, global conformational change in apoB that exposes hydrophobic motifs that apparently adhere from one digested LDL particle to the next .
Several lines of evidence implicate aggregation of apoB-lipoproteins within the arterial wall as a major accelerator of lipoprotein retention and atherogenesis. Once LDL and other apoB-lipoproteins in the arterial wall have aggregated, diffusion back into plasma becomes essentially impossible, due to the large size of the aggregates and their greatly enhanced affinity as multivalent ligands for arterial matrix, as well as conformational changes that expose additional positively charged domains on apoB. Lipid hydrolysis and other modifications of the retained, aggregated lipoproteins release biologically active byproducts that recruit macrophages and other cells into the developing lesion, while also blocking their emigration, thereby accelerating disease progression (Fig. 1; recently reviewed in ).
Ruuth et al. recently demonstrated that susceptibility of plasma LDL to aggregation upon exposure to SMase ex vivo varies considerably amongst human patients, predicts future deaths from ASCVD, and can be altered by diet. This work adds to a growing body of data implicating SMase in human atherosclerosis [9,75]. Crucially, the work identifies LDL aggregability in the presence of SMase as a new, potentially modifiable cardiovascular risk factor. Aggregation-prone LDL – dubbed ‘unstable’ LDL – exhibits several compositional characteristics, including an increased sphingomyelin : phosphatidylcholine (SM : PC) ratio . Interestingly, an increase in dietary polyunsaturated fatty acids and fiber decreased the SM : PC ratio and stabilized LDL, whereas an increase in dietary sucrose caused the opposite. Consistent with these findings, a diet rich in saturated fats has been shown to increase serum SMase activity and, consequently, increase LDL aggregation in mice . These results further emphasize the importance of LDL quality in human ASCVD. Moreover, measurement of LDL instability in the presence of SMase may serve as a predictive biomarker for the identification of patients at unrecognized risk of cardiovascular death who might benefit from specific, targeted interventions.
Retained lipoproteins induce maladaptive cellular responses in the arterial wall that accelerate further apolipoprotein-B-lipoprotein retention
Retained and aggregated lipoproteins provoke a series of local biological responses that eventually include a maladaptive reaction dominated by abnormally persistent macrophages and T cells that accelerate lipoprotein retention and other features of plaque development (Fig. 1). Aggregated apoB-lipoproteins are avidly taken up by macrophages [9,82] and by vascular SMCs  leading to foam-cell formation. These processes stimulate the release of proatherogenic factors that induce the synthesis of proteoglycans with enhanced affinity for atherogenic lipoproteins [9,82]. In addition, monocyte/macrophages recruited into atheromata secrete proretentive enzymes, notably lipoprotein lipase, sphingomyelinase, and PLA2, that accelerate further retention of atherogenic lipoproteins. In addition, persistent macrophages in atherosclerotic plaques secrete proteases that weaken the overlying fibrous cap, and these cells release tissue factor, a potent procoagulant. These maladaptive responses favor plaque rupture, robust clot formation that often occludes the arterial lumen, and downstream ischemia (Fig. 1).
A critical question is why retained apoB-lipoproteins induce this abnormal persistence of macrophages and T cells? It has been hypothesized that specific cellular and molecular programs that cause immune cells to remain in place may have evolved as a defense against Mycobacterium tuberculosis, an acid-fast bacillus that is not killed after phagocytosis and would therefore be spread throughout the body by emigrating macrophages. Interestingly, retained and modified apoB-containing lipoproteins within the arterial wall elicit many of the same antiemigration signals as M. tuberculosis does [6▪,11,84–86]. Unfortunately, the result is a crippling of the reticuloendothelial system, which otherwise has a huge capacity that could easily handle a few grams of intramural cholesterol and other debris.
New data regarding possible roles for HDL in the response-to-retention model of atherogenesis
The pathogenic importance in atherosclerosis of plasma HDL-cholesterol (HDL-C) levels has come into doubt, due to recent failures of clinical trials of agents that raise plasma HDL-C concentrations [87,88] and the lack of ASCVD protection from human gene polymorphisms that raise plasma concentrations of HDL-C . In animal models, however, injections of HDL, overexpression of apoA-I, and strategies to enhance HDL function delay atherosclerosis progression and even promote plaque stabilization and regression [11,85,88]. In the context of the response-to-retention hypothesis, roles for HDL in every step have been hypothesized  – namely, interfering with the irreversible binding of plasma LDL to arterial wall proteoglycans [90–92], blocking SMase-induced aggregation of LDL [79,93], removing toxic lipids, and resolving the maladaptive inflammatory infiltrate [94–98]. Along these lines, the apoA-I mimetic peptide 4F was recently shown to block SMase-induced LDL aggregation and the increase in binding of the modified LDL particles to human aortic proteoglycans [99▪]. In contrast, abnormal HDL or apoA-I within the arterial wall may have adverse effects [96,100,101▪,102].
Atherogenicity of apolipoprotein-B-lipoproteins
Based on our present understanding for how cholesterol-rich apoB-lipoproteins induce atherosclerosis, the atherogenicity of apoB-containing lipoproteins may depend on
- Their plasma concentrations, because high levels of circulating apoB-lipoproteins increase the probability that these particles will enter and be retained in the subendothelium.
- Their ability to become retained in the artery wall. This is influenced by their size (<70 nm) and their affinity for arterial-wall proteoglycans. The affinity is modulated by the lipid and protein composition of the lipoprotein particles. In particular, apoC-III on LDL increases its proteoglycan binding.
- The instability of retained lipoproteins, that is, how readily they aggregate in the presence of arterial-wall enzymes, particularly S-SMase. This property has been linked to LDL lipid composition and is affected by diet.
- The susceptibility of aggregated and retained lipoprotein to further modifications within the artery wall.
- The ability of the modified lipoproteins to induce a maladaptive cellular response.
Thus, it can be hypothesized that patients with atherogenic apoB-lipoproteins characterized by high binding affinity to arterial proteoglycans, increased susceptibility to aggregate, and features that promote a hyperresponsive maladaptive cellular infiltrate may develop atherosclerosis despite only moderately elevated plasma levels of cholesterol. It remains to be demonstrated whether assessments of these specific qualities of LDL and C-TRLs will add predictive power beyond conventional risk factors or help identify groups of patients for targeted therapies.
Reclassification of risk factors for atherosclerosis into causative agents, exacerbators, and mere bystander phenomena
Our understanding of the pathogenesis of ASCVD is based on laboratory investigation, human epidemiology, genetic studies, and clinical trials. Collectively, these studies have demonstrated beyond any doubt that cholesterol-rich apoB-lipoproteins are causally linked to atherogenesis and that lowering the plasma concentration of LDL is the most effective therapy to date against ASCVD. The critical step is that cholesterol-rich apoB-lipoproteins from plasma become pathogenic only after their retention within the arterial wall.
Using our extensive knowledge of the pathogenesis of atherosclerosis, we can now reclassify nearly all epidemiologic risk factors into causative agents, exacerbating factors, and bystander phenomena (Table 1) . Causative and exacerbating factors are targets for therapy, bystander phenomena are not.
It is hard to unravel the root cause of a condition from an end-stage lesion. Atherosclerosis was no exception. For more than a century and a half, many theories had been articulated to explain how a normal artery becomes atherosclerotic. As a testament to the importance of this area, most of these theories were tested in clinical trials. As a consequence, it is now established that increased plasma concentrations of cholesterol-rich apoB-containing lipoproteins are causatively linked to ASCVD. Accordingly, the most effective therapies against atherothrombotic cardiovascular disease – LDL-lowering drugs – are based upon the principle that decreasing the concentration of apoB-lipoproteins in the circulaton decreases the probability that they will enter and be retained in the subendothelium. At this point, we know enough about the pathophysiology of atherosclerosis that eradication of this major killer has become a genuine possibility.
Financial support and sponsorship
The authors acknowledge support from the Swedish Research Council (J.B.), Swedish Heart-Lung Foundation (J.B. and K.J.W.), ALF-medel Västra Götalandsregionen (J.B. and K.J.W.), and the Ruth and Yonatan Ben-Avraham Fund (K.J.W.).
Conflicts of interest
Dr Williams reports purchasing stock in Gemphire Therapeutics, Inc., a company focused on the treatment of dyslipidemias.
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