The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer's disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.

Plasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs).

The authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins.

Nested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs).

During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.

VLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.

Hypercholesterolemia affects over 34 million adults in the United States and is a major cause of coronary heart disease (CHD). Conventional therapies, such as statins, have demonstrated their ability to improve clinical end points and decrease morbidity and mortality in patients with CHD. Lomitapide (Juxtapid(®)), mipomersen (Kynamro(®)), and icosapent (Vascepa(®)) are 3 novel agents approved by the US Food and Drug Administration in the past 2 years, which offer new lipid-lowering treatment options with unique pharmacology.

IDL is considered an atherogenic lipoprotein but little progress has been made on methods to subfractionate this density class. Furthermore, previous work suggests that lipoproteins retained by the arterial wall, of which chondoitin sulphate is the major arterial wall proteoglycan, are potentially atherogenic. The aim of this study was to assess the subfractionation of IDL particles using chondroitin sulphate (CS). Forty healthy subjects were recruited from laboratory staff and/or their partners. Fasted plasma samples were obtained and IDL (1.006 g/ml<d<1.030 g/ml) was isolated. Approximately 1mg protein of IDL was allowed to interact with CS. The unbound and bound IDL particles were eluted using a low salt and high salt buffer, respectively. On average 70% of IDL bound to CS ranging from 56 to 92%. Total, unbound and bound IDL particles were analysed for lipid composition and particle size. The unbound IDL particles were larger (32 nm) and triglyceride rich (40% versus 33%, P<0.01), whereas the bound IDL particles were smaller (26-28 nm) and cholesterol rich (21% versus 14%, P<0.01). The unbound particles contain at least double the amount of apo C-II and apo C-III per IDL particle compared with the bound IDL particles. There are specific IDL particles that bind to CS in vitro, these being the cholesterol rich IDL particles. It remains to be determined if these cholesterol rich IDL particles are potentially more atherogenic than the triglyceride rich IDL particles.

Elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, hallmarks of the atherogenic lipid profile found in the metabolic syndrome and type 2 diabetes, are commonly seen in Japanese patients with coronary heart disease (CHD). In the setting of mildly to moderately elevated plasma TG (150-500 mg/dl), very-low-density lipoprotein (VLDL) accumulates and so do high levels of atherogenic TG-rich, cholesterol-enriched remnant particles. Indeed, in hypertriglyceridemia, abnormalities are seen in the quantity and quality of all lipoprotein B-containing lipoproteins. Non-HDL-C (total cholesterol minus HDL-C) provides a convenient measure of the cholesterol content of all atherogenic lipoproteins, and thus incorporates the potential risk conferred by elevated levels of atherogenic TG-rich remnants that is additional to the risk associated with low-density lipoprotein cholesterol (LDL-C). Non-HDL-C level has been found to be a strong predictor of future cardiovascular risk among patients whether or not they exhibit symptoms of vascular disease, and was recently recommended as a secondary treatment target (after LDL-C) in patients with elevated TG by the National Cholesterol Education Program Adult Treatment Panel III. Adoption of this readily available measure to assess risk and response to treatment in patients with elevated TG would improve treatment of dyslipidemia in a substantial number at risk for CHD.

Among the models of dyslipidemia and atherosclerosis, a number of wild-type, naturally defective, and genetically modified animals (rabbits, mice, pigeons, dogs, pigs, and monkeys) have been characterized. In particular, their similarities to and differences from humans in respect to relevant biochemical, physiologic, and pathologic conditions have been evaluated. Features of atherosclerotic lesions and their specific relationship to plasma lipoprotein particles have been critically reviewed and summarized. All animal models studied have limitations: the most significant advantages and disadvantages of using a specific animal species are outlined here. New insights in lipid metabolism and genetic background with regard to variations in pathogenesis of dyslipidemia-associated atherogenesis have also been reviewed. Evidence suggests that among wild-type species, strains of White Carneau pigeons and Watanabe Heritable Hyperlipidemic and St. Thomas's Hospital rabbits are preferable to the cholesterol-fed wild-type animal species in dyslipidemia and atherosclerosis research. Evidence for the usefulness of both wild-type and transgenic animals in studying the involvement of inflammatory pathways and Chlamydia pneumoniae infection in pathogenesis of atherosclerosis has also been summarized. Transgenic mice and rabbits are excellent tools for studying specific gene-related disorders. However, despite these significant achievements in animal experimentation, there are no suitable animal models for several rare types of fatal dyslipidemia-associated disorders such as phytosterolemia and cerebrotendinous xanthomatosis. An excellent model of diabetic atherosclerosis is unavailable. The question of reversibility of atherosclerosis still remains unanswered. Further work is needed to overcome these deficiencies.

Association between raised low-density lipoprotein cholesterol (LDL-C) levels and high risk for coronary heart disease (CHD) is well established and taken into account in guidelines on coronary prevention.

The relationship between risk for coronary heart disease (CHD) and the levels of fasting plasma triglycerides was studied in the cohort of the Turkish Adult Risk Factor Study, a representative random sample of an adult population.

In 829 men and 907 women aged > or =27 years (mean 48.5+/-11), plasma lipids and lipoproteins were measured by the enzymatic dry method in the postabsorptive state. A sample of values was validated in a reference laboratory. Apoliprotein (apo) A-I and B were measured by the turbidimetric immunoassay using commercial kits in part of the cohort. Blood pressure and anthropometric measurements were made. Criteria for the diagnosis of CHD were based on history, cardiovascular examination, and Minnesota coding of resting electrocardiograms. Coronary heart disease was diagnosed in about 7% of the subjects. Participants were divided into four categories depending on their triglyceride levels: I = < 100 mg/dl (282 men, 400 women), II = 100-139 mg/dl (204 men, 228 women), III = 140-212 mg/dl (188 men, 180 women), and IV = > or = 212 mg/dl (155 men, 99 women).

After adjustment for age, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, smoking, and body mass index by logistic regression analysis, and after assigning the CHD risk of 1 to Category I, the relative risk for men and women combined rose to 1.42 in Category III (p<0.045) while it diminished to 0.94 in Category IV (p = 0.79). In women, the odds ratio (OR) rose gradually up to 1.78 (p< 0.025) in Category III, only to decline in Category IV. The OR in men was slightly, insignificantly, and equally elevated in Categories III and IV. Patients with CHD in Category III were not distinguished from those in Category IV by the studied risk parameters. It was suggested that high risk for CHD--particularly in subjects with slightly elevated or normal cholesterol levels-is often not reflected by extreme increases of fasting triglycerides but best by modest elevations (140-212 mg/dl), which serve better as a marker of triglyceride-rich lipoprotein particles. This knowledge may prove to be of value in population screening and individual risk assessment.

We observed the appearance of two intermediate density lipoprotein (IDL) subfractions on gradient gel electrophoresis of lipoproteins in the density range 1.006-1.030 g/ml and estimated their approximate concentrations in plasma in subjects with a wide range of lipid levels, from 0.55 to 28.0 mmol/l plasma triglyceride and 3.75-10.0 mmol/l cholesterol. The larger species, IDL-I (31.7 +/- 0.7 nm, mean +/- SD), showed little variation in size in normal and moderate hyperlipidaemic individuals. The estimated concentration of IDL-I was positively related to plasma triglyceride (r = 0.63, P = 0.0004) and low density lipoprotein (LDL) cholesterol (r = 0.68, P = 0.0003). These findings are consistent with the view that IDL-I is a metabolic intermediate between very low density lipoprotein (VLDL) and LDL. The smaller subfraction, IDL-II (25.7 +/- 2.4 nm) was virtually the only true species observed in subjects with plasma triglyceride < 1.0 mmol/l and its estimated concentration fell as plasma triglyceride increased (r = -0.58, P = 0.0002). IDL-II particle size changed in concert with LDL particle size (r = 0.61, P < 0.0001), suggesting that they were influenced by common metabolic factors. These observations provide further support for the hypothesis outlined by Musliner et al. [1] that IDL-I was part of the delipidation chain from VLDL to LDL, whereas IDL-II arose from a separate source, possibly directly released from the liver. Hence the two subpopulations of IDL differ in their relationship to plasma triglyceride and cholesterol levels.

Epidemiologic and clinical studies have demonstrated a relation between plasma triglyceride levels and risk of coronary artery disease and an amplification of risk with combined elevations of triglyceride and low-density lipoprotein (LDL) cholesterol. In patients with coronary disease, angiographic progression and clinical events have been correlated with concentrations of smaller very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), consistent with evidence for enhanced atherogenicity of lipolytic products of triglyceride-rich lipoprotein metabolism, including postprandial lipoproteins. IDL levels also have been shown to be strongly and independently predictive of progression of carotid artery intimal-medial thickness, a measure of early atherogenesis that is related to coronary disease risk. Although there is evidence that these triglyceride-rich lipoprotein species may have direct atherogenic effects, other lipoprotein changes associated with altered triglyceride metabolism may be of particular importance in the development of coronary artery disease. These include reductions in high-density lipoprotein (HDL) and increases in small, dense LDL particles (LDL subclass pattern B). Because of the strong interrelations among elevated triglyceride, reduced HDL, and small dense LDL, it is difficult to use statistical techniques to determine the independent contributions of these traits to coronary disease risk. Based on their biologic properties, it is likely that each are involved in multiple steps of the disease process. Moreover, this cluster of lipoprotein changes is associated with other conditions that can promote vascular disease, including increases in coagulation factors and reduced insulin sensitivity. Analyses from intervention trials in patients with coronary disease have indicated that measurement of plasma triglyceride and LDL particle distributions can be of value in predicting the benefits of specific lipid-altering therapies on disease progression.

Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS).

MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (Sf 0 to 12), IDL (Sf 12 to 20), VLDL (Sf 20 to 400), and HDL (F1.20 0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B-containing lipoproteins were measured independently, IDL (r=.21, P<.005) but not VLDL (r=-.09, P=.24) or LDL (r=.09, P=.26) was associated with the progression of carotid artery intimamedia thickness.

These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (Sf 12 to 20) that is included within the traditional measurements of LDL-C.

We have demonstrated previously in a subset of Monitored Atherosclerosis Regression Study (MARS) subjects with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease that lovastatin significantly reduces cholesterol-rich lipoprotein B (LpB) but has little effect on complex, triglyceride-rich apolipoprotein (apo) B-containing LpBc (the sum of LpB:C, LpB:C:E and LpA-II:B:C:D:E) particles defined by their apolipoprotein composition. This differential effect of lovastatin on apoB-containing lipoprotein families offered the opportunity to determine in the same subset of MARS subjects the independent relationship of LpB and LpBc with the progression of coronary artery disease. Subjects randomized to either lovastatin (40 mg twice daily) or matching placebo were evaluated by coronary angiography before randomization and after 2 years of treatment, and the overall coronary status was judged by a coronary global change score. In the lovastatin-treated group, there were 22 nonprogressors (69%) and 10 progressors (31%), while in the placebo group 13 subjects (42%) were nonprogressors and 18 (58%) were progressors (P < .03). In the lovastatin-treated group, lipid and lipoprotein parameters did not differ between progressors and nonprogressors except for LpBc and LpA-II:B:C:D:E particle levels, which were statistically higher in progressors (P = .02). In the placebo-treated group, progressors differed from nonprogressors by having significantly higher levels of triglycerides (P = .03) and apoC-III in VLDL + LDL (P = .05), the characteristic constituents of triglyceride-rich lipoproteins. In the placebo- and lovastatin-treated groups combined, progressors had significantly higher on-trial levels of triglycerides (P = .003), VLDL cholesterol (P = .005), apoC-III in VLDL + LDL (P = .008), apoC-III (P = .01), apoB (P = .03), and total cholesterol (P = .04) than nonprogressors. Even after adjustment for treatment group, progressors in the combined placebo- and lovastatin-treated groups had significantly higher levels of LpBc, LpA-II:B:C:D:E, triglycerides, and apoC-III in VLDL + LDL than nonprogressors. Progressors in the placebo-treated, lovastatin-treated, and combined treatment groups had lower levels of LpA-1 but not LpA-I:A-II than non-progressors, and this difference reached statistical significance (P = .047) in the combined sample adjusted for treatment group. Results of this study show that elevated levels of triglyceride-rich LpBc in general and LpA-II:B:C:D:E in particular contribute significantly to the progression of coronary artery disease. Furthermore, they provide additional evidence for the potentially protective role of LpA-I particles in the atherogenic process and suggest that apolipoprotein-defined lipoprotein families may be more specific prognosticators of coronary artery atherosclerosis progression than lipids and apolipoproteins.

Previous results from this laboratory found that the arterial low-density lipoprotein (LDL) residence time in lesion-prone aortic sites was longer in hyperlipidemic rabbits before lesion formation than in the corresponding sites in normolipidemic rabbits. The calculation of residence time in the previous study assumed that the arterial wall was homogeneous; the present study reexamines the issue using a method that does not require such an assumption. The concentration of radiolabeled arterial LDL was measured in New Zealand White rabbits killed at several different times (0.5 to 72 hours) after injection of labeled LDL. Using a stochastic analysis, arterial LDL residence time was calculated from the pooled labeled arterial LDL measurements from these rabbits. In these studies, the arterial LDL residence times in normolipidemic and hyperlipidemic rabbits before lesion formation were similar in both the lesion-prone and -resistant sites. However, immediately upon development of early fatty streak lesions, the arterial LDL residence time increased dramatically. After only 16 days of cholesterol feeding, the residence time was 10 times longer in the lesioned aortic arch compared with similar tissue from normolipidemic rabbits (4 to 45 hours). After 21 days of cholesterol feeding, the residence time of LDL in the lesioned aortic arch increased to > 25-fold that of normolipidemic tissue. Similar results were observed in the lesioned tissue of the abdominal branchings. This early retention of LDL suggests that significant changes are taking place within the arterial wall during this critical stage of early lesion development.

A large proportion of a dense subfraction of LDL in plasma is coupled with an increased risk of coronary artery disease, CAD. This may reflect an increased inflow of such LDL subfractions into the intima, since the inflow of lipoproteins is supposed to be inversely related to the size of the particles. In order to evaluate this possibility we used an in vitro perfusion system for aortic intima-media from rabbits with experimental atherosclerosis. The uptake of human VLDL, LDL, HDL and subfractions of LDL (LDL1, 1.019-1.035 and LDL2, 1.035-1.063 g/ml) in lesions and non-involved areas was studied. Our results indicate that particle size is an important factor for the clearance of lipoproteins into the arterial tissue, both for plaques (VLDL 7.6, LDL 25, HDL 58 nl/mg wet wt./h) and in other areas (VLDL 3.8, LDL 4.1, HDL 12 nl/mg wet wt./h). Interestingly, the uptake of LDL2 was as much as 1.5-1.9 times higher than LDL1. This supports the view that an increased lipid load in the arterial wall may be one mechanism behind the association between denser LDL and CAD. Our data also suggest that the difference between LDL uptake in plaque (576 nl/mg wet wt.) and other areas (48 nl/mg wet wt.) not only reflects a rapid clearance but a large distribution volume of the intima (plaque > 60%, non-involved areas 5.7%).

To explore possible mechanisms whereby the triglyceride-rich lipoproteins IDL and VLDL may promote atherosclerosis, fractional loss of these lipoproteins from the intima-inner media was measured in vivo in genetically hyperlipidemic rabbits of the St Thomas's Hospital strain and compared with the fractional loss of LDL, HDL, and albumin. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL. In each rabbit, two aliquots of the same macromolecule, one iodinated with 125I and the other with 131I, respectively, were injected intravenously on average 24 and 3 hours, respectively, before removal of the aortic intima-inner media. The fractional loss from the intima-inner media of newly entered macromolecules was then calculated. The average fractional losses for VLDL, IDL, LDL, HDL, and albumin in lesioned aortic arches were 0.1%/h (n = 4), -0.2%/h (n = 3), 1.8%/h (n = 4), 11.4%/h (n = 3), and 26.3%/h (n = 1), respectively; in nonlesioned aortic arches fractional losses for IDL, LDL, HDL, and albumin were 1.7%/h (n = 1), 0.6%/h (n = 2), 14.6%/h (n = 3), and 25.9%/h (n = 3). In both lesioned and nonlesioned aortic arches, the logarithms of these fractional loss values were inversely and linearly dependent on the diameter of the macromolecules (R2 = .57, P = .001 and R2 = .84, P < .001), as determined from electron photomicrographs of negatively stained lipoproteins. These results suggest that after uptake into the arterial intima, VLDL and IDL as well as LDL are selectively retained in comparison with HDL and albumin.

One-month-old male New Zealand White rabbits were fed either a cholesterol-free casein diet (CAS; n = 10); low-level cholesterol-supplemented (0.125% to 0.5% by weight) chow (CH; n = 10); or standard laboratory rabbit chow (n = 3) for 24 weeks, during which total plasma cholesterol (TPC) levels were matched for the two experimental groups (TPCCAS = 475 +/- 39 mg/dL; TPCCH = 515 +/- 70 mg/dL). The percentage of cholesterol partitioned into each of the lipoprotein fractions except high-density lipoprotein (HDL) was significantly different for the experimental groups: casein-fed rabbits had a primarily low-density lipoprotein (LDL) hypercholesterolemia while cholesterol-fed rabbits had approximately equal levels of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL cholesterol. Despite matched TPC, lesions in CH animals covered twice the luminal surface area (as detected by oil red O staining; P < .05) and had three times the total volume compared with lesions in the CAS group (P < .05). Lesion volume was positively correlated with TPC and IDL and LDL cholesterol for the CAS group and with TPC and IDL cholesterol for the CH group. When the experimental groups were combined, TPC and VLDL and IDL cholesterol were positively correlated with the lesion volume. Probability of occurrence maps revealed, however, that both groups were virtually identical with respect to the topographic distribution of lesions in the thoracic and abdominal aortas. The data suggested that the differential partitioning of cholesterol into the lipoprotein fractions seen in CAS and CH rabbits influenced lesion area and volume but not topographic distribution.

The aim of this study was to investigate the possibility that the permeability characteristics of the arterial wall are related to the development of atherosclerosis. The in vivo regional variation of aortic permeability to iodinated human low density lipoprotein (LDL) in normal rabbits was compared with the regional variation in aortic cholesterol accumulation in cholesterol-fed rabbits. Aortas were divided into the aortic arch, thoracic aorta, and abdominal aorta, and each of these three parts was further subdivided into four segments of similar size. The permeability to LDL was 40 +/- 7 nl.cm-2.hr-1 (mean +/- SEM, n = 11) in the most proximal segment of the aortic arch and decreased throughout the length of the aorta to 3 +/- 1 nl.cm-2.hr-1 in the most caudal segment of the abdominal aorta. In such normal rabbits the aortic cholesterol content was similar in all 12 arterial segments at 0.08 +/- 0.005 mumol/cm2 (mean +/- SEM, n = 3 x 12). Aortic cholesterol accumulation was determined in other rabbits with an average plasma cholesterol level of 32 +/- 1 mmol/l for 96 days; the cholesterol content in the most proximal segment of the aortic arch was 2.7 +/- 0.5 mumol/cm2 (mean +/- SEM, n = 11) and decreased with increasing distance from the heart to 0.17 +/- 0.03 mumol/cm2 in the most caudal segment of the abdominal aorta. Linear regression analysis showed a close positive association between the permeability to LDL of a given aortic segment and the cholesterol accumulation in that same aortic segment after cholesterol feeding (r2 = 0.96, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

In humans with the lipoprotein lipase deficiency disorder large amounts of chylomicrons and large very low-density lipoprotein (VLDL) accumulate in plasma. In spite of this, atherosclerosis does not seem to develop at an accelerated rate, suggesting that these lipoproteins do not promote atherogenesis. In humans with dysbetalipoproteinemia remnant lipoproteins (intermediate density lipoprotein (IDL) plus beta-VLDL) accumulate in plasma and these particles may therefore be the factor causing accelerated atherosclerosis in this disorder. Epidemiological studies in humans suggest that IDL or remnant lipoproteins are predictors of the severity or progression of atherosclerosis. Similar studies in the St. Thomas' Hospital rabbit strain, an animal model with genetically elevated plasma levels of VLDL, IDL and low-density lipoprotein (LDL), showed that IDL or remnant lipoproteins were better predictors of the extent of atherosclerosis than were LDL or VLDL. Studies of lipoprotein/arterial wall interactions have demonstrated that the larger the lipoprotein particle, the lower the influx into intima. Very large VLDL and chylomicrons do not seem to enter intima. Although high-density lipoprotein (HDL) enters intima faster than other lipoproteins, the small HDL particles seem to penetrate the entire arterial wall and leave via lymphatics and vasa vasorum in the outer media and adventitia. In contrast, LDL, and possibly also IDL and smaller VLDL, may only leave the intima via the lumen of the artery. In conclusion, a substantial body of evidence suggests that remnant lipoproteins (IDL and smaller VLDL) share with LDL the potential for promoting atherosclerosis, whereas very large VLDL and chylomicrons do not seem to have this effect.

To compare the atherogenic potential of low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL) under conditions where plasma levels of these lipoproteins are elevated, the influx of cholesterol in these lipoproteins into the aortic intima was measured in vivo in genetically hyperlipidemic rabbits from the St. Thomas's Hospital strain, an animal model that shares many of the features of the human disorder familial combined hyperlipidemia. Univariate linear regression showed that the arterial influx of LDL cholesterol (n = 25), IDL cholesterol (n = 14), and VLDL cholesterol (n = 10) was positively and linearly associated with plasma concentrations of LDL cholesterol in the range 0.2-6.4 mmol/l, of IDL cholesterol in the range 0.1-7.0 mmol/l, and of VLDL cholesterol in the range 0.7-8.5 mmol/l, respectively, and also with the extent of lesions in the arterial intima in the range 0-100% of the surface area. Multiple linear regression suggested that the arterial influx of LDL, IDL, and VLDL cholesterol was linearly dependent on plasma concentration, independent of lesion size. Furthermore, it appeared that the arterial influx of the three lipoproteins was linearly dependent on the extent of the lesions, independent of lipoprotein concentration. When influx was normalized for plasma concentration (intimal clearance) and for lesion size (compared within the same aorta), the intimal clearance of the larger IDL and VLDL particles was 15-35% less than that of the smaller LDL particles. These findings suggest that the quantitatively most important mechanism for transfer of plasma lipoproteins into the arterial intima involves nonspecific molecular sieving and that at elevated plasma levels, IDL and VLDL share with LDL the potential for causing atherosclerosis.