The apoprotein pattern in normolipemic peripheral vascular disease

The relationship between peripheral vascular disease (PVD) and plasma apoproteins has still not been well defined. The lipid and apoprotein pattern of a group of 20 normolipemic patients affected by peripheral vascular disease has been compared with 20 healthy normolipemic subjects. Mean triglyceride plasma levels were higher in normolipemic patients than in the healthy controls (107.8 +/- 31.5 mg% vs 73.3 +/- 28.6 mg%; p less than 0.03) while mean HDL-cholesterol values were significantly lower (36.5 +/- 5.4 mg% vs 44.4 +/- 7.1 mg%; p less than 0.003). No significant difference was observed between the two groups in the mean values of the apoproteins AI (112.1 +/- 41.2 mg% in PVD vs 117.2 +/- 17.7 mg% in controls), AII (45.1 +/- 12.2 mg% vs 50.1 +/- 11.1 mg%), B (93.7 +/- 23.5 mg% vs 91.3 +/- 21.6 mg%), CII (3.9 +/- 2.6 mg% vs 2.6 +/- 1.7 mg%), CIII (6.7 +/- 1.5 vs 5.9 +/- 1.4 mg%) and E (3.09 +/- 1.4 mg% vs 3.3 +/- 0.9 mg%). On the contrary the mean triglyceride/Apo-E ratio was higher in PVD patients than in the controls (52.3 +/- 42 vs 23.3 +/- +/- 10; p less than 0.03).     

Lipoprotein profile in older patients with vascular dementia and Alzheimer's disease

Background

Some alterations of the lipoprotein profile have been associated with cerebrovascular disease. Recently, it has been suggested that cerebrovascular disease might play a role in the pathogenesis of both vascular dementia (VD) and Alzheimer's disease (AD). Nevertheless, the possible association of dyslipidemias with VD or AD is still a controversial issue.

Methods

We investigated the lipoprotein profile in 100 older patients with vascular dementia (VD; n°: 60) or Late Onset Alzheimer's Disease (LOAD; n°: 40). The patients were compared with 54 community dwelling non-demented older controls.

Results

After adjustment for functional status, blood sedimentation rate, and serum albumin levels, no differences in lipoprotein profile emerged between the three groups, with the exception of HDL-C that was lower in VD compared with controls. Low HDL-C (< 45 mg/dL) was associated with VD (O.R.: 6.52, C.I. 95%: 1.42–30.70 vs controls, and 4.31, C.I. 95%: 0.93–19.82 vs LOAD), after multivariate adjustment. No differences in plasma lipid levels emerged between the three groups after stratification for apo E4 genotype.

Conclusions

In this cross-sectional study low HDL-C levels are associated with VD, but not with LOAD, in a sample of older subjects.     

Lipoprotein [Lp(a)] and peripheral vascular disease.

Lipoprotein(a) [Lp(a)], which combines structural elements of the lipid and fibrinolytic systems, is a major independent risk factor for the development of coronary heart disease. Eighty-four consecutive patients with peripheral vascular disease (of whom 42 had concomitant ischaemic heart disease) and 43 healthy controls were enrolled in a case-control study. We found that the mean Lp(a) concentration in male patients with peripheral vascular disease (PVD) was almost threefold higher than that of controls, while in female patients the Lp(a) concentration was more than twice that of controls. This marked difference was borne out in patients with and without concomitant ischaemic heart disease (IHD). A multivariate logistic regression analysis indicated that Lp(a) is independently associated with PVD when adjusted for age and sex (odds ratio per 100 mg l-1 increase in Lp(a) = 1.35; P < 0.01). A similar association is observed for patients with concomitant IHD (odds ratio per 100 mg l-1 increase in Lp(a) = 1.65; P < 0.01).     

Role of apolipoprotein E in the lipolytic conversion of beta-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia.

The beta-very low density lipoproteins (beta-VLDL) that accumulate in type III hyperlipoproteinemic subjects can be divided into two fractions (fraction I and fraction II), which differ in size, lipid composition, and the type of apolipoprotein B (apo-B) present in the particles. The apo-B48-containing particles (fraction I) are of intestinal origin, while apo-B100-containing particles (fraction II) are derived from the liver. Both fractions contain a defective form of apo-E referred to as apo-E2. Intravenous infusion of heparin into two subjects with type III hyperlipoproteinemia resulted in the complete removal of fraction II particles from density less than 1.006 g/ml, while fraction I particles remained at this density. In vitro studies confirmed that fraction I particles did not change density when subjected to hydrolysis with lipoprotein lipase, while fraction II particles shifted to the intermediate density lipoprotein range (approximately equal to 1.02 g/ml). When the beta-VLDL were hydrolyzed by lipoprotein lipase in the presence of density greater than 1.21 g/ml lipoprotein-deficient plasma, the addition of normal apo-E (apo-E3), but not apo-E2, resulted in a shift of fraction II particles to the low density lipoprotein (LDL) range (approximately equal to 1.05 g/ml). Fraction I particles did not undergo a shift to this higher density, supporting previous observations that apo-B48-containing particles are not converted to LDL. The demonstration that apo-B100-containing particles in type III hyperlipoproteinemic subjects could be converted to particles with the density of LDL suggests that apo-E plays a role in the normal conversion of VLDL to LDL. The mutant form of apo-E (apo-E2) found in the beta-VLDL from type III hyperlipoproteinemic subjects appears to impede this conversion, whereas the addition of normal apo-E (apo-E3) allows the processing to occur.     

Serum lipoprotein (a) levels in men with peripheral vascular disease.

The authors quantified serum lipoprotein (a) (Lp) (a) by enzymo-immuno-analysis in 86 outpatient men suffering peripheral vascular disease (PVD) and in 53 age-matched healthy men. They further measured serum cholesterol, serum triglycerides, low density lipoproteins-cholesterol, high density lipoproteins (HDL)-cholesterol and serum apolipoprotein B. Serum triglycerides were significantly increased in patients with PVD versus controls (148 +/- 8 and 114 +/- 7 mg/dL, mean +/- SEM). HDL-cholesterol levels were significantly lower in patients versus controls (36 +/- 1 and 43 +/- 2 mg/dL, respectively). Serum Lp(a) levels in patients with PVD were 20 +/- 2 mg/dL, whereas in controls they were 16 +/- 3 (p: NS). Serum Lp(a) concentrations were identical in smoker and nonsmoker patients. There was no correlation between Lp(a) concentration and the other lipid parameters. Conversely, as occurs in coronary heart disease and in cerebrovascular disease, Lp(a) does not seem to be a marker for PVD, although a trend toward a higher mean levels was found.     

Plasma high density lipoproteins in coronary, cerebral and peripheral vascular disease The influence of various risk factors

High density lipoprotein (HDL) cholesterol and the HDL/total cholesterol ratio have been measured in 440 patients with coronary, cerebral or peripheral vascular disease and in 440 matched controls. The patients were subdivided into sex- and age-groups and according to physical activity, smoking, hypertension and non-insulin-dependent and insulin-dependent diabetes mellitus.

The average HDL cholesterol level was significantly decreased in all the three groups of localization of ischaemic vascular disease (IVD). Plasma HDL concentration in men was lower than in women in every age-group. Lowest values were measured in patients with cerebral vascular diseases.

From among the risk factors supposed to be related to IVD, lack of physical exercise resulted in a decrease of HDL cholesterol and HDL/total cholesterol values. In all the three localizations of IVD cigarette smokers had lower HDL levels than non-smokers. The influence of hypertension on serum HDL concentration was not unidirectional. The coexistence of non-insulin-dependent diabetes and IVD resulted in decreased lipid parameters. The sera of insulin-dependent depbetics had higher HDL contents and higher HDL/total cholesterol ratios than those of non-diabetics in all the three localizations of the vascular disease in men and in women suffering from peripheral vascular disease.     

Autoantibodies against oxidized low density lipoproteins in patients with stable angina, unstable angina or peripheral vascular disease; pathophysiological implications.

BACKGROUND: Antibody antioxidized low density lipoproteins (oxLDL) might play a role both in atherogenesis and in the pathogenesis of acute coronary syndromes. METHODS AND RESULTS: Antibody titres to oxLDL and levels of C-reactive protein were compared in unstable angina, stable angina or peripheral artery disease. Antibody titres to LDL oxidated by CuSO(4)for 2, 4 and 18 h (Cu-oxLDL-Ab(2-4-18)) or by peroxidase (HRP-oxLDL-Ab) were assessed by ELISA. Cu-oxLDL-Ab(2-4-18)were consistently higher in peripheral artery disease than in unstable angina (P<0.001, P<0.001, P=0.01, respectively) or in stable angina (P<0.001, P=0.01, P=ns) but similar in unstable and stable angina. Accordingly, HRP-oxLDL-Ab were higher in peripheral artery disease than in unstable angina (P<0.001) or stable angina (P=0.04) but similar in unstable and stable angina. The number of arterial stenoses was higher in peripheral artery disease than unstable and stable angina (P<0.01). Cu-oxLDL-Ab and HRP-oxLDL-Ab correlated with the severity of atherosclerosis (P<0.01, R=0.4;P=0.02, R=0.3 respectively). Conversely, C-reactive protein levels were higher in unstable than in stable angina (P<0.001) or in peripheral artery disease (P<0.03) but similar in stable angina and peripheral artery disease and did not correlate with the severity of atherosclerosis. CONCLUSION: The autoimmune response to oxLDL is likely to play an important role in atherogenesis but not in precipitating acute coronary syndromes.     

Role of angioscopy in the treatment of peripheral vascular disease with percutaneous atherectomy.

The role of adjunctive video angioscopy was evaluated in 43 patients with symptomatic peripheral vascular disease undergoing percutaneous atherectomy with the Simpson atherocath. There were 57 target lesions (superficial femoral, n = 46; popliteal, n = 11) of which 33 were stenotic (86 +/- 11%) and 24 were total occlusions of 0.5 to 10.6 cm in length, determined by angiography. Intraluminal inspection, with angioscopes of 0.85 to 1.5 mm in outer diameter housed within a guide catheter, could be performed in 55 of 57 lesions (96%) before atherectomy and in 39 of these 55 (71%) after atherectomy. Failure to obtain an adequate image was usually due to insufficient irrigation, especially in recanalized vessels. In 13 of 23 successfully recanalized arteries (54%) the occlusion could be crossed by the angioscope itself, whereas in 10 cases (42%) a guidewire or a sheath introducer was necessary. Angioscopic passage revealed that often long total occlusions, determined by angiography, consisted of greater than or equal to 1 discrete occlusion with interposed patent thrombus-free vascular segments. After atherectomy, in 15 instances with an acceptable angiographic result, angioscopy was helpful in identifying residual plaques and flaps which then selectively underwent atherectomy. In conclusion, angioscopy proved to be a useful adjunct to angiography in optimizing vascular recanalization with percutaneous atherectomy.     

Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits.

Rabbit livers express two genetically distinct receptors for plasma lipoproteins: (i) the low density lipoprotein (LDL) receptor and (ii) the chylomicron remnant receptor. In homozygous Watanabe-heritable hyperlipidemic (WHHL) rabbits, an animal model for human familial hypercholesterolemia, LDL receptors are genetically deficient, but chylomicron remnant receptors are normal. Hence, WHHL rabbits clear LDL from the circulation at an abnormally slow rate, but they clear chylomicron remnants at a normal rate. The current studies show that WHHL rabbits clear 125I-labeled very low density lipoprotein (VLDL) and its metabolic product, intermediate density lipoprotein (IDL), from plasma at a markedly decreased rate. The impaired clearance is due to a profound decrease in the rate of uptake of 125I-labeled VLDL and 125I-labeled IDL by the liver. Because of its rapid clearance in normal rabbits, only a fraction of the 125I-labeled apoprotein B component of VLDL is converted to LDL. In WHHL rabbits, the impaired clearance of VLDL leads to a markedly increased conversion of 125I-labeled apoprotein B from VLDL to LDL. These results indicate that: (i) in rabbits, the LDL receptor mediates the rapid removal of VLDL and IDL from plasma, and (ii), a deficiency of LDL receptors leads to an enhanced conversion of VLDL to LDL. The combination of overproduction and impaired plasma clearance of LDL, both resulting from a single gene mutation in the LDL receptor, leads to a massive increase of plasma LDL levels in homozygous WHHL rabbits.     

Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins.

To elucidate the precise metabolic roles of hepatic lipase (HL), a human HL cDNA in a liver-specific expression vector was used to generate transgenic lines in the rabbit, an animal that normally expresses low levels of this enzyme. HL was detected in the plasma of all rabbits only after the administration of heparin; HL activity in transgenic rabbits was found at levels up to 80-fold greater than that in nontransgenic littermates. This increase in enzyme activity was associated with as much as a 5-fold decrease in total plasma cholesterol levels. Expression of the transgene resulted in a dramatic reduction in the level of large high density lipoproteins (HDL1 and HDL2) as well as dense HDL3. A reduction in the quantity of intermediate density lipoproteins (IDL) was also observed. These results demonstrate that HL functions in the metabolism of HDL and IDL, thereby playing a key role in plasma cholesterol homeostasis.     

Lipid levels in high density lipoprotein subfractions in smokers with peripheral vascular disease

No significant difference in HDL cholesterol was found between smokers with PVD and corresponding controls. The ratio of HDL cholesterol to the sum of (VLDL + LDL) cholesterol was reduced in patients with PVD. Patients with PVD had significantly highly serum triglyceride levels. A slightly significant difference could be demonstrated for serum cholesterol and serum phospholipids concentrations in smoking patients with PVD.     

Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins.

Low density lipoprotein receptor-related protein (LRP) is a recently described cell-surface protein of 4544 amino acids that contains reiterated sequences found in the 839-amino acid receptor for low density lipoprotein (LDL). In the current studies, we purified LRP from rat liver, prepared polyclonal antibodies that recognize the extracellular domain, and demonstrated an immunoreactive protein of approximately 600 kDa in human fibroblasts. The function of this LRP was studied in mutant human fibroblasts that do not produce LDL receptors. The mutant cells were incubated with beta-migrating very low density lipoprotein (beta-VLDL) that was isolated from cholesterol-fed rabbits and artificially enriched with apoprotein (apo) E by incubation in vitro with human apo E produced in a bacterial expression system. The apo E-enriched beta-VLDL, but not unincubated beta-VLDL, stimulated incorporation of [14C]-oleate into cholesteryl [14C]oleate 20- to 40-fold in the mutant cells. This stimulation was blocked by chloroquine, suggesting that such stimulation resulted from receptor-mediated uptake and lysosomal hydrolysis of the cholesteryl esters in apo E-enriched beta-VLDL. Stimulation of cholesterol esterification was blocked by the antibody against LRP, but not by an antibody against the LDL receptor. Unlike the LDL receptor, the amount of LRP was not reduced when cells were incubated with oxygenated sterols. We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E.