Biomedical subjects

D J Rader

Publications and source records attributed to D J Rader.

At least 19 recordsLinked to original sources

PubMed1997

Gene therapy for atherosclerosis.

Although considerable progress has been made in the prevention and treatment of atherosclerotic cardiovascular disease, new therapeutic strategies are still needed. Atherosclerosis is a systemic disease and represents an attractive target for the development of somatic gene transfer intended to modulate systemic factors with the goal of inhibiting disease progression. This approach should be differentiated from localized vascular gene delivery to isolated atherosclerotic lesions such as that intended to prevent restenosis. Systemic gene therapy for atherosclerosis can involve either: 1) gene replacement therapy in patients with defined genetic disorder causing premature atherosclerosis, or 2) overexpression of proteins which directly or indirectly inhibit atherosclerosis or stabilize vulnerable lesions. The former is conceptually straightforward, and a pilot clinical gene therapy trial for one of these diseases, homozygous familial hypercholesterolemia, has already been reported. The latter has significant potential for eventual application to a large number of patients at risk for progressive atherosclerosis, independent of the specific cause. However, substantial progress in vector development and the demonstration of efficacy in relevant animal models will be required before gene therapy for atherosclerosis becomes a clinical reality.

Apolipoproteins E↗

PubMed1996

Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia.

OBJECTIVE: The purpose of this report was to provide detailed information on the safety and feasibility of surgical procedures associated with the first ex vivo liver-directed gene therapy trial for the treatment of vivo gene therapy for homozygous familial hypercholesterolemia (FH). SUMMARY BACKGROUND DATA: Familial hypercholesterolemia is an autosomal dominant disease in which the gene encoding the low density lipoprotein receptor is defective. Patients homozygous for this mutation have extraordinarily high levels of cholesterol and accelerated atherosclerosis and die prematurely of myocardial infarction. The concept of liver-directed gene therapy was based on the report of normalization of cholesterol levels by orthotopic cardiac/liver transplant in a child with homozygous FH. METHODS: Five patients with homozygous FH were selected for inclusion in this trial. The patients underwent hepatic resection and placement of a portal venous catheter. Primary hepatocytes cultures were prepared from the resected liver and transduced with a recombinant retrovirus encoding the gene for the human low density lipoprotein receptor. The genetically modified cells were then transplanted into the liver through the portal venous catheter. RESULTS: Numerous clinical, laboratory, and radiologic parameters were analyzed. Elevations of the hepatic transaminases and leukocyte counts and a decline in hematocrit count were noted. Transient elevations of the portal pressure were observed during cell infusion. No major perioperative morbidity--specifically, myocardial infarct, perioperative hemorrhage, or portal vein thrombosis--or death occurred as a result of this protocol. CONCLUSION: Liver-directed ex vivo gene therapy can be accomplished safely in humans and is appropriate for selected patients.

Adult↗

PubMed1996

Unravelling high density lipoprotein-apolipoprotein metabolism in human mutants and animal models.

Apolipoprotein A-I plays an essential structural and functional role in HDL metabolism and apolipoprotein A-II has important effects on HDL metabolism and function. Kinetic studies in humans have established that variation in plasma HDL-cholesterol and apolipoprotein A-I concentrations is primarily determined by variation in the rate of apolipoprotein A-I catabolism. In contrast, plasma apolipoprotein A-II levels are primarily determined by the rate of apolipoprotein A-II production. Genetic factors play an important role in modulating the plasma levels of HDL-cholesterol and apolipoproteins A-I and A-II. Studies in humans have established that mutations in genes encoding enzymes that esterify cholesterol (lecithin : cholesterol acyltransferase), transfer cholesterol (cholesteryl ester transfer protein) and hydrolyze lipids (hepatic lipase, lipoprotein lipase) regulate HDL-cholesterol and apolipoprotein A-I levels by modifying the lipid content (and therefore the size) of HDL particles. Recent studies in transgenic and knockout animals have confirmed the key role of HDL lipid-modifying proteins in HDL, apolipoprotein A-I and apolipoprotein A-II metabolism and have expanded our understanding of the role of lipid modification in determining plasma concentrations of HDL-cholesterol and apolipoprotein A-I, as well as the potential functional roles of apolipoprotein A-II.

Animals↗

PubMed1996

ApoA-II kinetics in humans using endogenous labeling with stable isotopes: slower turnover of apoA-II compared with the exogenous radiotracer method.

ApoA-II is a major apolipoprotein constituent of high density lipoproteins (HDL) and may play an important role in lipoprotein metabolism and predisposition to atherosclerosis. Previous radiotracer kinetic studies have suggested that the metabolism of apoA-II in humans may be different than the metabolism of apoA-I, the major HDL apolipoprotein. In the present study, we have used an endogenous labeling technique using stable isotopically labeled amino acids to study apoA-II metabolism and compared the results to those obtained by a simultaneous exogenous radiotracer labeling method. Seven subjects with HDL cholesterol levels ranging from 9 to 93 mg/dl and apoA-II levels from 13 to 60 mg/dl were investigated in this study. [13C6]phenylalanine and 131I-labeled apoA-II were simultaneously administered as a primed-constant infusion and a bolus injection, respectively. In the endogenous labeling study, plateau tracer/tracee ratios of VLDL apoB-100 were used as estimates for the precursor pool tracer/tracee ratios for apoA-II synthesis. Residence times of apoA-II using these two independent methods were found to be highly correlated (r = 0.973, P < 0.0002). These results indicate that the endogenous labeling of apoA-II using stable isotopically labeled amino acids is a reasonable alternative to the conventional exogenous radiotracer labeling method for the investigation of apoA-II turnover. However, under the conditions of our experimental design and modeling strategy, the apoA-II residence times as determined by endogenous labeling were significantly longer (mean 5.33 days) than by exogenous radiotracer (mean 4.65 days). This suggests that apoA-II turnover may be even slower than believed based on radiotracer studies, and further supports the concept that HDL containing apoA-II are metabolized differently than HDL without apoA-II.

Apolipoprotein A-I↗

PubMed1995

A 30-amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinemia.

The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the multifunctional enzyme, protein disulfide-isomerase, and a unique large, 97 kDa, subunit. It is found as a soluble protein within the lumen of the endoplasmic reticulum of liver and intestine and is required for the assembly of very low density lipoproteins and chylomicrons. Mutations in MTP which result in an absence of MTP function have been shown to cause abetalipoproteinemia. Here, the gene encoding the MTP 97-kDa subunit of an abetalipoproteinemic subject, which we have previously demonstrated lacks MTP activity and protein (Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., and Gregg, R. E. (1992) Science 258, 999-1001), was isolated and sequenced. A nonsense mutation, which predicts the truncation of the protein by 30 amino acids, was identified. To investigate if this apparently subtle change in MTP could explain the observed absence of MTP, protein disulfide-isomerase was co-expressed with either the normal or mutant MTP 97-kDa subunit in Sf9 insect cells using a baculovirus expression system. Although there were high levels of expression of both the normal and mutant forms of the MTP 97-kDa subunit, only the normal subunit was able to form a stable, soluble complex with protein disulfide-isomerase. These results indicate that the carboxyl-terminal 30 amino acids of the MTP 97-kDa subunit plays an important role in its interaction with protein disulfide-isomerase.

Abetalipoproteinemia↗

PubMed1995

Lipoproteins containing apolipoprotein B isolated from patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia: identification and characterization.

Abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HBL) are inherited disorders which are classically characterized by progressive retinal and spinocerebellar disease, fat-soluble vitamin deficiency, and absence of apolipoprotein (apo) B from the plasma. Using immunoaffinity chromatography with an anti-apo B antiserum, we isolated apo B-containing lipoprotein (LpB) particles from the plasma of 4 ABL and 2 HBL patients. The LpB particles were characterized and compared with low density lipoprotein (LDL) and LpB isolated from normal plasma. The ABL/HBL LpB particles were similar in size and charge to normal LpB particles but were relatively enriched in several other apolipoproteins. They contained alpha-tocopherol in a ratio to cholesterol that was proportionately much higher than the very low ratio of alpha-tocopherol to cholesterol in plasma. They bound saturably to fibroblasts and were internalized and degraded similarly to LDL. Hence, the molecular defects in ABL and HBL permit the secretion of a very small number of apo B-containing lipoproteins which may be important for transport of alpha-tocopherol to peripheral tissues.

Abetalipoproteinemia↗

PubMed1995

A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia.

The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholesterolaemia (FH) ranging in age from 7 to 41 years were enrolled; each patient tolerated the procedure well without significant complications. Transgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five patients. Significant and prolonged reductions in low density lipoprotein (LDL) cholesterol were demonstrated in three of five patients; in vivo LDL catabolism was increased 53% following gene therapy in a receptor negative patient, who realized a reduction in serum LDL equal to approximately 150 mg dl-1. This study demonstrates the feasibility of engrafting limited numbers of retrovirus-transduced hepatocytes without morbidity and achieving persistent gene expression lasting at least four months after gene therapy. The variable metabolic responses observed following low-level genetic reconstitution in the five patients studied precludes a broader application of liver-directed gene therapy without modifications that consistently effect substantially greater gene transfer.

Adult↗

PubMed1995

Lipoprotein (a) in patients with hyperlipidaemia.

Lipoprotein (a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to, but metabolically distinct from, LDL. Factors modulating plasma Lp(a) concentrations are poorly understood. We hypothesized that patients with hyperlipidaemia have elevated Lp(a) levels and determined the phenotype, concentration and distribution of Lp(a) in a group of hyperlipidaemic patients (n = 107) compared with a control group (n = 128). Lp(a) concentrations were significantly increased in the hyperlipidaemic patients (mean, 34 +/- 4 mg dL-1; median, 19 mg dL-1) as compared with the controls (20 +/- 3 mg dL-1; 9 mg dL-1) (P < 0.01). Interestingly, after dividing the patients into one group with elevated cholesterol (> 200 mg dL-1) (n = 44) and another group with elevated triglycerides (> 200 mg dL-1) (n = 51) we found that Lp(a) concentrations were 2.3-fold higher in the high cholesterol patients (mean, 45 +/- 5; median, 41 mg dL-1) compared to the high triglyceride subjects (20 +/- 4; 8 mg dL-1) (P < 0.01). Furthermore, a negative correlation between triglyceride and Lp(a) plasma concentrations was found in patients exhibiting triglyceride levels > 300 mg dL-1 (r = -0.41, P = 0.04, n = 36) and with triglycerides > 400 mg dL-1 (r = -0.52, P = 0.03, n = 17). These data indicate that plasma Lp(a) concentrations are elevated in hyperlipidaemia if the patients have high cholesterol levels, whereas Lp(a) is normal to low in patients with elevated triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Apolipoprotein A-II production rate is a major factor regulating the distribution of apolipoprotein A-I among HDL subclasses LpA-I and LpA-I:A-II in normolipidemic humans.

HDLs are heterogeneous in their apolipoprotein composition. Apolipoprotein (apo) A-I and apoA-II are the major proteins found in HDL and form the two major HDL subclasses: those that contain only apoA-I (LpA-I) and those that contain both apoA-I and apoA-II (LpA-I:A-II). Substantial evidence indicates that these two subclasses differ in their in vivo metabolism and effect on atherosclerosis, with LpA-I the more specifically protective subfraction against atherosclerosis. The purpose of this study was to investigate the effect of apoA-I and apoA-II production and catabolism on plasma LpA-I and LpA-I:A-II levels. Fifty normolipidemic subjects (those with HDL cholesterol levels in the top and bottom tenth percentiles were excluded) underwent kinetic studies with radiolabeled apoA-I and apoA-II, and the kinetic parameters of apoA-I and apoA-II were correlated with LpA-I and LpA-I:A-II levels. ApoA-I levels were strongly correlated with apoA-I residence times and less strongly correlated with apoA-I production rates. In contrast, apoA-II levels were correlated only with apoA-II production rates and not with apoA-II residence times. Levels of apoA-I in LpA-I were correlated with apoA-I residence times, whereas levels of apoA-I in LpA-I:A-II were correlated primarily with apoA-II production rates. The fraction of apoA-I in LpA-I was highly inversely correlated with apoA-II production rate (r = -.67, P < .001). In multiple regression analysis, apoA-II production rate was the most significant independent variable determining percent apoA-I in LpA-I among all the kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to low density lipoproteins (LDL). The role of the LDL receptor in the catabolism of Lp(a) has been controversial. We therefore investigated the in vivo catabolism of Lp(a) and LDL in five unrelated patients with homozygous familial hypercholesterolemia (FH) who have little or no LDL receptor activity. Purified 125I-Lp(a) and 131I-LDL were simultaneously injected into the homozygous FH patients, their heterozygous FH parents when available, and control subjects. The disappearance of plasma radioactivity was followed over time. As expected, the fractional catabolic rates (FCR) of 131I-LDL were markedly decreased in the homozygous FH patients (mean LDL FCR 0.190 d-1) and somewhat decreased in the heterozygous FH parents (mean LDL FCR 0.294 d-1) compared with controls (mean LDL FCR 0.401 d-1). In contrast, the catabolism of 125I-Lp(a) was not significantly different in the homozygous FH patients (mean FCR 0.251 d-1), heterozygous FH parents (mean FCR 0.254 d-1), and control subjects (mean FCR 0.287 d-1). In summary, absence of a functional LDL receptor does not result in delayed catabolism of Lp(a), indicating that the LDL receptor is not a physiologically important route of Lp(a) catabolism in humans.

Adult↗

PubMed1995

Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.

The cholesteryl ester transfer protein (CETP) transfers lipids among lipoprotein particles and plays a central role in lipoprotein metabolism. Humans with genetic deficiency of CETP have both elevated HDL cholesterol and apolipoprotein A-I concentrations as well as decreased LDL cholesterol and apolipoprotein B levels. The present study was undertaken to elucidate the metabolic basis for the decreased LDL cholesterol and apo B levels in CETP deficiency. We conducted a series of in vivo apo B kinetic studies in tow unrelated homozygotes with CETP deficiency and in control subjects. A primed constant infusion of stable isotopically labeled phenylalanine was administered to the two CETP deficient subjects and control subjects and apo B kinetic parameters in VLDL, intermediate density lipoproteins, and LDL were obtained by using a multicompartmental model. The fractional catabolic rates (FCR) of LDL apo B were significantly increased in the CETP-deficient subjects (0.56 and 0.75/d) compared with the controls (mean FCR of 0.39/d). Furthermore, the production rates of apo B in VLDL and intermediate density lipoprotein were decreased by 55% and 81%, respectively, in CETP deficiency compared with the controls. In conclusion, CETP-deficient subjects were demonstrated to have substantially increased catabolic rates of LDL apo B as the primary metabolic basis for the low plasma levels of LDL apo B. This result indicates that the LDL receptor pathway may be up-regulated in CETP deficiency.

Adult↗

PubMed1995

Apolipoprotein(a) deposition in atherosclerotic plaques of cerebral vessels. A potential role for endothelial cells in lesion formation.

Atherosclerosis is the leading cause of death and serious morbidity in economically developed societies through its sequelae of coronary artery and cerebrovascular disease. The causes and mechanisms of atherosclerosis are still largely unknown. Serum levels of a lipoprotein, Lp(a), have been shown, in retrospective and some prospective clinical studies, to be associated with increased risk of myocardial and cerebral infarction. The active part of Lp(a), apo(a), has > 80% homology with plasminogen; thus it may competitively inhibit the thrombolytic action of plasminogen and enhance thrombogenesis. Lp(a) has been shown to be deposited in the vascular wall of the aorta and coronary vessels, but its presence in the cerebral vessels has not yet been shown. Autopsy specimens of vessels of the circle of Willis from 23 patients were examined for degree of atherosclerosis and deposition of apo(a) by immunohistochemistry with apo(a)-specific monoclonal antibodies. The amount of apo(a) deposition in cerebral vessels correlated well with the degree of cerebral atherosclerosis. Arterial deposition of apo(a) was found entirely within the endothelial cell and subendothelial cell layers. There was no staining within the media and adventitia, with the exception of staining within the endothelial cells of the vasa vasorum. Correlation between the morphology of apo(a) deposition and plaque stage was found suggesting that detection of apo(a) in endothelial cells is an early event in the development of the atherosclerotic plaque of cerebral vessels.

Adult↗

PubMed1994

Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease.

PURPOSE: To review current knowledge of apolipoprotein quantitation used in the clinical management of persons with or at risk for the development of premature coronary artery disease. DATA SOURCES: The English-language literature was analyzed using MEDLINE (1975 to 1993) with key words "apolipoproteins," "quantitation," and "coronary artery disease." Article bibliographies were also reviewed to obtain additional references. STUDY SELECTION: Published, peer-reviewed retrospective and prospective studies relevant to the association of plasma apolipoprotein levels with coronary artery disease in humans. DATA SYNTHESIS: Most studies concerned apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), and lipoprotein(a) [Lp(a)]. In retrospective cross-sectional studies, apo A-l levels were not substantially more predictive of coronary artery disease than were high-density lipoprotein (HDL) cholesterol levels. In contrast, levels of apo B and Lp(a) were often more strongly associated with coronary artery disease than were traditional lipid measurements. In studies of the relation between apolipoprotein levels in children and premature coronary artery disease in their parents, Lp(a) levels, but not apo A-l and apo B levels, were consistently predictive of familial coronary artery disease. Prospective studies have yielded variable results for all three apolipoproteins. Low apo A-l levels were consistently associated with coronary artery disease in six prospective studies but were not more predictive than HDL levels. Apolipoprotein B levels were strongly associated with coronary artery disease in four of five prospective studies but were more predictive of coronary artery disease than were total cholesterol levels in only two of the four studies. Lipoprotein(a) levels were strongly associated with coronary artery disease in five of seven prospective studies but were not associated in two of the four largest studies. CONCLUSIONS: Too few large prospective studies of apolipoprotein quantitation using validated assay methods, both in general unselected populations and in subgroups of persons with premature coronary artery disease or family histories of premature coronary artery disease, are available to make definitive recommendations concerning clinical utility. The data do not support use of apolipoprotein quantitation as a screening tool to predict coronary artery disease risk in the general population. However, the data suggest that quantitation of apo B and Lp(a) may be indicated in subgroups of persons with premature coronary artery disease or with family histories of premature coronary artery disease. In these persons, an increased apo B or Lp(a) level or both could be a clinical indication for more aggressive treatment of low-density lipoprotein cholesterol.

Apolipoproteins↗

PubMed1994

Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women.

Oxidative modification of low-density lipoprotein (LDL) may be atherogenic. We studied the time of onset of LDL oxidation (lag) in 18 postmenopausal women before and after intraarterial infusion of 17 beta-oestradiol, after 3 weeks' patch administration in 12 of these women, and 1 month after discontinuation in 10. The lag increased from baseline after acute infusion (from 134 [SD41] to 167 [36] min, p = 0.01) and after the patch (132 [31] to 178 [45] min, p = 0.009). After discontinuation of oestradiol, the lag returned to baseline. This study shows an antioxidant effect of physiological levels of 17 beta-oestradiol, which may contribute to an anti-atherogenic action.

Administration, Cutaneous↗

PubMed1994

A comparison of Lp(a) levels in fresh and frozen plasma using ELISAs with either anti-apo(a) or anti-apoB reporting antibodies.

Sandwich ELISAs with an anti-apo(a) trapping antibody and either an anti-apolipoprotein B or anti-apolipoprotein(a) reporting antibody, were used to measure the concentrations of Lp(a) in 230 plasma samples that were either freshly drawn or stored at -20 degrees C for 4-6 weeks. The assays produced significantly different results for the fresh and frozen samples, however, the magnitudes of these differences were small, about 8% higher for the frozen samples, and independent of total cholesterol, HDL cholesterol, triglyceride, apolipoprotein B or Lp(a) concentration or assay configuration. A similar difference was seen for a freshly drawn plasma sample assayed at the time as the fresh and frozen samples, indicating the differences were due to inherent differences in the assays at the times the assays were performed. The assay configuration was an important factor in determining the Lp(a) concentrations for identically treated samples. ELISAs using the apoB reporting antibody yielded concentrations that were significantly less than those determined by ELISAs using the anti-apo(a) reporting antibody. The assay differences did not correlate with total cholesterol, HDL cholesterol, triglyceride, or apoB concentration. However, the magnitude of the difference did correlate well with Lp(a) amount. Low Lp(a) concentrations produced greater assay differences than high Lp(a) concentrations.

Antibodies↗

PubMed1994

Decreased plasma levels of lipoprotein(a) in patients with hypertriglyceridemia.

Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein which is similar in structure to, but metabolically distinct from, LDL. Factors modulating plasma Lp(a) concentrations are poorly understood. To investigate the possible interaction of Lp(a) with triglycerides, we determined the apo(a) phenotype, Lp(a) concentration, and distribution of Lp(a) in a group of patients with triglycerides > 400 mg/dl (n = 60) compared with a control group (n = 128). Lp(a) concentrations were significantly lower in hypertriglyceridemic patients (mean +/- S.E., 13 +/- 4 mg/dl; median, 6 mg/dl; 25/75 percentile, 2-13 mg/dl) as compared with the controls (mean, 22 +/- 2 mg/dl; median, 10 mg/dl; 25/75 percentile, 7-30 mg/dl). Plasma Lp(a) concentrations in the hypertriglyceridemic patients correlated negatively with triglyceride levels (r = -0.69, P = 0.03). The difference in Lp(a) levels between patients and controls was maintained when subjects were stratified by apo(a) phenotype and type of hyperlipidemia. After subdividing the hypertriglyceridemic patients into one group with apo(a) isoforms < or = S2 and one group with apo(a) isoforms > or = S3, we found that the differences in plasma Lp(a) concentrations between patients and controls were more pronounced in the group with the lower molecular weight apo(a) isoforms. These data indicate that hypertriglyceridemia is associated with lower plasma Lp(a) concentrations and suggest that increased levels of triglyceride-rich lipoproteins may influence the metabolism of Lp(a).

Adolescent↗

PubMed1994

Effect of antioxidant vitamins on low density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia.

OBJECTIVES: The aims of this study were to determine whether antioxidant vitamins could reduce the susceptibility of low density lipoprotein (LDL) to oxidation and improve endothelium-dependent vasodilator responsiveness in patients with hypercholesterolemia. BACKGROUND: Animals and humans with hypercholesterolemia have exhibited impaired endothelium-dependent vasodilation. In vitro studies suggest that oxidatively modified LDL can impair nitric oxide production. METHODS: Forearm blood flow was measured with strain gauge plethysmography and brachial artery drug infusions in 19 patients, aged 52 +/- 9 years, with hypercholesterolemia (mean +/- SD total cholesterol 283 +/- 22 mg/dl, LDL 197 +/- 31 mg/dl) and in 14 subjects, aged 48 +/- 8 years, with normal cholesterol levels (total cholesterol 169 +/- 20 mg/dl, LDL 102 +/- 25 mg/dl). Acetylcholine (7.5, 15 and 30 micrograms/min) was utilized as an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. Oxidative susceptibility of LDL was measured by a spectrophotometric assay of conjugated diene production after the addition of copper chloride. Hypercholesterolemic patients then received daily antioxidant vitamin supplements (beta-carotene [30 mg], ascorbic acid [vitamin C] [1,000 mg], vitamin E [800 IU]) for 1 month, with repeat measurement of both forearm blood flow responsiveness to the same agonists and LDL oxidizability. RESULTS: The maximal flow in response to acetylcholine was impaired in patients compared with that in normal subjects (9.8 +/- 7.8 vs. 15.9 +/- 8.1 ml/min per 100 ml, p = 0.03), with similar maximal flow responses to sodium nitroprusside (9.5 +/- 4.2 vs. 9.0 +/- 2.8 ml/min per 100 ml, p = 0.72). After 1 month of vitamin therapy, the onset of LDL oxidation was prolonged over baseline measurements by 71 +/- 67%, and the maximal rate of oxidation was decreased by 26 +/- 25% (both p < 0.001). However, the maximal forearm blood flow response to acetylcholine remained unchanged from baseline values (maximal flow after acetylcholine 9.0 +/- 6.2 vs. 9.8 +/- 7.8 ml/min per 100 ml, p = 0.57). This study had 80% power (alpha = 0.05) to exclude a 45% increase over baseline value in acetylcholine-stimulated flow during vitamin therapy. CONCLUSIONS: Although 1 month of administration of antioxidant vitamin supplements in hypercholesterolemic patients reduced the susceptibility of LDL to oxidation, impairment in endothelial function remained unaltered. The use of nonvitamin antioxidants or concomitant reduction in LDL levels, as well as more sensitive techniques for measuring vascular responsiveness, may be required to show a beneficial effect on endothelial vasodilator function.

Acetylcholine↗

PubMed1994

Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease.

Classic (complete) lecithin:cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal). In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I:A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal). The metabolic basis for the low levels of apoA-II and LpA-I:A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques. The mean plasma residence time of apoA-I was decreased at 2.08 +/- 0.27 d (controls 4.74 +/- 0.65 days); however, the residence time of apoA-II was even shorter at 1.66 +/- 0.24 d (controls 5.25 +/- 0.61 d). In addition, the catabolism of apoA-I in LpA-I:A-II was substantially faster than that of apoA-I in LpA-I. In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II. Because LpA-I has been proposed to be more protective than LpA-I:A-II against atherosclerosis, this selective effect on the metabolism of LpA-I:A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I.

Adult↗