International consensus statement on olive oil and the Mediterranean diet: implications for health in Europe. The Olive Oil and the Mediterranean Diet Panel.
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Coronary Disease↗
Biomedical subjects
G Assmann
Publications and source records attributed to G Assmann.
Effects of genotype and diet on cholesterol efflux into plasma and lipoproteins of normal, apolipoprotein A-I-, and apolipoprotein E-deficient mice.
We investigated the contribution of apoE to cholesterol efflux into plasmas of normal, apoA-I-, and apoE-deficient mice, which were fed with chow- and cholesterol-rich diets. Plasmas of normal and apoA-I-deficient mice contain apoE in pre-beta-migrating VLDL as well as in HDL-like lipoproteins, which have either electrophoretic alpha- or gamma-mobilities. The latter particle resembled gamma-LpE in human plasma also by its mobility on nondenaturing two-dimensional electrophoresis. No apoE-containing lipoproteins were found in plasmas of apoE-deficient mice. When apoA-I- and apoE-deficient mice received both chow- and fat-rich diets, their plasmas released significantly less 3H-cholesterol from radiolabeled fibroblasts than did plasma of normal mice. Removal of apoE from plasmas of normal and apoA-I-deficient mice by anti-apoE immunoaffinity chromatography decreased their cholesterol efflux capacities (per 1 minute/per 1 hour) by 26%/40% (P = 0.0092/0.0007) and 30%/26% (P = 0.0092/0.0003), respectively. Net cholesterol efflux from fibroblasts into apoA-I-deficient plasma was 45% lower compared with plasma of normal mice. Incubation of fibroblasts with apoE-deficient plasma caused net influx of cholesterol. Prior addition of human apoE to or removal of apoB-containing lipoproteins from apoE-deficient plasma restored its ability to cause net cholesterol efflux to 50% of normal plasma. Some of the differences between cholesterol efflux into normal and apoE-deficient plasmas were attributable to the failure of apoE-deficient plasmas to take up cell-derived 3H-cholesterol into gamma-LpE. Compared with normal plasma, both apoA-I-deficient and apoE-deficient plasmas were significantly decreased in their activity to esterify cell-derived 3H-cholesterol. Anti-apoE chromatography decreased significantly cholesterol esterification in normal plasma and apoA-I-deficient plasma but not in apoE-deficient plasma. Taken together, the data provide evidence that apoE is an important contributor to reverse cholesterol transport, partially because of initial uptake of cell-derived cholesterol by gamma-LpE and partially because of the contribution of apoE-containing lipoproteins to esterification of cholesterol in plasma.
Animals↗
Coagulation factor VII and the risk of coronary heart disease in healthy men.
Numerous investigations have demonstrated the role of thrombus formation in the pathogenesis of coronary heart disease (CHD). A tendency to thrombosis may also be indicated by elevated levels of coagulation factor VII clotting activity (FVIIc). Significant associations of FVIIc with increased coronary risk, however, have been found only in the Northwick Park Heart Study. Here we present the results of the 8-year follow-up of FVIIc measurements in 2780 healthy men of the Prospective Cardiovascular Münster study. In the study population (age at entry, 49.3 +/- 6.1 years, mean +/- SD), 130 CHD events occurred during follow-up. FVIIc was significantly higher in subjects with coronary events than in those without (112.4 +/- 20.1% vs 108.7 +/- 21.4%, P = .023). Compared with individuals without coronary events, FVIIc was not significantly higher in men with nonfatal events (111.7 +/- 20.4%; P = .196, n = 93), but there was a tendency toward higher FVIIc activity in subjects with fatal events (114.6 +/- 19.5%; P = .076, n = 37). In the multiple logistic regression analysis, we did not find FVIIc to be an independent risk factor for CHD, and the significance of FVIIc disappeared after total cholesterol, LDL-cholesterol, and triglycerides were taken into account. The increase in the number of CHD events through higher levels of FVIIc was more pronounced in the presence of additional cardiovascular risk factors: smoking; myocardial infarction events in family; angina pectoris; high levels of fibrinogen, total cholesterol, LDL cholesterol, and triglycerides; and a low level of HDL cholesterol. We conclude that FVIIc is a risk factor for CHD, especially in the presence of additional risk factors, and must be taken into account when assessing cardiovascular risk in men.
Adult↗
Downregulation of the selectin ligand-producing fucosyltransferases Fuc-TIV and Fuc-TVII during foam cell formation in monocyte-derived macrophages.
Identification of genes expressed during foam cell formation is important for understanding the molecular basis of atherosclerosis. We used polymerase chain reaction (PCR)-based differential display to isolate differentially expressed cDNA species in foam cells induced by incubation of human monocyte-derived macrophages in the presence of acetylated or oxidized LDL. This led to identification of a 306-bp cDNA with 100% homology to type IV fucosyltransferase (Fuc-TIV), which was downregulated by factors of 20 and 3 in acetylated LDL- and oxidized LDL-loaded macrophages, respectively. This enzyme is sufficient for the expression of Lewis X and sialyl Lewis X, carbohydrate adhesion molecules that bind to receptors of the selectin family. Expression of a second fucosyltransferase (Fuc-TVII) that synthesizes sialyl Lewis X but not Lewis X was shown by quantitative reverse transcription-PCR to also be reduced, by 40% and 20% in acetylated LDL- and oxidized LDL-loaded macrophages, respectively. alpha-(1,3)-Fucosyltransferase enzyme activity was reduced in lysates from both acetylated LDL- and oxidized LDL-loaded cells. Analysis by flow cytometry showed reduced expression of the CD15 (corresponding to Lewis X) and CD15s (sialyl Lewis X) antigens on the surface of cells loaded with either acetylated or oxidized LDL. Transformation of macrophages into foam cells results in reduced expression of selectin-binding ligands on the surface of such cells.
Acetylation↗
Suppression of endogenous testosterone in young men increases serum levels of high density lipoprotein subclass lipoprotein A-I and lipoprotein(a).
We investigated the effect of testosterone suppression on lipoprotein metabolism in men. After a baseline period of 14 days, 12 healthy young men received over a period of 3 weeks daily s.c. injections of Cetrorelix, an antagonist of GnRH. The volunteers were then followed-up for 10 additional weeks. Administration of Cetrorelix suppressed testosterone significantly up to day 35, after which values returned to baseline. Suppression of testosterone was associated with significant and consistent increases in mean serum levels of high density lipoprotein (HDL) cholesterol by 20% (P < 0.0001), apolipoprotein A-I (apoA-I) by 10% (P = 0.0032), apoA-II by 7% (P = 0.0112), HDL subclass lipoprotein A-I (LpA-I) by 23% (P = 0.002), and plasma lecithin:cholesterol acyltransferase by 7% (P < 0.001). Serum levels of HDL subclass LpA-I/LpA-II changed insignificantly. Moreover, suppression of testosterone significantly increased the median of lipoprotein(a) [Lp(a)] levels from 5.5 to 8.5 mg/dL (P < 0.0001). The increase in Lp(a) levels was positively correlated with baseline levels of Lp(a) (r = 0.91; P < 0.001) and amounted to 40-60% in individuals with baseline levels of Lp(a) higher than 3 mg/dL. We conclude that endogenous testosterone is involved in the regulation of HDL cholesterol and Lp(a) levels and may thereby influence cardiovascular risk.
Adult↗
A novel frameshift mutation in PMP22 accounts for hereditary neuropathy with liability to pressure palsies.
Peripheral myelin protein PMP22 deficiency is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Most HNPP cases are caused by a 1.5-megabase deletion in chromosome 17p11.2-12, a region that contains the PMP22 gene, whereas point mutations leading to HNPP are extremely rare. We have identified a family with clinical and electrophysiologic features of HNPP,in which all affected members are heterozygous carriers of a single base insertion in codon 94. This mutation is predicted to alter the reading frame and to result in a delayed termination signal. We conclude that the functional consequences of the frameshift are equivalent to those of the PMP22 deletion allele.
Adult↗
Lipoproteins and cardiovascular risk-from genetics to CHD prevention.
Dyslipidemia is said to be present when lipid or lipoprotein levels lie within a range which is known from epidemiological studies to be associated with secondary complications, in particular atherosclerosis of the coronary arteries, or when a lipid or lipoprotein grossly deviates from the norm as in abetalipoproteinemia, hypobetalipoproteinemia or the HDL deficiency syndromes. In most cases, dyslipidemia is due not to a single genetic or environmental factor, but to a combination of the effects of several genes of small effect (polygenes) and environment. In other cases, however, dyslipidemia is caused by a mutation in a single gene of large effect. In such cases, the extent and nature of the phenotype depends primarily on the identity of the gene involved, but is also modulated to an important degree by the nature of the mutation and the genetic and environmental background against which this mutation occurs. In addition, many cases of hyperlipidemia are secondary to other disorders such as hypothyroidism or renal dysfunction. Such disorders may also unmask or exacerbate a genetic lipoprotein disorder. Examples of the latter are the unmasking of type III hyperlipidemia by diabetes mellitus or the exacerbation of familial hypercholesterolemia by hypothyroidism.
Clinical Trials as Topic↗
Avoidance of false positives in PCR-based mRNA differential display during investigation of nonstandardized tissues or cells.
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Electrophoresis, Polyacrylamide Gel↗
Heterozygosity for apolipoprotein A-I(R160L)Oslo is associated with low levels of high density lipoprotein cholesterol and HDL-subclass LpA-I/A-II but normal levels of HDL-subclass LpA-I.
We studied a Norwegian patient and his family, who presented with low HDL-cholesterol. DNA sequence analysis of the apoA-I gene revealed heterozygosity for a mutation in the apoA-I gene that causes a leucine for arginine replacement at residue 160. Compared to unaffected family members, heterozygous carriers of apoA-1 (R160L)Oslo had 60-70% lower mean levels of HDL-cholesterol, 50-60% lower mean levels of apoA-I and 70-80% lower levels of apoA-II. Moreover, the serum concentration of the apoA-II-containing HDL-subclass LpA-I/A-II was decreased by 70% whereas the concentration of the apoA-II-free HDL-subclass LpA-I did not differ from that in unaffected family members. The decrease of LpA-I/A-II was associated with the lack of large LpA-I/A-II. ApoA-I(R160L)Oslo was present at increased concentrations relative to normal apoA-I in plasma, HDL3, and LpA-I. However, only trace amounts of the variant isoform were detectable in immunopurified LpA-I/A-II. Pre beta1-LpA-I contained normal and variant apoA-I isoforms. We conclude that the failure of apoA-I(R160L)Oslo to form LpA-I/A-II causes low HDL-cholesterol in heterozygous carriers of this apoA-I variant.
Adult↗
The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.
Lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes represent a group of rare genetic disorders of HDL metabolism that have been the subject of a large number of clinical, biochemical, and genetic studies. Of special interest are patients with LCAT-related disorders with severe HDL deficiency and the apparent absence of premature atherosclerosis. This finding is inconsistent with the general concept that low HDL cholesterol levels are an obligate risk factor for atherosclerosis. In this review, we describe 36 natural mutations in the LCAT gene that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED). We propose a new classification of the natural mutations of the LCAT gene that are described to date. The defects are divided into four classes based on both the clinical and biochemical characterization of the patient and data that were obtained from the functional assessment of the mutant proteins. We define FLD-associated mutations that underlie a complete or nearly complete loss of LCAT activity due to null mutations (Class 1), and missense mutations (Class 2), respectively. In addition, we distinguish two classes of FED-associated mutations (Classes 3, 4) that underlie a partial impairment of LCAT activity but differ in their lipoprotein substrate specificity. In addition, we review the evidence of atherosclerosis in subjects with LCAT deficiency syndromes. The observation that 6 (all males) of a total of 19 FED subjects suffered from premature CAD (as defined by < 55 years of age and < 60 years of age for women and men, respectively) challenges the earlier assumption that the FED phenotype is not associated with increased risk of CAD. However, premature CAD remains an unusual clinical complication in FLD subjects.
Adolescent↗
An improved method for quantification of cholesterol and cholesteryl esters in human monocyte-derived macrophages by high performance liquid chromatography with identification of unassigned cholesteryl ester species by means of secondary ion mass spectrometry.
The measurement of cholesteryl esters in human monocyte-derived macrophages using previously described high performance liquid chromatography methods is hampered by the presence in these cells of large amounts of triglycerides. We present a simple reversed phase high performance liquid chromatography protocol for quantification of cholesterol and cholesteryl esters in human monocyte/macrophages or other triglyceride-rich cells. Our method requires only lipid extraction and hydrolysis of triglycerides using a solution of ethanolic potassium hydroxide and is of sufficient sensitivity to allow measurement in 10(5) cells. Use of this protocol led to the isolation of eight previously unassigned cholesteryl ester peaks comprising 16% of the total cholesteryl ester content of human monocyte-derived macrophages. Using time-of-light secondary ion mass spectrometry and synthesized authentic standards, seven of these peaks were found to comprise cholesterol esterified with polyunsaturated n-3 (omega 3) (cholesteryl eicosapentaenoate, docosatrienoate, docosapentaenoate, and docosahexaenoate) and n-6 (omega 6) (cholesteryl docosatetraenoate, eicosadienoate, and eicosatrienoate) fatty acids. The remaining peak was shown to be the cholesteryl ester of n-7 (omega 7) palmitoleic acid by comparison with a commercially available standard. The identification of all the cholesteryl esters in cholesterol-loaded human monocyte-derived macrophages will assist future studies of lipid metabolism in these cells.
Animals↗
A natural apolipoprotein A-I variant, apoA-I (L141R)Pisa, interferes with the formation of alpha-high density lipoproteins (HDL) but not with the formation of pre beta 1-HDL and influences efflux of cholesterol into plasma.
ApoA-I(L141R)Pisa is a naturally occurring apolipoprotein A-I variant that causes virtual absence of HDL in hemizygotes and hypoalphalipoproteinemia with half-normal levels of HDL-cholesterol in heterozygotes. In this study we analyzed the distribution of HDL subclasses in plasmas of four hemizygotes for this mutation. We also investigated the abilities of these plasmas to esterify cholesterol and to promote cholesterol efflux. Residual apoA-I-containing lipoproteins in plasmas of hemizygotes for apoA-I(L141R)Pisa correspond to pre beta 1-LpA-I and small alpha-LpA-I. Unlike normal pre beta 1-LpA-I, pre beta 1-LpA-I of apoA-I(L141R)Pisa hemizygotes was not converted into a larger alpha-migrating particle. Plasmas of apoA-I(L141R)Pisa hemizygotes were significantly reduced in their activity to esterify cholesterol in either endogenous or exogenous lipoproteins. Cholesterol efflux capacity was significantly lower than that of normal plasma. Efflux of [3H] cholesterol from radiolabeled fibroblasts into apoB-depleted plasma of normal probands was biphasic with fast cholesterol efflux occurring in the first minute. Thereafter, cholesterol efflux was slow and unsaturable. After incubation with radiolabeled fibroblasts, efflux values of [3H]cholesterol into apoB-depleted plasma from normal controls and from apoA-I(L141R)Pisa hemizygotes were indistinguishable at 1 min. Longer incubations with apoB-free plasma from apoA-I(L141R)Pisa hemizygotes did not, however, lead to the unsaturable increase in cholesterol efflux that was observed during incubations with apoB-free plasma of normolipidemic probands. Pre beta 1-LpA-I of apoA-I(L141R)Pisa hemizygotes took up significantly less cell-derived [3H]cholesterol than pre beta 1-LpA-I of normal donors. We conclude that apoA-I(L141R)Pisa interferes with the formation of lipid-rich alpha-HDL but not with that of lipid-poor pre beta 1-LpA-I. Very low concentrations of alpha-HDL in plasmas of apoA-I(L141R)Pisa hemizygotes combined with reduced LCAT activity cause a decrease of the slow, unspecific, and LCAT-dependent components of cholesterol efflux into plasma.
Animals↗
Comparison of prostate-specific antigen (PSA) measured by four combinations of free PSA and total PSA assays.
We compared prostate-specific antigen (PSA) assay systems [i.e., free PSA (f-PSA) and the corresponding total PSA (t-PSA) assay] from four different manufacturers as well as the f-PSA/t-PSA ratios with regard to their ability to discriminate between benign prostate hyperplasia (BPH) and prostate cancer (PCA). ROC analysis showed similar areas under the curves (AUCs) with different assay systems. For the entire patient population the AUCs of the f-PSA/t-PSA ratio were not or slightly increased compared with the sole measurement of t-PSA (t-PSA, 0.792-0.820; f-PSA/t-PSA ratio, 0.685-0.859). In contrast, for only those patients who showed t-PSA concentrations within the diagnostic gray area of 4-25 micrograms/L t-PSA, the AUCs were greater for the f-PSA/ t-PSA ratio than for measurement of t-PSA alone (t-PSA, 0.608-0.647; f-PSA/t-PSA ratio, 0.690-0.806). These results were confirmed by the predictive values of the negative results (NPVs) of the t-PSA assays and the f-PSA/t-PSA ratios (assay thresholds corresponding to a 95% detection limit). Compared with the sole t-PSA measurement there was no mentionable increase in the NPVs due to the f-PSA/t-PSA ratio for the entire patient population, but an increase up to 49% when limited to t-PSA concentrations within 4-25 micrograms/L. We therefore conclude that the f-PSA/t-PSA ratio may be helpful for differential diagnosis of BPH and PCA within the diagnostic gray area of 4-25 micrograms/L t-PSA.
Aged↗
Multicenter evaluation of a homogeneous assay for HDL-cholesterol without sample pretreatment.
We evaluated a new homogeneous assay for the measurement of HDL-cholesterol (HDL-C) in six European laboratories. The assay includes two reagents and is applicable to most autoanalyzers, which allows full automation. The total CVs of the new method ranged between 1.3% and 6.7%. Thereby determined HDL-C values were in good agreement with those obtained by precipitation with phosphotungstic acid/MgCl2 or by a combination of ultracentrifugation and precipitation (0.956 < r < 0.994). The assay was linear up to at least 1500 mg/L HDL-C. Hemoglobin did not interfere, whereas icteric samples with bilirubin > 100 mg/L showed discrepancies between the homogeneous and the precipitation assay. Lipemia up to total triglyceride concentrations of 8000 mg/L did not interfere with the homogeneous HDL-C assay. The homogeneous HDL-C assay was easy to handle and produced similar results in all laboratories participating in this study. This method will significantly facilitate the screening of individuals at increased risk for cardiovascular disease.
Artifacts↗
No apparent restriction on measuring FVIIa in frozen plasma.
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Blood Preservation↗
[Increased CK in lipid-lowering therapy].
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Creatine Kinase↗
Interleukin-6 correlates with hemodynamic impairment during dobutamine administration in chronic heart failure.
Proinflammatory cytokines have been implicated in the pathophysiology of chronic heart failure. We determined mixed venous levels of interleukin-6 (IL6) in 18 heart transplant candidates before, 1, 4, and 24 h after initiation of dobutamine infusion (3 micrograms/kg/min) during hemodynamic evaluation. During the first 4 h of dobutamine, systemic vascular resistance decreased (1358 to 1024 dyn x s x cm-5, P = 0.01) while cardiac index (2.3 to 2.9 l/min/m2, P = 0.008) increased. Both returned to baseline after 24 h. IL6 was elevated at baseline compared to age-matched controls (1.5 (0/4.3) vs. 0 (0/0.5) P = 0.003). There was an increase in IL6 from 1.5 (0/4.3) to 3.6 (0.3/5.3) pg/ml after 24 h (P = 0.04). We found higher IL6 levels in the sicker half of patients as defined by pulmonary capillary wedge pressure > 24 mmHg (P = 0.005), mean pulmonary arterial pressure > or = 35 mmHg (P = 0.01), right atrial pressure > 13 mmHg (P = 0.02), and heart rate > or = 87/min (P = 0.02) as well as mean arterial pressure < 82 mmHg (P = 0.005). In conclusion, in this pilot study IL6 correlates with the severity of chronic heart failure during low dose dobutamine infusion.
Adult↗
Defective regulation of phosphatidylcholine-specific phospholipases C and D in a kindred with Tangier disease. Evidence for the involvement of phosphatidylcholine breakdown in HDL-mediated cholesterol efflux mechanisms.
The negative correlation between coronary heart disease and plasma levels of HDL has been attributed to the ability of HDL to take up cellular cholesterol. The HDL3-induced removal of cellular cholesterol was reported to be impaired in fibroblasts from patients with familial HDL deficiency (Tangier disease, TD). In addition, we have recently shown that HDL3 stimulates the hydrolysis of phosphatidylcholine (PC) in cholesterol-loaded fibroblasts. To investigate whether this cell signaling pathway is involved in cholesterol efflux mechanisms, we compared the HDL3-induced PC hydrolysis in normal fibroblasts and in fibroblasts from a TD kindred, in whom the HDL3- and apolipoprotein A-I (apo A-I)-induced mobilization of cellular cholesterol was found to be reduced by 50%. The HDL3-induced formation of phosphatidic acid (PA) via PC-specific phospholipase D (PC-PLD) was markedly reduced by 60-80% in these cells, whereas the formation of diacylglycerol (DG) via PC-specific phospholipase C (PC-PLC) was two- to threefold enhanced. Defective regulation of PC-PLC and PC-PLD was similarly observed in response to apo A-I and endothelin, but not in response to the receptor-independent stimulation of PC hydrolysis by PMA. A Tangier-like PA and DG formation pattern could be induced in normal cells after preincubation with pertussis toxin, suggesting the involvement of a G-protein. The impaired mobilization of radiolabeled cellular cholesterol in TD cells could completely be overcome by increasing the PA levels in the presence of the PA phosphohydrolase inhibitor propranolol. Conversely, the inhibition of PA formation in the presence of 0.3% butanol as well as the inhibition of DG formation in the presence of the PC-PLC inhibitor D 609 reduced the mobilization of cellular cholesterol both in normal and in TD cells. Our data indicate that the coordinate formation of PA and DG via PC-PLD and PC-PLC is essential for efficient cholesterol efflux. The molecular defect in this TD kindred appears to affect an upstream effector of protein kinase C responsible for the G-protein-dependent regulation of PC-specific phospholipases.
Apolipoprotein A-I↗