N.B. Myant
Medical Research Council
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Atherosclerosis | 1993
N.B. Myant
Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited disorder caused by the substitution of glutamine for arginine at position 3500 in apo B-100. The presence of mutant apo B-100 in low-density lipoproteins (LDL) markedly reduces their affinity for the LDL receptor, leading to hypercholesterolaemia and increased proneness to coronary artery disease. In some FDB heterozygotes the clinical picture is indistinguishable from that in heterozygous familial hypercholesterolaemia (FH). In European and N. American populations the frequency of FDB is at least as high as that of FH. In most lipid clinics, 2-5% of patients given a clinical diagnosis of FH have FDB, not FH. Most FDB heterozygotes respond well to drugs that lower plasma LDL levels by inducing receptor activity. This may be due partly to increased receptor-mediated hepatic removal of mutant and normal precursors of LDL, using apo E as recognition element. Several important lessons can be learnt from the study of FDB.
Heart | 1980
G. R. Thompson; N.B. Myant; D. Kilpatrick; Celia M. Oakley; M J Raphael; R E Steiner
The effectiveness of repeated plasma exchange with 2 to 4 litres of plasma protein fraction as long-term treatment for familial hypercholesterolaemia has been evaluated in six severely affected patients receiving conventional cholesterol lowering treatment. Cell-separator mediated exchange at monthly intervals for one to two years reduced mean serum cholesterol levels from 18.5 mmol/l (715 mg/dl) to 12.4 mmol/l (480 mg/dl) in two female homozygotes but failed to influence xanthomata or prevent a two- to threefold increase in their left ventricular aortic systolic pressure gradients. More effective reduction of mean serum cholesterol levels from 15.7 mmol/l (608 mg/dl) to 8.6 mmol/l (333 mg/dl) in two male homozygotes by plasma exchange at fortnightly intervals for two to three years was accompanied by resolution of xanthomata and by stabilisation of aortocoronary lesions. In two male heterozygotes with angina, coronary angiographic appearances were unaltered or improved after one to two years of thrice-monthly plasma exchange, which reduced mean serum cholesterol levels from 6.4 mmol/l (248 mg/dl) to 4.7 mmol/l (182 mg/dl). We conclude that plasma exchange every one to two weeks, combined with oral nicotinic acid and/or cholestyramine, retards the rate of progression of atheroma in homozygotes and possibly induces regression in heterozygotes.
Atherosclerosis | 1977
Anne K. Soutar; N.B. Myant; G. R. Thompson
Abstract The rates of synthesis of apolipoprotein B (apoB) in VLDL and LDL were measured simultaneously using [ 125 I]VLDL and [ 131 I]LDL in 5 patients with familial hypercholesterolaemia (FH). In 3 homozygotes the rate of synthesis of VLDL-apoB was in the normal range, whereas LDL-apoB synthesis was higher than normal and exceeded the rate of VLDL-apoB synthesis by 1.5–2-fold. In one Type IIb heterozygote, both VLDL-apoB synthesis and LDL-apoB synthesis were increased, but to an equal extent, whereas in one Type IIa heterozygote VLDL-apoB and LDL-apoB synthetic rates were both normal. These data suggest that an additional pathway for the synthesis of LDL exists in homozygous FH, involving direct secretion into the circulation of an apoB-containing lipoprotein of density >1.006 g/ml. Simultaneous measurements of VLDL-apoB and LDL-apoB turnover were carried out on one of the homozygotes before and after a portacaval shunt. Initially VLDL-apoB synthesis was normal, while LDL-apoB synthesis was elevated and exceeded VLDL-apoB synthesis. Two months after the operation, plasma cholesterol had decreased to 60% and plasma triglyceride to 45% of the pre-operative values. Although LDL-apoB synthesis decreased only slightly, it could now be accounted for entirely on the basis of VLDL-apoB synthesis. These data suggest that the liver may be the source of the VLDL-independent pathway of apoB synthesis in homozygous FH.
Biochimica et Biophysica Acta | 1973
Konstantinos A. Mitropoulos; S. Balasubramaniam; N.B. Myant
1. 1. Cholesterol 7α-hydroxylase activity was assayed by a direct method in liver microsomal preparations from rats adapted to controlled lighting and feeding and subjected to conditions known to modify hepatic synthesis of cholesterol and bile acids. The mass of microsomal cholesterol that acts as substrate for the enzyme (the substrate pool) was estimated in each set of conditions. 2. 2. In cholestyramine-fed and bile-fistula rats, the activity of the enzyme was increased, but the normal diurnal rhythm in activity was maintained. The size of the substrate pool was not increased in the treated animals. 3. 3. In bile-fistula rats the biliary excretion of bile acids and cholesterol assumed a diurnal rhythm, with a maximum at night and a minimum during the day. These results are discussed in relation to the diurnal rhythm in the activity of cholesterol 7α-hydroxylase and in the rate of synthesis of cholesterol in the liver. 4. 4. When cholesterol was added to the food, cholesterol 7α-hydroxylase activity was increased but enzyme activity continued to vary diurnally. Cholesterol feeding increased the size of the substrate pool, suggesting that the increase in activity may be due to an increase in the supply of substrate, rather than to increased capacity of the enzyme.
Atherosclerosis | 1989
N.B. Myant; John J. Gallagher; M. Barbir; G. R. Thompson; D. Wile; S. Humphries
We have determined the frequencies of the alleles at the EcoRI (E), XbaI (X) and PvuII (P) polymorphic restriction sites in the apo B gene in 124 white men with coronary artery disease (CAD) and in 146 white men free from CAD. The frequencies of the E- (restriction site absent) and X- alleles were both significantly higher in normocholesterolaemic men with CAD than in those without CAD, but the frequency of the P+ allele (restriction site present) was similar in the 2 groups. The frequency of the E- allele was significantly higher in CAD men with hypertriglyceridaemia than in normal men without hypertriglyceridaemia. In the normocholesterolaemic men without CAD, the mean serum cholesterol concentration was higher in those with genotype X++ than in those with genotype X--. Mean serum LDL-apo B and LDL-cholesterol concentrations did not differ significantly between men with different XbaI or EcoRI genotypes. Serum apo A-I levels differed significantly between normal men with different XbaI genotypes. Serum HDL-cholesterol levels differed significantly between CAD men with different XbaI genotypes. These results suggest that in white men the E- and X- alleles are in linkage disequilibrium with a nearby allele that is causally related to CAD. It is also possible that the amino acid substitution at position 4154 in apo B, brought about by the nucleotide change responsible for the EcoRI polymorphism, has a direct effect on the atherogenicity of LDL.
Heart | 1980
J M Allen; G. R. Thompson; N.B. Myant; R E Steiner; Celia M. Oakley
Seven patients with homozygous familial hypercholesterolaemia, two female and five male, aged 12 to 25 years, underwent clinical and angiographic assessment to define the associated cardiovascular abnormalities. Four patients had angina, two of whom also had syncope on exertion. All had an ejection systolic murmur but no ejection click and a loud aortic second sound. All but one had a systolic gradient between the left ventricle and aorta, ranging from 20 to 80 mmHg at the time of presentation. Angiography showed a characteristic narrowing of the aortic root in all and five of the seven patients had coronary ostial stenosis. One patient died after an aortocoronary bypass and aortic valvotomy and two others underwent aortocoronary bypass and aortic valve replacement, one of whom also died after operation. The survivor and three other patients are now undergoing regular plasma exchange and remain well. The seventh patient died suddenly before the latter form of treatment could be started. These findings confirm that premature, severe atheroma of the aortic valve and root is a characteristic feature of homozygous familial hypercholesterolaemia and carries a high mortality.
Atherosclerosis | 1982
Anne K. Soutar; N.B. Myant; G. R. Thompson
The metabolism of apolipoprotein B (apoB) in very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) was studied in normal subjects and in patients with familial hypercholesterolaemia (FH) after an intravenous injection of autologous VLDL labelled with 125I. There were no significant differences in half life, pool size and turnover rate (mg/kg/h) of VLDL-apoB between the normal subjects, the FH heterozygotes and the FH homozygotes. IDL-apoB metabolism in the FH patients differed significantly from that in the normal subjects. In the FH patients, the rise to the maximum of the specific activity curve was slower, the half life of the descending limb of the specific-activity curve was longer, the fractional rate of turnover was lower and the plasma concentration was higher than in the normals. The effect of cholestyramine on IDL-apoB metabolism in the normal subjects did not differ from that in the FH heterozygotes and homozygotes, though cholestyramine is known to stimulate hepatic uptake of low density lipoprotein (LDL) by the LDL receptor. It is suggested that in normal human subjects the LDL receptor makes some contribution to the hepatic uptake of IDL-apoB derived from VLDL, but that IDL uptake is mediated partly by a separate receptor that recognizes apolipoprotein E but not apoB.
Biochimica et Biophysica Acta | 1977
D. Reichl; N.B. Myant; J.J. Pflug
The concentration of apolipoprotein B (apoB) in human serum and peripheral lymph was measured by quantitative immunoelectrophoresis with anti-serum to human low-density lipoprotein. In four normal and six hyperlipidaemic subjects, total lymph apob/ml was 5-10% of total serum apoB/ml in the same subject. These ratios were equivalent to lymph apob concentrations of 60-120 microgram/ml. When the assays were carried out under conditions in which unmasking of immunoreactive sites on lymph and serum apoB was assumed to be maximal (delipidation with Nonidet P40), the lymph/serum apoB concentration ratios in three normal subjects were similar to those obtained with untreated lymph and serum.
Atherosclerosis | 1971
C.D. Moutafis; N.B. Myant; M. Mancini; P. Oriente
Abstract The effect of cholestyrainine alone, nicotinic acid alone and a combination of both drugs was investigated in 4 patients suffering from homozygous familial hyperbetalipoproteinaemia. When cholestyramine was given alone to 2 of the 4 patients there was no fall in plasma cholesterol level or in appearance of the skin lesions in either patient, though in one patient in whom faecal steroids were measured there was a marked increase in faecal excretion of steroids derived from the pool of exchangeable cholesterol. In one of these patients a combination of nicotinic acid plus cholestyramine lowered the plasma cholesterol level and abolished the skin lesions; in the other, this combination improved the skin lesions but did not cause a sustained fall in plasma cholesterol level. When nicotinic acid was given alone to the 2 other patients, there was little effect on the plasma cholesterol level in one, but a slight sustained fall in the other. It is suggested that a combination of cholestyramine and nicotinic acid decreases the mass of exchangeable cholesterol in the body by increasing cholesterol removal and inhibiting the compensatory increase in hepatic cholesterol synthesis that would otherwise occur in response to increased removal.
Atherosclerosis | 1989
D. Wile; M. Barbir; J. GallagherP; N.B. Myant; C.D. Ritchie; G. R. Thompson; Steve E. Humphries
We have investigated the association between serum high density lipoprotein-cholesterol (HDL-C) and apo A-I concentration and the PstI and XmnI restriction fragment length polymorphisms of the apolipoprotein AI-CIII-AIV multigene complex. Two groups of subjects were examined. The first comprised 174 unrelated male patients under 60 years of age with angiographic evidence of coronary artery disease (CAD). Of this group 34 were non-North European. The second group consisted of 104 unrelated healthy male North European subjects aged under 60 and free from demonstrable CAD, who attended a health screening clinic in London. For the PstI polymorphism, the frequency of the rarer P2 allele was 0.12 in both the North European and non-North European patients and this was higher than in the control group (P2 frequency 0.06, P less than 0.05). Healthy individuals with the genotype P1P2 had higher levels of apo A-I but similar levels of HDL-C compared to those with the genotype P1P1. However, CAD patients with the genotype P1P2 had lower serum levels of apo A-I and significantly lower serum levels of HDL-C compared to those with the genotype P1P1 (0.85 mmol/l vs. 1.0 mmol/l, P less than 0.05). The allele frequencies of the XmnI polymorphisms were not significantly different in the control group and the group of North European patients, although within the sample of non-North European patients, the frequency of the X2 allele was significantly higher than that found in the North European controls (0.26 vs. 0.09). Patients with the genotype X1X2 had a higher mean serum concentration of HDL-C and apo A-I compared with patients with the genotype X1X1 (1.14 and 0.93 mmol/l for HDL-C, P less than 0.05; 147 and 123 mg/dl for apo A-I, P less than 0.05). Associations between HDL-C and apo A-I levels and PstI and XmnI genotype were similar in patients taking and not taking beta-blockers. The data show that genetic variation in the apo AI-CIII-AIV gene cluster is associated with coronary artery disease although only weakly, and suggest that the mechanism of this association may operate through an effect in determining the serum concentration of apo A-I and HDL-cholesterol.