P.N. Durrington

APOLIPOPROTEINS (a), AI, AND B AND PARENTAL HISTORY IN MEN WITH EARLY ONSET ISCHAEMIC HEART DISEASE

Middle-aged men who had had a myocardial infarction were compared with controls matched for social background, age, cigarette-smoking, blood pressure, and alcohol consumption. Serum cholesterol, triglycerides, very low density lipoprotein, low density lipoprotein, high density lipoprotein (HDL), HDL2 and HDL3 cholesterol, and serum apolipoproteins (apo) (a), AI, and B were measured. Discriminant analysis showed that the combination of these variables that best distinguished patients from controls was provided by apo AI and apo B and a knowledge of parental history of early cardiac death, the most discriminating single factor being apo B. No other variable contributed more than these. Apo (a), however, could be substituted for parental history, which had a major influence on the serum concentration of apo (a). Apo (a) concentration accounted for much of the familial predisposition to cardiac ischaemia. These findings may prove valuable in the clinical assessment of genetic susceptibility to myocardial infarction. They also support the hypothesis that serum apo (a) concentration is a genetic trait that predisposes to arterial thrombosis. Apo B emerged as the main lipoprotein determinant of coronary disease risk.

Serum paraoxonase activity in patients with type 1 diabetes compared to healthy controls

Background The oxidation of low‐density lipoprotein (LDL) is central to current theories on the initiation and progression of atherosclerosis. Type 1 diabetes is associated with an increase in oxidative stress, which may be responsible for the increased susceptibility to coronary heart disease seen in type 1 diabetes. High‐density lipoprotein (HDL) associated paraoxonase (PON1) can retard the oxidation of LDL.

Serum lipoprotein(a) in patients heterozygous for familial hypercholesterolemia, their relatives, and unrelated control populations.

Serum lipoprotein(a) (Lp[a]) levels were significantly higher in 89 patients with heterozygous familial hypercholesterolemia (FH) (geometric mean, 22.7 mg/dl) than in 109 normocholesterolemic controls (10.0 mg/dl, p less than 0.05) and 40 controls (9.1 mg/dl, p less than 0.05) with similarly elevated low density lipoprotein cholesterol levels due to other primary hypercholesterolemias. To provide further evidence that the increased serum Lp(a) concentration was due to inheritance of the FH gene, 24 unaffected first-degree relatives were compared with their FH probands. Serum Lp(a) in affected individuals was significantly greater than in unaffected relatives (geometric means, 26.5 versus 13.7 mg/dl, respectively; p less than 0.05). Family membership exerted an effect on serum Lp(a) concentrations, indicating that other genetic influences were also operating, as is known to be the case in general populations. Serum Lp(a) in 30 of the FH patients, who had coronary heart disease, was not significantly different from 30 age- and sex-matched controls with FH but with coronary heart disease (geometric means, 23.6 versus 24.7 mg/dl, respectively). FH is associated with an increase in serum Lp(a). Elevated serum Lp(a) concentrations should probably now be regarded as a component of the clinical syndrome of FH. However, within our FH population Lp(a) did not distinguish those with clinically overt coronary heart disease from those without the disease.

Investigation of lipid transfer in human serum leading to the development of an isotopic method for the determination of endogenous cholesterol esterification and transfer

The rate at which radioactivity appeared in cholesteryl esters (CE) in whole serum and in very low density lipoproteins (VLDL) and low density lipoproteins (LDL) when radioactively labelled free cholesterol (FC) was incubated with serum was investigated. At 4 degrees C equilibration of radioactive FC with native FC occurred, but there was no conversion to CE. At 37 degrees C CE mass increased in parallel with radioactivity in CE both in whole serum and VLDL/LDL. Incubation at 37 degrees C with an inhibitor of lecithin cholesterol acyl transferase (LCAT) abolished the increase in the total CE radioactivity and mass in serum. Transfer of CE from high density lipoprotein (HDL) to VLDL/LDL, however, continued to occur. An assay for LCAT and for cholesteryl ester transfer protein (CETP) was developed, which employed the increases in radioactive CE in whole serum and VLDL/LDL during a single incubation as indices of LCAT and CETP activity, respectively. Determination of the initial serum FC concentration allowed the expression of these activities in nmol/ml per h. References ranges were established in 62 fasting normolipidaemic men and women and increases in both LCAT and CETP were found following a fatty meal. The experiments thus provided further information about the carrier-mediated transfer of CE from its site of esterification on HDL to VLDL/LDL and formed the basis of a relatively simple assay, which has advantages over previously published methods and which may be used in clinical and epidemiological studies to elucidate the role of CETP and LCAT in atherosclerosis.

LIPOPROTEIN ABNORMALITIES IN INSULIN-DEPENDENT DIABETES MELLITUS

Despite the increased risk of atherosclerosis in diabetes mellitus, levels of serum cholesterol, triglycerides, low-density-lipoprotein (LDL) cholesterol, and high-density-lipoprotein (HDL) cholesterol were similar in 57 men with insulin-dependent diabetes mellitus (IDDM) and 81 non-diabetic controls. However, substantially lower serum levels of apolipoprotein B, the principal apolipoprotein of LDL, and a concomitant increase in the cholesterol-loading of apolipoprotein B were found in IDDM. The likely changes in LDL density and particle size resulting from this compositional abnormality might lead to accelerated atherogenesis analogous to that seen in type III hyperlipoproteinaemia. In addition, there was an increase in the concentration of cholesterol in the smaller, denser, HDL3 subfraction of serum HDL in IDDM.

Increased transfer of cholesteryl esters from high density lipoproteins to low density and very low density lipoproteins in patients with angiographic evidence of coronary artery disease

Cholesterol esterification, transfer of cholesteryl esters from high density lipoproteins to very low density and low density lipoproteins (VLDL/LDL) and the composition of lipoproteins isolated by density gradient ultracentrifugation have been investigated in 18 men with angiographic evidence of severe coronary artery disease and in 27 healthy men without coronary artery disease. Patients had significantly higher serum cholesterol (P < 0.001), serum triglycerides (P < 0.02) and lower high density lipoprotein cholesterol (HDL) (P < 0.04) compared with healthy men. The transfer of cholesteryl ester from HDL to VLDL and LDL was 27.8 +/- 12.2 nmol/ml per h (mean +/- S.D.) in patients and was significantly higher than the value of 17.8 +/- 6.5 nmol/ml per h obtained in healthy men (P < 0.003) or 17.1 +/- 7.6 nmol/ml per h) in 16 controls (P < 0.03) with similar serum cholesterol and triglyceride concentrations. Lipoprotein protein concentrations were significantly higher in LDL (P < 0.05) and small VLDL (P < 0.01) in patients. In addition, patient LDL and large VLDL contained more free cholesterol than matched controls (P < 0.01, P < 0.05, respectively). This was reflected in the increased free cholesterol/phospholipid ratio (a measure of lipoprotein surface composition) in LDL (P < 0.002). These findings indicate that patients with established coronary artery disease have increased transfer of cholesteryl ester from HDL to VLDL and LDL, which is independent of serum triglyceride concentrations. This increased transfer of cholesteryl ester may be a result of the increased free cholesterol content of very low density lipoproteins.

Triglycerides are more important in atherosclerosis than epidemiology has suggested

Epidemiology call be a useful guide to risk prediction. If, for example, the value of serum cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides as predictors of future CHD events is considered, then generally the triglyceride level measured on a single occasion will add little to the prognostic information contained in cholesterol and HDL cholesterol. The serum triglyceride concentration is, however, often more strongly correlated with future CHD incidence in univariate analysis than is serum cholesterol. However, in multiple logistic regression analysis, particularly when HDL cholesterol is included, the strength of the apparent independent relationship between triglycerides and CHD incidence is weakened often to the point of insignificance in individual trials, although it is still evident on meta-analysis of all the epidemiological trials in which both HDL cholesterol and triglyceride levels were measured. The erosion of the relationship between triglycerides and CHD incidence when HDL is included in multiple logistic regression analysis is to some extent is an artefact of the greater biological variation of triglyceride concentrations compared with HDL cholesterol. When allowance is made for this triglycerides can have more predictive power than HDL. Important clinical decisions are generally not based on single measurements, but on a series which reduces the effect of biological variation. However, even more importantly epidemiology cannot tell us that lowering cholesterol or raising HDL cholesterol levels will have more therapeutic benefit than decreasing triglyceride levels. That can only be established in clinical trials. An overview of trials involving drugs, which have as their principal action triglyceride-lowering, revealed them to decrease CHD incidence as much as statins. In the trials the drugs, which principally lowered triglycerides, also produced small decreases in serum cholesterol. The decrease in CHD incidence was, however, more than would be predicted from a similar reduction in cholesterol achieved with statins. Epidemiology can thus be a poor guide to clinical decisions. Furthermore the epidemiological relationship between cholesterol, triglycerides, HDL and CHD gives us only limited insight into the mechanisms by which these lipids and lipoproteins are involved in atherogenesis and their relative importance in this process. Thus evidence from clinical studies linking hypertriglyceridaemia with potentially important atherogenic factors such as intermediate density lipoproteins, small dense LDL and increased cholesteryl ester exchange may provide a greater understanding of atherogenesis and potential sites of therapeutic intervention than epidemiology. There is thus evidence for the therapeutic value of lowering triglycerides and an emerging view that triglyceride-rich lipoproteins are frequently crucial in atherogenesis.

Lipoprotein (a) and Microvascular Disease in Type 1 (Insulin-dependent) Diabetes

The influence of albuminuria and proliferative retinopathy on concentrations of serum lipoprotein (a) was examined cross‐sectionally in 90 Type 1 diabetic patients. Concentrations of lipoprotein (a) were less in those with normoalbuminuria (90 (8–882) (median (range)) U l−1) than in those with micro‐ or macro‐albuminuria (137 (19–1722) U l−1, p < 0.05). The prevalence of patients whose lipoprotein (a) concentrations were greater than 200 U l−1 was also greater (45% vs 24%, p = 0.03) among patients with albuminuria, but no difference was found between the microalbuminuric and macroalbuminuric groups (53 and 41%, respectively), or between those with or without proliferative retinopathy. The present finding that lipoprotein (a) concentrations may be increased at an early stage of diabetic renal disease may in part account for the excess ischaemic heart disease associated with diabetic nephropathy.

The Hunt for Nutritional and Pharmacological Modulators of Paraoxonase

Considerable experimental evidence suggests that lipid peroxides on LDL and their breakdown products are responsible for the physical changes in the LDL particle and the fragmentation of its apolipoprotein B, which permit it to bind to a wide range of high-affinity receptors on cells in the arterial wall, such as endothelial cells, macrophages, and smooth muscle cells, which are key players in atherosclerosis.1 Fat-soluble antioxidant vitamins in vitro delay the oxidation of LDL,2 suggesting that they might have the therapeutic potential to protect against coronary heart disease (CHD). However, now that several clinical trials of antioxidant fat-soluble vitamins have been completed, the reality is that they do not prevent coronary or other atherosclerotic events.2–4⇓⇓ The reasons for this have been reviewed,5 but germane to the issue may be that the protection against oxidation afforded to LDL by fat-soluble antioxidants is relatively short lived, being principally in the extension of the early lag phase in lipid peroxidation (conjugated diene formation) by a matter of minutes. They act as antioxidants only when they are more susceptible to oxidation than the molecules they protect, and once oxidized, they can become pro-oxidants.2 Additionally, erosion of their potential benefit may stem from their effect in increasing cholesteryl ester heteroexchange6,7⇓ which is increasingly being viewed as proatherogenic.8–10⇓⇓ It could explain the amelioration by high-dose antioxidant vitamins of the regression of coronary …

Effects of treatment of hypertriglyceridaemia with gemfibrozil on serum lipoproteins and the transfer of cholesteryl ester from high density lipoproteins to low density lipoproteins

Lipoprotein composition and cholesterol esterification, before and after treatment with gemfibrozil, have been examined in the fasting and postprandial state in nine patients with primary hypertriglyceridaemia who participated in a double-blind, placebo controlled study. After 8 weeks of treatment fasting serum triglycerides were reduced significantly from 6.05 mmol/l (range 2.48-10.99 mmol/l) to 1.76 mmol/l (range 1.16-11.90 mmol/l) (P less than 0.001). This was mainly due to a decrease in the triglyceride content of the Sf 12-20, 60-400 and Sf greater than 400 lipoprotein fractions (P less than 0.05). The Sf 0-12 fraction showed an increase in cholesteryl ester, free cholesterol, phospholipids and protein. Consistent with these findings there was a net increase in the mass concentration of the Sf 0-12 fraction (P less than 0.05) and a decrease in that of small very low density lipoproteins (Sf 20-60) (P less than 0.05). In the 8 patients in whom it was measured there was a 40% reduction in the rate at which cholesteryl esters derived from radiolabelled-free cholesterol appeared in very low density lipoprotein (VLDL) and low density lipoprotein (LDL) measured in an in vitro system (P less than 0.02), but serum lecithin:cholesterol acyl transferase (LCAT) activity was unchanged. At the end of each treatment phase (placebo or gemfibrozil) patients were given a mixed meal containing 100 g of fat. Treatment with gemfibrozil resulted in a reduction in serum triglyceride concentrations at all time points for at least 5 h after the meal (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)