A. Van 't Laar

Intra-individual variation of serum cholesterol, triglycerides and high density lipoprotein cholesterol in normal humans

The intra-individual variation in the concentrations of serum cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-chol) was determined in 53 healthy subjects, without extreme standardization of test subjects and sampling conditions. Within 1 year, the intra-individual variation of the subjects ranged from 3.9 to 10.9% for cholesterol; from 12.9 to 40.8% for triglycerides, and from 3.6 to 12.4% for HDL-chol. More than 60% of the average total intra-individual variation was caused by biological fluctuations and the remainder was the result of analytical variation. Thus, a single measurement of these serum constituents in an individual can be misleading or meaningless, unless the value is considerably outside the normal range. No significant diurnal variation was found in the concentrations of serum cholesterol and HDL-chol. The maximal post-prandial increase of the serum triglycerides was twice as great in the men than in the women. Finally, significant trends in the fluctuations of serum lipids and HDL-chol during 1 year were not found.

Low density lipoprotein subfractions and relationship to other risk factors for coronary artery disease in healthy individuals.

By a recently developed sensitive density gradient ultracentrifugation method, the distribution of low density lipoprotein (LDL) subfractions was studied in the serum of healthy blood donors (20 to 62 years old). For each subject, we observed a specific LDL subfraction distribution characterized by the relative contribution of the three major LDL subfractions, LDL-1 (1.020 to 1.028 g/ml), LDL-2 (1.027 to 1.034 g/ml), and LDL-3 (1.033 to 1.039 g/ml), to total LDL. Statistical analysis was performed by using the LDL density variable defined as: (% of LDL-1) x 1.024 + (% of LDL-2) x 1.0305 + (% of LDL-3) x 1.036 as a continuous variable. Controlling for age, smoking habits, relative body weight and, when appropriate, for gender, it appeared that: 1) dense LDL subfraction patterns characterized by a predominant LDL-3 subfraction and a decreased LDL particle size were more likely to be found among men than among women, 2) with increasing density of LDL, the levels of serum triglycerides increased, whereas the concentration of HDL cholesterol and the ratio of LDL cholesterol to LDL apolipoprotein (apo) B decreased, and 3) the best model with significant contribution in the prediction of the LDL subfraction distribution was the three-variable model: total cholesterol, serum triglycerides, and LDL apo B (R2 = 0.40), whereas the best two-variable model consisted of serum triglycerides and high density lipoprotein cholesterol (R2 = 0.37). These data are consistent with results from a study described previously in which a different approach based on LDL subfraction quantification by gradient gel electrophoresis of whole plasma was used.

Does nifedipine suppress atherogenesis in WHHL rabbits

The effects of the calcium antagonist, nifedipine, on atherogenesis were investigated in WHHL rabbits, a unique animal model for human familial hypercholesterolemia. Nifedipine, in a daily dose of 40 mg, was fed orally to 9 rabbits over a period of 26 weeks, resulting in serum concentrations of between 740 and 1370 ng/ml. Rabbits were killed at an age of 40 weeks and atherosclerotic plaque formation in various aortic segments was quantified. Atherosclerosis was most pronounced in the aortic arch and the thoracic aorta, plaques covering, respectively, 59 +/- 17% and 17 +/- 9% of total vessel area. These results are similar to those observed in a control group, which received the same diet and no nifedipine and displayed lesions on 62 +/- 19% and 21 +/- 13% of total area of aortic arch and thoracic aorta, respectively. Although variations in plaque area between WHHL rabbits are large and thus preclude the observation of small effects, the efficacy of nifedipine as an anti-atherogenic agent in rabbits with hereditary hypercholesterolemia appears questionable.

Haemodynamic effects of adrenaline during treatment of hypertensive patients with propranolol and metoprolol.

SummaryA double blind cross-over trial of propranolol and metoprolol was carried out in eight hypertensive patients. At the end of each four-week period of medication, blood pressure and heart rate at rest were measured, and the haemodynamic effects of adrenaline infusion were studied. At rest, propranolol and metroprolol reduced the blood pressure and pulse rate to the same degree. Adrenaline infusion during propranolol medication caused a marked increase both in systolic and diastolic blood pressure, the blood flow in the forearm was unchanged, and the calculated vascular resistance showed a marked increase. Adrenaline infusion during metoprolol medication caused a less marked increase in systolic blood pressure and the diastolic pressure remained unchanged. Blood flow in the forearm increased and the vascular resistance in the forearm tended to decrease. Adrenaline infusion, therefore, caused different haemodynamic effects during non-selective β-blockade with propranolol and during β1-selective blockade with metoprolol. It seems probable that the adrenaline infusion test is comparable with adrenaline release during stress situations and the results may indicate that a β1-selective blocker is to be preferred to a non-selective one as a therapeutic agent in the treatment of hypertension.

The Size of the Loading Dose as an Important Determinant of the Results of the Oral Glucose Tolerance Test: A Study in Subjects with Slightly Impaired Glucose Tolerance

In the oral glucose tolerance test (OGTT), divergent doses of glucose remain in use by virtue of the prevailing conviction that the size of the loading dose hardly affects the outcome of the test. We compared the results of OGTTs with 100-gm. and 50-gm. loads in 85 patients, who were selected for slightly impaired glucose tolerance (plasma glucose at 120 minutes after 100 gm. of glucose was between 130 and 200 mg./dl.) The mean between-load difference in this group appeared to be nearly three times as great (54 mg./dl. at 120 minutes) as reported in the literature for normal subjects. The small impact of the dose in normal subjects could be confirmed in a group of 22 controls. As subjects with normal and with slightly impaired glucose tolerance react divergently to a change in the glucose dose, tests with different loads are not comparable and select different populations. The results can therefore also not be converted to one another by conversion formulas. The finding might be explained by the delay of the additional rise of the plasma insulin in patients after the higher load.

A comparative study of the effects of acipimox and clofibrate in type III and type IV hyperlipoproteinemia

Acipimox, an analogue of nicotinic acid, is a hypolipidemic drug with antilipolytic activity. Ten patients with type III and 10 with type IV hyperlipoproteinemia participated in a comparative open cross-over study of the effect of acipimox (750 mg/day) and clofibrate (2 g/day) on lipoproteins, apoliproproteins and postheparin lipase activities during 6 weeks. During acipimox treatment 2 type III patients complained of flushing, resulting in one drop-out. In the type III patients serum cholesterol decreased 30% (P less than 0.01) during treatment with acipimox and 24% (P less than 0.01) with clofibrate, and serum triglycerides 48% (P less than 0.01) and 34% (P less than 0.01), respectively. In the type IV patients serum cholesterol remained unchanged and serum triglycerides decreased 34% (P less than 0.05) and 35% (P less than 0.01), respectively. HDL cholesterol increased during treatment with both drugs in both groups between 6 and 15% (P less than 0.05) mainly due to a rise in HDL3 cholesterol (d greater than 1.100 g/ml). LDL cholesterol increased significantly during treatment with clofibrate, but not with acipimox. There were no or slight changes in the apoproteins A and B. Postheparin lipoprotein lipase increased during clofibrate treatment and hepatic lipase decreased during acipimox treatment. We concluded that acipimox in a dose of 750 mg/day has a similar hypolipidemic effect as 2 g clofibrate daily in type III and IV hyperlipoproteinemia.

Serum lipids, lipoproteins and apolipoprotein E phenotypes in relatives of patients with type III hyperlipoproteinaemia

Abstract. Eighty‐six relatives of nineteen probands with type III hyperlipoproteinaemia were studied to determine the occurrence of hyperlipidaemia and to investigate the relation between apo E phenotypes, the occurrence of hyperlipidaemia, and the composition of the very low density lipoprotein (VLDL) fraction. Thirty‐nine relatives were hyperlipidaemic: four type IIa or IIb, nine type III and twenty‐six type IV. The predisposition for hyperlipidaemia was independent of the apo E phenotype.

Nifedipine in Primary Raynaud's Phenomenon and in Scleroderma: Oral Versus Sublingual Hemodynamic Effects

In 16 patients with Raynauds phenomenon a placebo‐controlled single‐dose study was performed on the hemodynamic effects of 10 mg nifedipine, sublingually administered, followed by an open eight‐week study on the therapeutic efficacy of chronic oral nifedipine, 10 mg qid. After the acute sublingual nifedipine administration, a pronounced objective improvement of finger skin (P = .013) and forearm muscle blood flow (P = .04) during a standard finger‐cooling test was found. During the chronic oral study the improvement in objective efficacy parameters disappeared, except for laser Doppler estimated shunt flow (P = .07). The acute hemodynamic effects did not predict the long‐term results in individual patients. Patients with systemic sclerosis reacted as well as patients with primary Raynauds phenomenon. This study shows that orally administered nifedipine does not convey long‐term objective benefit to patients with Raynauds phenomenon. The apparent increase in vasodilation during acute administration suggests that sublingual nifedipine prophylactically or during a vasospastic attack may be more useful.

Plasma lipoproteins, apolipoproteins, and triglyceride metabolism in familial hypertriglyceridemia.

Several parameters of lipoprotein metabolism were examined in 38 men with primary hypertriglyceridemia (phenotype IV). Family investigation showed that 17 men had familial combined hyperlipidemia (FCH), seven had familial hypertriglyceridemia (FHT), and 14 had unclassified hypertriglyceridemia (UNC). In all three groups, plasma high density lipoprotein (HDL) cholesterol and the concentrations of apolipoprotein A-l and A-I1 were decreased, and apolipoprotein B was increased, each to the same extent. These results are compatible with an increased risk of cardiovascular disease in both FCH and FHT patients. The mean concentration of LDL cholesterol and the ratio of LDL to HDL cholesterol were significantly higher in FCH subjects, which could explain their increased risk. Postheparin lipoprotein lipase and hepatic lipase were the same in both groups. Determination of apolipoprotein C composition, which may modulate lipoprotein lipase activity, did not reveal any abnormalities in the different groups. In both FCH and FHT, the mean turnover rate of plasma triglycerides was almost twice normal, indicating that overproduction of plasma triglyceride plays an important role in both disorders. However, there was an overlap with normal controls, indicating impaired triglyceride removal in some subjects. The underlying mechanism of hypertriglyceridemia in FCH and FHT therefore seems to be heterogeneous.

Treatment of severe diabetic ketoacidosis. A comparative study of two methods.

SummaryPatients with severe diabetic ketoacidosis (pH<7.10) were treated according to two protocols. Protocol I consisted of high-dose insulin therapy by intravenous and intramuscular injections and bicarbonate infusion and was used in the first 12 patients; they received an average of 260 U insulin and 167 mmol bicarbonate in the first 6 h of treatment. Protocol II consisted of low-dose continuous intravenous insulin therapy, 8 U/hour, without bicarbonate in a further 12 patients. Rehydration and potassium-supplementation were the same in both methods. Basal data of both groups were not significantly different. The fall of plasma glucose concentration, rise in arterial pH and decrease in 3-hydroxy-butyrate were similar in the two groups. The mean time to achieve a pH ⩾ 7.30 was 6.8 hours in the high-dose group and 7.6 hours in the low-dose group (p>0.10). Potassium supplementation and potassium concentration during both treatments were the same. During the low-dose treatment the mean (±SD) plasma insulin concentration was 121±46 μU/ml. The presence of insulin binding antibodies did not result in lower free insulin concentrations. Thus, in the treatment of severe ketoacidosis continuous intravenous therapy with low-dose insulin is as effective as high-dose therapy and bicarbonate-adminis-tration is probably unnecessary.