EskoA. Nikkilä

FAMILY STUDY OF SERUM LIPIDS AND LIPOPROTEINS IN CORONARY HEART-DISEASE

Abstract In 412 first-degree relatives of 101 Summary young survivors of myocardial infarction the mean levels of serum-cholesterol and serum-triglyceride were significantly higher than in a control population but less than in the index patients. Hypercholesterolaemia (type IIa) occurred 1·8 times, hypertriglyceridaemia (type IV) 1·3 times, and combined hyperlipidaemia (type IIb) 2·5 times more commonly in relatives than in controls. There was little difference between the rates of hyperlipidaemia in the families of normolipidaemic and hyperlipidaemic probands. There was significant clustering of hyperlipoproteinaemia in thirty-three of the hundred and one families examined. Of these, only nine families had a single-type disease. Familial hypercholesterolaemia (type-IIa disease) was reported in 6% of families. In twenty-four families several abnormal lipoprotein phenotypes coexisted and half the members of these families were affected. A rather specific marker of this multiple-type familial hyperlipoproteinaemia was the presence of phenotype IIb, which was six times more common in first-degree relatives than in the control population. The results suggest that there is a familial trait of hyperlipidaemia in one-third of patients with premature coronary heart-disease, but it is not established whether the trait is inherited or produced by environmental factors.

Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes.

To study the effect of rigorous inslulin on serum llpoproteins in patients with noninsulin-dependent diabetes not controlled with oral only, we measured serum llpoproteins, apoproteins, lipolytic enzymes, and glucose disposal using anf insulin clamp technique before and after 4 weeks of insulin therapy. Lipoproteins were isolated by ultracentrifugation and high density llpoprotein (HDL) subfractions, by rate-zonal density graddient ultracetrifugation. The group included 11 subfractions, by rate-zonal density gradient ultracentrifugation. The group included 11 women and eight men (age 58 ± 1 years adn RBW 125 ± 4%). Body weight, glycosylated hemoglobin, mean dlurnal glucose, plasma free insulin, and glucose uptake (M-value) were 75 vs. 76 kg; 11.9 vs. 8.9%; 234 vs. 124 mg/di; 123 vs. 27 μU/ml; and 5.0 ± 0.4 vs. 7.1 ± 0.6 mg/kg/min before and after insulin therapy, respectively. After Insulin therapy there was decrease of very low density lipoprotein (VLDL) triglyceride (−60%, p < 0.001) but an increase of HDL2 cholesterol (+21%, p < 0.001); HDL2 phosphollpids (+38%, p < 0.001); HDL2 proteins (+23% p < 0.01); and HDL2 mass (127 ± 11 vs. 158 ± 12 mg/dl, p < 0.001). There was a decrease of HDL3 cholesterol (−13%, p < 0.05); HDL3 phosphollpids (+38%, p < 0.001); HDL2 proteins (+23%, p < 0.01); and HDL2 mass (127 ± 11 vs. 158 ± 12 mg/dl, p < 0.001). There was a decrease of HDL3 cholesterol (−13%, p < 0.025<; HDL3 phospholipids (−16%, p < 0.05); HDL3 proteins (−18%, p < 0.001); and HDL3 mass (179 ± 6 vs. 146 ± 6, p < 0.01). Zonel profiles showed a redisttribution of particles from HDL3 to HDL2. Serum apo A-l increased (p < 0.05), apo A-ll remained constant, but apo B decreased (−29%, p < 0.001). The most marked change during insulin therapy was a 2.3-fold increase in adlpose tissue fllploprotein llpase (LPL) activity (p < 0.001). The changes of VLDL and HDL subfractions were not explained by respective changes of the blood glucose, free insulin, or M-value. The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2

NATURAL ŒSTROGEN AS AN EFFECTIVE TREATMENT FOR TYPE-II HYPERLIPOPROTEINÆMIA IN POSTMENOPAUSAL WOMEN

Abstract Seventeen postmenopausal women with raised serum total and low-density-lipoprotein (L.D.L.) cholesterol concentrations were treated with œstradiol valerianate for 6 months. Serum-L.D.L.- cholesterol decreased in sixteen patients—the average change at 6 months was -18%. Serum-high-density-lipoprotein (H.D.L.) cholesterol increased by 30% during treatment and the mean H.D.L./L.D.L. cholesterol molar ratio rose significantly from 0·21 to 0·34. There was a significant positive correlation between the size of the decrease in L.D.L. cholesterol and initial L.D.L.-cholesterol concentration. Serum triglyceride and very-low-density-lipoprotein (V.L.D.L.) concentrations were not significantly changed by the treatment. The results suggest that type II hypercholesterolaemia may be taken as another indication for oestrogen therapy in postmenopausal women.

Post-menopausal hormone replacement therapy: effects of progestogens on serum lipids and lipoproteins. A review

Until a few years ago, post-menopausal hormone replacement therapy was based on oestrogen alone. There was a general feeling that oestrogen, if it had any effect at all on the risk of coronary heart disease (CHD), was probably beneficial as long as conventional doses of natural oestrogen were used [1,2]. Some studies indicated quite convincingly that the menopause was associated with an increased risk of coronary heart disease [3,4]. Moreover, published data suggested that this risk could be diminished by oestrogen substitution [5,6], although this was not confirmed by all studies [7,8]. Post-menopausal oestrogen replacement therapy was found to be associated with ‘beneficial’ effects on at least two major CHD risk factors: high-density lipoprotein (HDL) cholesterol was increased and low-density lipoprotein (LDL) cholesterol was decreased by oestrogen treatment [9-111. The magnitude of the fall in LDL cholesterol was directly proportional to the initial LDL cholesterol level, suggesting that oestrogen could be the drug of choice in the treatment of postmenopausal hypercholesterolaemia lipid disorder [ 121. The recent recommendation (for review, see [13]) that sequential progestogen should be added to cyclic oestrogen therapy in order to reduce the risk of endometrial cancer has greatly increased the use of progestational agents ‘by postmenopausal women. Since many of the effects of oestrogen, including changes in lipoproteins, are opposed by some progestogens, great interest has been focused on the potential merits and demerits of combining progestogens with oestrogen. In this review we attempt to summarise current knowledge concerning the effects on serum lipids and lipoproteins of progestogens used either alone or as a supplement to post-menopausal oestrogen replacement therapy.

Comparison of the effects of two different doses of alcohol on serum lipoproteins, HDL‐subfractions and apolipoproteins A‐I and A‐II: a controlled study

Abstract Our earlier studies have shown that heavy alcohol intake increases the serum concentration of HDL2. The present study aimed to test which HDL subfraction is affected by moderate alcohol intake, and to examine the time‐ and dose‐dependency of alcohol‐induced changes in serum lipoproteins. Therefore, 30 or 60 g day‐1 of alcohol were given to 10 healthy male volunteers during two 3‐week periods separated by an abstinence period of 3 weeks. Lipoproteins were fractioned by sequential flotation. On both doses the total HDL3 concentrations rose progressively, the maximum increases being 10 and 25% at the end of respective drinking periods. In contrast, the HDL2 increased slightly only on the dose of 60 g day‐1. The serum concentrations of apoprotein A‐I and A‐II increased on both doses but significantly only on the dose of 60 g day‐1; the increments being 22 and 35%, respectively. On the basis of these and our earlier findings we conclude that (i) the effects of heavy and moderate alcohol intake on serum HDL‐subfractions are different: the former preferentially increases the HDL2 whereas the latter augments the HDL3; (ii) alcohol‐induced changes in serum lipoproteins are both time‐ and dose‐dependent.

Treatment of Post-Menopausal Hypercholerolaemia with Estradiol

Abstract. Replacement therapy with estradiol valerate in 29 post‐menopausal women reduced low‐density lipoprotein (LDL) cholesterol concentrations by 22% and increased high‐density lipoprotein (HDL) cholesterol by 21% after 12 months. Apart from a 67% increase of HDL‐triglyceride estradiol had only a slight effect on the levels of lipoprotein triglycerides. Post‐heparin plasma lipoprotein lipase (LPL) activity was significantly decreased in subjects with normal pre‐treatment very‐low‐density lipoprotein (VLDL) triglyceride levels, and hepatic lipase (HL) activity was significantly decreased in the group as a whole. It is suggested that estradiol replacement therapy should be considered in climacteric women with high LDL‐cholesterol or low HDL‐cholesterol levels, or both.

Very low density lipoprotein triglyceride metabolism in relatives of hypertriglyceridemic probands. Evidence for genetic control of triglyceride removal.

The production and catabollsm of very low density lipoprotein triglycerides (VLDL-TG) were determined In 11 index patients with primary hypertriglycerldemla and In their 70 first-degree relatives. In the probands the mean value for VLDL-TG production rate was twice normal, and the mean fractional catabollc rate (FCR) was reduced to 50% from normal. A similar kinetic pattern was also observed In most hypertriglyceridemic relatives. In the normotrlglycerldemlc relatives the mean values of both kinetic parameters were comparable to those of controls. No kinetic differences were observed between families with familial hypertriglycerldemla, familial combined hyperllpldemla, or genetically unclassified hypertriglyceridemia (all diagnosed by lipoprotein phenotypes). Thus, no explanation for the phenotyplc differences between the two forms of familial hyperilpoprotelnemla was found In plasma VLDL-TG metabolism. When the families were grouped according to the VLDL-TG production rate of the proband, there was no significant difference between the VLDL-TG production rates of relatives of “overproducer” probands and relatives of the probands with normal VLDL-TG production rate. In contrast, relatives of low FCR probands had significantly lower mean FCR than the relatives of probands with a normal FCR. This difference In FCR was present both In hypertriglyceridemic and normotrlglycerldemlc relatives. These results suggest that the catabollsm (llpolysls) of VLDL-TG Is under genetic control, whereas the VLDL-TG production rate Is mainly related to obesity. It Is likely that hypertriglyceridemia often develops on the basis of VLDL overproduction In individuals who have a genetically low VLDL triglyceride removal (llpolytlc) capacity.

Very low density lipoprotein triglyceride kinetics during hepatic lipase suppression by estrogen: Studies on the physiological role of hepatic endothelial lipase

The exact role of the heparin‐releasable hepatic endothelial lipase has remained controversial. It has been suggested that it acts in concert with lipoprotein lipase in the step‐wise delipidation of triglyceride‐rich lipoproteins. On the other hand, there is evidence indicating that high density Iipoprotein2 is the preferred substrate for hepatic lipase. Here, it is shown that a moderate (27%) suppression of hepatic lipase activity by estrogen did not impair removal of 3H‐labeled very low density lipoproteins (VLDL) triglycerides, suggesting that this enzyme is not a major regulator of VLDL catabolism under physiological circumstances.

Post-heparin plasma hepatic lipase activity as predictor of high-density lipoprotein response to progestogen therapy: studies with cyproterone acetate.

Cyproterone acetate (CPA) was administered to 13 menstruating women from day 14 to day 27 of the cycle at a dose of 5 mg/day. Serum lipoprotein lipid levels and postheparin plasma lipase activity were determined on day 27 of the cycle before treatment and during two treatment cycles. No significant changes were observed in hepatic lipase activity or in very-low-density (VLDL) or low density lipoprotein (LDL) concentrations. However, analysis of high-density-lipoprotein (HDL) subfractions by precipitation demonstrated a significant reduction in HDL2 cholesterol (-24%, P less than 0.05) during cyproterone acetate treatment. It is suggested that this change is related to oestrogen deficiency induced by inhibition of luteinizing hormone (LH) secretion.

MENOPAUSAL OESTROGEN THERAPY, SERUM LIPOPROTEINS, AND ISCHAEMIC HEART DISEASE

A case-control study by Dr. Ross and colleagues on the association between menopausal estrogen replacement therapy and death from coronary heart disease is the first to suggest that estrogen substitution may protect postmenopausal women against fatal ischemic heart disease (IHD). This protective effect, if real, is of major clinical importance. Ross et al. conclude that their findings, together with other evidence, point to a cause-and-effect relation between estrogen use and protection against fatal IHD. However, after citing cross-sectional studies which report lower serum-cholesterol, lower very-low-density lipoprotein (LDL) cholesterol, and higher high-density lipoprotein (HDL) cholesterol in postmenopausal users compared with non-users, Ross et al. conclude that it is unclear whether estrogen replacement alters plasma lipid levels or whether lipid levels are associated with indications for estrogen replacement therapy. It was found by the authors that type 2 hyperlipoproteinemia (increased LDL) is common in postmenopausal women; nevertheless the treatment of this form of lipid disorder has been largely neglected. Their results showed that a natural estrogen lowered serum LDL cholesterol in hypercholesterolemic postmenopausal women whereas serum HDL cholesterol increased and triglycerides were unchanged. The estrogen-induced decrease in LDL cholesterol was directly related to the initial LDL cholesterol level so that subjects with severe hypercholesterolaemia responded best to treatment. There was a highly significant increase of the HDL/LDL cholesterol ratio. Published evidence thus supports the possibility that the suggested protective effect of estrogen against death from IHD in postmenopausal women is a result of the diminution of 2 major IHD risk factors, high serum LDL cholesterol and low serum HDL cholesterol by estrogen replacement therapy.