The mechanism and mitigation of niacin-induced flushing.

AIMS: To summarise the metabolic responses to niacin that can lead to flushing and to critically evaluate flushing mitigation research. METHODS AND RESULTS: This comprehensive review of the mechanism of action of niacin-induced flushing critically evaluates research regarding flushing mitigating formulations and agents. Niacin induces flushing through dermal Langerhans cells where the activation of G protein-coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)), subsequently activating prostaglandin D(2) receptor (DP(1)), prostaglandin E(2) receptor (EP(2)) and prostaglandin E receptor 4 (EP(4)) in capillaries and causing cutaneous vasodilatation. Controlling niacin absorption rates, inhibiting prostaglandin production, or blocking DP(1), EP(2) and EP(4) receptors can inhibit flushing. Niacin extended-release (NER) formulations have reduced flushing incidence, duration and severity relative to crystalline immediate-release niacin with similar lipid efficacy. Non-steroidal anti-inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing. An antagonist to the DP(1) receptor (laropiprant) combined with an ER niacin formulation can reduce flushing; however, significant residual flushing occurs with clinically-relevant dosages. CONCLUSIONS: Niacin is an attractive option for treating dyslipidemic patients, and tolerance to niacin-induced flushing develops rapidly. Healthcare professionals should particularly address flushing during niacin dose titration.

Interchange of apolipoproteins between chylomicrons and high density lipoproteins during alimentary lipemia in man.

Apolipoproteins of the "C" group in human blood plasma, which contain the activator of the lipoprotein lipase-substrate interaction, were found to be transferred specifically from serum to phospholipid-stabilized fat emulsion. Content and distribution of apoprotein activator were measured in healthy men in the postabsorptive state and 4 h after ingestion of meals containing 100 g fat. Content of activator protein in whole serum did not change after ingestion of the fat-rich meals but that contained in triglyceride-rich lipoproteins of density (d) <1.006 approximately doubled whereas that of high density lipoproteins fell by half. The increased activator content of triglyceride-rich lipoproteins was virtually confined to chylomicrons and its concentration in chylomicron apoprotein was substantially greater than that in very low density lipoproteins. This difference could be ascribed largely to a higher content of C apoproteins in chylomicron protein since both the concentration of C apoproteins and of apoprotein activator were directly proportional to particle diameter while the pattern of fast-migrating C apoproteins in polyacrylamide gels was similar among chylomicrons and subfractions of very low density lipoproteins. Apparent concentration of activator protein was much greater in the high density lipoprotein subfraction of d 1.063-1.125 than in the subfraction of d 1.125-1.21. In the subfraction of d 1.063-1.125, the concentration of activator protein and of fast-migrating C apoproteins in polyacrylamide gels decreased after the fat-rich meal. Concentration of phospholipids in this fraction increased gradually to a peak 43% above the basal value 6 h after the meal. The results obtained demonstrate that high density lipoproteins contribute certain functionally important polar constituents to chylomicrons during alimentary lipemia in man and suggest that they also receive surface constituents from chylomicrons during the course of their metabolism.

Mechanism of action of gemfibrozil on lipoprotein metabolism.

Gemfibrozil is a potent lipid regulating drug whose major effects are to increase plasma high density lipoproteins (HDL) and to decrease plasma triglycerides (TG) in a wide variety of primary and secondary dyslipoproteinemias. Its mechanism of action is not clear. Six patients with primary familial endogenous hypertriglyceridemia with fasting chylomicronemia (type V lipoprotein phenotype) with concurrent subnormal HDL cholesterol levels (HDL deficiency) were treated initially by diet and once stabilized, were given gemfibrozil (1,200 mg/d). Each patient was admitted to the Clinical Research Center with metabolic kitchen facilities, for investigation of HDL and TG metabolism immediately before and after 8 wk of gemfibrozil treatment. Gemfibrozil significantly increased plasma HDL cholesterol, apolipoprotein (apo) AI, and apo AII by 36%, 29%, and 38% from base line, respectively. Plasma TG decreased by 54%. Kinetics of apo AI and apo AII metabolism were assessed by analysis of the specific radioactivity decay curves after injection of autologous HDL labeled with 125I. Gemfibrozil increased synthetic rates of apo AI and apo AII by 27% and 34%, respectively, without changing the fractional catabolic rates. Stimulation of apo AI and apo AII synthesis by gemfibrozil was associated with the appearance in plasma of smaller (and heavier) HDL particles as assessed by gradient gel electrophoresis and HDL composition. Postheparin extra-hepatic lipoprotein lipase activity increased significantly by 25% after gemfibrozil, and was associated with the appearance in plasma of smaller very low density lipoprotein particles whose apo CIII:CII ratio was decreased. These data suggest that gemfibrozil increases plasma HDL levels by stimulating their synthesis. Increased transport (turnover) of HDL induced by gemfibrozil may be significant in increasing tissue cholesterol removal in these patients.

High density lipoproteins stimulate the production and secretion of endothelin-1 from cultured bovine aortic endothelial cells.

The concentration of HDL in the blood inversely correlates with the incidence of cardiovascular disease, probably related to the ability of these lipoproteins to efflux cholesterol from vascular cells. it is also possible that HDL affect the production or action of vasoactive peptides implicated in the development of vascular diseases. Therefore, we determined the effects of human HDL on the production and secretion of endothelin-1 (ET-1) from cultured bovine aortic endothelial cells. HDL produced a highly significant stimulation of endothelin secretion (maximum 240% of control), even at very low levels of lipoproteins (1 microgram/ml). HDL also stimulated the translation of ET-1 by twofold in the bovine aortic endothelial cells. In contrast, HDL had no significant effect on steady state mRNA levels, transcript degradation, or transcription. Stimulation of ET-1 secretion by HDL was dependent on protein kinase C activation. Purified apo A-I, the major apoprotein of HDL, increased ET-1 secretion and translation approximately 85% as potently as HDL. Our results indicate that low concentrations of human HDL strongly stimulate the production of ET-1, a powerful vasoconstrictor and mitogen for the vascular smooth muscle cell. We propose that HDL may participate in the regulation of vasomotor tone through this potentially important effect in the vasculature.

Apolipoprotein C-II deficiency syndrome. Clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients.

Two patients (brother and sister, 41 and 39 yr of age, respectively) have been shown to have marked elevation of plasma triglycerides and chylomicrons, decreased low density lipoproteins (LDL) and high density lipoproteins (HDL), a type I lipoprotein phenotype, and a deficiency of plasma apolipoprotein C-II (apo C-II). The male patient had a history of recurrent bouts of abdominal pain often accompanied by eruptive xanthomas. The female subject, identified by family screening, was asymptomatic. Hepatosplenomegaly was present in both subjects. Analytical and zonal ultracentrifugation revealed a marked increase in triglyceride-rich lipoproteins including chylomicrons and very low density lipoproteins, a reduction in LDL, and the presence of virtually only the HDL3 subfraction. LDL were heterogeneous with the major subfraction of a higher hydrated density than that observed in plasma lipoproteins of normal subjects. Apo C-II levels, quantitated by radioimmunoassay, were 0.13 mg/dl and 0.12 mg/dl, in the male and female proband, respectively. A variant of apo C-II (apo C-IIPadova) with lower apparent molecular weight and more acidic isoelectric point was identified in both probands by two-dimensional gel electrophoresis. The marked hypertriglyceridemia and elevation of triglyceride-rich lipoproteins were corrected by the infusion of normal plasma or the injection of a biologically active synthesized 44-79 amino acid residue peptide fragment of apo C-II. The reduction in plasma triglycerides after the injection of the synthetic apo C-II peptide persisted for 13-20 d. These results definitively established that the dyslipoproteinemia in this syndrome is due to a deficiency of normal apo C-II. A possible therapeutic role for replacement therapy of apo C-II by synthetic or recombinant apo C-II in those patients with severe hypertriglyceridemia and recurrent pancreatitis may be possible in the future.

Radioimmunoassay of human apolipoprotein CII. A study in normal and hypertriglyceridemic subjects.

A specific, precise, and sensitive double-antibody radioimmunoassay for the measurement of human apolipoprotein CII (apoCII) was developed. ApoCII was labeled with (125)I (chloramine-T) and monospecific antibody was raised in rabbits. No appreciable cross-reactivity with apolipoproteins CI, CIII, AI, AII, low density lipoproteins, and lipoprotein-free plasma was observed. Lipoproteins containing apoCII displaced the standard curve in parallel. ApoCII measurement was not affected by pretreatment of plasma with tetramethylurea, ethanol-diethyl ether, or heating. Mean (+/-SE) plasma-immunoreactive apoCII in 47 normotriglyceridemic subjects was 51.8+/-3.2 mug/ml, generally comparable with previous estimates of its concentration by other methods. ApoCII levels in 9 subjects with type IIB lipoprotein pattern, 14 with the type IV lipoprotein pattern, and 5 with type V lipoprotein pattern were respectively, 89.9+/-4.6, 85.4+/-6.9, 132.8+/-21.0 mug/ml, all higher than normals (P < 0.001). Plasma apoCII and triglyceride concentrations correlated in normo- and hypertriglyceridemics (r = 0.36 and 0.58, P < 0.05). Plasma triglycerides correlated inversely with the fraction of total apoCII in very low density lipoprotein (VLDL)-free plasma (r = -0.75, P < 0.01). There was no correlation between plasma apoCII and high density lipoprotein cholesterol. In normotriglyceridemics, VLDL apoCII levels correlated with in vitro lipoprotein lipase (LPL) activator activities (r = 0.89, P < 0.01). In hypertriglyceridemic subjects the mean concentrations of apoCII per milligrams VLDL protein, LPL activator activity per milligrams VLDL protein, and LPL activator activity per micrograms VLDL apoCII were all lower than in normotriglyceridemics, P < 0.05. As plasma triglycerides and apoCII increase, apoCII is redistributed from high density lipoprotein to VLDL. However, the amount of apoCII per milligram VLDL protein and its LPL activator potency per milligram VLDL protein are reduced. These factors may contribute to impaired VLDL catabolism.

Human plasma lipid transfer protein catalyzes the speciation of high density lipoproteins.

The role of purified plasma lipid transfer protein complexes in determining the particle size distribution of human plasma high density lipoproteins (HDL) was examined in vitro. Incubation of HDL2 or HDL3, isolated from normolipemic subjects with very low density lipoproteins (VLDL) or VLDL-remnants and lipid transfer protein complex had little or no effect on HDL particle size. In contrast, HDL isolated from patients with hypertriglyceridemia, designated HDL3D, showed speciation of particle size distribution when incubated with VLDL-remnants and the transfer protein. Incubation of HDL3D with VLDL-remnants and lipid transfer complex resulted in the production of two particles of radius 4.3 and 3.7 nm; incubation with VLDL or in the absence of the transfer protein did not result in a redistribution of particle size. We suggest that the action of lipid transfer protein complex on triacylglycerol-rich lipoprotein remnants and HDL accounts for the low levels of HDL-cholesterol observed in subjects with severe hypertriglyceridemia.

Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol.

Evidence indicates that the high density lipoprotein (HDL) subfraction containing apolipoprotein A-I without apolipoprotein AII (LP-AI) is more antiatherogenic than HDL particles containing apolipoprotein A-I and apolipoprotein A-II (LP-AI+AII). This study examined the effect of extended-release niacin (niacin-ER) and gemfibrozil on LP-AI and LP-AI+AII particles in patients with low levels of HDL cholesterol (HDL-C). Mechanisms by which these agents modulate HDL particles were investigated by in vitro studies using human hepatoblastoma (Hep G2) cells. A total of 139 patients with low HDL-C (

Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group.

OBJECTIVE: To provide a direct comparison of agents that raise plasma levels of high-density lipoprotein cholesterol (HDL-C) to help devise strategies for coronary risk reduction. METHODS: In a multicenter, randomized, double-blind trial, we compared the effects of extended-release niacin (Niaspan), at doses increased sequentially from 1000 to 2000 mg at bedtime, with those of gemfibrozil, 600 mg given twice daily, in raising low levels of HDL-C. Enrollment criteria included an HDL-C level of 1.03 mmol/L or less (< or =40 mg/dL), a low-density lipoprotein cholesterol level of 4.14 mmol/L or less (< or =160 mg/dL) or less than 3.36 mmol/L (<130 mg/dL) with atherosclerotic disease, and a triglyceride level of 4.52 mmol/L or less (< or =400 mg/dL). RESULTS: Among 173 patients, 72 (82%) of the 88 assigned to Niaspan treatment and 68 (80%) of the 85 assigned to gemfibrozil treatment completed the study. Niaspan, at 1500 and 2000 mg, vs gemfibrozil raised the HDL-C level more (21% and 26%, respectively, vs 13%), raised the apolipoprotein A-I level more (9% and 11% vs 4%), reduced the total cholesterol-HDL-C ratio more (-17% and -22% vs -12%), reduced the lipoprotein(a) level (-7% and -20% vs no change), and had no adverse effect on the low-density lipoprotein cholesterol level (2% and 0% change vs a 9% increase). Significance levels for comparisons between medications ranged from P<.001 to P<.02. Gemfibrozil reduced the triglyceride level more than Niaspan (P<.001 to P = .06, -40% for gemfibrozil vs -16% to -29% for Niaspan, 1000 to 2000 mg). Effects on plasma fibrinogen levels were significantly favorable for Niaspan compared with gemfibrozil (P<.02), as gemfibrozil increased the fibrinogen level (from 5% to 9%) and Niaspan tended to decrease the fibrinogen level (from -1% to -6%). CONCLUSIONS: In patients with a low baseline HDL-C level, Niaspan at its higher doses provided up to 2-fold greater HDL-C increases, decreases in lipoprotein(a), improvements in lipoprotein cholesterol ratios, and lower fibrinogen levels compared with gemfibrozil. Gemfibrozil gave a greater triglyceride reduction but also increased the low-density lipoprotein cholesterol level, which did not occur with Niaspan.

Influence of polyunsaturated and saturated fats on plasma lipids and lipoproteins in man.

The effects of varying polyunsaturated/saturated (P/S) fat ratios on the plasma levels of lipids, lipoproteins, and apolipoprotein A-I were assessed in six normal healthy subjects (three males, three females) with a particular focus on the P/S ratio which would offer optimal concentrations of both low-(LDL) and high-density lipoproteins (HDL). The isocaloric experimental diets contained 40% of calories as carbohydrate, 40% fat, and 20% protein; dietary cholesterol was 400 mg/day. The P/S ratio for the diets was 0.4, 1.0, or 2.0. Each diet was sequentially consumed for periods of 2 wk each. At the end of each 2-wk study period, plasma lipid, apolipoprotein A-I, and LDL and HDL cholesterol concentrations were determined; HDL were fractionated by zonal ultracentrifugation and lipid and protein composition determined. Compared to the P/S = 0.4 diet, mean plasma total cholesterol fell by approximately 6 and 12% on the P/S = 1.0 or P/S = 2.0 diets, respectively; plasma concentrations of LDL-cholesterol, HDL-cholesterol, and apolipoprotein A-I were also decreased on the polyunsaturated fat diets. The mean +/- SEM concentration (mg/dl) of HDL-cholesterol was 49.0 +/- 5.2 (P/S = 0.4), 44.0 +/- 3.8, (P/S = 1.0) and 41.0 +/- 3.7 (P/S = 2.0). As a result of a reduction in both LDL- and HDL-cholesterol on the polyunsaturate-rich diets, the ratios of HDL-cholesterol to plasma total cholesterol and HDL- to LDL-cholesterol were not significantly changed on the three diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Alimentary lipemia: plasma high-density lipoproteins and apolipoproteins CII and CIII in healthy subjects.

Three healthy male and three female inpatient volunteers consumed isocaloric diets for 4 wk. At weekly intervals, a fatty meal (100 g fat) was consumed by each fasting subject and blood drawn at 2 h intervals for 12 h. Of the four oral fat loads, two contained saturated fat (polyunsaturated/saturated fat ratio = 0.34) and two contained unsaturated fat (polyunsaturated/saturated fat = 2.21). The magnitude of alimentary lipemia, expressed as area under the plasma triglyceride curve, was 3- to 4-fold higher in males than females. Alimentary lipemia was inversely related to the subjects' fasting plasma high-density lipoprotein (HDL)-cholesterol, HDL apolipoprotein (apo) CIII and directly related to plasma triglycerides. The P/S ratios of the daily diet or the fat meal did not significantly influence the plasma triglyceride curve. After fat intake, mean (+/- SEM) plasma total apoCII and CIII fell to 54 +/- 20% and 73 +/- 5% of base-line, respectively, at 12 h in five of six subjects. After oral fat, an initial fall and a subsequent rise in apoCII and CIII in HDL was associated with reciprocal changes in apoC concentrations in very low-density lipoproteins. We speculate from the data that 1) plasma HDL and their apoC concentrations are important determinants of chylomicron clearance and 2) transfer of apoCs from HDL to triglyceride-rich lipoproteins in the early phase of fat absorption does not result in the total recycling of apoCs from these lipoproteins to HDL during the late phase of alimentary lipemia.

Characterization of high density lipoproteins from patients with severe hypertriglyceridemia.

High density lipoproteins (HDL) were isolated by zonal ultracentrifugation from 6 subjects with severe hypertriglyceridemia. Four subjects had familial endogenous hypertriglyceridemia with fasting chylomicronemia; 2 subjects were non-insulin-dependent diabetics. Plasma triglycerides ranged from 920 to 5440 mg/dl and HDL-cholesterol from 12 to 23 mg/dl. The major HDL from these hypertriglyceridemic subjects had a peak mean density of 1.153 g/ml as compared to 1.140 g/ml for HDL3 from normal subjects. None of the subjects had significant amounts of HDL corresponding to normal HDL2. The major subpopulation of hypertriglyceridemic HDL had a mean diameter of 8.4 +/- 0.1 nm (range 7.6-9.0 nm). The HDL were enriched in triacylglycerols and depleted in cholesteryl esters and the C apoproteins as compared to control HDL3. The mass ratio of triacylglycerols to cholesteryl esters ranged from 4.00 to 5.22 for the patients versus 0.41 for normal HDL3. The increased content of triacylglycerols partially explains the decreased amount of cholesterol associated with these hypertriglyceridemic HDL.

Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate-albumin complex.

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin-oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.

Composition of HDL-2 and HDL-3 in familial hyperalphalipoproteinemia.

The content and percent composition of cholesterol, triglyceride, phospholipids, and total proteins in HDL-2 and HDL-3 were quantitated in 5 women with familial hyperalphalipoproteinemia to determine if there are any distinctive characteristics of the high density lipoproteins in this heritable disorder. The 5 women with familial hyperalphalipoproteinemia (FHA) were compared to 4 normal women, with the groups being comparable in regards to age (40 +/- 3 and 37 +/- 5 years), total plasma cholesterol (202 +/- 9 and 188 +/- 16 mg/100 ml), triglyceride (75 +/- 12 and 95 +/- 19), and differing in levels of high density lipoprotein cholesterol (C-HDL, 84 +/- 6 and 61 +/- 3 mg/100 ml) respectively. Total cholesterol in the HDL-2 and HDL-3 fractions obtained by ultracentrifugation were 43.2 +/- 3.3 and 33.8 +/- 4.1 in FHA subjects, higher than total cholesterol in HDL-2 and HDL-3 in normals, 25.8 +/- 6.2 and 21.5 +/- 1.3 mg/100 ml, P less than 0.025. Total concentration of HDL-3 was higher in FHA than in normal subjects, respectively 222.4 +/- 22.6 and 149 +/- 7.2 mg/100 ml, P less than 0.025. Lipid-protein percent composition of HDL-2 and HDL-3 in FHA and normals was nearly identical, and polyacrylamide gel electrophoresis revealed no qualitative differences in band migration and appearance of the HDL-2 and HDL-3 fractions in normal and FHA subjects. In these women with FHA, there appears to be an increased concentration of normal HDL-2 and HDL-3.

Effect of a high carbohydrate diet on the content of apolipoproteins C-II, C-III and E in human plasma high density lipoprotein subfractions.

The effect of isocaloric high and low carbohydrate (Carb) diets on the structure and apoprotein composition of plasma high density lipoproteins (HDL) was assessed in four healthy men. The high Carb diet contained 65% calories as Carb and 15% as fat; the low Carb was 15% and 65%, respectively, with protein fixed at 20% of calories in each case. Cholesterol was 400 mg/day and the P/S ratio of the fat was 0.4. Each diet was sequentially consumed for periods of 3 weeks. At the end of each 3-week study period, plasma HDL2 and HDL3 were isolated by zonal ultracentrifugation and their apoprotein and lipid compositions were determined. Compared to the low Carb diet, the high Carb diet was associated with an increase in the size of HDL2 (116.0 +/- 1.8 vs. 109.1 +/- 1.8 A) and in the content (mean weight % +/- SEM) of apoE (2.81 +/- 0.71 vs. 1.79 +/- 0.49, P less than 0.01) and of apoC-II (1.73 +/- 0.09 vs. 1.11 +/- 0.12, P less than 0.01). HDL2 apoC-III content was not significantly different on the two diets (6.49 +/- 0.50 vs. 7.42 +/- 1.21). On the two diets, HDL3 size and HDL3 apoE content were not significantly changed. HDL3 apoC-II and apoC-III, however, were higher on the high Carb diet, P less than 0.05. The ratio (by weight) of HDL2 apoE/HDL2 apoC-II + C-III increased on the high Carb diet compared to the low Carb diet (0.344 +/- 0.058 vs. 0.228 +/- 0.053, P less than 0.01). We suggest that the increased amount of apolipoprotein E in HDL2 may influence its rate of catabolic clearance and may account for the well-known decrease in plasma HDL-cholesterol in subjects on high Carb diets.

Post-heparin plasma lipoprotein and hepatic lipases. Relationships to high density lipoprotein cholesterol and to apolipoprotein CII in familial hyperalphalipoproteinemic and in normal subjects.

Post-heparin lipoprotein lipase (PH-LPL)-high density lipoprotein cholesterol (HDL-C) interrrelationships were assessed in 9 subjects with documented familial hyperalphalipoproteinemia (FHA) and in 8 controls to focus on potential biochemical etiologies of FHA and relationships of HDL-C to triglyceride hydrolysis and PH-LPL. FHA subjects had mean HDL-C and HDL2-C levels > twice controls; their PH-LPL levels (mean +/- SEM) (3.14 +/- 2.3 mumol FFA/h/ml) were also > twice that of controls (15.0 +/- 1.6) (P < 0.01), but post-heparin hepatic lipase levels (PH-HL) in the FHA and control subjects did not differ (18.1 +/- 1.6 vs 26.6 +/- 4.3, P > 0.1). For all subjects (FHA and controls) PH-LPL was positively correlated with HDL-C (r = 0.79, P < 0.01) and with HDL2-C (r = 0.90, P < 0.01), but not with HDL3-C (r = --0.02). There were no significant PH-HL and HDL-C interrelationships, P > 0.1. The amount of apo CII (the primary activator of PH-LPL) in HDL2 was greater in the FHA (mean +/- SEM) (16.1 +/- 2.5 microgram/ml plasma) than in control subjects (4.7 +/- 0.9, P < 0.01). There were strong positive correlations between HDL2 apo CII and both PH-LPL (r = 0.79, P < 0.01) and HDL2-C (r = 0.80, P < 0.01). Apo CII as a percentage of HDL2 protein was higher in FHA than control subjects (mean +/- SEM) (1.2 +/- 0.3% vs 0.5 +/- 0.2%, P < 0.01). Apo CII as a percentage of HDL3 protein was similar in FHA and control subjects. We postulate that increased turnover rate of triglyceride-rich lipoproteins due to high LPL activity may be an important factor leading to the elevation of HDL-C in FHA. The highly significant positive correlation between HDL2-C and PH-LPL provides strong clinical evidence for the theory that HDL2 is formed during the hydrolysis of triglycceride-rich lipoproteins. The high concentration of HDL2 apo CII in FHA subjects may be caused by increased catabolism of triglyceride-rich lipoproteins in the presence of high endothelial LPL, with transfer of apo CII from very low to high density lipoproteins.

In vitro catabolism of human plasma very low density lipoproteins. Effects of VLDL concentration on the interconversion of high density lipoprotein subfractions.

The effect of lipolysis of human plasma very low density lipoproteins (VLDL) on the distribution of high density lipoprotein subfractions was studied in an in vitro system consisting of purified bovine milk lipoprotein lipase and albumin. The distribution of lipids and apoproteins (apoC-II and apoC-III) within the lipoprotein fractions corresponding to HDL2 (d = 1.063-1.120 g/ml) and HDL3 (d = 1.120-1.210 g/ml) was dependent upon the concentration of VLDL in the incubation mixture. After lipolysis of an incubation mixture containing VLDL-triglyceride (0.6 mg triglyceride/ml) and HDL3 (0.1 mg protein/ml), most of the lipid and apoproteins were recovered in HDL3. At higher concentrations of VLDL-triglyceride relative to HDL3-protein (1.8 or 2.4 mg of VLDL-triglyceride and 0.1 mg of HDL3-protein) the amount of lipid and apoprotein isolated in the HDL3 density fraction decreased after lipolysis and there was an increase in the amount isolated between d 1.063-1.120 g/ml. These results provide additional evidence for the conversion of HDL3 to HDL2 during lipolysis. Furthermore, they suggest that the relative distribution of plasma HDL2 and HDL3 is related to the rate of catabolism of triglyceride-rich lipoproteins.

C-II anapolipoproteinemia and severe hypertriglyceridemia. Report of a rare case with absence of C-II apolipoprotein isoforms and review of the literature.

A new case of C-II anapolipoproteinemia (complete apolipoprotein C-II deficiency) as the cause of severe hypertriglyceridemia with chylomicronemia (type I lipoprotein phenotype) is described. The patient was a five-year-old boy living in Connecticut. He had splenomegaly, episodic abdominal pain, and bloody stools. Absence of apolipoprotein C-II (and its isoforms C-II1 and C-II2) was documented by a sensitive and specific radioimmunoassay, analytical isoelectric focusing, and in vitro lipolytic assay. Decreased levels of high- and low-density lipoprotein cholesterol and apolipoproteins A-I and A-II and increased levels of plasma triglycerides and apolipoprotein E were found. Post-heparin extra-hepatic lipoprotein lipase activity was within normal range. Incorporation of exogenous purified human apolipoprotein C-II to an incubation mixture of purified lipoprotein lipase and the patient's triglyceride-rich lipoproteins resulted in a dramatic increase in the catabolic rate of the defective triglyceride-rich lipoproteins. The absence of the isoforms of apolipoprotein C-II in this patient indicates that a common gene exists for the C-II isoproteins, which appear to be necessary for normal triglyceride transport in humans. A literature review of 23 reported cases indicates that xanthomas and hepatosplenomegaly are less common in C-II anapolipoproteinemia than in lipoprotein lipase deficiency, the other major etiologic cause of genetic chylomicronemia.

Cardiovascular disease in the elderly: current considerations.

Today, elderly patients account for one-third of the total United States health care costs and for one-third of all drug prescriptions. As the United States population grows older, health care costs are expected to grow proportionately unless cost reduction strategies are developed. Cardiovascular disease is ranked as the primary cause of mortality and disability in this age group. It is estimated that 80% of cardiovascular disease in the elderly arises as complications of atherosclerosis. Whereas modern technologic advances--cardiac catheterization, coronary angiography, coronary angioplasty, coronary bypass surgery, pacemaker insertion--can help to treat the effects of atherosclerosis, such advances are costly. The most effective cost reduction strategy lies in prevention of atherosclerosis and its complications. A number of studies have linked reduction of risk factors for atherosclerosis to reduction of coronary disease events. However, it is not certain that these data apply directly to the elderly; more research is necessary to develop effective preventive and management strategies.

Basic considerations in the reversal of atherosclerosis: significance of high-density lipoprotein in stimulating reverse cholesterol transport.

Atherosclerotic cardiovascular disease in the elderly is the result of several decades of cholesterol accretion. Advanced lesions may not be amenable to treatment, but a reversal of cholesterol accumulation may be possible. High-density lipoproteins (HDL) could serve an important function in this reversal through their role in the process of reverse cholesterol transport, which removes cholesterol from the body. Reverse cholesterol transport could be stimulated by raising plasma HDL level, but the efficacy of the process may be determined by the way in which HDL level is elevated. The increase of HDL synthesis rate may be the best approach. The antiatherosclerotic effects of gemfibrozil, a lipid-lowering agent that appears to raise HDL synthesis rate, may be mediated through this mechanism.