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.

Do all angiotensin II type 1 receptor blockers have the same beneficial effects?

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are highly selective for the AT(1) receptor, which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects (hypertension, hypertrophy, heart failure, proteinuria etc.) of angiotensin II. Many ARBs are in clinical use and have been shown to be safe and effective. Over the past several years, reports have discussed the different degrees of the beneficial effects of ARBs. As ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. These different effects may be due to differences in the molecular characteristics of ARBs. The results reported by Le et al. in this issue highlight the different characteristics of two ARBs, olmesartan and telmisartan, and suggest that the higher degree of insurmountability, slower dissociation, and higher affinity of olmesartan compared to telmisartan for AT(1) receptors may help it to form a tight binding complex with this receptor. A better understanding of the different molecular mechanisms for each ARB could be useful for the treatment of patients.

In vitro conversion of recombinant human proapolipoprotein A-I to apolipoprotein A-I.

We recently investigated the in vivo conversion of recombinant human proapolipoprotein A-I (rh-Met-proapo A-I) from E. coli to apolipoprotein (apo) A-I in rabbits. In vitro incubation of rh-Met-proapo A-I with rabbit serum produced mature apo A-I3 isoproteins, as determined by the immunoblotting method. However, at the time we were unable to chemically confirm a newly produced protein band which appeared at the position of human apo A-I3. Since then, we have confirmed the amino acid sequence of the protein using a membrane protein sequence technique, and have concluded that it corresponds to human apo A-I3.

Putative mechanisms of action of probucol on high-density lipoprotein apolipoprotein A-I and its isoproteins kinetics in rabbits.

Probucol is a widely prescribed lipid-lowering agent, the major effects of which are to lower cholesterol in both low- and high-density lipoproteins (LDL and HDL, respectively). The mechanism of action of probucol on HDL apolipoprotein (apo) A-I kinetics was investigated in rabbits, with or without cholesterol feeding. 125I-labeled HDL was injected intravenously, and blood samples were taken periodically for 6 days. Kinetic parameters were calculated from the apo A-I-specific radioactivity decay curves. Fractional catabolic rate (FCR) and synthetic rate (SR) of apo A-I in rabbits fed a normal chow and normal chow with 1% probucol were similar. Apo A-I FCR of the rabbits fed 0.5% cholesterol was significantly increased but there were no changes in SR, compared to findings in the normal chow-fed group. Apo A-I FCR of the rabbits fed 1% probucol with 0.5% cholesterol (both 1 month and 2 months) was significantly increased compared to findings in rabbits fed the normal chow as well as 0.5% cholesterol diet group, while SR of apo A-I was significantly reduced in the former groups. Kinetics at 1 month after discontinuation of 1% probucol (under cholesterol feeding) showed a similar FCR of HDL-apo A-I to that of the rabbits fed 0.5% cholesterol, but the SR of apo A-I remained lower. Apo A-I isoproteins kinetics assessed by autoradiography of isoelectric focusing slab gels showed that the synthesis of proapo A-I was significantly reduced in the 1% probucol with 0.5% cholesterol administered, compared to the 0.5% cholesterol group. Thus, the action of probucol on HDL apo A-I kinetics was only prominent in case of higher serum cholesterol levels. The decreased HDL or apo A-I seen with probucol was apparently the result of an increase in FCR and a decrease in SR of HDL-apo A-I. A decreased synthesis of apo A-I remained evident even 1 month after discontinuing probucol. The action of probucol on the intracellular synthetic processes of apo A-I was revealed by the reduced synthesis of proapo A-I.

Polymorphic site study at codon 347 of apolipoprotein A-IV in a Japanese population.

In a population of Japanese subjects, we surveyed codon 347 of the apolipoprotein (apo) A-IV gene and found that the frequency of a rare allele at this point was extremely low compared to that in western populations. Only one of 850 unrelated samples showed mutation at the enzyme recognition site by agarose gel electrophoresis. However, direct sequencing of the coding region revealed that it did not result from the ACT (Thr) to TCT (Ser) mutation which has been reported in western countries, but from an ACT to ACG (Thr) mutation, which does not affect the primary structure of apo A-IV. Two additional family members showed the same point mutation at codon 347.

Mechanism of action of probucol on cholesteryl ester transfer protein (CETP) mRNA in a Chinese hamster ovary cell line that had been stably transfected with a human CETP gene.

Probucol, a widely used lipid-lowering agent, is associated with a significant reduction of plasma high density lipoprotein (HDL)-cholesterol levels. To examine the mechanism of probucol HDL-lowering and probucol's effects on cholesteryl ester transfer protein (CETP) and cholesterol metabolism in cells, we used a Chinese hamster ovary (CHO) cell line that had been stably transfected with a human CETP gene (hCETP-CHO). After this cell line was incubated with various concentrations of probucol (5, 10 and 50 microM) for 24 h, mean intracellular probucol concentrations reached 0.47, 0.67, and 1.52 microg/mg cell protein, respectively. Northern blot analysis showed that cellular CETP mRNA was increased by probucol in a dose-dependent manner (137%, 162%, and 221% of the control, respectively). The specific CET activity in the culture medium, measured as the percentage of [3H]cholesterol oleate transferred from discoidal bilayer particles (which mimic HDL) to LDL, also increased in a dose-dependent manner. Intracellular total cholesterol levels were decreased to 87.5%, 74.9%, and 52.5% of the control, respectively. Probucol had no effects on HMG-CoA reductase activity or cholesterol synthesis from [14C]acetate in hCETP-CHO. However, 14C-incorporated cholesterol secretion into the culture medium from hCETP-CHO was increased to 181%, 256% and 354% of the control by 5, 10 and 50 microM probucol, respectively. We concluded that (1) treatment with probucol increased the CETP mRNA level and specific CET activity in the hCETP-CHO cell line, and (2) probucol promoted cholesterol efflux from hCETP-CHO, which resulted in a decrease in intracellular cholesterol levels.

In vivo conversion of recombinant human proapolipoprotein AI (rh-Met-proapo AI) to apolipoprotein AI in rabbits.

In vivo conversion of recombinant human proapolipoprotein AI (rh-Met-proapo AI) from E. coli to apolipoprotein (apo) AI was investigated. rh-Met-proapo AI was labeled with 125I, and then administered intravenously to rabbits. Blood was sampled periodically for 6 days. The plasma decay curves of radioiodinated rt-Met-proapo AI were similar to those of human mature apo AI (fractional catabolic rate (FCR); 1.018 +/- 0.090/day vs. 0.976 1 0.031/day, respectively). In vivo conversion of rh-Met-proapo AI to mature apo AI was examined by autoradiography of the isoelectric focusing (IEF) slab gel, i.e., the HDL fraction from each sampling point was semiquantitatively applied to IEF. It was found that the radioactivity of rh-Met-proapo AI migrated to more acidic isoproteins, the conversion was complete within 24 h, and the FCR of rh-Met-proapo AI was 9.20 +/- 1.34/day. Although the plasma decay curves of both human pro (rh-Met-proapo AI) and mature apo AI were significantly steeper than those of rabbit mature apo AI4 and apo AI5 (FCR; 0.703 +/- 0.027/day and 0.795 +/- 0.031/day, respectively), the conversion rate of human rt-Met-proapo AI to mature apo AI in rabbit was assumed to be 1:1. In vitro incubation of rh-Met-proapo AI with rabbit serum produced mature apo AI isoproteins, as determined by the apo AI immunoblotting method. Prediction of the amino acid sequence at the NH2 terminus of rabbit proapo AI showed that the prosegment consisted of an alpha helix with a high probability of a beta turn at Pro9, which is close to that in humans. Thus, (1) the proteolytic cleavage of proapo AI is an extracellular event, (2) the converting enzyme in rabbits can also process human proapo AI, (3) this converting enzyme does not specifically and directly attack the Gln6-Asp7 bond which links the carboxyl-terminal residue of the hexapeptide to the amino-terminal residue of human mature apo AI. The conformation of proapo AI at the NH2 terminus (alpha helix of the prosegment and a beta turn at Pro9) may have a key role in this cleavage, and (4) the examination of rh-Met-proapo AI in rabbits helps to explain the early events of HDL biogenesis.

Quantity and function of high density lipoprotein as an indicator of coronary atherosclerosis.

OBJECTIVES: To examine the association between the fractional esterification rate of cholesterol (C) in low density lipoprotein- and very low density lipoprotein-depleted plasma (FER(HDL)) and coronary artery disease (CAD) and the influence of serum HDL-C levels. BACKGROUND: The function of HDL in reverse cholesterol transport is involved in the antiatherogenic action of HDL, and FER(HDL) is a newly established quantitative measure of HDL function in vivo. METHODS: Cases (n = 185, F/M: 43/142) and controls (n = 74, F/M:27/47) were defined as subjects with/without angiographically proven CAD, respectively. RESULTS: The cases had significantly (p < 0.05) higher FER(HDL) values (13.2+/-0.3 %/h vs. 12.1+/-0.5 %/h) and lower HDL-C levels (39.0+/-1.0 mg/dL vs. 46.8+/-1.4 mg/dL) than the controls. The associations of FER(HDL) and HDL-C with CAD were linear and significant (p < 0.05). Multiple logistic regression analysis indicated that the association of FER(HDL) with CAD varied with the HDL-C level: significant for the low HDL-C tertile (chi-square = 6.20, p < 0.05) but not significant for the middle and high HDL-C tertiles (chi-square = 0.08 and 0.03, n.s.). The risk of CAD, relative to that in patients with low FER(HDL) and high HDL-C, was higher in patients with low FER(HDL) and low HDL-C (odds ratio [95% confidence interval]: 2.37 [1.12-4.97], p < 0.05) and was highest in patients with high FER(HDL) and low HDL-C (3.85 [1.84-8.06], p < 0.01). CONCLUSIONS: The functional assay of HDL (FER(HDL)) is an independent risk factor for CAD. The combination of FER(HDL) and HDL-C could be a potent indicator for CAD, and may reflect a potential mechanism of atherosclerosis.

Hyperinsulinemic hypoalphalipoproteinemia as a new indicator for coronary heart disease.

OBJECTIVES: The purpose of this study was to investigate the association among insulin resistance, high density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD), and to test the hypothesis that HDL-C may ameliorate the adverse effects of insulin. BACKGROUND: Serum low HDL-C (hypoalphalipoproteinemia) and hyperinsulinemia are independent predictors for CHD, but a strong negative correlation exists between them, as in patients with syndrome X. METHODS: Fifty-four pairs of cases (M/F: 49/5), defined as patients with angiographically proved CHD, and control subjects (M/F: 49/5) matched with cases with regard to gender and age were included. Insulin resistance was assessed by the homeostasis model assessment (HOMA). RESULTS: Cases had increased HOMA insulin resistance and lower serum levels of HDL-C than controls. A receiver operating characteristic (ROC) curve analysis indicated that HDL-C and insulin resistance were significant discriminators of CHD (area under ROC curve: 0.72 and 0.69, respectively). The interaction between HDL-C and the association of insulin resistance with CHD was significant: subjects with hyperinsulinemia and high HDL-C had no increased risk of CHD. Multivariate conditional logistic regression analysis showed that hyperinsulinemic hypoalphalipoproteinemia was a stronger indicator for CHD than either HDL-C or insulin resistance alone (-2 log likelihood: 19.0 vs. 12.6 or 15.7). CONCLUSIONS: Hyperinsulinemic hypoalphalipoproteinemia was a more potent indicator for CHD than either insulin resistance or low serum HDL-C levels alone, and the adverse effects of hyperinsulinemia seem to be ameliorated by high HDL-C levels.

Angiotensin II provokes cesium-induced ventricular tachyarrhythmias.

OBJECTIVE: The purpose of this study was to investigate whether angiotensin II provokes ventricular tachyarrhythmias and to clarify its mechanism using the cesium-induced arrhythmia model, which has been widely used as an afterdepolarization and triggered activity model. METHODS: Eighteen adult mongrel dogs of either sex weighing 9.6-23.0 kg were studied. The dogs were randomly divided into three groups. In the control group (n=6), the subjects received intravenous saline solution at a 0.45 ml/kg/h, and intravenous bolus injections of cesium (0.25, 0.5, 1.0 mmol/kg) were given at 20-min intervals. In the captopril-treated group (n=6), captopril was administered intravenously at 15 microg/kg/min, and cesium was injected as above. After the infusion of only captopril, in the captopril-treated group, angiotensin II was simultaneously infused at a dose of 0.1 ng/kg/min, and cesium was injected as above. When the dog survived, the dose of angiotensin II was increased to 1.0 ng/kg/min, and the same procedure was repeated. The remaining six dogs were simultaneously infused with captopril (15 microg/kg/min), angiotensin II (1.0 ng/kg/min), and U-73122 (10 microg/kg/min), a selective phospholipase C blocker, and injected with cesium (1.0 mmol/kg). Forty minutes after termination of U-73122 infusion, the dogs were injected with the same dose of cesium. RESULTS: Sustained ventricular tachycardia or ventricular fibrillation was induced by cesium in all of the dogs in the control group. In the captopril-treated group, none of the dogs showed these arrhythmias when only captopril was infused. The treatment of captopril significantly reduced lethal arrhythmias (P<0.01 vs. control group). During the simultaneous infusion of captopril and angiotensin II (0.1 ng/kg/min), cesium produced sustained ventricular tachycardia in all six dogs and the arrhythmia developed into ventricular fibrillation in three dogs. By increasing the dose of angiotensin II (1.0 ng/kg/min), the surviving three dogs died following induced ventricular fibrillation. The additional infusion of angiotensin II (0.1 and 1.0 ng/kg/min) significantly increased fatal arrhythmias (P<0.01 vs. only captopril- infused period, respectively). None of the dogs in the third group exhibited ventricular tachycardia during the infusion of U-73122, and ventricular fibrillations were recorded in all six dogs in the absence of U-73122. The treatment of U-73122 significantly reduced lethal arrhythmias. (P<0.01 vs. control period). CONCLUSIONS: These results suggest that angiotensin II provokes cesium-induced ventricular tachyarrhythmias by increasing calcium release from sarcoplasmic reticulum in myocytes via activation of a phosphatidylinositol response.

Oxidized low density lipoprotein stimulates collagen production in cultured arterial smooth muscle cells.

We examined the interactive effect of oxidized low density lipoprotein (LDL) and ascorbic acid on collagen production in cultured smooth muscle cells (SMCs). Porcine aortic SMCs were incubated with 50-200 micrograms/ml of human LDL with/without 5 microM Cu2+ for 24 h. Collagen production was assayed by successive salt precipitation at acidic and neutral pH after pepsin digestion of 3H-proline-labeled collagenous protein. Oxidation of LDL was evaluated by electrophoresis and by the level of thiobarbituric acid reactive substances (TBARS). Ascorbic acid reduced the oxidation of LDL + Cu2+ (53% reduction). In the presence of ascorbic acid, no differences were noted in collagen production between LDL and LDL + Cu2+. Without ascorbic acid, collagen production with LDL + Cu2+ was increased dose-dependently up to 6-fold with 150 micrograms/ml LDL, while no such effects were observed at any doses of native LDL. The addition of butylated hydroxytoluene to LDL + Cu2+ strongly suppressed oxidation (88% reduction), and significantly reduced collagen production close to that seen with native LDL. These results indicate that oxidized LDL stimulates collagen production in SMCs, while native LDL does not. Therefore, oxidized LDL may play a direct role in stimulating collagen production in SMCs, which could lead to collagenosis in atherosclerosis.

The associations among thoracic aortic atherosclerosis, coronary atherosclerosis and the function of high density lipoprotein.

We sought to determine the associations among thoracic aortic atherosclerosis, coronary atherosclerosis and the function of high density lipoprotein (HDL) in a case-control study. The function of HDL can be assessed by the fractional esterification rate of cholesterol in low density lipoprotein (LDL)- and very low density lipoprotein (VLDL)-depleted plasma (FER(HDL)), which reflects a balance of cholesterol uptake by HDL and cholesterol ester (CE) transport in the reverse cholesterol transport (RCT) system in humans. Cases (n=51, age: 64.3+/-8.0 years) and controls (n=51, age: 58.7+/-13.1 years) were defined as subjects with/without angiographically proven coronary artery disease (CAD), respectively and examined for thoracic aortic atherosclerosis (TAA) by transesophageal echocardiography. The severity of TAA was determined by the ratio of average sclerotic areas (ASA) and average sclerotic lengths (ASL). The cases had significantly (P<0.05) higher values of ASA (0.22+/-0.18 vs. 0.10+/-0.11), ASL (0.82+/-0.56 vs. 0.48+/-0.45), ASA/ASL ratio (0.23+/-0.08 vs. 0.17+/-0.09) and FER(HDL) (10.3+/-3.8 vs. 8.3+/-3.5% per hour) and lower HDL-C and apolipoprotein A-I levels than the controls. A receiver operating characteristic (ROC) curve analysis showed that ASA/ASL and FER(HDL) had moderate discriminating ability for CAD and the diagnostic accuracy of ASA/ASL was better than that of FER(HDL) (area under ROC curve: 0.703 and 0.656, respectively). Multivariate logistic regression analysis indicated that ASA/ASL and FER(HDL) were independent indicators for CAD [odds ratio (95% CI): 7.5 (2.4-27), P<0.01 and 4.0 (1.2-15), P<0.05] after adjusting for age, gender and other conventional risk factors, and that a high FER(HDL) value greatly increased the relative risk of CAD associated with a high ASA/ASL. The function of HDL, as assessed by FER(HDL), enhances the ability of TAA to predict CAD.

Comparison of children and coronary heart disease patients with low high density lipoprotein cholesterol levels.

Low plasma high density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD) in adults. In the field of pediatrics, subjects with low plasma HDL-C are often found among obese or dyslipidemic children. However, it is not clear whether low HDL-C in children should be considered a risk factor for CHD. The purpose of this study was to evaluate the risk for CHD in children with low HDL-C by comparing their lipid and apolipoprotein levels and physicochemical characteristics of their HDL with those of age-matched children with normal HDL-C and CHD patients with low HDL-C. Plasma lipids and apolipoproteins were measured in 206 dyslipidemic children (dyslipidemic), 65 obese children (obese), 93 CHD patients with low HDL-C (< 40 mg/dl) and 128 children with normal HDL-C (controls). To evaluate the physicochemical characteristics of HDL, molar and fractional esterification rates of cholesterol in plasma (MER(plasma) and FER(plasma)) and HDL (MER(HDL) and FER(HDL)) were determined in 128 children with normal HDL-C, 71 dyslipidemic, 33 obese and 93 CHD who allowed second blood samples to be taken. Compared to controls, children with low HDL-C showed atherogenic profiles of lipid and apolipoprotein levels and physicochemical characteristics of HDL (lower apo A-I, lower ratio of apo A-I to apo B and higher FER(HDL)). Therefore, the differences in lipid and apolipoprotein profiles between children with low HDL-C and CHD patients with low HDL-C were examined next. The two groups of subjects based on the HDL-C level (Group I: < 30 mg/dl, Group II 30 < or = HDL-C < 40 mg/dl) were studied. Compared to CHD, Group I children showed less atherogenic apolipoprotein profiles (lower apo B and higher ratio of apo A-I to apo B). Similar findings were also found in Group II children, but the differences were less prominent than those in Group I children. FER(HDL) in children with low HDL-C were similar to those in CHD. These findings suggest that the physicochemical characteristics of HDL in children with low HDL-C are similar to those in CHD, but the abnormalities of apo B-containing lipoproteins are milder than those in CHD patients. Thus, if further changes in the nature of apo B-containing lipoproteins could be prevented, children with low HDL-C might not become high risk for CHD in later life.

Fractional esterification rate of cholesterol in high density lipoprotein (HDL) can predict the particle size of low density lipoprotein and HDL in patients with coronary heart disease.

Fractional esterification rate of cholesterol in high density lipoprotein (HDL) (FER[HDL]) can predict the size distribution and physicochemical characteristics of HDL in plasma. In the present study, we investigated the correlation of FER(HDL) with the particle size of low density lipoprotein (LDL) (LDL-size) in 111 patients (81 males and 30 females) with coronary heart disease (CHD). The correlations of FER(HDL) and LDL-size with conventional lipid and lipoprotein parameters were also studied. FER(HDL) was closely associated with LDL-size (males: r = -0.618, females: r = -0.629, P < 0.001). Plasma levels of TG, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C) and apo B were also associated with LDL-size in male CHD patients (r = -0.534, 0.314, 0.358, and -0.482, P < 0.01 or 0.001), while plasma levels of TG and apo B were associated with LDL-size in female patients (r = -0.350 and -0.348, P < 0.05). In a stepwise multiple regression analysis, FER(HDL) alone accounted for 38 and 40% of the variability in LDL-size in male and female CHD patients, respectively. Other parameters accounted for an additional 6-10%. With respect to the relation between FER(HDL) and HDL subfractions, FER(HDL) related only to HDL2-C (males: r = -0.640, females: r = -0.652, P < 0.001). This result suggests that FER(HDL) is better able to predict the presence (or absence) of large HDL, rather than that of small HDL. All these data taken together, suggest that FER(HDL) is a useful tool to predict the particle size of both LDL and HDL, even in CHD patients.

Kinetics of HDL-apo A-I in the WHHL rabbit, an animal model of familial hypercholesterolemia.

Plasma high density lipoproteins (HDL) and their major protein, apolipoprotein (apo) A-I, are deficient in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. As the pathophysiology of subnormal HDL-apo A-I is unclear, we examined kinetic parameters of HDL-apo A-I in WHHL rabbits and normolipidemic Japanese White (control) rabbits. The total plasma mass of HDL-apo A-I was significantly smaller (P less than 0.01) in WHHL rabbits than in controls (less than one-third). Mean fractional catabolic rates (FCR) computed from the specific radioactivity decay curves of HDL-apo A-I were significantly greater (P less than 0.01) in WHHL rabbits than in controls (0.874 +/- 0.052 vs. 0.502 +/- 0.060/day, respectively). Mean synthetic rates of HDL-apo A-I were significantly lower (P less than 0.01) in WHHL rabbits than in controls (8.67 +/- 0.59 vs. 18.14 +/- 3.75 mg/kg body weight/day, respectively). We conclude that the deficiency of plasma HDL-apo A-I in the WHHL rabbits resulted from an increase in FCR and a decrease in apo A-I synthesis.

Plasma fibrinogen levels as an independent indicator of severity of coronary atherosclerosis.

The relationship between plasma fibrinogen levels and the severity of coronary atherosclerosis was examined in 229 patients, aged 25-82 years (162 men and 67 women), undergoing coronary angiography. Severity of coronary atherosclerosis was assessed in terms of the number of vessels with a 75% or greater stenosis and Gensini's severity score. Fibrinogen levels increased progressively with the severity of coronary atherosclerosis, determined by both the number of involved vessels and Gensini's severity score in men, and the relationships were statistically significant. Similar patterns were noted among women, but the trends were not statistically significant. The association was evident even after adjustment for age, hypertension, total cholesterol, cigarette smoking, alcohol intake, high density lipoprotein cholesterol and body mass index. These results provide evidence that in the Japanese also plasma fibrinogen levels can serve as an independent indicator of the progression of coronary atherosclerosis.

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.

Alcohol consumption, serum lipids and severity of angiographically determined coronary artery disease.

The relation of alcohol consumption to serum lipids and the severity of coronary atherosclerosis was examined in 212 men undergoing coronary angiography. The severity of coronary atherosclerosis was assessed in terms of the presence of greater than or equal to 75% diameter stenosis and the Gensini severity score. Alcohol consumption was divided into 4 categories: none (0 ml alcohol/week), light (1 to 100 ml alcohol/week), moderate (101 to 300 ml alcohol/week) and heavy (greater than or equal to 301 ml alcohol/week). Alcohol consumption was positively related to high-density lipoprotein cholesterol and inversely related to total cholesterol, but was not associated with triglyceride. After adjustment for these serum lipids as well as for cigarette smoking and systemic hypertension, the risk of coronary stenosis was significantly decreased in the moderate drinkers. A decreased risk among moderate drinkers also was noted in terms of Gensini's severity score. These findings suggest that moderate alcohol consumption may protect against severe coronary atherosclerosis.

Troglitazone lowers blood pressure and enhances insulin sensitivity in Watanabe heritable hyperlipidemic rabbits.

Although an association has been demonstrated between insulin resistance and hypertension, the mechanism of this association is not clear. Clarification of this point is important in hyperinsulinemic Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia, as hypertension markedly stimulates atherosclerosis in WHHL rabbits. The purpose of the present study was to determine whether troglitazone, a new thiazolidinedione drug for insulin resistance, could reduce blood pressure (BP) by improving hyperinsulinemia in WHHL rabbits. The effects of troglitazone, administered as a food admixture (24 mg/day) for 6 months, on hyperinsulinemia and BP were examined in WHHL rabbits. Insulin sensitivity (IS) was measured by the minimal model method using an intravenous glucose tolerance test (IVGTT). Troglitazone significantly reduced fasting insulin levels and the area-under-the-curve of insulin IVGTT profiles, indicating improved hyperinsulinemia. Troglitazone also significantly increased IS and reduced BP and heart rate (HR). Due to a significant correlation between HR and BP, a covariance analysis was performed. When BP was considered as a covariance factor, the change in HR was significant in treated rabbits. However, when HR was considered as a covariance factor, the change in BP was not significant, suggesting that reduced BP may be partly associated with changes in the sympathetic nervous system activity. In conclusion, troglitazone increases insulin sensitivity and lowers blood pressure in WHHL rabbits. Due to its dual effects on insulin resistance and hypertension, troglitazone offers a new pharmacological approach for the treatment of insulin-resistance syndrome.

Angiotensin I converting enzyme gene polymorphism and insulin resistance in patients with angina pectoris.

The association between insertion/deletion polymorphism of the angiotensin I converting enzyme (ACE) gene and insulin resistance (IR) was investigated in 64 consecutive patients (F/M: 11/53) with angina pectoris without clinically manifest diabetes mellitus who underwent diagnostic coronary angiography. The observed frequency distribution of ACE genotypes did not deviate from that predicted from the Hardy-Weinberg equilibrium in this group. Patients with the ACE-ID genotype had significantly lower IR, as assessed by an oral glucose tolerance test (OGTT) and by homeostatic model assessment (HOMA), compared to those with the ACE-II genotype, as assessed by a multiple comparison analysis. Patients were divided into two groups with low and high HOMA-IR, and the I allele was seen more frequently in the high HOMA-IR group than in the low HOMA-IR group (0.62 v 0.47, respectively, by chi2 test, P < .05). Logistic regression analysis showed that the odds ratio for insulin resistance in patients with the II genotype, compared to those with the ID and DD-genotypes (assuming that the I allele has a recessive effect), was 4.0 (95% confidence interval, 1.2 to 16.5; P = .037), after adjusting for the presence of significant coronary atherosclerosis. In conclusion, the D allele was not associated with higher insulin resistance in patients with angina pectoris; that is, patients with the ID and DD genotypes were associated with a significantly lower risk of insulin resistance, compared to those with the II genotype.