Hyperapobetalipoproteinemia with compositional abnormality of LDL and IDL, a characteristic lipoprotein alteration in essential hypertension.

The number and composition of apoprotein B (apoB)-containing lipoproteins that are very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) have been analyzed in subjects with essential hypertension who have no obesity and glucose intolerance. Twenty-three essential hypertensive subjects without diabetes mellitus and obesity were recruited. VLDL, IDL, LDL, and high-density lipoprotein (HDL) were separated by ultracentrifugation in the 23 hypertensive and 17 healthy subjects (control group). ApoB was determined by highly sensitive latex agglutination method in each lipoprotein fraction. There were no significant differences in age and body mass index between the hypertension and control groups. In hypertension, cholesterol levels significantly increased in plasma (13%, P < .05) and in LDL (20%, P < .05), but decreased in HDL (-14%, P < .05). Triglyceride significantly increased in plasma (66%, P < .05) and in VLDL (105%, P < .05). ApoB also significantly increased in plasma and all lipoprotein fractions except HDL. (plasma, 35%; VLDL, 94%; IDL, 82%; LDL, 42%; P < .05). With respect to lipoprotein composition, the ratio of cholesterol to apoB significantly decreased in IDL (P < .05) and LDL (P < .05). In essential hypertension, the number of apoB-containing lipoproteins (VLDL, IDL, LDL) all increased. A low ratio of cholesterol to apoB without changes in the ratio of triglyceride to apoB was noted in IDL and LDL, indicating the presence of small dense lipoprotein particles. Characteristic disorders of pure essential hypertension are characterized by hyperapobetalipoproteinemia and small dense LDL.

Evaluation of factors during OGTT to correlate insulin resistance in non-diabetic subjects.

The correlation between various factors obtained during oral glucose tolerance tests (OGTT) and insulin sensitivity tests (steady state plasma glucose, SSPG method) were analyzed in non-diabetic subjects by Pearson's simple correlation. Similar data were obtained for normal as well as normal and impaired glucose tolerance (IGT) subjects. Three factors (AUCI(120)0AUCG(120)0, AUCI(120)0 and AUCI(120)60, area of under curve (AUC), insulin (I), glucose (G)) were found to have significant correlation (r=0.47-0.54) with SSPG, thus indicating insulin resistance. Those with hyperinsulinemia were noted to have insulin resistance with high precision (98%), but insulin resistant subjects without hyperinsulinemia were all judged to have normal sensitivity. These three factors all had high specificity (98%), but low sensitivity (21-25%) with false negative results being obtained in 75-78%, and false positive results in less than 2%. It was difficult to distinguish positive and negative for the insulin resistance by receiver operating characteristic (ROC) curve of I0G0. The sensitivity of which was 12.8% and specificity 93.8%. By ROC curve, the specificities and sensitivities for the proposed factors, including homeostatic model assessment (HOMA) product (I0G0, I0-120, G0-120, insulin and glucose at 0-120' during OGTT) ranged from 60 to 70%, which is far from an acceptable level of 90% or more. Therefore, these factors were useful to correlate insulin sensitivity with OGTT results in hyperinsulinemic subjects or in general non-diabetic subjects, but less useful when it came to identifying individual cases with insulin resistance. These parameters should be used only in non-diabetic subjects and their significance is thought to be restricted to cases with hyperinsulinemia.

Effect of bezafibrate treatment on the altered lipoprotein profiles in hypertriglyceridemic subjects.

The effects of bezafibrate treatment on lipoprotein metabolism were investigated in hypertriglyceridemic subjects. Bezafibrate, a fibric acid derivative, was administered at 200-400 mg/day to 8 patients with hyperlipoproteinemia (type IIb and IV) for 3-6 months. We evaluated the effects of bezafibrate on the plasma levels of total cholesterol(chol), triglyceride(TG), and apoB. In addition, the lipid and apoB contents were also analyzed in VLDL, IDL, LDL and HDL fractions before and after the treatment. It was revealed that plasma levels of chol, TG and apoB significantly decreased after the treatment, 236.3 vs 210.9,192.4 vs 90.2 (p< 0.01) and 129.8 vs 116.2 (p<0.05) mg/dl respectively. VLDL-chol, VLDL-TG and VLDL-apoB dropped from 26.5,127.6 and 11.1 mg/dl to 9.1, 49.5 and 6.7 mg/dl respectively after the treatment. Regarding qualitative alterations of VLDL, TG/apoB, chol/apoB and TG + chol/apoB ratios in VLDL were significantly reduced, indicating that the size of VLDL was diminished by the treatment. In addition, HDL-chol increased from 40.4 to 60.8 mg/dl after the treatment. Consequently LDL-chol/HDL-chol significantly decreased. In conclusion, bezafibrate administration decreased the TG, chol and apoB content in VLDL, suggesting a reduced number of VLDL. Significant rise of HDL-chol and decrease of LDL-chol/HDL-chol are additional beneficial effects following bezafibrate treatment.

Development of approximate formula for LDL-chol, LDL-apo B and LDL-chol/LDL-apo B as indices of hyperapobetalipoproteinemia and small dense LDL.

Estimation of LDL-chol and LDL-apo B is useful for the diagnosis of hyperapobetalipoproteinemia (normal LDL-chol with increased LDL-apo B), which is one of the most commonly occurring lipoprotein disorders associated with atherosclerotic cardiovascular diseases. The LDL-chol/LDL-apo B ratio reflects the level of small dense LDL, which is an important risk factor for IHD, CVD and ASO. In order to estimate LDL-apo B and LDL-chol/LDL-apo B ratio from blood chol, TG, HDL-chol and apo B values, we developed a formula for LDL-chol ¿0.94Chol- 0.94HDL-chol - 0.19TG¿, LDL-apo B ¿apo B - 0.09Chol + 0.09HDL-chol-0.08TG¿, and LDL-chol/LDL-apo B [¿0.94Chol-0.94HDL-chol - 0.19TG¿/¿apo B - 0.09Chol + 0.09HDL-chol-0.08TG¿] using ultracentrifugal data from 2179 subjects. These were calculated by the least squares method on the assumption that a certain compositional relationship exists between Chol, TG and apo B in VLDL, IDL and LDL. Friedewald's formula for LDL-chol (Chol - HDL-chol - 0.2TG) includes IDL-chol, but the present new formula theoretically excludes IDL-chol. It suggests a better estimation for the correct LDL-chol. Estimated LDL-apo B is useful for the diagnosis of hyperapobetalipoproteinemia and detection of small dense LDL. Without performing ultracentrifuge, additional information is obtained for the quantitative and qualitative alteration of LDL, such as small dense LDL. The above formulae and a new classification of lipoproteinemia including apo B were applied to the analyses of lipoprotein profiles of subjects with cardiovascular diseases, which were compared with those in the general population. Hyperapobetalipoproteinemia with high TG was observed 2-3 times more frequently in subjects with CAD, MI and ASO than in the Suita population. Lower ratios of LDL-chol/LDL-apo B, reflecting preponderance of small dense LDL, were observed in the above three groups. Type IIb and combined low HDL-chol were also frequent phenotypes in CAD, A-Th and ASO. The present formulae are useful for the detailed analyses of lipoprotein disorders in both qualitative as well as quantitative aspects.

Effects of simvastatin on the number and composition of apoproteinB-containing lipoproteins in hypercholesterolemia: analysis of apoproteinB in each lipoprotein fraction by highly sensitive latex method.

We investigated the effects of simvastatin on the number and composition of apoproteinB (apoB)-containing lipoproteins in thirteen patients with hypercholesterolemia type IIa or IIb by measuring apoB by a highly sensitive latex method. Patients received simvastatin 5-10 mg (7.7 +/- 0.7 mg, mean +/- SEM) daily for 83-218 days (131 +/- 13 days). In both types of patients, treatment with simvastatin significantly reduced plasma cholesterol levels (mean +/- SEM mg/dl: in type IIa from 234.4 +/- 5.4 to 171.4 +/- 7.8, in type IIb from 242.4 +/- 11.6 to 178.8 +/- 9.6), low density lipoprotein (LDL) cholesterol levels (from 122.6 +/- 5.2 to 68.5 +/- 4.6, and from 115.6 +/- 14.0 to 70.4 +/- 11.6 in the two types, respectively) and LDL apoB levels (from 94.5 +/- 6.6 to 60.6 +/- 7.0, and from 85.0 +/- 8.4 to 56.6 +/- 6.2, respectively). There was no significant change in cholesterol, triglyceride (TG) or apoB in very low density lipoprotein (VLDL). High density lipoprotein (HDL) cholesterol did not change in this study. With respect to lipoprotein composition, the ratio of either cholesterol or TG to apoB in VLDL, intermediate density lipoprotein (IDL) and LDL did not change significantly, but that of TG to apoB in the IDL fraction increased in type IIa. Simvastatin promotes more effective reduction in cholesterol and apoB in LDL than in VLDL, probably by increasing the hepatic LDL receptor which preferentially binds LDL.

Clinical impact of insulin resistance syndrome in cardiovascular diseases and its therapeutic approach.

In subjects with coronary artery diseases (obstructive and vasospastic angina pectoris (AP)) who have no diabetes, hypertension, obesity and physical inactivity, insulin sensitivity was significantly reduced with compensated hyperinsulinemia on OGTT. Insulin resistance significantly correlated with coronary atherosclerosis score. In vasospastic AP (VAP), those who fulfilled more than 3 risk factors out of 5 (hyperinsulinemia, obesity, glucose intolerance, hypertension, dyslipidemia) consist of 70 and 40% for smokers and nonsmokers respectively. Insulin resistance syndrome who fulfilled all the criteria was 9-10% for VAP. In atherothrombotic brain infarction (ATTI) with the same exclusion criteria, the similar insulin resistance and hyperinsulinemia have been observed, but not in embolic (cardiac origin) or lacunar infarction. In ATTI, high TG and apo B with low HDL-chol were noted in blood. In essential hypertension without diabetes and obesity, hyperinsulinemia was noted in 25-35% and insulin resistance in 56-88%. Reduction of blood pressure with alpha blocker (bunazosin), ACE inhibitor (cilazapril), long-acting Ca++ blocker (amlodipine) significantly improved lowered insulin sensitivity. Insulin resistance rather than hyperinsulinemia is more closely associated with blood pressure. Cardiovascular diseases (vasospastic and obstructive AP, brain cortical artery diseases) are prone to develop diabetes because of insulin resistance and also promote the generation of cumulative risk factors resulting in a vicious cycle. Efforts to alleviate insulin resistance is crucial for the primary and secondary prevention of cardiovascular diseases.