Ichiro Michishita

Deficiency of Serum Cholesteryl-Ester Transfer Activity in Patients with Familial Hyperalphalipoproteinaemia

Lipoprotein patterns and cholesteryl ester transfer activity (CETA) were examined in 2 patients with familial hyperalphalipoproteinaemia (FHALP). The proband was a healthy 58-year-old Japanese male who had an HDL cholesterol of 7.83 mmol/l (301 mg/dl). His sisters HDL cholesterol was 4.52 mmol/l (174 mg/dl), which suggested that both were homozygous carriers of FHALP. In both subjects HDL showed a high cholesterol/apo A-I ratio and appeared to be a larger-sized particle than normal HDL on agarose gel chromatography. Two of the probands children showed higher HDL cholesterol levels (1.74 mmol/l, 2.16 mmol/l) than normal, but another 2 children showed normal levels (1.48 mmol/l, 1.40 mmol/l). However, the ratios of HDL cholesterol to total cholesterol and to apo A-I in all children were higher than normal. These data suggest, but do not prove, that all his children were heterozygotes. Apo B levels in all of the family members studied were lower than normal (47-80 mg/dl). Deceased members of the same family had not died from cardiovascular disease. Cholesteryl-ester transfer activity was studied in both patients. When serum or lipoprotein deficient serum (d greater than 1.21) and [3H]cholesteryl ester labelled HDL3 were incubated in the presence of an LCAT inhibitor, there was no evidence of cholesteryl ester transfer from HDL to VLDL and/or LDL, unlike normal subjects. The deficiency of CETA in these patients with FHALP presumably accounted for the increase in particle size and cholesterol enrichment of HDL.

A new low density lipoprotein apheresis system using two dextran sulfate cellulose columns in an automated column regenerating unit (LDL continuous apheresis)

We describe a new low density lipoprotein (LDL) apheresis system using dextran sulfate cellulose column in an automated column regenerating unit (LDL continuous apheresis). Two columns containing 150 ml of dextran sulfate cellulose were used, and the whole extracorporeal circulation was about 400 ml in volume. After 600 ml of plasma was adsorbed into the first column, the second column was used as an adsorbent and meanwhile the first column was regenerated. Thus, the 2 columns were used alternately without losing the potency of the columns. As the apparatus was automatically controlled by a computerized unit, no extra manipulation is necessary compared with the conventional single-column method. By treating 4-5 liters of plasma, non-high density lipoprotein (HDL)-cholesterol levels decreased by 63-71%, and HDL-cholesterol levels remained unchanged. Thus, this new method of LDL apheresis can safely reduce LDL-cholesterol to any desired level and will be applicable for the treatment of child and adult family hypercholesterolemic patients with severe coronary heart disease.

Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis

BACKGROUND Systemic therapy with statin has been shown to lower the risk of coronary events; however, the in vivo effects of statin therapy on plaque volume and composition are less understood. METHODS We conducted a prospective, open-labeled, randomized, multicenter study in 11 centers in Japan. A total of 164 patients were randomized to receive either 4 mg/d of pitavastatin (intensive lipid-lowering therapy) or 20 mg/d of pravastatin (moderate lipid-lowering therapy). Analyzable intravascular ultrasound data were obtained for 119 patients at baseline and at 8-month follow-up. The primary end point was the difference of volume changes in each of the 4 main plaque components (fibrosis, fibrofatty, calcium, and necrosis), assessed by virtual histology intravascular ultrasound, between the 2 groups. RESULTS The mean low-density lipoprotein cholesterol level at follow-up was significantly lower in the pitavastatin than in the pravastatin group (74 vs 95 mg/dL, P < .0001). During the 8-month follow-up period, statin therapy reduced the absolute and relative amount of fibrofatty component (pitavastatin: from 1.09 to 0.81 mm(3)/mm, P = .001; pravastatin: from 1.05 to 0.83 mm(3)/mm, P = .0008) and increased in the amount of calcium (pitavastatin: from 0.42 to 0.55 mm(3)/mm, P < .0001; pravastatin: from 0.44 to 0.55 mm(3)/mm, P = .005), whereas volume changes in both plaque components were not statistically different between the 2 groups. CONCLUSIONS Both pitavastatin and pravastatin altered coronary artery plaque composition by significantly decreasing the fibrofatty plaque component and increasing the calcified plaque component.

Effects of CS-514 on serum lipoprotein lipid and apolipoprotein levels in patients with familial hypercholesterolemia

Effects of CS-514, a new competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on serum lipoprotein lipid and apolipoprotein levels were studied in 13 heterozygous patients with familial hypercholesterolemia. Treatment with 10 mg of CS-514 twice daily reduced total serum cholesterol, low-density lipoprotein (LDL), and intermediate-density lipoprotein (IDL) cholesterol levels by 25%, 33%, and 33%, respectively, and increased high-density lipoprotein (HDL) cholesterol levels by 15%. Apolipoprotein B, E, and C-II levels decreased by 24%, 20%, and 19%, and apolipoproteins A-I and A-II levels increased by 10% and 7%, respectively. One patient showed abnormally high levels of SGOT, SGPT, and serum alkaline phosphatase, which returned to normal levels immediately after the cessation of CS-514. No other adverse effects were observed. Thus, CS-514 reduces atherogenic lipoproteins and apolipoprotein B, and increases HDL and apolipoprotein A-I and A-II, and appears to be a useful drug for heterozygous familial hypercholesterolemia.

Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease.

A low ratio of n-3 to n-6 polyunsaturated fatty acids has been associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined. The purpose of the present study was to evaluate the correlations between the n-3 to n-6 polyunsaturated fatty acid ratio and coronary atherosclerosis. Coronary atherosclerosis in nonculprit lesions in the percutaneous coronary intervention vessel was evaluated using virtual histology intravascular ultrasound in 101 patients at the time of percutaneous coronary intervention and 8 months after statin therapy. Forty-six patients (46%) showed atheroma progression and the remaining 55 patients (54%) showed atheroma regression at 8-month follow-up. Significant negative correlations were observed between percentage change in plaque volume and change in the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (r = -0.190, p = 0.05), docosahexaenoic acid (DHA)/AA ratio (r = -0.231, p = 0.02), and EPA+DHA/AA ratio (r = -0.240, p = 0.02). Furthermore, percentage change in the fibrous component volume was negatively and significantly correlated with change in the EPA/AA ratio (r = -0.206, p = 0.04) and EPA+DHA/AA ratio (r = -0.217, p = 0.03). Multivariate regression analysis showed that change in the EPA+DHA/AA ratio was a significant predictor of percentage change in plaque volume and fibrous component volume (β = -0.221, p = 0.02, and β = -0.200, p = 0.04, respectively). In conclusion, decreases in serum n-3 to n-6 polyunsaturated fatty acid ratios are associated with progression in coronary atherosclerosis evaluated using virtual histology intravascular ultrasound in statin-treated patients with coronary artery disease.

Comparison of haemodialysis patients and non-haemodialysis patients with respect to clinical characteristics and 3 year clinical outcomes after sirolimus-eluting stent implantation: insights from the Japan multi-centre post-marketing surveillance registry

AIMS Long-term outcomes after sirolimus-eluting stent (SES) implantation in haemodialysis (HD) patients have remained controversial. We investigated the impact of HD on outcomes after SES implantation. METHODS AND RESULTS We analysed the data on 2050 patients who underwent SES implantation in a multi-centre prospective registry in Japan. Three-year clinical outcomes were compared between the HD group (n = 106) and the non-haemodialysis (NH) group (n = 1944). At the 3-year clinical follow-up, the rates of unadjusted cardiac mortality (HD: 16.3 vs. NH: 2.3%) and target-lesion revascularization (TLR) (HD: 19.4 vs. NH: 6.6%) were significantly higher in the HD group than the NH group (P < 0.001). Although HD group had a numerically higher stent thrombosis rate, the difference in stent thrombosis between the two groups (HD: 2.0 vs. NH: 0.7%) did not reach statistical significance. Using Coxs proportional-hazard models with propensity score adjustment for baseline differences, the HD group had higher risks of TLR [HD: 16.3 vs. NH: 6.1%; hazard ratio, 2.83; 95% confidence interval (CI): 1.62-4.93, P = 0.0003] and cardiac death (HD: 12.3 vs. NH: 2.3%; hazard ratio, 5.51; 95% CI: 2.58-11.78, P < 0.0001). The consistent results of analyses, whether unadjusted or adjusted for other baseline clinical and procedural differences, identify HD as an independent risk factor for cardiac death and TLR. CONCLUSIONS Percutaneous coronary intervention with SES in HD patients has a higher incidence of repeat revascularization and mortality compared with those in NH patients. Haemodialysis appears to be strongly associated with mortality and repeat revascularization even after SES implantation.

Treatment of homozygous patients with familial hypercholesterolemia by double-filtration plasmapheresis

Two homozygous patients with familial hypercholesterolemia were treated by double-filtration plasmapheresis. The plasma separated by the first filter was subsequently led to the second filter of ethylene vinylalcohol co-polymer hollow fibers, which trap very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) preferentially to other plasma constituents. Serum, VLDL, IDL, LDL cholesterol levels decreased by 55, 68, 59 and 55%, respectively. HDL cholesterol levels decreased by 39%. Immunoglobulins and fibrinogen levels decreased significantly. Cutaneous and tendinous xanthomas became smaller. off

New variant of low density lipoprotein receptor gene. FH-Tonami.

A new variant of the low density lipoprotein receptor (LDLR) gene was ascertained through Southern biotting analysis fof LDLR genes of 35 unrelated Japanese patients with heterozygous familial hypercholesterolemia (FH). This mutant gene had a 6 kilo-base deletion which had eliminated only exon 15, an exon that encodes the O-linked sugar domain. The mutation was recognized in two patients with heterozygous FH. We refer to these patients as ‘FH-Tonami’, since they were both born in the Japanese district of Tonami. Although there is no evidence of a relation between families, the possibility of a common ancestor with FH does exist. Neonatal diagnosis of FH in two fetuses from one family was possible through analyses of their LDLR genes in cord blood samples at delivery.

Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance

AIM To evaluate the effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. METHODS Seventy-six patients with diabetes and glucose intolerance were enrolled in this study. At baseline and 12 weeks after treatment with ezetimibe 10mg/day, we measured the levels of lipid and glucose parameters. RESULTS Ezetimibe reduced the mean levels of low-density lipoprotein cholesterol (LDL-C) (-20%, P<0.001), remnant-like particle cholesterol (-22%, P<0.001), small dense-LDL (-19%, P<0.001), apolipoprotein B-48 (-2%, P<0.01), malondialdehyde modified-LDL (-15%, P<0.001), and serum immunoreactive insulin (IRI) (-4%, P<0.01). In the insulin resistance subgroup, ezetimibe reduced the abdominal circumference (-1%, P<0.05) and mean levels of fasting plasma glucose (-7%, P<0.05), IRI (-36%, P<0.01), s-CPR (-27%, P<0.01), HOMA-IR (-39%, P<0.01) and HbA1c tended to decrease (-2%, P=0.06). CONCLUSIONS Ezetimibe reduced atherogenic lipoproteins in patients with diabetes and glucose intolerance; besides, it improved glucose metabolism in patients with insulin resistance.

A new 0.010‐inch guidewire and compatible balloon catheter system: The IKATEN registry

To evaluate the safety and feasibility of a new 0.010‐inch guidewire and a specialized balloon catheter for the 0.010‐inch guidewire in routine percutaneous coronary intervention (PCI).