Kikuo Arakawa’s research while affiliated with Ashikaga University and other places

Apolipoprotein (apo) E modulates the catabolism of chylomicrons and of very low density lipoprotein remnants. It has three major isoforms (apo E2, E3, E4) and some rare variants. To detect the variants of apo E, blood specimens from 1269 Japanese subjects were analyzed using isoelectric focusing with immunoblotting. The E5 and E7 variants were identified by IEF in 2 and 18 subjects, respectively. Both E5 (Glu3→Lys) carriers were confirmed by PCR-mediated site-directed mutagenesis, and all E7 (Glu244→Lys, Glu245→Lys) carriers were confirmed by the amplification refractory mutation system. The relative frequencies of the ε5 and ε7 alleles were 0.001 and 0.007, respectively. High concentrations of total cholesterol (>220 mg/dl) were detected in five of the subjects expressing apo E7 and one subject expressing apo E5, and eight subjects heterozygous for apo E7 showed elevated plasma triglyceride concentrations (>150 mg/dl). In 621 healthy subjects, the mean triglyceride concentration in subjects with apo E7/3 appeared to be higher than in those with apo E3/3, but the difference was not statistically significant.

We identified two apolipoprotein (apo) A-I variants, using isoelectric focusing gel electrophoresis: apo A-I Karatsu, which had a relative charge of+ 1 compared to normal apo A-I4, and apo A-I Kurume, which had a relative charge of -1. Direct sequence analysis of the PCR-amplified DNA from the proband of apo A-I Karatsu revealed a single substitution of tyrosine (TAC) for histidine (CAC) at position 100. Sequence analysis of apo A-I Kurume revealed a single substitution of histidine (CAT) for glutamine (CAG) at position 162. Probands of these two mutants and limited family study showed no accelerated atherosclerosis.

Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population. In this prospective, randomised, open-labelled, blinded study, patients with hypercholesterolaemia (total cholesterol 5.69-6.98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10-20 mg pravastatin daily. The primary endpoint was the first occurrence of coronary heart disease. Statistical analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00211705. 3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49-0.91; p=0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups. Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Risk factors for cerebral infarction have not been well clarified, except for hypertension (HT), and few studies have examined the risk factors in the elderly. Clinical and behavioral risk factors for cerebral infarction were examined in 4,349 Japanese men aged 45-74 years with a serum total cholesterol (TC) concentration of 220 mg/dl or greater who participated in the Kyushu Lipid Intervention Study. A total of 81 men developed definite cerebral infarction in a 5-year follow-up period. The Cox proportional hazards model was used with serum TC at baseline and during the follow-up, serum high-density lipoprotein-cholesterol (HDL-C), HT, diabetes mellitus (DM), and other factors as covariates. Serum TC during the follow-up, not at baseline, was positively associated with cerebral infarction, showing a stronger association in the elderly (>or=65 years old) than in the middle-aged (<65 years old). Statin use was related to a moderate decrease in the risk of cerebral infarction when follow-up TC was not considered, but the decrease was almost nullified after adjustment for follow-up TC. A low concentration of serum HDL-C, diabetes mellitus, hypertension, and angina pectoris were each related to an increased risk. No clear association was observed for body mass index, smoking or alcohol use. Lowering cholesterol is important in the prevention of cerebral infarction in men with moderate hypercholesterolemia. A low concentration of HDL-C, DM, and HT are independent predictors of cerebral infarction.

Background Although cholesterol management reportedly reduces fatal and non-fatal coronary heart disease (CHD) events in subjects with or without evident atherosclerotic disease, it is still uncertain whether these benefits extend to Japanese. Methods and Results The study group comprised 8,009 subjects with mildly elevated total cholesterol who were randomized to treatment with 10-20 mg pravastatin plus diet (2,691 women, 1,267 men) or diet alone (2,758 women, 1,293 men). The groups were extremely well balanced with respect to baseline demographics and risk factors such as blood pressure and plasma lipids. Over a 5-year period of follow-up, the primary end-points will be a composite of fatal and non-fatal coronary events. Secondary end-points will include stroke and transient ischemic attack, all cardiovascular events and total mortality. Conclusions The 2 groups will be followed up until the end of March 2004 and end-points will be analyzed by full analysis set.

We stratified findings from the Japan Multicenter Investigation for Cardiovascular Diseases-B according to whether or not the patients had diabetes and compared the incidence of cardiac events occurring over a 3-year period between treatment with nifedipine retard and angiotensin converting enzyme (ACE) inhibitor. The primary endpoint was the overall incidence of cardiac events (cardiac death or sudden death, myocardial infarction, hospitalization for angina pectoris or heart failure, serious arrhythmia, and coronary interventions), and the secondary endpoints were a composite of other events (cerebrovascular accidents, worsening of renal dysfunction, non-cardiovascular events, and total mortality). The results showed no significant difference in the incidence of the primary endpoint between the nifedipine group (n=199) and the ACE inhibitor group (n=173) in diabetic patients: 15.08% vs. 15.03%, relative risk 1.06, p=0.838. Also in nondiabetic patients, no significant difference was observed between the former (n=629) and the latter (n=649): 13.67% vs. 12.33%, relative risk 1.04, p=0.792. Similar results were obtained for the incidence of the secondary endpoints: in diabetic patients, 5.03% vs. 5.20%, relative risk 0.89, p=0.799; in nondiabetic patients, 2.70% vs. 2.47%, relative risk 1.07, p=0.842. Achieved blood pressure levels were 138/76 and 136/77 mmHg in the nifedipine group and 140/78 and 138/79 mmHg in the ACE inhibitor group in diabetic and nondiabetic patients, respectively. This study showed that nifedipine retard was as effective as ACE inhibitors in reducing the incidence of cardiac events in extremely high-risk hypertensive patients with complications of diabetes and coronary artery disease.