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Nishiwaki M.,Keyaki Naika Clinic | Ikewaki K.,National Defense Medical College | Ayaori M.,National Defense Medical College | Mizuno K.,Nippon Medical School | And 4 more authors.
Journal of Cardiology | Year: 2013

Background: The beneficial effect of statins for cardiovascular disease (CVD) prevention has been well established. However, the effectiveness among different phenotypes of dyslipidemia has not been confirmed. Objective: We evaluated the effect of pravastatin on the incidence of CVD in relation to the phenotype of dyslipidemia. Methods: The MEGA Study evaluated the effect of low-dose pravastatin on primary prevention of CVD in 7832 Japanese patients, who were randomized to diet alone or diet plus pravastatin and followed for more than 5 years. These patients were classified into phenotype IIa (n=5589) and IIb (n=2041) based on the electrophoretic pattern for this post hoc analysis. Results: In the diet group there was no significant difference in the incidence of coronary heart disease (CHD), stroke, CVD, and total mortality between the two phenotypes. Phenotype IIb patients, compared to phenotype IIa, had lower levels of high-density lipoprotein cholesterol (HDL-C) and a significantly higher incidence of CVD in relation to a low HDL-C level (<47.5. mg/dL; p=0.02). Furthermore, pravastatin decreased the relative risk for each major endpoint in both type IIa and type IIb dyslipidemia. Significant risk reductions were observed for CHD by 38% (p=0.04) and CVD by 31% (p=0.02) in type IIa dyslipidemia but not in phenotype IIb. Conclusion: Pravastatin therapy provided significant risk reductions for CHD and CVD in patients with phenotype IIa dyslipidemia, but not in those with phenotype IIb dyslipidemia. © 2012 Japanese College of Cardiology. Source

Yokoyama M.,Keio Research Consortium for Migraine Epidemiology | Suzuki N.,Keio Research Consortium for Migraine Epidemiology | Yokoyama T.,Japan National Institute of Public Health | Yokoyama A.,Kurihama Alcoholism Center | And 3 more authors.
Journal of Headache and Pain | Year: 2012

The aim of the study was to investigate associations between headache types and alcohol drinking, alcohol flushing, and hangover. Alcohol consumption is inhibited by the presence of inactive aldehyde dehydrogenase- 2 (ALDH2) whose carriers are susceptible to alcohol flushing and hangovers. We conducted a cross-sectional study of the 2,577 subjects (men/women: 1,018/1,559) who reported having ever experienced headaches unrelated to common colds and alcohol hangovers among 5,408 (2,778/ 2,630) Tokyo health checkup examinees. We used a questionnaire inquiring about current and past facial flushing after drinking a glass of beer which identifies the presence of inactive ALDH2 with a sensitivity and specificity of approximately 90%. Based on ICHD-II criteria migraine was diagnosed in 419 (75/344) subjects, and tension-type headache (TTH) in 613 (249/364). We classified the headaches of the remaining 1,545 (694/851) of headaches sufferers into the category ''other headaches (OH)''. The migraineurs drank alcohol less frequently than the subjects with TTH among current/past alcohol flushers and than the subjects with OH regardless of flushing category. No such difference in drinking frequency was observed between TTH and OH. Current/past flushers drank alcohol less frequently than never flushers, and the likelihood that male migraineurs would avoid alcohol drinking than men with TTH or OH was stronger among current/past flushers than among never flushers. Flushers and women were more susceptible to hangover than never flushers and men, respectively, regardless of headache type. Among never flushers, women with migraine were more susceptible to hangover than women with OH. The difference in alcohol sensitivity may partly explain less alcohol consumption by migraineurs. © The Author(s) 2012. Source

Hisada T.,National Defense Medical College | Ayaori M.,National Defense Medical College | Ohrui N.,Japan Air Self Defense Force Aeromedical Laboratory | Nakashima H.,National Defense Medical College | And 11 more authors.
Cardiovascular Research | Year: 2012

Aims Endothelin-1 (ET-1) contributes to the pathogenesis of cardiovascular diseases with multiple properties such as vasoconstriction. Human ET-1 gene expression is up-regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) through hypoxia response element (HRE). Although previous studies suggested that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) alter HIF-1-related gene expression, it remained unclear whether statins modulate HIF-1-mediated ET-1 expression. Therefore, we investigated the effect of fluvastatin on hypoxia-induced human ET-1 expression in vascular smooth muscle cells (VSMC).Methods and resultsHypoxia (1 O2), compared with the normoxic condition (21 O2), significantly induced the expression of preproET-1 mRNA, ET-1 protein, and ET-1 secretion in VSMC. Hypoxia induced a 2.3-fold increase in HRE-dependent ET-1 reporter gene activation. Under concentrations of 1 mol/L or greater, fluvastatin attenuated the hypoxia-induced ET-1 gene expression through the accelerated ubiquitin/proteasome-dependent degradation of HIF-1α, thus consequently attenuating HIF-1α binding to the HRE of the ET-1 gene. These inhibitory effects of fluvastatin were cancelled by concomitant treatment with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate, but not squalene. Conclusion The present study suggests that fluvastatin attenuates HIF-1-dependent ET-1 gene expression in conjunction with the stimulation of HIF-1α ubiquitin/proteasome-dependent degradation via isoprenoid-dependent mechanisms. © 2012 The Author. Source

Nakamura H.,Mitsukoshi Health and Welfare Foundation | Mizuno K.,Nippon Medical School
Lipids in Health and Disease | Year: 2014

Methods: A total of 7832 patients with mild hypercholesterolemia were randomly allocated to either the National Cholesterol Education Program step 1 diet alone (n = 3966) or the diet plus pravastatin (n = 3866) and followed for 5 years. The incidences of coronary heart disease (CHD), CHD plus cerebral infarction (CI), cardiovascular disease (CVD), and cancer were calculated using the Cox proportional hazards model according to the level of HDL cholesterol (HDL-C).Results: CHD incidence was lower in patients with HDL-C >60-90 mg/dL (-52%, p = 0.0018) and HDL-C > 90 mg/dL (-46%, p = 0.4007) than in patients with HDL-C ≤ 60 mg/dL. The incidences of CHD, CHD plus CI, and CVD were significantly lower in patients with HDL-C >60-90 mg/dL than in those with HDL-C ≤ 60 mg/dL in both diet-alone and diet-plus-pravastatin groups. Cancer incidence was not increased in patients with HDL-C >60-90 mg/dL.Background: The prognosis for hyper-high-density lipoprotein (HDL) cholesterolemic patients has not been fully elucidated. We conducted a post hoc analysis of MEGA study data to investigate prospectively the incidence of cardiovascular events and cancer in hyper-HDL cholesterolemic patients.Conclusion: Patients not receiving statin therapy should aim for a target HDL-C of between 60 and 90 mg/dL to achieve a significant reduction in CHD without the occurrence of adverse events. Trial registration. Clinical trials.gov NCT00211705. © 2014 Nakamura and Mizuno; licensee BioMed Central Ltd. Source

Teramoto T.,Teikyo University | Nakaya N.,Nakaya Clinic | Yokoyama S.,Nagoya City University | Ohashi Y.,University of Tokyo | And 2 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2010

Aims: To evaluate the relationship between low-density lipoprotein cholesterol (LDL-C) change and reduction of cardiovascular disease in the Management of Elevated cholesterol in the primary prevention Group of Adult Japanese (MEGA) study. &Methods: Patients in the diet plus pravastatin group were divided into tertiles by their on-treatment LDL-C level, and the hazard ratios (HRs) in each tertile were compared with the diet group at 5 years using the Cox proportional hazards model. In addition, the treatment groups were combined and divided into quintiles according to the on-treatment LDL-C level during follow-up, and the incidence of cardiovascular events was compared among the 5 groups. &Results: In the tertiles of the diet plus pravastatin group, HR was lowest in the second tertile against the diet group (HR 0.57, p =0.01) with on-treatment LDL-C range of 119.8-133.4 mg/dL. In the analysis of quintiles of the total population, a significant risk reduction of CVD was found in the fourth quintile (HR 0.48, p = 0.0015) with an on-treatment LDL-C range of 120.9-133.3 mg/dL, and in the fifth quintile (HR 0.64, p =0.048) with an on-treatment LDL-C range of 56.7-120.8 mg/dL against tertile 1 with an on-treatment LDL-C range of 157.5-206.2 mg/dL. &Conclusions: The usual Japanese dose of pravastatin therapy is sufficient in this low-risk patient population to reduce cardiovascular risk, with an achieved LDL-C level <133.4 mg/dL. Further risk reduction was not found with an achieved LDL <120 mg/dL. Source

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