Impact of combined lipid lowering and blood pressure control on coronary plaque: myocardial ischemia treated by percutaneous coronary intervention and plaque regression by lipid lowering and blood pressure controlling assessed by intravascular ultrasonography (MILLION) study.

The aim of the study was to elucidate the aggressive reduction of both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) reduced coronary atherosclerotic plaque volume compared with a standard treatment of LDL-C and BP in Japanese patients with coronary artery disease (CAD). This study is a prospective, randomized, and open-labelled with a blind-endpoint evaluation study. A total of 97 patients (81 men, mean age 62.0 ± 9.6) with CAD undergoing intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) were randomized, and 68 patients had IVUS examinations at baseline and at 18-24 months follow-up. Patients were randomly assigned to standard or aggressive strategies targeting LDL-C and a BP of 100 mg/dL and 140/90 mmHg vs. 70 mg/dL and 120/70 mmHg, respectively. The primary endpoint was the percent change in coronary plaque volume. Both standard and aggressive strategies succeeded to achieve target levels of LDL-C and BP; 74.9 ± 14.7 vs. 63.7 ± 11.9 mg/dL (NS) and 124.1 ± 9.4/75.8 ± 7.7 vs. 113.6 ± 9.6/65.8 ± 9.4 mmHg (systolic BP; NS, diastolic BP; p < 0.05), respectively. Both groups showed a significant reduction in the coronary plaque volume of -9.4 ± 10.7% and -8.7 ± 8.6% (NS) in standard and aggressive therapies, respectively. Both standard and aggressive intervention significantly regressed coronary plaque volume by the same degree, suggesting the importance of simultaneous reductions of LDL-C and BP for prevention of CAD.

Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins　- ODYSSEY JAPAN Randomized Controlled Trial.

BACKGROUND: The ODYSSEY Japan study was designed to demonstrate the reduction in low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on to existing lipid-lowering therapy in Japanese patients with heterozygous familial hypercholesterolemia (heFH) or non-FH at high cardiovascular risk who require additional pharmacological management to achieve their LDL-C treatment goal (<2.6 or <3.1 mmol/L, depending on risk category). METHODS AND RESULTS: This randomized, double-blind, parallel-group, 52-week study was conducted in Japan. Patients (n=216) with heFH, non-FH at high cardiovascular risk with coronary disease, or classified as category III were enrolled. The prespecified safety analysis was done after the last patient completed 52 weeks. Patients were randomized (2:1, alirocumab:placebo) with stratification for heFH to s.c. alirocumab (75 mg every 2 weeks [Q2 W] with increase to 150 mg if week 8 LDL-C ≥2.6/3.1 mmol/L) or placebo for 52 weeks plus stable statin therapy. At week 24, mean±SE change in LDL-C from baseline was -62.5±1.3% in the alirocumab group and 1.6±1.8% in the placebo group (difference, -64.1±2.2%; P<0.0001); the reduction was sustained to week 52 (alirocumab, -62.5±1.4%; placebo, -3.6±1.9%). No patterns were evident between treatment groups for adverse events at 52 weeks. CONCLUSIONS: In high-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab markedly reduced LDL-C vs. placebo and was well tolerated over 52 weeks. (Circ J 2016; 80: 1980-1987).

Impact of combined lipid lowering with blood pressure control on coronary plaque regression: rationale and design of MILLION study.

A line of epidemiological studies suggests that the accumulation of coronary risk factors promotes the progression of coronary atherosclerosis. Recent clinical studies showed that aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy using statins could regress coronary atheroma and reduce major cardiovascular events. Additionally, therapy that controlled amlodipine-based blood pressure reduced major cardiovascular events in patients with hypertension compared with an atenolol-based regimen. An open-label randomized multicenter study is primarily planned to evaluate the changes in coronary atheroma volume using intravascular ultrasonography 18-24 months after intensive lowering of LDL-cholesterol and blood pressure compared with a standard therapy indicated by current guidelines in Japanese patients with coronary artery disease (CAD). The secondary endpoints include changes in serum lipid levels, inflammatory markers, glucose markers and blood pressure. In total, 100 subjects with CAD who are undergoing percutaneous coronary intervention will be tested. The MILLION study will provide new evidence and therapeutic standards for the prevention of CAD in Japanese patients by controlling both LDL-C levels and blood pressure.

Large-cell Neuroendocrine Carcinoma of the Lung with Carcinoid Syndrome.

A 76-year-old woman was admitted to our hospital for refractory diarrhea with a poor antidiarrheal effect. Chest and abdominal computed tomography revealed a 24×22-mm mass in the left upper lobe of lung and multiple masses in the liver. Urine 5-Hydroxy indol acetic acid was markedly elevated. A liver biopsy revealed large-cell neuroendocrine carcinoma with serotonin production, suggestive of a lung origin, and a lung biopsy revealed combined large-cell neuroendocrine carcinoma and squamous cell carcinoma. Therefore, we made a definitive diagnosis of carcinoid syndrome caused by large-cell neuroendocrine carcinoma of the lung. Although chemotherapy was performed after diagnosis, the patient died 50 days postadmission.

A case with familial hypercholesterolemia complicated with severe systemic atherosclerosis intensively treated for more than 30 years.

We present a case of a Japanese patient with familial hypercholesterolemia (FH) caused by a low-density lipoprotein (LDL) receptor gene mutation. A 47-year-old female was referred to our hospital due to her systemic xanthomatosis associated with elevated LDL-cholesterolemia (292 mg/dl). She was diagnosed with heterozygous FH, and started to be treated with simvastatin 10 mg. During her clinical course, she underwent percutaneous coronary intervention (PCI) (at 69 years), coronary artery bypass grafting (CABG) twice (at 62 years, and 75 years), femoral popliteal bypass surgery (at 67 years), together with intensification of lipid-lowering therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. She was admitted to our hospital due to dyspnea on effort, caused by severe aortic valve stenosis as well as sick sinus syndrome at the age of 78 years. transcatheter aortic valve implantation (TAVI) using balloon expandable valve was successfully performed after DDD pacemaker implantation. She was discharged from our hospital without any symptoms. During more than 30 years of treatment period in our institute, we have introduced the latest therapeutic strategies, and treated her intensively. We are proud that we can save life even in this severe case through multiple strategies developed over the decades; however, this case clearly suggests that lipid-lowering therapies should be started much earlier in patients with FH. .

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

Limited effects of long-term enzyme replacement therapy on the cardiac conduction system in Fabry disease.

The long-term effects of enzyme replacement therapy (ERT) on cardiac function and the conduction system in Fabry disease are not clearly understood. We report a case of a 48-year-old man with non-classical Fabry disease treated with ERT for 11 years. He was diagnosed with Fabry disease at age 27 years based on the presence of decreased alpha-galactosidase A activity in the peripheral leukocytes and of the causal alpha-galactosidase A mutation (Val339Gln). Subsequently, peritoneal dialysis was initiated for renal failure at age 35 years. ERT was initiated at age 39 years to halt the progression of cardiac dysfunction. Electrical conduction disturbances progressed gradually to complete atrioventricular block with atrial standstill during 9 years of ERT despite the lack of progression of ventricular hypertrophy. Although he underwent permanent pacemaker implantation to prevent sudden cardiac death, the atrioventricular junctional rhythm remained, thereby lowering the ventricular pacing rate. Based on this case, we recognize that the effects of ERT are limited for inhibiting the progression of Fabry disease and especially for inhibiting arrhythmia and conduction disturbances. Early diagnosis of Fabry disease and early initiation of ERT might be the key to further improvements in this disease and its associated conditions. .

Acute necrotizing eosinophilic myocarditis complicated by complete atrioventricular block promptly responded to glucocorticoid therapy.

Acute myocarditis is frequently accompanied with conduction disturbances. Complete atrioventricular (AV) block may occur in acute myocarditis, but rarely in eosinophilic myocarditis. Acute necrotizing eosinophilic myocarditis, the most severe form of eosinophilic myocarditis, is generally fatal, and rarely complicated by complete AV block. We report a case of a 66-year-old woman with acute necrotizing eosinophilic myocarditis who presented with general malaise and nausea. She suddenly fell into cardiogenic shock because of complete AV block and worsened heart failure. Ultrasound cardiography revealed pericardial effusion, edematous myocardium, and reduced contractility of the left ventricle. The biopsied specimens showed marked interstitial infiltration with predominant eosinophils accompanied with myocardial necrosis. Oral administration of glucocorticoid in moderate dose promptly resolved the complete AV block, her clinical symptoms, and cardiac function. We recognized that acute necrotizing eosinophilic myocarditis can be complicated by complete AV block. Steroid therapy could be effective in the treatment of conduction disturbance as well as myocardial inflammation. .

Impact of evolocumab treatment on low-density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemic patients withdrawing from regular apheresis.

BACKGROUND AND AIMS: Low-density lipoprotein (LDL) apheresis has been used to treat refractory hyperlipidemia such as familial hypercholesterolemia (FH). Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor used in clinical settings, can reduce LDL cholesterol (LDL-C) levels by >70%. Therefore, this study aimed to assess the impact of evolocumab on withdrawal from regular LDL apheresis in patients with heterozygous FH (HeFH). METHODS: Eleven patients with HeFH undergoing biweekly LDL apheresis were enrolled and were subsequently switched to a biweekly subcutaneous injection of 140 mg of evolocumab. The primary endpoints were percent changes in mean LDL-C and apolipoprotein B (apoB) serum levels, which were averages of two different time point measurements, due to the switch in the treatment method. RESULTS: The mean LDL-C and apoB serum levels significantly reduced from 2.55 ± 0.62 mmol/L to 0.96 ± 0.40 mmol/L (-62.5%, p < 0.0001) and from 82.8 ± 12.3 mg/dL to 45.4 ± 10.9 mg/dL (-45.2%, p < 0.0001), respectively. Serum lipoprotein (a) levels also significantly reduced from 148 (116-351) mg/L to 91 (53-289) mg/L (-38.5%, p < 0.01). The reduction in LDL-C and apoB levels was not associated with the basal serum levels of PCSK9 or cholesterol production/absorption markers. Although evolocumab significantly reduced serum vitamin E levels, they were still within the normal range, and no subjective or objective side effects were observed. CONCLUSIONS: Compared to biweekly LDL apheresis, biweekly evolocumab injection therapy is less expensive, less invasive, less time-consuming, and more effective in reducing atherogenic lipoprotein levels without severe adverse side effects.

Cholesterol-years score is associated with development of senile degenerative aortic stenosis in heterozygous familial hypercholesterolemia.

We retrospectively evaluated the frequency and identified the factors associated with the development of aortic stenosis (AS) in 96 patients with heterozygous familial hypercholesterolemia (FH). The frequency of AS was 31% (4/13) and that of critical stenosis was 15% (2/13) in older patients over the age of 70 years. All 4 patients with AS were female aged more than 70 years who were diagnosed with FH when aged more than 60 years. There were no significant differences in conventional coronary risk factors; however, the age at cardiac catheterization, age at diagnosis of FH and the cholesterol-years score (CYS) with AS were significantly higher than those without AS (p=0.006, p=0.017, p=0.021, respectively). In multiple regression analysis, CYS was a significant independent predictor for the development of AS (p=0.037) in 13 older patients over the age of 70 years. These results suggest that physicians should be aware that AS needs attention in older patients with heterozygous FH, especially women who have been diagnosed late in life and those who have been inadequately treated.

Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis.

CONTEXT: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by LPL gene mutation and is characterized by severe hyperchylomicronemia. Patients with LPL deficiency suffer from the frequent recurrence of acute pancreatitis, but the underlying mechanisms are not fully understood. CASE REPORT: A 22-yr-old male Japanese patient with severe hyperchylomicronemia was admitted to our hospital in 1973. He had no consanguinity and no family history of hyperlipidemia. He was genetically diagnosed as LPL deficiency (homozygous for LPL(Arita)) with no LPL mass or activity in postheparin plasma. He has experienced recurrent acute pancreatitis 22 times during our 31-yr clinical follow-up, but no pancreatic pseudocyst, irregularity of the pancreatic duct, or abnormal pancreatic calcification was observed in computed tomography. Moreover, his pancreatic endocrine function, as assessed by the oral glucose tolerance test, has preserved more than 30 yr. Although he was a current smoker, no clinically significant atherosclerotic lesion had been observed. CONCLUSIONS: From the long-term observation of this patient, we propose that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.

Cutoff point separating affected and unaffected familial hypercholesterolemic patients validated by LDL-receptor gene mutants.

Familial hypercholesterolemia (FH) results from low-density lipoprotein (LDL) receptor gene mutations. Heterozygotes have twice normal LDL-cholesterol concentrations in early childhood, and experience early myocardial infarction. We demonstrated bimodal cholesterol frequency distributions, independently confirming existence of an identifiable hypercholesterolemic subpopulation. We assayed blood lipids in 181 FH patients genetically diagnosed and 100 unaffected relatives. Receiver operating characteristics curves were constructed. Total cholesterol and LDL-cholesterol concentrations showed bimodality. A total cholesterol cutoff of 225 mg/dl produced results agreeing with DNA testing (specificity, 98.5%; sensitivity, 99.4%). An LDL-cholesterol cutoff of 161-163 mg/dl produced 98.5% specificity and 98.3% sensitivity. Areas under curves were 0.9826 +/- 0.0058 for total cholesterol, and 0.9852 +/- 0.0043 for LDL-cholesterol. In conclusion, we define total cholesterol and LDL-cholesterol levels of 225 and 160 mg/dl, respectively, as cutoff points of normal subjects and FH patients.

Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients.

Reduction of serum cholesterol levels with statin therapy decreases the risk of coronary heart disease. Inhibition of HMG-CoA reductase by statin results in decreased synthesis of cholesterol and other products downstream of mevalonate, which may produce adverse effects in statin therapy. We studied the reductions of serum ubiquinol-10 and ubiquinone-10 levels in hypercholesterolemic patients treated with atorvastatin. Fourteen patients were treated with 10 mg/day of atorvastatin, and serum lipid, ubiquinol-10 and ubiquinone-10 levels were measured before and after 8 weeks of treatment. Serum total cholesterol and LDL-cholesterol levels decreased significantly. All patients showed definite reductions of serum ubiquinol-10 and ubiquinone-10 levels, and mean levels of serum ubiquinol-10 and ubiquinone-10 levels decreased significantly from 0.81 +/- 0.21 to 0.46 +/- 0.10 microg/ml (p < 0.0001), and from 0.10 +/- 0.06 to 0.06 +/- 0.02 microg/ml (p = 0.0008), respectively. Percent reductions of ubiquinol-10 and those of total cholesterol showed a positive correlation (r = 0.627, p = 0.0165). As atorvastatin reduces serum ubiquinol-10 as well as serum cholesterol levels in all patients, it is imperative that physicians are forewarned about the risks associated with ubiquinol-10 depletion.

Association of estrogen receptor-alpha gene polymorphisms with coronary artery disease in patients with familial hypercholesterolemia.

To investigate the association of estrogen receptor (ER)-alpha gene polymorphisms with coronary artery disease (CAD), we studied 197 men and 98 postmenopausal women with heterozygous familial hypercholesterolemia. We examined the known polymorphisms, including PvuII, XbaI, TA repeat, and CA repeat, and identified 6 novel polymorphisms in the ER-alpha gene. The distributions of -1989T/G (a novel polymorphism in promoter B) and XbaI in intron 1 were associated with CAD in postmenopausal women and in men, with a higher frequency of the G/G genotype (P=0.03) or X1/X1 genotype (P=0.02) in the CAD group. The frequency of alleles of TA repeats >17 was found to be significantly higher in postmenopausal women with CAD than in those without CAD (P=0.04), but not in men. Logistic regression analysis with all coronary risk factors as covariates showed that the G/G genotype was a higher risk for CAD (odds ratio 4.5, 95% CI 1.0 to 19.5;P=0.04) but that X1/X1 was not. We conclude that -1989T/G or its linked polymorphisms in the ER-alpha gene may confer risk for CAD and that the G/G genotype may be an independent predictor for CAD in patients with familial hypercholesterolemia.

Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism.

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the [gaaa](n) repeat ("S" denotes [gaaa](n)=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, [gaaa](n), -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the [gaaa](n) repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa](n) repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.

Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

To determine the molecular basis of familial hypercholesterolemia (FH) in Japan, 200 unrelated patients with clinically diagnosed heterozygous FH were screened for mutations in coding and promoter region of the low density lipoprotein (LDL) receptor gene using denaturing gradient-gel electrophoresis (DGGE), DNA sequencing and Southern blotting analysis. About 37 different mutations in the LDL receptor gene were identified in 125 (62.5%) of the patients, 22 of these mutations have not been described before. The most common mutations were K790X (19.5%), P664L (6.0%), FH-Tonami-1 (6.0%), IVS15-3C>A (5.5%) and FH-Tonami-2 (4.5%), whereas the other mutations were rare. No apolipoprotein B (apoB) mutations responsible for familial ligand-defective apoB-100 (FDB) were identified. Polymorphisms of apolipoprotein E (apoE) and scavenger receptor class B type I (SR-BI) were observed to have minor effects on the lipid and lipoprotein profile. In 75 (32.5%) of the FH patients, LDL receptor gene mutations could not be identified. These patients had significantly lower total cholesterol (7.71+/-1.64 vs. 8.68+/-1.47 mmol/l, P<0.001) and LDL-cholesterol (6.02+/-1.51 vs. 6.87+/-1.47 mmol/l, P<0.001) in plasma, also a lower incidence of coronary heart disease (CHD) (22 vs. 29%, P=0.05) compared with patients with a LDL receptor gene mutation, suggesting that besides LDL receptor, defect of other genes involved in LDL metabolism may be a cause of FH with a milder phenotypic expression in Japanese population.

Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia.

The clinical efficacy and safety of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor, during long-term treatment, were examined in 25 patients (male/female=11/14, mean age=53+/-13 (mean+/-SD) years) with heterozygous familial hypercholesterolemia (FH). After a period on placebo of >4 weeks, 2 mg/day of pitavastatin was administered for 8 weeks, and the dose was increased to 4 mg/day for up to 104 weeks. Total cholesterol (TC) decreased by 31% from the initial value of 340+/-57 to 237+/-40 mg/dl (P<0.0001) at week 8. During treatment with the higher dose, TC decreased even further to 212+/-35 mg/dl at week 12; it decreased by 37% from the initial value (P<0.0001). Similarly, the baseline low-density lipoprotein (LDL)-cholesterol (LDL-C) decreased by 41% at week 8, and by 49% at week 12, from 267+/-61 mg/dl at baseline. These findings indicate a dose-dependent effect of the drug on TC and LDL-C concentrations. To examine whether the levels of circulating matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases: TIMPs) are altered during lipid-lowering therapy, we also measured their plasma levels. The mean levels of MMP-2 and -3 were significantly increased. No significant alteration was found in MMP-9, TIMP-1 and -2 levels. As for the safety of pitavastatin, adverse reactions were observed in one case (4%) of subjective and objective symptoms. The effects of pitavastatin on TC and LDL-C were stable during long treatment of patients with heterozygous FH.

Clinical efficacy and safety of rosuvastatin in Japanese patients with heterozygous familial hypercholesterolemia.

Rosuvastatin is a new statin that has been shown to produce substantial dose-dependent reductions in low-density lipoprotein cholesterol (LDL-C) in Western and Japanese hypercholesterolemic patients. Rosuvastatin efficacy and safety were assessed in an open-label, dose-titration trial of 37 Japanese patients with heterozygous familial hypercholesterolemia. After an 8-week dietary lead-in period, patients received rosuvastatin on the following schedule: 10 mg/day during weeks 0-6; 20 mg/day during weeks 6-12, and 40 mg/day for weeks 12-18. Mean percentage reductions from baseline in LDL-C (49.2-56.7%), total cholesterol (39.4-45.4%), and non-high-density lipoprotein cholesterol (non-HDL-C) (46.7-54.3%) were highly significant at each dose (p < 0.0001). Similar significant reductions in triglycerides (18.2-25.0%; p < 0.006) and increases in HDL-C (9.6-13.6%; p < 0.005) were observed. Rosuvastatin was well tolerated. Two patients withdrew from the study because of adverse events unrelated to the study treatment. No patients had clinically significant elevations in liver transaminases. Two patients exhibited a single increase in creatine kinase (one unrelated to study treatment, the other possibly related) with no muscle symptoms. Rosuvastatin produced significant beneficial changes in all lipid parameters in Japanese patients with heterozygous familial hypercholesterolemia and was well tolerated.

Detailed analysis of serum lipids and lipoproteins from Japanese type III hyperlipoproteinemia with apolipoprotein E2/2 phenotype.

BACKGROUND: To clarify a detailed profile of serum lipids, lipoproteins and apolipoproteins (apo) in type III hyperlipoproteinemia (HLP) with apolipoprotein E (apo E) phenotype 2/2. METHODS: Nineteen consecutive Japanese type III HLP (9 men, 10 women) were studied. All had hypertriglyceridemia and 74% showed hypercholesterolemia. RESULTS: The degree of hyperlipidemia [total cholesterol (TC) 8.1 +/- 3.2 mmol/l, triglycerides (TG) 5.2 +/- 2.9 mmol/l] was milder than that in type III HLP in western countries. Lipoprotein fractions analyzed by ultracentrifugation showed that very low density lipoprotein cholesterol (VLDL-C) concentrations were considerably increased and that intermediate density lipoprotein cholesterol (IDL-C) concentrations were also increased, whereas low-density lipoprotein cholesterol (LDL-C) concentrations were low. Serum apo A-I, A-II and B concentrations were not increased, while apo C-II, C-III and E concentrations were considerably increased. However, the increase of apo E concentrations in the study subjects was far more pronounced than that of apo C-III, causing the ratio of apo E/C-III to be considerably higher than hyperlipidemia with other apo E phenotypes. CONCLUSION: By using this index apo E/C-III, it is possible to segregate type III HLP with apo E2/2 phenotype from other types of hyperlipidemia.