Assessing the effects of interprofessional education by hospital pharmacists on pharmaceutical students using a self-evaluation scale

Journal of Pharmaceutical Health Care and Sciences


モンゴル国 A 病院のモンゴル人看護師のリスク感性の分析

モンゴル国 A 病院のモンゴル人看護師のリスク感性の分析


Comparison of Four Types of Airway Management Simulator in Tracheal Intubation

心肺蘇生教育に用いる気道管理シミュレータ4種類の気管挿管手技における比較

The Journal of Japanese Dental Education Association

日本歯科医学教育学会雑誌


Medical English Education in Japan: Developing a Curriculum to Motivate Students by Providing Visualizing Opportunities Using Near-peer Teaching

Despite advancements in the pedagogy of medical education in various fields, Japan has no standardized medical English education. The U.S. Medical Licensing Examination (USMLE) Study Group of Tokushima is an extracurricular activity in which medical students and recent graduates meet every 1-2 months. The aim is to stimulate students' curiosity ; cultivate their initiative, self-efficacy, and English learning goals ; and motivate them to be self-regulated learners. Accordingly, we conducted near-peer teaching style lectures that focused on sharing medical English-related experiences, so students could have regular opportunities to visualize the benefits of learning medical English. Following the activities, we observed increased motivation and self-study among students, resulting in a high USMLE passing rate. Furthermore, five members started their training at American hospitals and pursued careers in English-speaking environments. Thus, near-peer teaching style leads to shared medical English-related experiences that help students to visualize English-related opportunities. This education style taught by similar generations aids in setting a specific goal by providing access to role models, cultivating their initiative and self-efficacy, motivating them to learn English, and producing positive outcomes.Modifying the curriculum to actively create opportunities for students to visualize themselves in an international environment can motivate them to continue learning English. J. Med. Invest. 69 : 332-334, August, 2022.

The Journal of Medical Investigation : JMI


Congenital Hypogonadotropic Hypogonadism with Early-Onset Coronary Artery Disease.

The patient with congenital hypogonadotropic hypogonadism (HH) shows low serum levels of androgen, which is a group of sex hormones including testosterone, caused by the decreased gonadotropin release in the hypothalamus. Recent reports showed androgens exert protective effects against insulin resistance or atherosclerotic diseases, such as diabetes mellitus or coronary artery disease. However, whether the juvenile hypogonadism affects the diabetes or cardiovascular disease is unclear. We report a case of a middle-aged man with congenital HH who had severe coronary artery disease complicated with metabolic disorders. J. Med. Invest. 68 : 189-191, February, 2021.


【最先端医療を支える解剖学】呼吸器外科における最先端手術手技とCAL(Clinical Anatomy Laboratory)

Recently, endoscopic surgery is the most common procedurein the field of thoracic surgery. The newestthoracic surgeryapproaches are the video-assisted thoracic surgery(VATS), the one-port video-assisted thoracic surgery, and the robotic surgery. The individual advantages and disadvantages of these procedures have been discussed. VATS covers a field of view of the surgical field from the leg to the head. The basic method in performing VATS is that the surgeon operates on the abdominal area of the patient and the assistant expands the surgical field from the patient's back. It is currently the standard surgical procedure. The advantage of one-port VATS is the one port itself and its cosmetic advantages and pain reduction. The advantage of robotic surgery is that it has a clear three-dimensional enlarged field of view and can be performed using the delicate moving robotic arm. However, a good surgical training system should be established for the familiarization of these procedures. The clinical anatomy laboratory is the most efficient surgical training in addition to dry and wet lab training. Our institution has fresh-frozen cadavers, which are rare in Japan. The participating thoracic surgeons underwent training for VATS lobectomy, subxiphoid extended thymectomy, and pleurectomy decortication. This training is beneficial for educational and clinical purposes. In the future, we must obtain consistent surgical education before and after graduation using fresh-frozen cadavers. At the same time, a good organ model for training is also necessary. The surgeon has to cooperate with anatomy doctors for the development of a good surgical organ model. For the development of future surgical medicine, surgical training programs should be implemented.


教育連動型AO入試の設計と実施ーー地方国立大学における研究医の養成・確保をめざしてーー

The Journal of University Admissions Research


内視鏡手術の教育システム

内視鏡手術の教育システム

Official Journal of the Japan Association of Endocrine Surgeons and the Japanese Society of Thyroid Surgery

日本内分泌・甲状腺外科学会雑誌


Association of Decreased Docosahexaenoic Acid Level After Statin Therapy and Low Eicosapentaenoic Acid Level with In-Stent Restenosis in Patients with Acute Coronary Syndrome

It is speculated that statin therapy modulates the synthesis of polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the data available on the effects of statin therapy on the serum levels of PUFA and the subsequent impact on in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) are limited. A total of 120 ACS patients who received emergent coronary stent implantation, follow-up coronary angiography to evaluate ISR, and new statin therapy were enrolled. We measured the serum levels of the PUFA and lipids at the onset of ACS and at the follow-up coronary angiography. The follow-up coronary angiography revealed 38 ISR cases. New statin therapy significantly reduced the serum levels of DHA and low-density lipoprotein cholesterol (LDL-C), while it did not affect EPA level. Single regression analysis revealed that a decreased serum level of LDL-C was associated with decreased DHA level. The multiple logistic regression analysis revealed that the decreased DHA level after statin therapy and low serum level of EPA on admission were determinants of prevalence of ISR. Statin therapy decreased the serum level of DHA with a parallel reduction in LDL-C level in patients with ACS. Decreased DHA level after statin therapy and low EPA level on admission are risk factors for ISR, indicating that in patients with ACS, decreased serum levels of DHA may be a residual target for the prevention of ISR.

Journal of Atherosclerosis and Thrombosis


Osteolytic primary bone lymphoma in the multiple bones

Primary non-Hodgkin bone lymphoma (PBL) can involve solitary or multiple destructive bone lesions such as those of the femur or pelvis humerus, and some cases have osteolytic lesions. PBL is a rare disease in adults. Thus, PBL is rarely considered a differential diagnosis of the osteolytic tumor. In addition, PBL can be underdiagnosed because patients do not experience symptoms or show objective abnormalities in the early stage. Here, we reported an elderly patient with PBL in multiple bones, including the cranial and femoral bones that were fractured due to falling. J. Med. Invest. 66 : 347-350, August, 2019.


Lambda-like J wave due to acute myocardial infarction of the diagonal branch

The culprit lesion of acute myocardial infarction could be predicted by electrocardiogram findings. However, we experienced some cases with coronary angiographic finding in the area of ST-T elevation that was different from that predicted. The lambda-like J wave could be caused by ischemia although the mechanism has not been fully elucidated. We report a case of acute myocardial infarction that showed discrepancy between ST-T elevation with lambda-like ischemic J wave in a broad area and coronary angiographical finding of diagonal branch occlusion. J. Med. Invest. 66 : 185-187, February, 2019.


Detection and management of cardiomyopathy in female dystrophinopathy carriers

Regular health checkups for mothers of patients with Duchenne muscular dystrophy have been performed at National Hospital Organization Tokushima Hospital since 1994. Among 43 mothers participated in this study, 28 dystrophinopathy carriers were identified. Skeletal and cardiac muscle functions of these subjects were examined. High serum creatine kinase was found in 23 subjects (82.1%). Obvious muscle weakness was present in 5 (17.8%) and had progressed from 1994 to 2015. Cardiomyopathy was observed in 15 subjects (60.0%), including dilated cardiomyopathy-like damage that was more common in the left ventricular (LV) posterior wall. Late gadolinium enhancement on cardiac MRI was found in 5 of 6 subjects, suggesting fibrotic cardiac muscle. In speckle tracking echocardiography performed seven years later, global longitudinal strain was decreased in these subjects, indicating LV myocardial contractile abnormality. These results suggest that female dystrophinopathy carriers should receive regular checkups for detection and treatment of cardiomyopathy, even if they have no cardiac symptoms.


Implementation of clinical research coordinator hospital certification course to spread understanding of clinical trials

Japanese Journal of Clinical Pharmacology and Therapeutics


Edoxaban improves acute venous thromboembolism while preserving protein C and protein S levels

It is well known that warfarin inhibits the synthesis of vitamin K-dependent anticoagulants, including thrombin, protein C and S, and factor Xa, leading, paradoxically, to an initial hypercoagulable state. Edoxaban, a direct inhibitor of activated factor X is widely used for the treatment of acute venous thromboembolism (VTE). However, the effect of edoxaban on circulating coagulation factors, in patients with acute VTE, remains unknown. We enrolled 57 patients with acute VTE with/without pulmonary embolism treated with edoxaban (n=37) or warfarin (n=20) in a clinical setting. Before treatment and 2 weeks after treatment, we evaluated thrombotic burden using ultrasound or computed tomography angiography. We also evaluated thrombin generation, represented by prothrombin fragment F1+2; thrombus degradation, represented by D-dimer; and levels of anticoagulants, including protein C, protein S, and antithrombin III. Both edoxaban and warfarin treatment improved thrombotic burden and decreased prothrombin fragment F1+2, and D-dimer. Edoxaban treatment preserved protein C and protein S levels. In contrast, warfarin decreased protein C and protein S levels. Neither treatment affected antithrombin III. Edoxaban improves VTE while preserving protein C and protein S levels, thereby indicating that edoxaban improves thrombotic burden while maintaining levels of anticoagulants.


Predictors for the Treatment Effect of Sodium Glucose Co-transporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus.

Predictors for the effect of sodium glucose co-transporter 2 (SGLT2) inhibitors at lowering hemoglobin A1c (HbA1c) levels in type 2 diabetes mellitus patients remain unclear. We therefore aimed to elucidate these predictors in type 2 diabetes patients after 3 months of SGLT2 treatment. A total of 302 consecutive type 2 diabetes patients who had been treated with SGLT2 inhibitors as monotherapy or add-on therapy to existing antidiabetic treatments were enrolled retrospectively. After excluding 27 patients whose HbA1c levels could not be evaluated 3 months after treatment, the glucose-lowering effects of SGLT2 inhibitors were assessed in 275 patients by measuring HbA1c levels before and 3 months after treatment. The predictors for changes in HbA1c levels after 3 months of treatment were evaluated. SGLT2 inhibitor treatment for 3 months decreased HbA1c levels from 7.8 ± 1.2% to 7.4 ± 1.0% (p < 0.0001). A multiple regression analysis showed that the independent determinants for SGLT2 inhibitor treatment effect included decreased HbA1c levels after 1 month of treatment, high baseline HbA1c levels, and a high estimated glomerular filtration rate (eGFR). We show that type 2 diabetes patients who received the greatest glucose-lowering effect with SGLT2 inhibitor treatment were those with preserved renal function (high baseline eGFR) and high baseline HbA1c levels. Moreover, SGLT2 inhibitor treatment efficacy could be predicted by the patients' initial response to treatment.


Low Serum Levels of Eicosapentaenoic Acid and Docosahexaenoic Acid are Risk Factors for Cardiogenic Syncope in Patients with Brugada Syndrome

The n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antiarrhythmic effects, possibly via modulation of the cardiac ion channels. Nevertheless, it is unknown whether low serum levels of n-3 PUFAs are risk factors for ventricular fibrillation in patients with Brugada syndrome (BrS). We retrospectively reviewed data from 62 men with BrS and evaluated their serum levels of EPA and DHA, and the risk factors for sudden cardiac death, including a history of cardiogenic syncope. Nineteen patients had a history of cardiogenic syncope, and their EPA and DHA levels were significantly lower than those of the patients without syncope. Multivariate logistic regression analysis revealed that low EPA and DHA levels were associated with the incidence of syncope. The receiver-operator characteristic curve showed the area under the curves of EPA and DHA for history of syncope were 0.84 and 0.72, respectively. In conclusion, low levels of EPA and DHA are risk factors for cardiogenic syncope in patients with BrS, which suggests that n-3 PUFAs play important roles in preventing ventricular fibrillation in BrS.


Improved Exercise Capacity After Cardiac Rehabilitation Is Associated with Reduced Visceral Fat in Patients with Chronic Heart Failure.

Participation in a comprehensive cardiac rehabilitation (CR) program has been shown to reduce mortality and improve exercise capacity and symptoms in patients with chronic heart failure (CHF). Reduced exercise capacity leads to a concomitant reduction of skeletal muscle mass and accumulation of body fat. However, it is currently unknown whether CR reduces visceral adipose tissue (VAT) and/or subcutaneous abdominal adipose tissue (SAT) in patients with CHF. In addition, the body composition associated with improved exercise capacity after CR in patients with CHF has not been previously studied. Nineteen CHF patients who were categorized as NYHA functional class II or III and had received optimal medical treatment including a CR program for 5 months were enrolled in this study. The CR program significantly increased peak VO and reduced B-type natriuretic peptide. In addition, fat and body composition analysis showed reductions in the visceral fat tissue (VAT) area, subcutaneous abdominal adipose tissue (SAT) area, body weight, and total fat weight after CR. There were no changes in total water weight and total muscle weight. Single regression analysis revealed that the amelioration of reduced exercise capacity seen after CR is associated with reduced VAT area but not with SAT area or body weight. In conclusion, CR reduces VAT and improves exercise capacity in patients with CHF. This suggests that reducing VAT is important for CR to be most effective in the treatment of CHF.


Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus.

It is unknown whether canagliflozin, a selective sodium glucose co-transporter 2 inhibitor, reduces epicardial adipose tissue (EAT) thickness, which is associated with insulin resistance and is a risk factor for coronary artery disease. We administered 100 mg of canagliflozin for 6 months to 13 patients with type 2 diabetes mellitus. We evaluated glycemic control, visceral adipose tissue (VAT) area and subcutaneous adipose tissue (SAT) area, and skeletal muscle mass by using impedance methods, and EAT thickness by using echocardiography. Canagliflozin treatment for 6 months decreased hemoglobin A1c level from 7.1 ± 0.5% to 6.7 ± 0.6% (P < 0.05) and decreased EAT thickness from 9.3 ± 2.5 to 7.3 ± 2.0 mm (P < 0.001), along with a trend of decreasing VAT and SAT area. No association was found between any of these changes. Canagliflozin reduced EAT thickness in patients with type 2 diabetes mellitus independent of its effect on lowering blood glucose, suggesting that canagliflozin may have an effect in preventing cardiovascular events in these patients (UMIN000021327).


n-3 Polyunsaturated Fatty Acids: Promising Nutrients for Preventing Cardiovascular Disease.

The adoption of the Western-style diet, with decreased fish intake and lack of exercise, has increased the prevalence of cardiovascular disease (CVD) in Japan. Statin treatment has been established to reduce the risk of cardiovascular events; however, 60%-70% of these events occur despite its use. Thus, the residual risk for CVD should be identified and resolved to reduce further cardiovascular events. The serum levels of n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, are reportedly associated with an increased incidence of cardiovascular events and mortality, whereas the addition of n-3 PUFA treatment to the statin treatment decreases cardiovascular events. Similar to statins, n-3 PUFAs have pleiotropic effects in addition to lipid-modifying effects. Pre-clinical and clinical studies have shown that n-3 PUFAs prevent cardiovascular events by ameliorating endothelial function and attenuating lipid accumulation, vascular inflammation, and macrophage recruitment, thereby causing coronary plaque development and rupture. Taken together, n-3 PUFAs are comprehensively able to attenuate the atherogenic response. Therefore, n-3 PUFA intake is recommended to prevent cardiovascular events, particularly in patients with multiple cardiovascular risk factors.

Journal of Atherosclerosis and Thrombosis


Paget-Schroetter Syndrome in a Baseball Pitcher.

Paget-Schroetter syndrome (PSS) is thrombosis of the deep veins draining the upper extremity due to anatomic abnormalities of the thoracic outlet that cause subclavian compression and subsequent thrombosis, leading to thrombus formation in the subclavian vein. Vigorous arm activity in sports is a known risk factor. Here, we report a case of Paget-Schroetter syndrome in a 31-year-old male non-professional baseball pitcher.


Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice.

Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.

In Study 1, pitavastatin attenuated plaque formation and medial fibrosis of the aortic root with decreased macrophage infiltration in eNOS(-/-) ApoE(-/-) mice. PCR array analysis showed reductions in aortic gene expression of proatherogenic factors, including Ccl2 and Ccr2 in pitavastatin-treated double mutant mice. In addition, pitavastatin activated not only atherogenic p38MAPK and JNK but also anti-atherogenic ERK1/2 and ERK5 in the aorta of the double mutant mice. In Study 2, pitavastatin prolonged hind-limb survival after the surgery with increased BCL2-to-BAX protein ratio and inactivated JNK. Enhanced expression of anti-apoptotic genes, including Vegf, Api5, Atf5, Prdx2, and Dad1, was observed in the ischemic limb of pitavastatin-treated eNOS(-/-) mice. Furthermore, pitavastatin activated both aortic and skeletal muscle AMPK in the eNOS-deficient vascular injury models.


Response prediction and influence of tolvaptan in chronic heart failure patients considering the interaction of the renin-angiotensin-aldosterone system and arginine vasopressin.

The renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP) regulate body fluids. Although conventional diuretics have been used for treating heart failure, they activate RAAS and exacerbate renal function. Tolvaptan, a newly developed vasopressin-2 receptor antagonist, elicits aquaresis and improves volume overload in heart failure patients, however, the predictors of tolvaptan effectiveness and the influence on the RAAS and renal function according to tolvaptan therapy are not established. We evaluated 26 chronic heart failure patients receiving therapy with 15 mg/day tolvaptan and examined their laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a body weight decrease by more than 2 kg in a week and a urine volume increase by 500 mL/ day compared with that before tolvaptan administration. Body weight, urine volume, and brain natriuretic peptide levels significantly improved (P < 0.05), without any worsening of renal function represented by serum creatinine, sodium, and potassium. Moreover, no significant changes were observed in the plasma renin activity and plasma aldosterone concentration (PAC). In the responder group, urine osmolality before tolvaptan administration was significantly higher (P < 0.05) but declined significantly after tolvaptan administration (P < 0.05). The AVP/PAC ratio before administration was positively correlated with the efficacy of tolvaptan. Tolvaptan treatment could prevent RAAS activation in chronic heart failure patients. Moreover, monitoring the AVP/PAC ratio may be useful in predicting the tolvaptan response.


Factor VII Tokushima: the first case of factor VII Cys22Gly with the development of myocardial infarction in the proband receiving recombinant factor VIIa replacement therapy.

An 81-year-old man was referred to our department because of suspected factor VII (FVII) deficiency. His FVII activity was under 1%, whereas the FVII activity levels of his son and granddaughter were 65 and 109%, respectively. The nucleotide at position 3886 of his FVII gene was homozygous for G. A single T to G substitution results in the replacement of wild-type Cys at residue 22 by Gly. His son was heterozygous for G and T at position 3886, whereas his granddaughter was homozygous for wild-type T. These results suggest that he was homozygous for FVII Cys22Gly. He underwent radiofrequency ablation (RFA) for hepatocellular carcinoma, receiving 20 μg/kg of recombinant FVIIa prior to RFA and 10 μg/kg of recombinant FVIIa twice after RFA. He showed no bleeding tendency; however, a myocardial infarction was diagnosed and percutaneous coronary intervention was performed.


Reduced ratio of eicosapentaenoic acid and docosahexaenoic acid to arachidonic acid is associated with early onset of acute coronary syndrome.

BACKGROUND: The hospitalization rate for acute coronary syndrome (ACS) for people aged 50 has remained stable over the past decade. Increased serum levels of n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a decreased incidence of cardiovascular events and mortality in older patients; however, it is currently unknown whether reduced serum levels of n-3 PUFAs is also a risk factor for ACS in patients aged 50 years.METHODS AND RESULTS: We retrospectively reviewed 102 (male/ female 73/29) Japanese ACS patients whose serum levels of EPA/arachidonic acid (AA) and DHA/AA were evaluated on admission. The EPA/AA ratio was the lowest in patients aged 50 compared to patients aged 51-74 and 75. Pearson correlation analysis showed that early ACS onset was associated with low EPA/AA and DHA/AA ratios, and multiple regression analysis determined that decreased ratios of EPA/AA and DHA/AA, and male sex, current smoker status, increased body mass index and triglyceride levels, independently correlated with early ACS onset. Conversely, low-density and high-density lipoproteins, glycated hemoglobin, and hypertension did not correlate with early ACS onset. Subgroup analyses of male patients revealed that decreased ratios of EPA/AA and DHA/AA independently correlated with early ACS onset.CONCLUSION: Decreased EPA/AA and DHA/AA ratios may be risk factors for early onset of ACS, suggesting that reduced EPA/AA and DHA/AA may represent targets for preventing ACS in Japanese young people.


Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus.

BACKGROUND: Predictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors for lowering glycosylated hemoglobin (HbA1c) remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.METHODS: A total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years), who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.RESULTS: After 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P<0.01), and from 7.5%±1.3% to 6.9%±0.9% (P<0.01) respectively, without severe side effects. Multiple regression analysis showed that predictors of DPP-4 inhibitor treatment efficacy in lowering HbA1c level after 12 months were a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and the absence of coronary artery disease.CONCLUSION: Most suitable candidates for treatment with DPP-4 inhibitors are diabetics who are not obese and do not have coronary artery disease. In addition, long-term efficacy of DPP-4 inhibitors can be predicted by decrement of HbA1c after 3 months of treatment.


Transdermal patch of bisoprolol for the treatment of hypertension complicated with aortic dissection.


Effects of docosahexaenoic acid on the endothelial function in patients with coronary artery disease.

AIM: The consumption of n-3 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid DHA), reduces the incidence of cardiovascular events, and reduced serum levels of n-3 PUFA may be associated with an increased risk of cardiovascular events. However, controversy remains regarding which components of PUFA are associated with the endothelial function in patients with coronary artery disease (CAD). We therefore examined the associations between the n-3 and n-6 PUFA levels and CAD.METHODS: We retrospectively reviewed 160 consecutive Japanese patients with CAD whose endothelial function was measured according to the percent change in flow-mediated dilation (FMD) and the serum levels of n-3 PUFA, including eicosapentaenoic acid (EPA) and DHA, and n-6 PUFA, including arachidonic acid (AA) and dihomo-gamma-linolenic acid (DHLA).RESULTS: A single regression analysis showed no relationships between the FMD and the serum levels of PUFA, including EPA, DHA, AA and DHLA. In contrast, a multiple regression analysis showed that the DHA level was a positive (P0.01) and age was a negative (P0.001) contributor to an increased FMD; however, sex, body mass index, systolic and diastolic blood pressure, current/past smoking and the levels of HbA1c, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, EPA, AA and DHLA did not significantly affect the outcome.CONCLUSIONS: The serum level of DHA is associated with the endothelial function evaluated according to the FMD in patients with CAD, thus suggesting that a low serum level of DHA may be a predictive biomarker for endothelial dysfunction.


Impact of supervised cardiac rehabilitation on urinary albumin excretion in patients with cardiovascular disease.

Urinary albumin excretion is a predictor of cardiovascular death. Cardiac rehabilitation (CR) with exercise training (ET) has been shown to improve exercise capacity and prognosis in patients with cardiovascular disease (CVD). However, it remains unclear whether CR reduces urinary albumin excretion in CVD patients. We performed a retrospective, observational study using data obtained from 98 male CVD patients without macroalbuminuria and estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m(2) who participated in CR with ET during hospitalization. Twenty-three patients continued supervised ET for 6 months (supervised group) and 75 patients quit supervised ET (non-supervised group). The supervised ET program consisted of 60 minutes of supervised sessions 1-3 times a week and 30-60 minutes of home exercise at least twice a week. Urinary albumin/creatinine ratio (ACR) was significantly decreased in the supervised group at 6 months after enrollment (43 ± 71 mg/g to 17 ± 20 mg/g creatinine, P < 0.05) but not in the non-supervised group. eGFR was unchanged in the supervised group but was significantly decreased in the non-supervised group (72 ± 18 mL/minute/1.73 m(2) to 67 ± 17 mL/minute/1.73 m(2), P < 0.001). The results of multiple regression analysis showed that only supervised ET was an independent contributor to ACR. CR with supervised ET decreased urinary albumin excretion without deterioration of renal function. These findings suggest that continuation of a supervised ET program is associated with reduction in the development of CVD and reduction in cardiovascular morbidity and mortality in CVD patients.


Effect of combination tablets containing amlodipine 10 mg and irbesartan 100 mg on blood pressure and cardiovascular risk factors in patients with hypertension.

Background: Hypertension is one of the major risk factors for cardiovascular and cerebrovascular disease and mortality. Patients who receive insufficient doses of antihypertensive agents or who are poorly adherent to multidrug treatment regimens often fail to achieve adequate blood pressure (BP) control. The aim of this study was to determine the efficacy of an angiotensin II receptor blocker (ARB) and calcium channel blocker (CCB) combination tablet containing a regular dose of irbesartan (100 mg) and a high dose of amlodipine (10 mg) with regard to lowering BP and other risk factors for cardiovascular disease.Methods: We retrospectively evaluated data from 68 patients with essential hypertension whose treatment regimen was changed either from combination treatment with an independent ARB and a low-dose or regular-dose CCB or from a combination tablet of ARB and a low-dose or regular-dose CCB to a combination tablet containing amlodipine 10 mg and irbesartan 100 mg, because of incomplete BP control. Previous treatments did not include irbesartan as the ARB.Results: The combination tablet decreased systolic and diastolic BP. In addition, it significantly decreased serum uric acid, low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol levels, independent of the BP-lowering effect. Treatment with the combination tablet did not affect serum triglycerides, plasma glucose, glycated hemoglobin, serum potassium or creatinine levels, or the urinary albumin excretion rate.Conclusion: The combination tablet containing amlodipine 10 mg and irbesartan 100 mg had a greater BP-lowering effect than an ARB and a low-dose or regular-dose CCB. In addition, the combination tablet had more favorable effects on serum uric acid, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels in patients with hypertension.

Therapeutics and Clinical Risk Management


Serum concentration of eicosapentaenoic acid is associated with cognitive function in patients with coronary artery disease.

BACKGROUND: Recent studies have shown that intake of n-3 polyunsaturated fatty acids (PUFAs) is associated with reduced risk of cognitive impairment and coronary artery disease (CAD); however, it is currently unknown whether reduced serum n-3 PUFA is associated with cognitive impairment in patients with CAD.METHODS: We retrospectively evaluated cognitive function with the mini-mental state examination (MMSE), serum levels of PUFAs (including eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], dihomogammalinolenic acid [DGLA], and arachidonic acid [AA]), cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, and history of current/previous smoking), and parameters of cardiac function (left ventricular ejection fraction and brain natriuretic peptide levels) in 146 Japanese CAD patients. The associations between the MMSE scores and the other parameters were evaluated.RESULTS: Pearson correlation analysis showed that EPA (R =0.25, P <0.01), EPA/AA ratio (R =0.22, P =0.01), and left ventricular ejection fraction (R =0.15, P =0.04) were positively associated with MMSE score, and that age (R = -0.20, P <0.01) and brain natriuretic peptide levels (R = -0.28, P <0.01) were inversely associated with MMSE score. Multiple regression analysis showed that age (P <0.05) was negatively associated with MMSE score, while EPA (P <0.01) and EPA/AA ratio (P <0.05) were positively associated with MMSE score; however, sex; body mass index; left ventricular ejection fraction; levels of DHA, AA, and DGLA; DHA/AA ratio; brain natriuretic peptide; and presence of hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, and history of current/previous smoking were statistically excluded.CONCLUSIONS: Serum EPA concentration is associated with cognitive function in patients with CAD, suggesting that a low serum EPA level is a risk factor for cognitive impairment independent of cardiac function, including left ventricular ejection fraction. This correlation potentially lends further support to a role of dietary n-3 PUFAs in preventing the cognitive decline in CAD patients.


Cardiac rehabilitation reduces serum levels of oxidized low-density lipoprotein.

BACKGROUND: Oxidized low-density lipoprotein (oxLDL) levels have been found to play an important role in the progression of atherosclerosis. However, methods for effectively reducing oxLDL levels have not been established. Comprehensive cardiac rehabilitation (CR) with exercise training prevents the progression of atherosclerosis, and might reduce oxLDL levels.MethodsandResults:We measured the serum levels of malondialdehyde-modified LDL (MDA-LDL), a marker of oxLDL, in 136 patients who were enrolled in a 6-month CR program. Peak oxygen consumption (VO2) and MDA-LDL levels were analyzed, before and 6 months after enrolment. In total, 67 patients completed the CR program (CR group) and 69 patients failed to complete the program (non-CR group). Peak VO2increased significantly in the CR group (P<0.01). The levels of MDA-LDL decreased significantly in the CR group (P<0.01) but not in the non-CR group. VO2(peak VO2after CR-peak VO2before CR) was negatively associated with MDA-LDL (MDA-LDL after CR-MDA-LDL before CR) (R(2)=0.11, P=0.01). Multiple regression analysis showed that continuing CR was an independent determining factor for lowering MDA-LDL levels.CONCLUSIONS: CR decreases oxLDL levels in patients with cardiovascular diseases. Moreover, CR may prevent cardiovascular events through an antioxidative effect. (Circ J 2014; 78: 2682-2687).


Identification of Activators of ERK5 Transcriptional Activity by High-Throughput Screening and the Role of Endothelial ERK5 in Vasoprotective Effects Induced by Statins and Antimalarial Agents.

Because ERK5 inhibits endothelial inflammation and dysfunction, activating ERK5 might be a novel approach to protecting vascular endothelial cells (ECs) against various pathological conditions of the blood vessel. We have identified small molecules that protect ECs via ERK5 activation and determined their contribution to preventing cardiac allograft rejection. Using high-throughput screening, we identified certain statins and antimalarial agents including chloroquine, hydroxychloroquine, and quinacrine as strong ERK5 activators. Pitavastatin enhanced ERK5 transcriptional activity and Kruppel-like factor-2 expression in cultured human and bovine ECs, but these effects were abolished by the depletion of ERK5. Chloroquine and hydroxychloroquine upregulated ERK5 kinase activity and inhibited VCAM-1 expression in an ERK5-dependent but MAPK/ERK kinase 5- and Kruppel-like factor 2/4-independent manner. Leukocyte rolling and vascular reactivity were used to evaluate endothelial function in vivo, and we found that EC-specific ERK5 knockout (ERK5-EKO) mice exhibited increased leukocyte rolling and impaired vascular reactivity, which could not be corrected by pitavastatin. The role of endothelial ERK5 in acute cardiac allograft rejection was also examined by heterotopic grafting of the heart obtained from either wild-type or ERK5-EKO mice into allomismatched recipient mice. A robust increase in both inflammatory gene expression and CD45-positive cell infiltration into the graft was observed. These tissue rejection responses were inhibited by pitavastatin in wild-type but not ERK5-EKO hearts. Our study has identified statins and antimalarial drugs as strong ERK5 activators and shown that ERK5 activation is preventive of endothelial inflammation and dysfunction and acute allograft rejection.


Utility of lower limb positive pressure test for diagnosis of diastolic heart failure: a case report.

A 70-year-old woman with dyspnea on exertion was admitted to our hospital. She had a history of apical hypertrophic cardiomyopathy (HCM) and repeated hospitalization for heart failure. Results of physical examination were normal except for leg edema. Echocardiography showed apical HCM with preserved LV systolic function (LVEF = 70%). Although dyspnea on exertion and leg edema improved rapidly with the use of diuretics, her symptoms soon worsened when daily activity was started again. In order to examine the effect of preload on hemodynamics, we performed a lower limb positive pressure test by compressing both legs using a household air leg massager. Echocardiography showed increases in mitral E velocity, E/A ratio and pulmonary venous D flow as well as decrease in stroke volume during the lower limb positive pressure test. Simultaneously-recorded pressure study also showed elevated LVEDP and increased v wave of pulmonary capillary wedge pressure. These results suggested that even a small increase in preload led to elevation of LVEDP and symptomatic worsening due to severe diastolic heart failure in the present case. The lower limb positive pressure test may be useful for assessing the effect of preload on hemodynamics in patients with diastolic heart failure.

The Journal of Medical Investigation : JMI


Increase in serum triglyceride was associated with coronary plaque vulnerability in a patient with rheumatoid arthritis.

Rates of morbidity and mortality from cardiovascular disease are high in patients with rheumatoid arthritis (RA); however, the mechanisms and biomarkers that reflect coronary plaque vulnerability have not yet been established. We present a case of acute coronary syndrome (ACS) presumably caused by exacerbation of chronic inflammation of RA, in which an abrupt increase in serum triglyceride was seen on the day of onset of ACS but not during effort angina. This case suggests that RA patients with an abrupt increase in triglyceride need intensive care including anti-platelet and statin therapy for the prevention of coronary plaque rupture.<Learning objective: Triglyceride might be a sensitive biomarker of activated macrophages and plaque vulnerability in patients with RA. RA patients with an abrupt increase in triglyceride might need intensive care including anti-platelet and statin therapy for the prevention of coronary plaque rupture.>


High serum parathyroid hormone and calcium are risk factors for hypertension in Japanese patients.

Excess parathyroid hormone (PTH), known as primary hyperparathyroidism (pHPT), results in hypercalcemia and bone loss. Recent studies have shown that PTH is associated with the occurrence of hypertension in Western countries; however, controversy remains regarding high serum levels of PTH and calcium as risk factors for hypertension in Japanese patients. We retrospectively enrolled 114 consecutive Japanese patients who visited our hospital for examination and treatment of hypercalcemia and/or hypertension with serum calcium levels ≥ 9.8 mg/dL. To estimate the prevalence of hypertension, the patients were categorized according to calcium levels into hypercalcemic (10.2-13.4 mg/dL) and normocalcemic (9.8-10.1 mg/dL) groups, which were further categorized into high PTH (50-440 pg/mL) and low PTH (8-49 pg/mL) groups. The prevalence of hypertension was higher in patients with hypercalcemia than in patients with normocalcemia in both the high and low PTH groups. The prevalence of hypertension was higher in patients with high serum PTH levels than in patients with low serum PTH levels in both the hypercalcemic and normocalcemic groups. Logistic multiple regression analysis determined that serum calcium (P < 0.05) and PTH (P < 0.01) levels were positive contributors to hypertension. In conclusion, high serum levels of PTH and calcium are risk factors for hypertension in Japanese patients.


Efficacy and safety of Citrus sudachi peel in obese adults:A randomized, double-blind, pilot study


Congenital long QT syndrome with compound mutations in the KCNH2 gene.

Congenital long QT syndrome is a genetic disorder encompassing a family of mutations that can lead to aberrant ventricular electrical activity. We report on two brothers with long QT syndrome caused by compound mutations in the KCNH2 gene inherited from parents who had no prolonged QT interval on electrocardiography. The proband had syncope, and his elder brother suffered from ventricular fibrillation. Genetic testing revealed that both brothers had multiple mutations in the KCNH2 gene, including a missense mutation of C1474T (exon 6) as well as a frameshift/nonsense mutation, resulting from the insertion of 25 nucleotides, which caused an altered amino acid sequence beginning at codon 302 and a premature termination codon (i.e., TAG) at codon 339 (exon 4). Family genetic screening found that their father had the same frameshift mutation, and their mother and sister had the same missense mutation, in the KCNH2 gene. However, these other family members were asymptomatic, with normal QT intervals on electrocardiography. These results suggest that compound mutations in the KCNH2 gene inherited independently from the parents made the phenotypes of their sons more severe.


Support System for Women Doctors by Tokushima City Medical Association

徳島市医師会の女性医師支援事業

In recent years, an increase in the ratio of female physicians in Tokushima Prefecture, with a particularly notable rise among younger generations that has exceeded the national average, has been observed. However, these physicians continue to face severe working environments, and support measures are required for female physicians during childbirth and in the early stages of parenthood. To this end, the Tokushima City Medical Association has been involved in initiatives to support female physicians since 2008. First, we developed ``Net Joy,'' a website that provides the information necessary for female physicians to continue their clinical work through a bulletin board system that offers information on topics such as employment and childcare. Furthermore, we have administered questionnaire surveys related to working environments and support systems in clinical training hospitals and compiled a booklet entitled Support Notebook for Female Physicians that is available on the Net Joy website. Since 2011, as post-residency training in ultrasound techniques, we have held six separate practical training seminars at the Tokushima University Hospital Ultrasound Examination Center and the Tokushima City Medical Association Hall. Since 2014, we have been involved in efforts to enhance its training content and develop it into a long-term program.


ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis.

Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.


Acute pulmonary thromboembolism from deep vein thrombosis induced by trauma to the popliteal vein with a tennis racket.

Acute pulmonary thromboembolism (PTE) is mainly caused by deep vein thrombosis (DVT) and sometimes leads to a fatal outcome. Few cases of sport-related lower extremity DVT, involving direct external trauma, have been reported. A 58-year-old man, without any risk factors for thromboembolism suffered acute PTE from DVT after playing tennis. A detailed history revealed that he had hit his popliteal vein with each swing of his tennis racket and the site of the trauma, at popliteal fossa, was exactly the same as the site of the DVT formation. Therefore, the cause of DVT was suspected to be the repeated trauma to the popliteal vein. The repeated external trauma to the popliteal vein may have caused vascular endothelial damage, leading to DVT.


Association of lower limb muscle mass and energy expenditure with visceral fat mass in healthy men

A high-calorie diet and physical inactivity, an imbalance between caloric intake and energy consumption, are major causes of metabolic syndrome (MetS), which manifests as accumulation of visceral fat and insulin resistance. However, the lifestyle-related factors associated with visceral fat mass in healthy men are not fully understood. We evaluated visceral fat area (VFA), skeletal muscle mass, caloric intake, and energy expenditure in 67 healthy male participants (mean age, 36.9 ± 8.8 years; body mass index 23.4 ± 2.5 kg/m2). Multiple regression analysis showed that the total skeletal muscle mass (P < 0.001) were negatively and age (P < 0.001) were positively associated with VFA. Lower limb muscle mass (P < 0.001) was strongly associated with VFA. However, total caloric intake, total energy expenditure, and energy expenditure during exercise were not associated with VFA. Skeletal muscle mass especially lower limb muscle mass negatively contributes to visceral fat mass in healthy men. Therefore, maintaining lower limb muscular fitness through daily activity may be a useful strategy for controlling visceral obesity and metabolic syndrome.


Ghrelin protects the heart against ischemia-induced arrhythmias by preserving connexin-43 protein.

Vagal nerve stimulation has been postulated to confer an antifibrillatory effect. We studied whether ghrelin administration would exert an antiarrhythmic effect via modulation of autonomic nerve activity in rats after acute myocardial ischemia (MI). Male Sprague-Dawley rats were exposed to 30 min of ischemia following ligation of the left coronary artery. Animals were then randomized to receive either ghrelin (n = 26) or saline (n = 26) during the period of coronary ligation. Power spectral analysis of heart-rate variability revealed that the administration of ghrelin increased the high-frequency (HF) power and decreased the low-frequency (LF)/HF ratio. Ventricular tachyarrhythmias were less frequent in rats after MI who received ghrelin in comparison with rats that received saline. Immunoblotting and immunohistochemistry revealed that rats given saline alone during MI exhibited a marked reduction in phosphorylated connexin-43 within the left ventricle, whereas those that received ghrelin displayed only minor reductions in comparison with sham-operated rats. These effects of ghrelin were diminished by the coadministration of atropine or the blockade of vagal afferents. These data demonstrate that the beneficial effect of ghrelin might be mediated by modulation of cardiac autonomic nerve activity.


Renin-angiotensin-aldosterone system has a pivotal role in cognitive impairment.

Because dementia is associated with both deterioration in the quality of life and poor prognosis, the prevention of cognitive impairment (CI) is a critical problem in public health promotion. Hypertension is a risk factor for the aggravation of CI, and the renin-angiotensin-aldosterone system (RAAS) is a key player in the increased incidence and development of hypertension. Therefore, the RAAS is considered to be a promoting factor for CI development. Conversely, recent studies have shown that lowering blood pressure with RAAS inhibitors decreases the incidence of CI, dementia and cardiovascular disease. Blood-brain barrier-penetrating RAAS inhibitors appear to have advantages in preventing cognitive decline because they can suppress the RAAS in the hippocampus, which has an important role in cognition. Thus, RAAS blockage is a notable strategy for preventing CI.


Androgen receptor promotes sex-independent angiogenesis in response to ischemia and is required for activation of vascular endothelial growth factor receptor signaling.

These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.


Pharmacology of Aldosterone and the Effects of Mineralocorticoid Receptor Blockade on Cardiovascular Systems.


Serum carboxy-terminal telopeptide of type I collagen (ICTP) as a surrogate marker for vulnerable plaques in atherosclerotic patients: A pilot study.

Evaluation of atherosclerotic plaques depends on invasive intravascular ultrasonography (IVUS). Carboxy-terminal telopeptide of type I collagen (ICTP) is produced by matrix metalloproteinase (MMP)-dependent digestion of type I collagen. Because vulnerable plaques are rich in type I collagen and MMPs from macrophages, we examined the association between serum ICTP and coronary plaques in patients with coronary disease. We recruited 46 men and 17 women without renal failure or bone diseases affecting serum ICTP, who underwent coronary IVUS. Serum ICTP levels were higher in patients with coronary plaques containing more than 10% necrotic core area than in patients with less than 10% necrotic core area. A positive correlation was found between serum ICTP and necrotic core area. Only serum ICTP was positively correlated with necrotic core area by multivariate analysis (p < 0.05). These results suggest that serum ICTP can be used as a non-invasive marker of vulnerable plaques in atherosclerotic patients.


Ulcer-like projection caused by a penetrating branch to the bronchial artery.

Journal of the American College of Cardiology


Cardiac rehabilitation reduces level of oxidized LDL

心臓リハビリテーションは酸化LDLを低下させる


Heparin cofactor II, a serine protease inhibitor, promotes angiogenesis via activation of the AMP-activated protein kinase-endothelial nitric-oxide synthase signaling pathway

We previously clarified that heparin cofactor II (HCII), a serine proteinase inhibitor, exerts various protective actions on cardiovascular diseases in both experimental and clinical studies. In the present study, we aimed to clarify whether HCII participates in the regulation of angiogenesis. Male heterozygous HCII-deficient (HCII(+/-)) mice and male littermate wild-type (HCII(+/+)) mice at the age of 12-16 weeks were subjected to unilateral hindlimb ligation surgery. Laser speckle blood flow analysis showed that blood flow recovery in response to hindlimb ischemia was delayed in HCII(+/-) mice compared with that in HCII(+/+) mice. Capillary number, arteriole number, and endothelial nitric-oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and liver kinase B1 (LKB1) phosphorylation in ischemic muscles were decreased in HCII(+/-) mice. Human purified HCII (h-HCII) administration almost restored blood flow recovery, capillary density, and arteriole number as well as phosphorylation levels of eNOS, AMPK, and LKB1 in ischemic muscles of HCII(+/-) mice. Although treatment with h-HCII increased phosphorylation levels of eNOS, AMPK, and LKB1 in human aortic endothelial cells (HAECs), the h-HCII-induced eNOS phosphorylation was abolished by compound C, an AMPK inhibitor, and by AMPK siRNA. In a similar fashion, tube formation, proliferation, and migration of HAECs were also promoted by h-HCII treatment and were abrogated by pretreatment with compound C. HCII potentiates the activation of vascular endothelial cells and the promotion of angiogenesis in response to hindlimb ischemia via an AMPK-eNOS signaling pathway. These findings suggest that HCII is a novel therapeutic target for treatment of patients with peripheral circulation insufficiency.


(若手優秀演題セッション)尿中アルブミン排泄量に及ぼす心臓リハビリテーションの効果


ロスバスタチンによる脂質低下作用非依存的な形態的および機能的頸動脈硬化改善作用

ロスバスタチンによる脂質低下作用非依存的な形態的および機能的頸動脈硬化改善作用


Ezetimibe monotherapy ameliorates vascular function in patients with hypercholesterolemia through decreasing oxidative stress.

Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent. However, anti-atherogenic effects of ezetimibe have not been fully elucidated. Therefore, the objective in this study was to clarify the vascular protective effects of ezetimibe in patients with hypercholesterolemia. Ezetimibe was administered to 20 patients with hypercholesterolemia (group E), and 20 age- and sex-matched patients with hypercholesterolemia were followed as controls (group C). Difference in metabolic profiles and cardiovascular surrogate markers before ezetimibe treatment and after 12 weeks of ezetimibe treatment were statistically evaluated. Ezetimibe treatment significantly reduced serum levels of low-density lipoprotein cholesterol (LDL-C) and malondialdehyde-modified low-density lipoprotein (MDA-LDL). In addition, the values of body mass index, body weight, waist circumference, plasma HbA1c and urinary albumin were significantly decreased in group E compared to those in group C. On the other hand, high-density lipoprotein cholesterol (HDL-C) and adiponectin levels were significantly increased in group E compared to those in group C. The values of brachial-ankle pulse wave velocity (ba-PWV), mean arterial blood pressure (m-ABP), and % of flow-mediated dilation (FMD) were significantly improved in group E. Furthermore, ultrasonic studies demonstrated amelioration of the vascular stiffness of common carotid arteries in group E but not in group C. These vascular protective effects of ezetimibe were statistically correlated with the decreased values of MDA-LDL and MDA-LDL-to-LDL-C ratio but not with those of LDL-C. Ezetimibe has a lipid lowering-independent vascular protective effect in patients with hypercholesterolemia through decreasing oxidative stress.

Journal of Atherosclerosis and Thrombosis


Local persistent hypercoagulability after sirolimus-eluting stent implantation in patients with stable angina.

Late stent thrombosis (LST) after sirolimus-eluting stent (SES) implantation has been demonstrated previously. Although incomplete neointimal coverage after SES implantation has been reported, local long-term hypercoagulability remains unknown. We evaluated the local persistent coagulative response in eighty-three consecutive patients with stable angina, treated with either SES (n=51) or BMS (n=32) implantation for isolated de novo left anterior descending (LAD) stenosis. We measured prothrombin fragment F1+2 (frF1+2) and D-dimer levels sampled in the coronary sinus (CS) and sinus of Valsalva (V). The transcardiac gradient (Δ) was defined as the CS level minus V level. The ΔfrF1 + 2 and ΔD-dimer were significantly greater in the SES group than in the BMS group (0.50 ± 0.35 vs -0.14 ± 0.15 nmol/l, p=0.009 and 0.24 ± 0.21 vs -0.05 ± 0.16 μg/ml, p=0.041, respectively). We selected the hypocoagulative [ΔfrF1 + 2<0.15 (mean value-SD) nmol/l, n=21] and hypercoagulative [ΔfrF1 + 2>0.85 (mean value+SD) nmol/l, n=14] groups out of the SES patients. Multivariate analysis was performed to identify independent predictors of local hypercoagulability. Total SES length was the only independent predictor of local hypercoagulability. There was a significant positive correlation between the ΔfrF1 + 2 and total stent length in the SES group (r=0.57, p<0.05). An increased local coagulative response was observed in the convalescent phase after SES implantation as compared to BMS. Careful long-term follow-up of patients after longer SES implantation is recommended in order to avoid LST.


Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability.

Inflammation is a critical contributing factor to the development and progression of atherosclerosis. Pentraxin 3 (PTX3) is produced abundantly in atherosclerotic lesions while C-reactive protein (CRP) is mainly produced in the liver. In this study, we investigated whether plasma levels of PTX3 might be a sensitive marker both for the severity of coronary artery disease and vulnerable plaques. Next, we determined whether assays for inflammatory molecules can be used to monitor the therapeutic effects of telmisartan on stabilization of vulnerable atherosclerotic plaques. We measured PTX3 concentrations in the peripheral and coronary sinus plasma of 40 patients with angina pectoris (AP) and 20 control subjects. Next, in 28 patients with AP, we determined the correlation between levels of inflammatory molecules and the computed tomography (CT) density of plaques as a quantitative index of plaque vulnerability. There was no significant difference in peripheral plasma PTX3 concentrations between patients with AP and control subjects, while coronary sinus plasma PTX3 concentrations were significantly higher in AP patients than control subjects. The concentrations of PTX3 in coronary sinus and peripheral plasma correlated with Gensini scores as an index of severity of coronary atherosclerosis. Interestingly, there was a significantly negative correlation between plasma PTX3 concentrations and CT density (r=-0.67, p<0.01). On the other hand, CT density did not correlate with the peripheral plasma concentrations of monocyte chemoattractant protein-1 (MCP-1) or high-sensitivity CRP (hsCRP). Furthermore, telmisartan treatment for 6 months decreased plasma concentrations of PTX3 but not those of MCP-1 or hsCRP in 12 patients with essential hypertension. Multivariate regression analysis revealed that changes in PTX3 levels were independent of blood pressure changes. PTX3 is likely more specific than hsCRP as an indicator of coronary plaque vulnerability that could lead to plaque rupture.


Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue.

The purpose of this report was to assess the link between macrophage polarization in epicardial adipose tissue and atherosclerosis in patients with coronary artery disease (CAD).


Comparison of chronic-stage histopathological findings among 3 coronary stents implanted in the same patient.

A 73-year-old woman suffering from anterior thoracic pain on exertion presented to our hospital. We performed coronary angiography and noted three stenotic legions in each coronary artery. For each angiographic finding, we implanted a bare metal stent (BMS), sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) into the right coronary artery, left anterior descending and left circumflex coronary arteries, respectively. Nine months later, she died of lung disease, and we could compare the histopathological findings among the three coronary stents. In the drug-eluting stents, very thin intima, infiltration of inflammatory cells, and fibrin deposition were observed, while thick intima and no inflammatory findings were observed in the BMS. Fibrin deposition was more marked in the PES than in the SES. This report shows marked differences in the subsequent pathological course among three stents in the same patient.


Ventricular tachycardia in cardiac sarcoidosis controlled by radiofrequency catheter ablation.

We report a case of a 78-year-old woman with cardiac sarcoidosis with a history of syncope and palpitation. Further assessment with echocardiography, gadolinium-enhanced cardiovascular magnetic resonance (CMR) and histology led to a diagnosis of cardiac sarcoidosis. As the patient suffered from ventricular tachycardia (VT) despite active corticosteroid therapy, an implantable cardioverter-defibrillator (ICD) was positioned. She was also administered a beta blocker, but an electrical storm appeared every several days requiring ICD therapy. The drug-refractory VT was finally controlled with a catheter ablation session, during which we could detect the VT focus in the right ventricular outflow tract next to the aneurysm by using an electroanatomic mapping system (CARTO). Referring to echocardiographic and CMR images proved very useful in detecting the aneurysm using the CARTO system.


Serial imaging changes during treatment of Takayasu arteritis with pulmonary artery stenosis.

Most cases of chronic stenosis or occlusive lesions of the pulmonary arteries are attributed to thromboembolism, and pulmonary arteritis is extremely rare as the primary cause of these entities. We report a case of pulmonary stenosis and occlusion caused by Takayasu arteritis. The patient was a 54-year-old woman who presented with dyspnea. Total occlusion of the left pulmonary artery and significant stenosis of the right pulmonary artery caused by Takayasu arteritis were confirmed by various imaging modalities including pulmonary angiography, (18)fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging and real-time three-dimensional transesophageal echocardiography. After 6 weeks of steroid therapy, follow-up imaging studies showed that the stenotic lesion had resolved.


Acute hemodynamic effects of adaptive servo ventilation in patients with pulmonary hypertension.


Effect of low-dose (1 mg/day) pitavastatin on left ventricular diastolic function and albuminuria in patients with hyperlipidemia.

The aim of the present study was to evaluate the factors that modulate the protective action of statins on cardiorenal function, regardless of the lipid-lowering effect. To treat abnormal serum lipid profiles, low-dose pitavastatin (1.0 mg/day) was administered to 65 hyperlipidemic patients. The exclusion criteria included left ventricular ejection fraction <40% and apparent renal disease. Age- and gender-matched patients with hyperlipidemia (n = 40) served as the controls. After 12 to 16 weeks of pitavastatin treatment, pitavastatin had decreased low-density lipoprotein cholesterol (from 143.5 ± 31.4 to 98.2 ± 19.4 mg/dl, p <0.01), triglycerides (from 157.7 ± 57.2 to 140.5 ± 60.7 mg/dl, p <0.01), E/e' (from 10.8 ± 6.2 to 9.0 ± 4.5, p <0.05), a parameter of left ventricular diastolic function, and albuminuria (from 47.6 ± 55.9 to 28.5 ± 40.0 mg/g creatinine, p <0.01). Furthermore, pitavastatin decreased serum transforming growth factor-1 (from 709 ± 242 to 550 ± 299 pg/ml, p <0.01), urinary 8-hydroxy-2'-deoxyguanosine (from 6.6 ± 4.1 to 5.0 ± 3.1 g/g creatinine, p <0.01), an oxidative stress marker, and increased urinary nitrate and nitrite (from 22.5 ± 14.6 to 29.4 ± 27.6 nmol/g creatinine, p <0.05). No such changes were observed in the controls. Multiple regression analysis in the pitavastatin group revealed the effect of pitavastatin on cardiorenal function was associated with suppression of oxidative stress, but not on low-density lipoprotein cholesterol reduction. In conclusion, pitavastatin decreases E/e' and albuminuria, which is associated with suppression of oxidative stress.


Bosentan improves systemic sclerosis-related peripheral circulation insufficiency.


Enhanced inflammation in epicardial fat in patients with coronary artery disease.

It has been hypothesized that epicardial fat, a local visceral fat depot with close proximity to coronary arteries, may serve as a source of inflammatory cytokines and cells in coronary atherosclerotic lesions. Here, we characterized infiltration of inflammatory cells and expression of adipocytokines in epicardial adipose tissue in patients with and without coronary artery disease (CAD). Pare samples were obtained from epicardial and subcutaneous adipose tissue during elective cardiac surgery (CAD, n = 8; non-CAD, n = 9). Inflammatory cell infiltration was investigated by immunohistochemical staining using antibodies against CD3, CD4, CD8 and CD68. Expression of adipocytokines was evaluated by real-time quantitative reverse transcription-polymerase chain reaction. Infiltration of macrophages and CD8-positive T cells in the epicardial adipose tissue in the CAD group was greater than that in the non-CAD group. In contrast, there was no significant difference between the two groups in the number of inflammatory cells in subcutaneous adipose tissue. No statistical difference could be found between the CAD group and the non-CAD group in the expression levels of adiponectin and inflammatory cytokines in epicardial adipose tissue. Our findings suggest that inflammatory cell infiltration is enhanced in epicardial adipose tissue, but not in subcutaneous fat, in patients with coronary artery disease. Chronic inflammation in epicardial fat may influence the pathogenesis of coronary atherosclerosis.


Activation of peroxisome proliferator-activated receptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets.

Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets. The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1β or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10(5) platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia. Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.

Journal of Atherosclerosis and Thrombosis


Validation of longitudinal peak systolic strain by speckle tracking echocardiography with visual assessment and myocardial perfusion SPECT in patients with regional asynergy.

Automated function imaging (AFI) is a recently developed method of calculating the longitudinal peak systolic strains (LS) of the regional left ventricular (LV) wall using speckle tracking echocardiography and displaying them on a single bull's-eye map. The feasibility of AFI in patients with regional LV wall motion abnormalities caused by myocardial infarction (MI) was evaluated by comparison with visual assessment and myocardial perfusion single-photon emission computed tomography (SPECT). Segmental LS was measured by AFI in 60 patients with MI (67 ± 11 years) and 58 controls (71 ± 9 years). Wall thickening (WT) was measured by SPECT in 20 patients with MI. There was a strong positive linear relationship between the wall motion score index by expert visual assessment and global LS. The receiver-operating characteristic analysis revealed the best cutoff value of 11% < LS to identify hypokinetic segments. The overall accuracy of wall motion scoring by LS in the 2,006 segments was 96.8% (κ = 0.90) compared with visual assessment. The correlation coefficient between LS and WT was R² = 0.65 in the 340 segments. Assessment of LV regional asynergy by AFI showed good agreement with visual and SPECT assessments. AFI is clinically useful for quantitative assessment of LV regional wall motion abnormalities.


繰り返す心不全と維持透析導入から離脱しえた腎動脈狭窄症の一例

繰り返す心不全と維持透析導入から離脱しえた腎動脈狭窄症の一例


Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors.

Thrombin has a crucial role in cardiac remodeling through protease-activated receptor-1 activation in cardiac fibroblasts and cardiomyocytes. As heparin cofactor II (HCII) inhibits the action of tissue thrombin in the cardiovascular system, it is possible that HCII counteracts the development of cardiac remodeling. We investigated the relationships between plasma HCII activity and surrogate markers of cardiac geometry, including left atrial volume index (LAVI), relative wall thickness (RWT) and left ventricular mass index, and deceleration time (DcT) and the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) as surrogate markers of left ventricular diastolic dysfunction measured using echocardiography in 304 Japanese elderly individuals without systolic heart failure (169 men and 135 women; mean age: 65.4 ± 11.8 years). Mean plasma HCII activity in all participants was 95.8 ± 17.0% and there was no difference between the mean plasma HCII activities in males and females. Multiple regression analysis revealed that there were significant inverse relationships between plasma HCII activity and LAVI (coefficient: -0.2302, P<0.001), between HCII activity and RWT (coefficient: -0.0007, P<0.05), between HCII activity and DcT (coefficient: -0.5189, P<0.05) and between HCII activity and E/e' ratio (coefficient: -0.0558, P<0.01). Plasma HCII activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. These findings suggest that cardiac tissue thrombin inactivation by HCII is a novel therapeutic target for cardiac remodeling and atherosclerosis.


Bosentan ameliorated exercise-induced pulmonary arterial hypertension complicated with systemic sclerosis.

Pulmonary arterial hypertension (PAH) is a frequent complication in patients with systemic sclerosis. Bosentan is used in patients with symptomatic PAH; however, it has not been established whether or not bosentan ameliorates the progression of PAH in patients with no PAH-related symptoms. We present a case of systemic sclerosis with no PAH-related symptoms in which bosentan ameliorated exercise-induced PAH evaluated by 6-minute walk stress echocardiography, brachial flow-mediated dilation, and skin temperature of hands and feet. The results suggest that administration of bosentan in patients with early-stage PAH ameliorates pulmonary arterial vasodilatation through improvement of endothelial function.


High plasma aldosterone concentration is a novel risk factor of cognitive impairment in patients with hypertension.

Cognitive impairment leading to dementia is associated with high prevalence of hypertension, decreased quality of life and poor prognosis. Aldosterone is known as a risk factor for cardiovascular and cerebrovascular diseases. In addition, mineral corticoid receptors are abundantly expressed in the hippocampus, which plays a pivotal role in cognitive function; however, it has not been determined whether plasma aldosterone level is associated with cognitive impairment in patients with hypertension. We enrolled 68 patients with essential hypertension and assessed their cardiovascular risk factors, including blood pressure, hyperlipidemia, diabetes mellitus, obesity, smoking, history of cerebral infarction, renal function, parameters of inflammation, oxidative stress and nitric oxide bioavailability, a parameter of cerebral blood flow and carotid plaque by ultrasound examination, plasma renin activity and plasma aldosterone concentration (PAC). The mini-mental state examination (MMSE) was used to evaluate cognitive function. The relevance of cardiovascular risk factors and MMSE score was statistically evaluated. Multiple regression analysis showed that age (P<0.01), PAC (P<0.01) and history of cerebral infarction (P<0.05) were inversely and independently associated with MMSE score. Mineral corticoid receptor antagonists, including spironolactone and eplerenone, increased MMSE score in seven patients with hypertension, but not in the controls. In conclusion, increased PAC is associated with impaired cognitive function and mineral corticoid receptor blockade may protect against not only cardiovascular mortality, but also cognitive impairment in patients with hypertension.Hypertension Research advance online publication, 23 September 2010; doi:10.1038/hr.2010.179.


Heparin cofactor II protects against angiotensin II-induced cardiac remodeling via attenuation of oxidative stress in mice.

Heparin cofactor II (HCII), a serine protease inhibitor, inhibits tissue thrombin action after binding with dermatan sulfate proteoglycans in the extracellular matrix of the vascular system. We previously reported that heterozygous HCII-deficient (HCII(+/-)) humans and mice demonstrate acceleration of vascular remodeling, including atherosclerosis. However, the action of HCII on cardiac remodeling never has been determined. HCII(+/+) and HCII(+/-) mice at age 25 weeks were infused with angiotensin II (Ang II; 2.0 mg/kg/d) for 2 weeks by an osmotic mini-pump. Echocardiography revealed acceleration of cardiac concentric remodeling in HCII(+/-) mice and larger left atrial volume in HCII(+/-) mice than in HCII(+/+) mice. Histopathologic studies showed more prominent interstitial fibrosis in both the left atrium and left ventricle in HCII(+/-) mice than in HCII(+/+) mice. Daily urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and dihydroethidium-positive spots, indicating superoxide production in the myocardium, were markedly increased in Ang II-treated HCII(+/-) mice compared to those in HCII(+/+) mice. Cardiac gene expression levels of atrial natriuretic peptides and brain natriuretic peptides, members of the natriuretic peptide family, Nox 4, Rac-1, and p67(phox) as components of NAD(P)H oxidase, and transforming growth factor-beta1 and procollagen III were more augmented in HCII(+/-) mice than in HCII(+/+) mice. However, administration of human HCII protein attenuated all of those abnormalities in Ang II-treated HCII(+/-) mice. Moreover, human HCII protein supplementation almost abolished cardiac fibrosis in Ang II-treated HCII(+/+) mice. The results indicate that HCII has a protective role against Ang II-induced cardiac remodeling through suppression of the NAD(P)H oxidase-transforming growth factor-beta1 pathway.


View of physicians on and barriers to patient enrollment in a multicenter clinical trial: experience in a Japanese rural area

Clinical trials in the general practice setting are important for providing evidence on the effectiveness and safety of different agents under various conditions. In conducting these trials, the participation of physicians and patient recruitment are important issues. Various investigations in the literature have reported views and attitudes of physicians on various types of clinical trials. Nevertheless, there is still little information concerning physicians participating in a clinical trial and among them, those who could not recruit any patients (unsuccessful physician recruiters). In 2003, we collaborated in a large-scale multicenter study of Japanese hypertensive patients (COPE Trial). In Tokushima University Hospital and 18 other medical institutions, we investigated the views and attitudes of unsuccessful physician recruiters in comparison with successful physician recruiters, using a questionnaire. The questionnaire was provided by mail to 47 physicians and 27 (57%) responded. The response rate was 79% for successful physician recruiters compared to 43% (P = 0.014) for unsuccessful physician recruiters. More successful physician recruiters (73%) than unsuccessful physician recruiters (42%) stated they had participated and enrolled patients in previous multicenter clinical trials. A significantly higher number of successful physician recruiters than unsuccessful physician recruiters (42%; P = 0.040) considered the presence of a support system with clinical research coordinators (CRC) as the reason for participation (80%). A large number of unsuccessful physician recruiters experienced difficulty in obtaining informed consent (67%), whereas a significantly smaller number of successful physician recruiters experienced such difficulty (20%; P = 0.014). The difficulties experienced by unsuccessful physician recruiters in the trial were as follows: inability to find possible participants (100%), difficulty in obtaining informed consent (58%), cumbersome procedures (58%), difficulty in long-term follow up (33%), and insufficient tools for explanation and obtaining informed consent (8%). This survey showed that successful physician recruiters consider a support system with CRC of value, and that they are skillful in obtaining informed consent. These views and attitudes may have originated from past experience involving clinical trials. In this regard, we need to develop an infrastructure to enlighten physicians on this support system for the promotion of clinical trials.


Dehydroepiandrosterone sulfate is inversely associated with sex-dependent diverse carotid atherosclerosis regardless of endothelial function.

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. However, its biological significance in atherosclerosis remains controversial. Therefore, the aim of this study was to determine whether DHEAS is associated with development of carotid atherosclerosis in subjects with cardiovascular risk factors. SUBJECTS AND METHODS: A total of 419 Japanese individuals (208 males and 211 females) were recruited from Tokushima University Hospital, Japan. In all subjects, maximum intima-media thickness (max-IMT) in all carotid arteries, and mean-IMT and mean blood flow volume (BFV) in the common carotid arteries (CCA) were measured by ultrasonography; endothelial function was assessed by flow-mediated vasodilation of the brachial artery (%FMD). Serum DHEAS and classical cardiovascular risk factors were also evaluated. Statistical significance was determined by multiple regression analysis to elucidate independent determinants of max-IMT, mean-IMT, mean CCA-BFV, and %FMD. RESULTS: Serum DHEAS levels were higher in males than in females. Multiple regression analysis revealed that DHEAS was an independent negative factor for both max-IMT and mean-IMT in males but not in females. In contrast, DHEAS was the sole positive factor for mean CCA-BFV in females but not in males. In addition, there was no significant relationship between %FMD and DHEAS regardless of sex and other confounding factors. CONCLUSION: Although DHEAS is not involved in endothelial function, DHEAS is inversely associated with sex-dependent diverse carotid atherosclerosis such as increased max-IMT and mean-IMT in males and decreased CCA-BFV in females.


Androgen receptor counteracts Doxorubicin-induced cardiotoxicity in male mice.

Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.


Images in cardiovascular medicine. Cardiac magnetic resonance imaging and 2-dimensional speckle tracking echocardiography in secondary cardiac amyloidosis.


Congenital ventricular aneurysm as an unexpected complication of monomorphic premature ventricular contractions.

Congenital ventricular diverticulum (CVD) in adults is a rare cardiac malformation, which includes fibrous type congenital ventricular aneurysm (CVA). CVA is often clinically asymptomatic and shows no abnormality in the electrocardiogram or chest X-ray. However, some cases of sudden death resulting from ventricular tachycardia, cardiac embolism or ventricular rupture have been reported. Therefore, physicians should perform further cardiac imaging studies to detect a CVA if ventricular arrhythmia originating from the left ventricle is observed. Here, we report two successfully followed cases of CVA which were diagnosed from premature ventricular contractions.


Endothelial nitric oxide synthase-independent protective action of statin against angiotensin II-induced atrial remodeling via reduced oxidant injury.

Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation and thrombosis, especially in a condition with decreased NO bioavailability. Recently, it has been reported that statins reduce the incidence of atrial fibrillation through attenuation of atrial remodeling; however, the mechanisms have not been completely elucidated. Therefore, we aimed to clarify the beneficial effect of statin on atrial remodeling in condition with reduced NO bioavailability. Endothelial NO synthase(-/-) mice were sham operated or infused with angiotensin II (Ang II) via an osmotic minipump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: pitavastatin, Tempol (a free radical scavenger), or vehicle. Echocardiography and electrocardiography showed that Ang II infusion caused left atrial enlargement and a high incidence of atrial fibrillation, whereas pitavastatin and Tempol prevented these abnormalities. In histological analysis, Ang II-induced atrial interstitial fibrosis, perivascular fibrosis, and cardiomyocyte hypertrophy were all attenuated by pitavastatin and Tempol. Immunohistochemical staining showed that Ang II downregulated thrombomodulin and tissue factor pathway inhibitor and upregulated tissue factor and plasminogen activator inhibitor 1 in the left atrium and that pitavastatin and Tempol corrected the thrombogenic condition. Moreover, pitavastatin and Tempol reduced Ang II-induced atrial superoxide production and atrial transforming growth factor-beta1 expression and Smad 2/3 phosphorylation. Atrial rac1-GTPase activity, known to activate NADPH oxidase, was attenuated by pitavastatin but not by Tempol. In conclusion, pitavastatin exerts endothelial NO synthase-independent protective actions against Ang II-induced atrial remodeling and atrial fibrillation with enhanced thrombogenicity through suppression of oxidant injury.


Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia.

AIM: Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, has been shown to reduce the intestinal absorption of cholesterol. We investigated whether it also has beneficial effects on metabolic disorder and/or renal insufficiency in patients with hypercholesterolemia. METHODS: Ezetimibe was administered to 38 Japanese patients with hypercholesterolemia to obtain appropriate low-density lipoprotein cholesterol (LDL-chol) levels. Age- and sex-matched patients with hypercholesterolemia (n=38) were the controls. We evaluated the effects of ezetimibe before and 4 to 8 weeks after ezetimibe treatment. RESULTS: Ezetimibe significantly decreased LDL-chol levels and metabolic syndrome-related factors, including body weight, waist circumference, blood pressure; homeostasis model assessment insulin resistance (HOMA-IR), and urinary albumin excretion, were significantly reduced. In addition, it decreased the level of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-alpha, the urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and increased the urinary excretion of nitrate and nitrite (NOx). In the controls we observed no such changes. Excepting the decrease in the serum TNF-alpha level, the effects of ezetimibe were not correlated with decreased LDL-chol levels. CONCLUSION: Ezetimibe ameliorated the status of metabolic syndrome and microalbuminuria, reduced inflammation and oxidative stress, and increased nitric oxide bioavailability in a LDL-chol reduction-dependent and -independent manner.

Journal of Atherosclerosis and Thrombosis


Role of Hypoxia-Inducible Factor 1α in T Cells as a Negative Regulator in Development of Vascular Remodeling

Recent studies have shown that the cellular immune response in the development of vascular remodeling modulates the resulting pathological alterations. We show that hypoxia-inducible factor 1 (Hif-1) (specifically expressed in T cells) is involved in the immune response to vascular remodeling that accompanies arteriosclerosis. To study the role of T cells in the development of vascular remodeling, femoral arterial injury induced by an external vascular polyethylene cuff was examined in mice lacking Hif-1 (specifically in T cells). We found that cuff placement caused prominent neointimal hyperplasia of the femoral artery in Hif-1- (T-cell)-deficient mice compared with that in control mice and that infiltration of inflammatory cells at the adventitia was markedly increased in the mutant mice. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice showed enhanced production of cytokines by activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice. The results of this study revealed that Hif-1alpha in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury as a negative regulator of T cell-mediated immune response. Potential new therapeutic strategies that target Hif-1alpha are described.

Arteriosclerosis, Thrombosis, and Vascular Biology


Diagnostic utility of cardiac magnetic resonance for detection of cardiac involvement in female carriers of Duchenne muscular dystrophy.


Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice.

The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. It also reduced adipocyte size and macrophage infiltration into adipose tissue. The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation.


Synthetic prostacycline agonist, ONO-1301, ameliorates left ventricular dysfunction and cardiac fibrosis in cardiomyopathic hamsters.

Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood flow and increased collagen synthesis. Administration of growth factors was reported to attenuate left ventricular (LV) remodeling and dysfunction in animal models of dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor and vascular endothelial growth factor from various cell types and ameliorate ischemia-induced LV dysfunction in mice and pigs. We evaluated therapeutic efficacy of ONO-1301 in the Syrian hamster (TO-2), a model of genetically determined dilated cardiomyopathy. Either vehicle or a slow releasing form of ONO-1301 (ONO-1301-PLGA, 10mg/kg/3 weeks) was administered subcutaneously every 3 weeks to TO-2 hamsters from 24 to 32 weeks of age (n=12 for each group). Age-matched F1B hamsters were used as a control. Plasma concentration of HGF was elevated in ONO-1301-PLGA group (p<0.05). Echocardiographic study demonstrated that LV fractional shortening was significantly improved in the ONO-1301-PLGA group (25+/-4%, p<0.01) compared with that in the vehicle group (19+/-2%). Cardiac fibrosis was significantly reduced by ONO-1301-PLGA (p<0.05) as determined by Azan-Mallory staining. Capillary density of left ventricle was markedly reduced in TO-2 hamsters. ONO-1301-PLGA significantly increased capillary density in TO-2 group (p<0.05). ONO-1301 improved LV dysfunction and reduced cardiac fibrosis in the hamster model of dilated cardiomyopathy. ONO-1301 might hold a therapeutic potential in the treatment of dilated cardiomyopathy.


Clinical Utility of Single Beat E/e' Obtained by Simultaneous Recording of Flow and Tissue Doppler Velocities in Atrial Fibrillation with Preserved Systolic Function.

We evaluated the usefulness of the ratio of the early diastolic transmitral flow velocity (E) to the mitral annular velocity (e') calculated from simultaneously recorded E and e' in atrial fibrillation (AF). The ratio of the E to the e' (E/e') has been reported as a useful index even in AF patients. However, E and e' were measured during different beats in the previous studies. Fifty-six AF patients with preserved systolic function (mean age 66 +/- 11 years) underwent routine echocardiographic study. The E/e' was calculated from the E and e' simultaneously recorded by the dual Doppler echocardiography. A single-beat E/e' was calculated from simultaneously recorded E and e' when the preceding RR interval/pre-preceding RR interval = 1. Brain natriuretic peptide (BNP) levels were also examined. Twenty-one patients underwent simultaneous pulmonary artery catheterization. The single-beat lateral E/e' correlated with pulmonary capillary wedge pressure (PCWP) (r = 0.74, p < 0.001). The single-beat lateral E/e' of >or=11 could predict elevated PCWP (>or=15 mm Hg) with a sensitivity of 90% and a specificity of 90%. The single-beat lateral E/e' also correlated well with the log BNP concentration. The single-beat lateral E/e' of >or=9.2 predicted a plasma BNP level of >or=200 pg/ml with 88% sensitivity and 84% specificity. The single-beat lateral E/e' correlated with plasma BNP level and PCWP in AF patients with preserved systolic function. In addition, the single-beat lateral E/e' (>or=11) was a good predictor of elevated PCWP (>or=15 mm Hg). Dual Doppler echocardiography offers an advantage of providing the single-beat lateral E/e' correctly even in AF patients, for the evaluation of left ventricular diastolic function.


Local delivery of synthetic prostacycline agonist augments collateral growth and improves cardiac function in a swine chronic cardiac ischemia model.

It was reported that administration of angiogenic growth factors can augment collateral growth in ischemic tissues. It is assumed that angiogenic effects of cell transplantation may be mainly mediated by secretion of angiogenic cytokines. We tested feasibility of clinical use of ONO-1301, a synthetic small molecule that stimulates secretion of growth factors from various cell types, to treat patients with chronic myocardial ischemia. Effects of ONO-1301 on fibroblasts and endothelial cells were evaluated in vitro. We examined the efficacy of local delivery of ONO-1301 in models of rat hindlimb ischemia and swine chronic ischemic myocardium. ONO-1301 stimulated hepatocyte growth factor secretion from human fibroblasts. ONO-1301 promoted vascular-like tube formation by endothelial cells in vitro. Direct injection of a slow-release form of ONO-1301 (SR-ONO) to rat hindlimb ischemic muscle enhanced perfusion recovery. In a swine cardiac ischemia model, direct injection of SR-ONO into the ischemic myocardium significantly augmented collateral formation (SR-ONO vs. control; 1.7+/-0.2 vs. 1.0+/-0.2 Rentrop score), with improved local ventricular wall motion, reduced enlargement of left ventricular diastolic volume (49.5+/-1.9 mL vs. 59.7+/-4.2 mL) and increased cardiac index (4.2+/-0.1 vs. 3.4+/-0.2 L/min/m(2)). Histological analysis revealed that SR-ONO suppressed fibrosis in ischemic tissue (collagen volume fraction; 7.5+/-1.1% vs. 12.8+/-2.2%) and enhanced neovascularization (capillary density, 275.6 vs. 159.3/mm(2); arterioles 36.6 vs. 25.5 /mm(2)). Local delivery of SR-ONO might be effective for therapeutic angiogenesis and propose that local administration of slow-release of synthetic small molecules represents new strategy for therapeutic angiogenesis.


Heparin cofactor II is an independent protective factor against peripheral arterial disease in elderly subjects with cardiovascular risk factors.

AIM: Heparin cofactor II (HCII) specifically inactivates thrombin action at the injured vascular wall. We have reported that HCII is a protective factor against coronary in-stent restenosis and carotid atherosclerosis; however, it is unclear whether there is any correlation between plasma HCII levels and the development of peripheral arterial disease (PAD). METHODS: Plasma HCII activity and the ankle brachial pressure index (ABI) were determined in 494 elderly subjects with cardiovascular risk factors. PAD was diagnosed by ABI below 0.9, and 62 subjects were diagnosed with PAD. The relationship between factors that affect cardiovascular events and the prevalence of PAD was statistically evaluated. RESULTS: Mean HCII activity in PAD subjects was significantly lower than in non-PAD subjects (87.5+/-19.7% v.s. 94.6+/-17.8%, p=0.009). Multivariate logistic regression analysis showed that age (odds ratio [OR]: 1.062, p=0.0016), current smoking (OR 3.028, p=0.002) and diabetes mellitus (OR 2.656, p=0.008) were independent and progressive determinants of PAD. In contrast, HCII was an independent inhibitory factor of PAD (OR: 0.982, p=0.048). CONCLUSIONS: Plasma HCII activity is inversely related to the prevalence of PAD. HCII may function as the sole protective factor against PAD in elderly people with cardiovascular risk factors.


アンジオテンシンII受容体拮抗薬バルサルタンのNO bioavailability改善効果に関する臨床的検討

バルサルタンの降圧作用，動脈硬化抑制作用および糖代謝改善作用に一酸化窒素(NO)のバイオアベイラビリティの改善効果が関与しているか検討した．高血圧治療目的で通院加療中の42例を対象とした．バルサルタン投与にて，BMIやリポプロテイン(a)を含む脂質プロファイルに有意な変化は認めなかったが，収縮期血圧，脈圧，baPWVおよびHbA1cは有意に低下した．投与3ヵ月後には投与前と比較して，NOのバイオアベイラビリティのマーカーである血清硝酸/亜硝酸イオン(NOx)は約1.5倍に増加した．血清NOxの増加が，他の測定因子にどのように影響を与えているか，単変量および多変量解析を用いて解析し，血清NOxの増加量は収縮期血圧の低下と脈圧の減少との間においてそれぞれ有意な相関がみられた．また，HbA1cはバルサルタン投与3ヵ月後に有意に低下していたが，その変化はNOxの増加量と有意な相関がみられた．


Platypnea-orthodeoxia syndrome associated with patent foramen ovale and aortic ectasia.

A 59-year-old man was admitted for dyspnea on exertion and edema. The patient did not have any pulmonary diseases that could cause dyspnea. Transesophageal echocardiography on the tilting bed with contrast infusion revealed a right-to-left shunt through the patent foramen ovale. Therefore, he was diagosed as platypnea-orthodeoxia syndrome due to the patent foramen ovale. Surgical closure was done and all of his symptoms had improved.


A case of neurogenic myocardial stunning presenting transient left ventricular mid-portion ballooning simulating atypical takotsubo cardiomyopathy.

A 57-year-old female patient, who was initially suspected to have subarachnoid hemorrhage, was admitted to our hospital. She experienced severe dyspnea and chest pain owing to pneumonia on the fourth admission day. Electrocardiography showed ST-segment elevation in leads V(2) through V(5), and echocardiography revealed hypokinetic left ventricular wall motion. No stenosis was found in the coronary arteries by urgent coronary angiography. However, left ventriculography revealed that the basal and apical areas were hyperkinetic and the mid portion was akinetic. After a month, left ventricular wall motion was improved and coronary artery spasm provocation tests were negative. Although the clinical course of this patient was similar to that of neurogenic myocardial stunning, the shape of her left ventricle was not typical.


高コレステロール血症患者に対するピタバスタチンの有効性 総合的脂質プロファイルに関する検討

高コレステロール血症患者を対象にピタバスタチンを投与し，総合的脂質プロファイルへの影響について検討した．高コレステロール血症と診断され，ピタバスタチンを投与した87例を対象とした．ピタバスタチン投与によりTC，LDL-Cは有意に低下した．HDL-Cは有意な上昇，TGは有意な低下を認めた．ピタバスタチンを新規に投与した症例で，TC，LDL-Cは有意かつ良好な低下作用を認めた．また，HDL-Cは有意な上昇，TGは有意な低下作用を示した．Non HDL-Cは有意に低下し，LDL-C/HDL-C比は有意に減少した．動脈硬化指数は，いずれも有意に改善した．投与前後でLp(a)を測定した76例で，有意な変化は認めなかった．投与前後におけるALT，ASTの平均変化量に，有意な変化は認めなかった．CKも有意な変化は認めなかった．治療上，問題となる副作用は認めなかった．