Addition of Ezetimibe to Intensive Lipid-Lowering Therapy Is Associated With a Lower Incidence of Heart Failure in Patients With Acute Coronary Syndrome.

BACKGROUND: This study investigated whether intensive lipid-lowering therapy with pitavastatin and ezetimibe lowers the incidence of heart failure (HF) events in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: In the HIJ-PROPER study, 1,734 patients with ACS were randomly assigned to either pitavastatin plus ezetimibe therapy (n=864) or pitavastatin monotherapy (n=857). We examined the incidence of HF between these 2 groups over a 3.9-year period after ACS. The primary endpoint of the study was hospitalization for HF. The mean low-density lipoprotein cholesterol levels during the follow-up period were 65.1 mg/dL in the pitavastatin plus ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. The incidence of HF hospitalization was significantly lower in the pitavastatin plus ezetimibe group than in the pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio 0.47, 95% confidence interval 0.27-0.81; P<0.005). This trend was consistent after multivariable analysis using multiple models. CONCLUSIONS: Intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

[Repeated Pericardial Effusion Leading to the Diagnosis of Synovial Sarcoma:Report of a Case].

The patient is a 76-year-old man. His chief complaint of chest pain led to a diagnosis of pericardial effusion of unknown cause, and pericardial drainage was performed. On the 30th day, chest pain appeared again. Echocardiography revealed a pericardial fluid reaccumulation and a substantial mass in the pericardial space. Surgical drainage was performed to find the cause. A hematoma/mass was present on the epicardium. The pericardial sac was filled with hematoma. The hematoma was removed, but part of the mass infiltrated close to the anterior descending branch of the left coronary artery, and removal of that part was abandoned. The intrapericardial hematoma and epicardium were submitted to pathology leading to the diagnosis of synovial sarcoma. The patient was discharged home 14 days after surgery.

Safety and Efficacy of Low-Dose Prasugrel as Part of Triple Therapy With Aspirin and Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention　- From the TWMU-AF PCI Registry.

BACKGROUND: Using the standard maintenance dose of prasugrel (10 mg/day) as part of triple therapy with aspirin and an oral anticoagulant (OAC) is not recommended in the current guidelines because it increases the risk of bleeding compared with clopidogrel. However, the safety and efficacy of low-dose prasugrel (3.75 mg/day) as part of triple therapy has not been reported. Methods and Results: We registered 816 consecutive patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) from January 2011 to June 2016 at 8 hospitals in Japan. We examined the clinical outcomes of patients who received either low-dose prasugrel (n=57) or clopidogrel (n=451) as part of triple therapy after PCI. The incidences of bleeding (TIMI major and minor) and major adverse cerebrocardiovascular events (MACCE; all-cause death, nonfatal myocardial infarction, stent thrombosis, unplanned revascularization, and stroke) were evaluated. The cumulative 1-year incidence of bleeding was not significantly different (prasugrel 5.6% vs. clopidogrel 8.1%, log-rank P=0.55). In addition, the cumulative 1-year incidence of MACCE was also not significantly different (prasugrel 11.5% vs. clopidogrel 12.3%, log-rank P=0.88). CONCLUSIONS: Low-dose prasugrel, as part of triple therapy, did not increase the risk of bleeding compared with clopidogrel. Therefore, it can be an alternative to clopidogrel for patients with AF undergoing PCI.

(E)- and (Z)-stereodefined enol phosphonates derived from ß-ketoesters: stereocomplementary synthesis of fully-substituted α,ß-unsaturated esters.

A versatile, robust, and stereocomplementary synthesis of fully-substituted (E)- and (Z)-stereodefined α,ß-unsaturated esters 3 from accessible α-substituted ß-ketoesters 1via (E)- and (Z)-enol phosphonates was achieved. The present method involves two accessible reaction sequences: (i) (E)- and (Z)-stereocomplementary enol phosphorylations of a wide variety of ß-ketoesters 1 (24 examples; 71­99% yield, each >95: 5 ds), and (ii) (E)- and (Z)-stereoretentive Suzuki­Miyaura cross-coupling (16 examples; 71­91% yield, >81/19 ds) and Negishi cross-coupling (32 examples; 65­96% yield, >95 : 5 ds) using (E)- and (Z)-enol phosphonates 2. 1H-NMR monitoring for a key reactive N-phosphorylammonium (imidazolium) intermediate I and an application in the synthesis of both (E)- and (Z)-tamoxifen precursors 6 are described.

Impact of myocardial reperfusion status on QT dispersion after successful recanalization of the infarct-related artery in acute myocardial infarction.

OBJECTIVE: To determine whether adequate myocardial perfusion status after transluminal recanalization is associated with prompt improvement of QT dispersion (QTd). BACKGROUND: Transluminal recanalization of the infarct-related coronary artery in acute myocardial infarction aims to promptly restore myocardial perfusion, to maximize electrical and mechanical recovery. QTd represents the heterogeneity of ventricular repolarization, which may affect electrical stability. METHODS: Forty patients who underwent primary percutaneous coronary intervention for their first anterior acute ST-elevation myocardial infarction were prospectively enrolled. Myocardial reperfusion status was assessed by myocardial blush grade (MBG) on the final angiogram after successful recanalization (Thrombolysis In Myocardial Infarction Grade 3 flow). RESULTS: Preprocedural QTd was similar in patients with final MBG 0-1, 2, and 3 (76 ± 24, 67 ± 13, and 69 ± 13 milliseconds, respectively; P = 0.661). After recanalization, QTd decreased in patients with MBG 3 (39 ± 16 milliseconds, P < 0.001) but not in patients with MBG 0-1 (74 ± 20 milliseconds) or MBG 2 (82 ± 16 milliseconds). Multivariate analysis showed that postprocedural MBG was an independent predictor of QTd after recanalization (standardized regression coefficient = -0.628, P < 0.001). CONCLUSIONS: Adequate tissue perfusion may be crucial for electrical stability of the myocardium after reperfusion.

Clinical and computed tomographic evaluation of safety and efficacy of facet screw fixation in the subaxial cervical spine.

DESIGN: A retrospective study comparing screw positioning and associated complications between 2 different facet screw placement methods. OBJECTIVE: To review the anatomic location, clinical safety, efficacy, and limitations of 2 facet screw placement techniques. BACKGROUND: Facet screw fixation in the subaxial cervical spine penetrates 4 cortical layers and affords better stability than lateral mass screws. Takayasu and colleagues recommended placing screws in the sagittal plane. We modified the trajectory to direct the screws laterally from the sagittal plane to place the root at less risk and improve fixation by increasing the excursion of the screws into bone. No clinical reports exist describing the quadricortical facet screw placed in a lateral direction. METHODS: A total of 95 screws were used in 18 consecutive patients who underwent posterior cervical stabilization for various spinal disorders: 34 screws used sagittal plane screw placement and 61 used our technique. Screw-related complications were reviewed. Screw trajectories and screw tip positions related to the ventral cortical margin and vertebral artery were evaluated using postoperative 3-dimensional computed tomograms taken within 6 months after surgery. Instrumentation failures were evaluated from postoperative 3-dimensional computed tomograms taken 2 years after surgery. RESULTS: There was 1 complication, nerve root irritation due to screw malposition. Postoperative computed tomographic images revealed that drilling was 30 degrees lateral from the sagittal plane in our method. Fourth cortex penetration failed in 29% of the screws placed in the sagittal plane and in 5% by our method. Screw loosening was significantly increased using screws placed in the sagittal plane (24% vs. 2%). CONCLUSIONS: Quadricortical facet screw placement aimed at the juncture between the transverse process and the facet is practicable. Screw loosening was significantly reduced using this lateral screw direction. One of the disadvantages of this technique is that extensive cranial exposure is required to align the instruments in the proper sagittal trajectory.

Effect of ultrasonic frequency and surfactant addition on microcapsule destruction.

In a previous study, we found that cavitation bubbles cause the ultrasonic destruction of microcapsules containing oil in a shell made of melamine resin. The cavitation bubbles can be smaller or larger than the resonance size; smaller bubbles cause Rayleigh contraction, whereas larger bubbles are not involved in the sonochemical reaction. The activity in and around the bubble (e.g., shear stress, shock wave, microjet, sonochemical reaction, and sonoluminescence) varies substantially depending on the bubble size. In this study, we investigated the mechanism of the ultrasonic destruction of microcapsules by examining the correlations between frequency and microcapsule destruction rate and between microcapsule size and cavitation bubble size. We evaluated the bubbles using multibubble sonoluminescence and the bubble size was changed by adding a surfactant to the microcapsule suspension. The microcapsule destruction was frequency dependent. The main cause of microcapsule destruction was identified as mechanical resonance, although the relationship between bubble size and microcapsule size suggested that bubbles smaller than or equal to the microcapsule size may also destroy microcapsules by applying shear stress locally.

Divergent Synthetic Access to E- and Z-Stereodefined All-Carbon-Substituted Olefin Scaffolds: Application to Parallel Synthesis of (E)- and (Z)-Tamoxifens.

A highly substrate-general synthesis of all-carbon-substituted E- and Z-stereodefined olefins is performed. The method comprises two sets of parallel and stereocomplementary preparations of (E)- and (Z)-α,ß-unsaturated esters involving two robust and distinctive reactions: 1) stereocomplementary enol tosylations using readily available TsCl/diamine/(LiCl) base reagents, and 2) stereoretentive Negishi cross-coupling using the catalysts [Pd(dppe)Cl2] (for E) and [Pd(dppb)Cl2] (for Z). The present parallel approach is categorized as both type I (convergent approach: 16 examples, 56-87 % yield) and type II (divergent approach: 18 examples, 70-95 % yield). The obtained (E)- and (Z)-α,ß-unsaturated ester scaffolds are successfully transformed into various E- and Z-stereodefined known and novel olefins (8×2 derivatization arrays). As a demonstration, application to the parallel synthesis of both (E)- and (Z)-tamoxifens, a representative motif of all-carbon-substituted olefins, is accomplished in a total of eight steps with an overall yield of 58 % (average 93 %) and 57 % (average 93 %), respectively.

A case of osteochondroma of the atlas causing obstructive sleep apnea syndrome.

Most osteochondromas affect the long bones, but rarely originate in the spine. We report an extremely rare case of osteochondroma of the atlas causing obstructive sleep apnea syndrome (OSAS) in a 61-year-old female. The osteochondroma was removed completely using a transoral approach, and the symptoms of OSAS disappeared. A review of the literature regarding osteochondroma confirms the rarity of this lesion and the use of a transoral approach is discussed.

Why Can dl-Sotalol Prolong the QT Interval In Vivo Despite Its Weak Inhibitory Effect on hERG K(+) Channels In Vitro? Electrophysiological and Pharmacokinetic Analysis with the Halothane-Anesthetized Guinea Pig Model.

In order to bridge the gap of action of dl-sotalol between the human ether-a-go-go-related gene (hERG) K(+) channel inhibition in vitro and QT-interval prolongation in vivo, its electropharmacological effect and pharmacokinetic property were simultaneously studied in comparison with those of 10 drugs having potential to prolong the QT interval (positive drugs: bepridil, haloperidol, dl-sotalol, terfenadine, thioridazine, moxifloxacin, pimozide, sparfloxacin, diphenhydramine, imipramine and ketoconazole) and four drugs lacking such property (negative drugs: enalapril, phenytoin, propranolol or verapamil) with the halothane-anesthetized guinea pig model. A dose of each drug that caused 10 % prolongation of Fridericia-corrected QT interval (QTcF) was calculated, which was compared with respective known hERG K(+) IC50 value and currently obtained heart/plasma concentration ratio. Each positive drug prolonged the QTcF in a dose-related manner, whereas such effect was not observed by the negative drugs. Drugs with more potent hERG K(+) channel inhibition showed higher heart/plasma concentration ratio, resulting in more potent QTcF prolongation in vivo. The potency of dl-sotalol for QTcF prolongation was flat middle, although its hERG K(+) channel inhibitory property as well as heart/plasma concentration ratio was the smallest among the positive drugs, which may be partly explained by its lack of binding to plasma protein.

Effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 on the left ventricular pressure-volume relationship in the halothane-anesthetized dogs.

Cardiac effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 were assessed in the halothane-anesthetized dogs under the monitoring of left ventricular pressure-volume relationship, which were compared with those of clinically recommended doses of dopamine, dobutamine and milrinone (n=4-5 for each treatment). ONO-AE1-329 was intravenously administered in doses of 0.3, 1 and 3 ng/kg/min for 10 min with a pause of 20 min. Dopamine in a dose of 3 µg/kg/min for 10 min, dobutamine in a dose of 1 µg/kg/min for 10 min and milrinone in a dose of 5 µg/kg/min for 10 min followed by 0.5 µg/kg/min for 10 min were intravenously administered. Low dose of ONO-AE1-329 increased the stroke volume. Middle dose of ONO-AE1-329 increased the cardiac output, left ventricular end-diastolic volume, ejection fraction, maximum upstroke/downstroke velocities of the left ventricular pressure and external work, but decreased the end-systolic pressure and internal work besides the change by the low dose. High dose of ONO-AE1-329 increased the heart rate and maximum elastance, but decreased the end-systolic volume besides the changes by the middle dose. Dopamine, dobutamine and milrinone exerted essentially similar cardiac effects to ONO-AE1-329, but they did not significantly change the end-diastolic volume, end-systolic volume, stroke volume, ejection fraction, end-systolic pressure, maximum elastance, external work or internal work. Thus, EP4-receptor stimulation by ONO-AE1-329 may have potential to better promote the passive ventricular filling than the conventional cardiotonic drugs, which could become a candidate of novel therapeutic strategy for the treatment of heart failure with preserved ejection fraction.

Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO--AE1--329 in the halothane-anesthetized dogs.

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.

A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure.

Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.

Industry meets theory: computational R & D for innovative products.

We introduce our activities for applications of first-principles theoretical calculations to various research and development processes for innovative electronic products. We present our recent selected results for four kinds of materials, which are the rare-earth element doped ceramic dielectric material BaTiO(3), BaTiO(3) ceramic nanoclusters and alkali-metal Li storage materials, i.e., graphite and sulfide Li(x)FeS(2).

Telmisartan induces proliferation of human endothelial progenitor cells via PPARgamma-dependent PI3K/Akt pathway.

OBJECTIVE: Although recent clinical trials have suggested that angiotensin II type 1 receptor blockers (ARBs) reduced cardiovascular events, the precise mechanisms involved are still unknown. Telmisartan, an ARB, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other hand, since endothelial progenitor cells (EPCs) are thought to play a critical role in ischemic diseases, we investigated effects of telmisartan on proliferation of EPCs. METHODS AND RESULTS: Human peripheral blood mononuclear cells were isolated from healthy volunteers, and cultured on fibronectin-coated dishes in the presence or absence of telmisartan. Four days after starting culture, adherent cells were collected, and equal numbers of cells were reseeded into methylcellulose medium with or without telmisartan. In the presence of telmisartan, numbers of colonies increased in a dose-dependent manner. DiI-AcLDL uptake and lectin and CD31, CD34 staining revealed that these colonies were EPCs. Increase in colony number by treatment with telmisartan was absolutely inhibited when cultured with a specific inhibitor of PPARgamma. In addition, we observed that specific inhibitors of phosphoinositide-3 kinase (PI3K) abolished telmisartan-stimulated increase of monocytic EPC-like cells and telmisartan induced phosphorylation of Akt. Furthermore, mRNA expression of p21 was downregulated in a dose dependent manner, suggesting that growth inductive effects of telmisartan might be regulated by the PI3K/Akt and p21 signaling pathway. CONCLUSIONS: These findings suggest that telmisartan might contribute to endothelial integrity and vasculogenesis in ischemic regions by increasing numbers of EPCs.

Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice.

Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1-positive (Sca-1-positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.