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.

Effects of pitavastatin on walking capacity and CD34+/133+ cell number in patients with peripheral artery disease.

This multi-center prospective non-randomized comparative study investigated the effects of pitavastatin in patients with peripheral artery disease (PAD) in terms of exercise tolerance capacities and peripheral CD34+/133+ cell numbers. At baseline, a peripheral blood test was administered to 75 patients with PAD, along with a treadmill exercise test using the Skinner-Gardner protocol to measure asymptomatic walking distance (AWD) and maximum walking distance (MWD). Each patient was assigned to a 6-month pitavastatin treatment group (n = 53) or a control group (n = 22), according to the patient's preference. The tests were repeated in both groups at 3 and 6 months. Baseline AWD and MWD correlated positively with the ankle-brachial pressure index (r = 0.342, p = 0.0032 and r = 0.324, p = 0.0054, respectively). Both AWD and MWD values improved at 3 and 6 months compared with baseline, and the degrees of their improvement were higher in the pitavastatin treatment group. CD34+/133+ cell numbers did not change over time or between groups. Eighty-seven percent of patients in the treatment group attained low-density lipoprotein cholesterol levels below 100 mg/dL after 3 months. The study shows that pitavastatin may be effective in increasing exercise tolerance capacity in patients with PAD.

IL-1 receptor accessory protein-Ig/IL-1 receptor type II-Ig heterodimer inhibits IL-1 response more strongly than other IL-1 blocking biopharmaceutical agents.

INTRODUCTION: Interleukin (IL)-1 is a key orchestrator of inflammation and IL-1 inhibitors are expected to be promising pharmaceutical agents for such pathologies. IL-1 is bound to the complex of two receptor components with much higher affinity than with either receptor component alone. MATERIALS AND METHODS: We examined the effect of a heterodimer of IL-1 receptor accessory protein (Acp)-immunoglobulin (Ig) and IL-1R type II (IL1R2)-Ig named AcP-Ig/IL1R2-Ig heterodimer, and compared its effects with other IL-1 inhibitors reported previously. RESULTS AND DISCUSSION: Our results demonstrated that the rat AcP-Ig/IL1R2-Ig heterodimer (IC50=1.95 pM) inhibited IL-1 response to a greater extent than IL1RA (IC50=1,935 pM), Acp-IL1R type I (IL1R1)-Ig homodimer (IC50=73.7 pM) and Acp-IL1R2-Ig homodimer (IC50=72.8 pM). Moreover, human AcP-Ig/IL1R2-Ig heterodimer (IC50=0.14 pM) inhibited it to a greater extent than Acp-IL1R1-Ig homodimer (IC50=4.48 pM) and strongly inhibited responses of both IL-1α and IL-1ß. CONCLUSIONS: The AcP-Ig/IL1R2-Ig heterodimer, which is similar to the original extracellular structure of the Acp/IL1R1 complex, may inhibit the IL-1 response more vigorously than other IL-1 blocking biopharmaceutical agents.

Clinical and angiographic outcomes with sirolimus-eluting stent for coronary bifurcation lesions. The J-PMS study.

BACKGROUND: Long-term outcomes of patients with bifurcated lesions and the restenotic response of the side branches after sirolimus-eluting stent (SES) implantation, comparing 1-stent with 2-stent treatment, are still under discussion. METHODS AND RESULTS: Japan Post-Marketing Surveillance Registry (J-PMS) is a prospective registry designed to evaluate the safety and efficacy of the SES in routine clinical practice. Angiograms of 1,063 patients with 1,250 lesions were analyzed at the independent core lab. Of these, 324 patients with bifurcation lesions were enrolled. Clinical endpoints were assessed at 3 years. Both main and side branches were evaluated by quantitative coronary angiography at post-procedure (n=349) and 8-month follow up (n=293). Two-stent treatment was performed in 12% of the cases. In-segment restenosis rates at 8 months were 25.6% in the side branch, but newly developed restenosis was seen in only 6.8%. Late loss at the carina of the side branch was -0.11mm in the 1-stent group. Major adverse cardiovascular events rate was 18.3% at 3 years. Target-lesion revascularization rate up to 3 years was 21.6% in the 2-stent group and 8.7% in the 1-stent group (P=0.037). Stent thrombosis occurred in 6 cases (2.0%) until 3 years. Of these, 4 cases were treated with 2-stent (10.81% vs. 0.76% in 1-stent, P=0.003, respectively). CONCLUSIONS: In a real-world setting, treatment of coronary bifurcation lesions using SES demonstrated favorable long-term outcomes as long as the side branch was not stented.

Lipocalin-2/neutrophil gelatinase-B associated lipocalin is strongly induced in hearts of rats with autoimmune myocarditis and in human myocarditis.

BACKGROUND: Lipocalin-2/neutrophil gelatinase-B associated lipocalin (Lcn2/NGAL) is involved in the transport of iron and seems to play an important role in inflammation. A recent study has reported that it is also expressed in the failing heart and may be a biomarker not only for renal failure but also for heart failure. Because Lcn2/NGAL is thought to be induced by interleukin-1, it might be strongly induced in the presence of myocarditis. METHODS AND RESULTS: This study investigated the expression of Lcn2/NGAL in rat experimental autoimmune myocarditis (EAM) and in human myocarditis. In EAM hearts, the expression of Lcn2/NGAL was markedly increased (>100-fold at an early stage), and in human myocarditis it was also highly expressed compared with non-inflammatory failing hearts. Lcn2/NGAL expressing cells in hearts with EAM and human myocarditis were identified as cardiomyocytes, vascular wall cells, fibroblasts and neutrophils. Lcn2/NGAL in EAM rats was also expressed in the liver. Plasma Lcn2/NGAL levels abruptly increased at an early stage of EAM, and high levels were initially sustained during the inflammatory stage, then decreased with recovery. In contrast, levels of B-type natriuretic peptide increased only slowly as the disease progressed. CONCLUSIONS: Cardiomyocytes, vascular wall cells and fibroblasts in myocarditis strongly express Lcn2/NGAL via proinflammatory cytokines.

Effect of Aggressive Lipid-Lowering Therapy in Single-Vessel vs. Multivessel Coronary Artery Disease Patients With Acute Coronary Syndrome　- Heart Institute of Japan-Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome (HIJ-PROPER) Substudy.

Background: The effects of aggressive lipid-lowering therapy according to the number of diseased coronary arteries in acute coronary syndrome (ACS) are still controversial. This study investigated the efficacy of this therapy in ACS patients with multivessel disease (MVD) and single-vessel disease (SVD). Methods and Results: The subjects were derived from the HIJ-PROPER study, in which ACS patients with dyslipidemia were randomized to receive either pitavastatin+ezetimibe (targeting low-density lipoprotein cholesterol [LDL-C] <70 mg/dL) or pitavastatin monotherapy (targeting LDL-C <90 mg/dL). In this study, treatment efficacy was compared between patients with MVD and SVD. The primary endpoint was a composite of major advanced cardiovascular events (MACE; all-cause death, non-fatal myocardial infarction, non-fatal stroke, and ischemia-driven revascularization). We identified 1,702 eligible patients (MVD, n=869; SVD, n=833; mean age, 65.6 years; male, 75.6%; acute revascularization, 96.2%). MACE incidence was significantly higher in the MVD group than in the SVD group (43.7% vs. 25.9%, HR, 1.95; 95% CI: 1.65-2.31, P<0.001). In the SVD group, pitavastatin+ezetimibe had significantly fewer MACE than pitavastatin monotherapy (34.6% vs. 47.4%, HR, 0.72; 95% CI: 0.55-0.94, P=0.02). Conclusions: The benefits of aggressive lipid-lowering therapy, with the addition of ezetimibe to statins, were enhanced in ACS patients with SVD, but not with MVD, in the early invasive strategy era.

Clinical characteristics of hospitalized heart failure patients with preserved, mid-range, and reduced ejection fractions in Japan.

AIMS: There are regional differences in the patient characteristics, management, and outcomes of hospitalized patients with heart failure (HF). The aim of this study was to evaluate the clinical characteristics and outcomes of Japanese patients who are hospitalized with HF on the basis of the left ventricular ejection fraction (LVEF) stratum. METHODS AND RESULTS: We retrospectively conducted a multicentre cohort study of 1245 hospitalized patients with decompensated HF between 2013 and 2014. Of these patients, 36% had an LVEF < 40% [HF with reduced ejection fraction (HFrEF), median age 72 years, 71% male], 21% had an LVEF 40-49% [HF with mid-range EF (HFmrEF), 77 years, 56% male], and 43% had an LVEF ≥ 50% [HF with preserved EF (HFpEF), 81 years, 44% male]. The primary outcome was death from any cause, and the secondary outcomes were cardiac death and re-hospitalization due to worsened HF after hospital discharge. There were high proportions of non-ischaemic cardiomyopathy (32%) in HFrEF patients, coronary artery disease (44%) in HFmrEF patients, and valvular disease (39%) in HFpEF patients. The frequencies of intravenous diuretic and natriuretic peptide administration during hospitalization were 66% and 30%, respectively. The median hospital stay for the overall population was 19 days, and the length of stay was >7 days for >90% of patients. In-hospital mortality was 7%, but was not different among the LVEF groups (HFrEF 7%, HFmrEF 6%, and HFpEF 8%). After a median follow-up of 19 months (range, 3-26 months), 192 (17%) of the 1156 patients who were discharged alive died, and 534 (46%) were re-hospitalized after hospital discharge. There were no significant differences in mortality after hospital discharge among the three LVEF groups (HFrEF 18%, HFmrEF 16%, and HFpEF 16%). There were no differences in cardiac death or re-hospitalization due to worsened HF after hospital discharge among the LVEF groups (cardiac death: HFrEF 8%, HFmrEF 7%, and HFpEF 7%; re-hospitalization due to worsened HF: HFrEF 19%, HFmrEF 16%, and HFpEF 17%). Multivariable-adjusted analyses showed that the HFmrEF and HFrEF groups, compared with the HFpEF group, were not associated with an increased risk for in-hospital death or death after hospital discharge. Non-cardiac causes of death and re-hospitalization after hospital discharge accounted for 35% and 38%, respectively. CONCLUSIONS: Our results revealed different clinical characteristics but similar mortality rates in the HFrEF, HFmrEF, and HFpEF groups. The most common cause of death and re-hospitalization after hospital discharge was HF, but non-cardiac causes also contributed to their prognosis. Integrated management approaches will be required for HF patients.

Free heme is a danger signal inducing expression of proinflammatory proteins in cultured cells derived from normal rat hearts.

Endogenous molecules from damaged tissue act as danger signals to trigger or amplify the immune/inflammatory response. In this study, we examined whether free heme induced pro-inflammatory proteins in cultured cells derived from normal hearts and investigated the cells targeted by heme, together with its mechanism of action in these cells. We cultured collagenase-isolated heart-derived cells from normal rats and examined whether free heme induced pro-inflammatory proteins, reactive oxygen species (ROS) production and NF-κB activation, by quantitative RT-PCR, ELISA and flow cytometry. Free heme increased mRNA of various pro-inflammatory proteins in cultured cardiac resident cells (CCRC) (at least 100-fold) and induced intracellular ROS formation. Approximately 85-90% of CCRC are fibroblast/smooth muscle cells and 10-15% are CD11bc-positive macrophages; therefore to examine individual target cells, macrophage-deleted (CD11bc-negative) CCRC, primary cultured cells (cardiac fibroblasts, arterial smooth muscle cells and cardiac microvascular endothelial cells) and macrophage cells lines (NR8383) were similarly treated. Free heme activated NF-κB and induced expression of some pro-inflammatory proteins, including IL-1 and TNF-α in NR8383. On the other hand, macrophage-deleted CCRC strongly increased expression of these proteins on treatment with IL-1 or TNF-α, but not free heme. Induction of expression of pro-inflammatory proteins by free heme was not inhibited by intracellular ROS reduction, but by protease and proteasome inhibitors capable of regulating NF-κB. These data suggest that free heme strongly induces various pro-inflammatory proteins in injured hearts through NF-κB activation in cardiac resident macrophages and through cross-talk between macrophages and fibroblast/smooth muscle cells mediated inter alia by IL-1, TNF-α.

Seasonal trend and serotype distribution of rotavirus infection in Japan, 1981-2008.

A total of 10,917 fecal specimens from infants and children with gastroenteritis in seven different regions of Japan in the last 3 decades were examined for rotavirus. We observed that the rotavirus peak shifted gradually from January to April (winter to early spring) during 17 seasons and the G1P[8] combination was the most predominant genotype in the last 28 years in Japan.

Expression of the peptide hormone hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction.

The micronutrient iron is an essential component that plays a role in many crucial metabolic reactions. The peptide hormone hepcidin is thought to play a central role in iron homeostasis and its expression is induced by iron overloading and inflammation. Recently, hepcidin has been reported to be expressed also in the heart; however, the kinetics of altered hepcidin expression in diseases of the heart remain unknown. In this study, we examined cardiac expression of hepcidin in rat experimental autoimmune myocarditis (EAM), human myocarditis and rat acute myocardial infarction (AMI). In rat EAM and AMI hearts, hepcidin was expressed in cardiomyocytes; ferroportin, which is a cellular iron exporter bound by hepcidin, was also expressed in various cells. Analysis of the time course of the hepcidin to cytochrome oxidase subunit 6a (Cox6a)2 expression ratio showed that it abruptly increased more than 100-fold in hearts in the very early phase of EAM and in infarcted areas 1 day after MI. The hepcidin/Cox6a2 expression ratio correlated significantly with that of interleukin-6/gamma-actin in both EAM and AMI hearts (r=0.781, P<.0001 and r=0.563, P=.0003). In human hearts with histological myocarditis, the ratio was significantly higher than in those without myocarditis (0.0400+/-0.0195 versus 0.0032+/-0.0017, P=.0045). Hepcidin is strongly induced in cardiomyocytes under myocarditis and MI, conditions in which inflammatory cytokine levels increase and may play an important role in iron homeostasis and free radical generation.

Molecular and epidemiological trend of rotavirus infection among infants and children in Japan.

This study investigated the prevalence of group A, B, and C rotavirus (RAV, RBV, RCV) and adenovirus (AdV) infections in infants and children with acute gastroenteritis in Japan from July 2006 to June 2007. A total of 628 fecal specimens collected from infants and children with acute gastroenteritis in five different places (Maizuru, Tokyo, Sapporo, Saga and Osaka) in Japan during the period of July 2006-June 2007 were examined for RAV, RBV, RCV and AdV by RT-multiplex PCR. RAV was further characterized to G-typing and P-typing by RT-multiplex PCR and sequencing method. It was found that 123 (19.6%) fecal specimens were positive for RAV followed by AdV of 4.5%. RBV and RCV could not be detected in this study. Serotype G1 (58.5%) was identified at high levels followed by G9 (20.3%), G2 (11.4%), and G3 (7.3%). P genotyping revealed P[8] as predominant (84.6%) followed by P[4] (13.8%) and P[6] (1.6%). During the 2006/2007 rotavirus season, G1P[8] strains were most common with G9P[8], G2P[4], G3P[8], G1P[4] and G9P[6] also detected. It is clear from this study that RAV is still the cause of diseases in Japan. To our knowledge, this is the first report of RV P[6] strain in humans in Japan.

Promoter-specific function of the TATA element in undifferentiated P19 cells.

P19 embryonal carcinoma cells differentiate into neuronal cells when treated with retinoic acid (RA). To explore the importance of core promoter structures in the regulation of gene expression during neuronal differentiation, the activities of three classes of modified or unmodified model promoters (Spec2a, OtxE, and Ars) were compared in P19 cells before and after RA treatment. The Spec2a promoter was activated in undifferentiated cells specifically when the E-box was located at a proximal position, whereas the OtxE promoter was activated when the E-box was in a distal position. The Ars promoter was only slightly activated by this element. In addition, the TATA element reduced the level of activation provided by the E-box, but only when it was located in the Spec2a core promoter. These results indicate that the core promoter structure may govern, at least in part, the stage-specific expression of endogenous genes involved in the neuronal differentiation of P19 cells.

[Impact of intravenous thrombolysis prior to percutaneous coronary intervention in reperfusion therapy for acute myocardial infarction].

OBJECTIVES: To elucidate the effectiveness and safety of intravenous thrombolysis (IVT) with mutant tissue plasminogen activator prior to percutaneous coronary intervention (PCI) in patients with acute myocardial infarction. METHODS: Ninety consecutive patients were recruited with the following criteria: acute myocardial infarction with ST segment elevation or bundle branch block on electrocardiography, admission within 6 hr from onset, age of < or = 80 years and without previous PCI or coronary bypass graft surgery. They were divided into two groups. Group IV consisted of 53 patients treated with IVT prior to PCI and Group D consisted of the other 37 patients with direct PCI. Mutant tissue plasminogen activator, monteplase, was administered with a dose of 27,500 U/kg in Group IV (maximum injection dose, 160 x 10(4) U). The clinical features and in-hospital outcome were compared between the two groups. RESULTS: Patients in Group IV acquired earlier reperfusion estimated by electrocardiography recovery at 60 min after admission and higher Thrombolysis in Myocardial Infaction (TIMI) flow grade on the first coronary angiogram (TIMI 2 or 3 flow rate; Group IV vs Group D = 75% vs 35%, p < 0.0001). The duration from onset to TIMI 3 flow grade was not significantly different between Group IV and Group D (230 vs 260 min, p = 0.15). The incident of ST segment re-elevation with chest pain at recanalization was lower in Group IV than in Group D (23% vs 46%, p < 0.05). The duration from TIMI 3 recognition to peak creatine kinase level was longer in Group IV (466 vs 359 min, p = 0.039). Subacute thrombotic occlusion occurred in two patients in Group IV and three in Group D (NS). One patient in each group died from pump failure (NS). No severe bleeding complication was found in any patient. CONCLUSIONS: IVT prior to PCI was considered to be a safe, effective and useful therapy in patients with acute myocardial infarction. Different patterns of reperfusion might occur, because of the low frequency of ST re-elevation and elongation of duration from reperfusion to peak creatine kinase level in patients treated with IVT prior to PCI.

Fascicular torsion in the median nerve within the distal third of the upper arm: three cases of nontraumatic anterior interosseous nerve palsy.

Three patients with nontraumatic anterior interosseous nerve palsy are presented. All patients also had paralysis of the pronator teres, flexor carpi radialis, and/or palmaris longus. One patient also had sensory disturbance and palsy of the thenar muscles. An hourglass-like constriction was seen within a 7-cm section of the nerve fascicles (2-9 cm proximal from the medial epicondyle of the humerus) in the median nerve trunk. All constrictions exhibited approximately 30 degrees of fascicular torsion. Because this nerve section is anatomically proximal to the branching point for the earlier mentioned motor branches and the anterior interosseous nerve, the nerve fascicles may have been structurally twisted before the onset of palsy. Structural abnormalities causing inflammation and edema of nerve fascicles as well as factors such as compression from surrounding small vessels may have maximized torsion, resulting in the formation of constrictions.

Clinical significance of prolonged P wave width after right atrial appendage pacing in sick sinus syndrome.

The present study investigated both the clinical significance of atrial fibrillation (AF) before right atrial appendage (RAA) pacing and the influence of prolonged P wave on AF occurrence in RAA-paced patients with sick sinus syndrome (SSS). Fifty-seven patients (age 68+/-10 years; 19 men, 38 women) with SSS who underwent RAA pacing were divided into 2 groups: 23 patients without AF before pacing (I + II; Rubenstein I or II) and 34 patients with AF before pacing (III; Rubenstein III). The P wave duration in intrinsic rhythm and with RAA pacing were measured on the standard electrocardiography in leads II and V(1) with the use of a digitizing tablet. Group III was further subdivided into 2 groups: 20 patients (IIIb) with a paced P wave >130 ms in both leads II and V(1) and the other 14 patients (IIIa). The duration of the intrinsic P wave in leads II and V(1) was significantly greater in group III than in group I + II (119+/-20 vs 108+/-21 ms, p=0.0417, 106+/-16 vs 95+/-21 ms, p=0.0258, respectively). During the follow-up of 40+/-21 months, AF recurrence was significantly higher in group IIIb than in groups IIIa and I + II (17/20 vs 5/14 vs 2/23 p<0.0001). A few occurrences of AF were observed by conventional RAA pacing in patients without AF before pacing. However, SSS with AF before pacing caused a significant intra-atrial conduction disturbance and a high incidence of AF recurrence after implantation of RAA pacing, especially in patients with a prolonged paced P wave, in whom new pacing modalities may be needed to shorten paced P wave duration and prevent AF.