Acute myocardial infarction due to simultaneous spasm of 3 coronary arteries that worsened over time.

Coronary artery spasm (CAS) rarely worsens from single-vessel to simultaneous multivessel CAS naturally, and simultaneous multivessel CAS leads to serious conditions such as cardiopulmonary arrest (CPA). A 77-year-old Japanese man who took medications for CAS was transferred to our hospital due to persistent chest pain. On arrival, his vital signs were stable, but his electrocardiogram (ECG) showed ST-segment elevation in leads II, III and aVF. Ventricular fibrillation developed suddenly. Although routine cardiopulmonary resuscitation (CPR) including intravenous administration of epinephrine was performed immediately, he could not be resuscitated. After initiation of percutaneous cardiopulmonary support (PCPS), there was a return of spontaneous circulation. His ECG showed exacerbation of myocardial ischemia with ST-segment elevation in leads I, II, III, aVL, aVF and V3-V6. Emergency coronary angiography revealed severe CAS of the right and left coronary arteries, which was relieved completely by intracoronary administration of nitrates. He was diagnosed with acute myocardial infarction due to simultaneous 3-vessel CAS that progressed over time. About 6h after arrival, he developed hemodynamic instability and died. CAS worsened from single-vessel to simultaneous 3-vessel spasm, and intracoronary administration of nitrates was effective in relieving CAS, which was documented by the ECG and coronary angiogram. Since CAS can progress over time, nitrates must be administered immediately. When CAS leads to CPA, epinephrine may be ineffective in CPR because of its vasoconstrictive effect on coronary arteries; therefore, PCPS should be initiated, and intracoronary nitrates should be administered.

Silent Cerebral Ischemic Lesions After Catheter Ablation of Atrial Fibrillation in Patients on 5 Types of Periprocedural Oral Anticoagulation　- Predictors of Diffusion-Weighted Imaging-Positive Lesions and Follow-up Magnetic Resonance Imaging.

BACKGROUND: The aim of this study was to identify the predictors of silent cerebral ischemic lesions (SCIL) after catheter ablation of atrial fibrillation (AF) and to determine whether SCIL develop into cerebral infarcts in patients with 5 types of oral anticoagulants (OAC). METHODS AND RESULTS: We retrospectively studied 286 consecutive patients (median, 67 years; 208 male; paroxysmal/persistent/long-standing persistent AF [LSP-AF], 147/90/49) who received periprocedural OAC and underwent MRI after the procedure. Warfarin (n=46) was continued, while dabigatran (n=47), rivaroxaban (n=89), apixaban (n=87), and edoxaban (n=17) were discontinued on the day of the procedure. I.v. heparin was infused to maintain an activated clotting time of 300-350 s during the procedure. Fifty-eight SCIL in 40 patients (14.0%) were identified on diffusion-weighted MRI. On multivariate logistic analysis, LSP-AF and dabigatran use were significant positive predictors of SCIL (OR, 2.912 and 2.287; P=0.006 and 0.042, respectively). Among 34 patients with 49 SCIL undergoing follow-up MRI, 45 (91.8%) of the lesions disappeared and 4 lesions developed into chronic cerebral infarcts. The SCIL with development into infarcts had a larger lesion diameter than those without (median, 6.55 mm vs. 4.2 mm; P=0.002). CONCLUSIONS: LSP-AF and dabigatran use were independent risk factors for post-ablation SCIL in patients with uninterrupted warfarin and interrupted non-vitamin K antagonist OAC, but the majority of SCIL disappeared.

Prospective open-label randomized comparative, non-inferiority study of two initial antibiotic strategies for patients with nursing- and healthcare-associated pneumonia: Guideline-concordant therapy versus empiric therapy.

BACKGROUND AND OBJECTIVE: The nursing- and healthcare-associated pneumonia guideline, proposed by the Japan Respiratory Society, recommends that patients at risk of exposure to drug-resistant pathogens, classified as treatment category C, be treated with antipseudomonal antibiotics. This study aimed to prove the non-inferiority of empirical therapy in our hospital compared with guideline-concordant therapy. METHODS: This was a randomized controlled trial conducted from December 2011 to December 2012. Patients were randomized to the Guideline group receiving guideline-concordant therapy, and the Empiric group treated with sulbactam/ampicillin or ceftriaxone. The primary endpoint was in-hospital relapse of pneumonia and mortality within 30 days, with a predefined non-inferiority margin of 10%. The secondary endpoints included duration, adverse effects, and cost of antibiotic therapy. RESULTS: One hundred and eleven patients were assigned to the Guideline group (n = 55) and the Empiric group (n = 56; 3 of which were excluded). The incidence of relapse and death within 30 days was similar in the Guideline and the Empiric groups (31% vs. 26%, risk difference -4.5%, 95% CI -21.5% to 12.5%). While the duration of antibiotic therapy was slightly shorter in the Guideline group than in the Empiric group (7 vs. 8 days), there were no significant differences in adverse effects or cost. CONCLUSIONS: The efficacy of empiric therapy was comparable to guideline-concordant therapy, although non-inferiority was not proven. The administration of broad-spectrum antibiotics to patients at risk of exposure to drug-resistant pathogens may not necessarily improve the prognosis. TRIAL REGISTRATION: UMIN000006792.

Stereoselective recognition of amethopterin enantiomers by the rat proton-coupled folate transporter.

The stereoselective transport of methotrexate (L-amethopterin, L-MTX) and its enantiomer (D-amethopterin, D-MTX) by the rat proton-coupled folate transporter (rPCFT) were examined using rPCFT-expressing HEK293 cells. The initial rate of uptake of [3H]-L-MTX by the rPCFT followed Michaelis-Menten kinetics, with a Km value of 2.1 µM. Dixon plots revealed that the uptake of L-MTX by the rPCFT was inhibited in a competitive manner by unlabeled L-MTX and D-MTX, with Ki values of approximately 1.3 and 150 µM, respectively. The initial rate of uptake of D-MTX by the rPCFT also followed Michaelis-Menten kinetics, with a Km value of 190 µM. The results of the current study demonstrate that the different enantiomers of MTX are transported in a highly stereoselective manner by the rPCFT, with the uptake clearance of L-MTX being approximately 46-fold greater than that of D-MTX. The observed stereoselectivity of the rPCFT was found to be comparable with that of the human PCFT.

Serum level of fibrinogen Aα chain fragment increases in chronic thromboembolic pulmonary hypertension.

BACKGROUND: The cause of chronic thromboembolic pulmonary hypertension is unknown and there is no specific circulating biomarker for its detection. The aim of the present study was to use proteomic analysis to detect serum biomarkers by evaluating the serum profiles of low-molecular-weight peptides using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry in patients with chronic thromboembolic pulmonary hypertension. METHODS AND RESULTS: Serum low-molecular-weight peptide profiling using the spectrophotometric technique was studied retrospectively in patients with chronic thromboembolic pulmonary hypertension and in controls matched for sex and age. The serum level of a 2989-Da peptide in the sera of patients was significantly higher compared to that of controls. Tandem mass spectrometry indicated that the peptide was a fragment of fibrinogen Aα chain (KMADEAGSEADHEGTHSTKRGHAKSRPV). The serum level of fibrinogen Aα chain fragment, measured using a heavy isotope internal standard, tended toward negative correlation with plasmin-α2-plasmin inhibitor complex (P=0.073) and had a positive correlation with thrombin-anti-thrombin complex (P=0.031). CONCLUSIONS: This fragment may be a potential diagnostic biomarker for chronic thromboembolic pulmonary hyper-tension.

Inhibition of secretory phospholipase A2 activity attenuates acute cardiogenic pulmonary edema induced by isoproterenol infusion in mice after myocardial infarction.

Several types of secretory phospholipase A2 (sPLA2) are expressed in lung tissue, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary edema in mice. Acute cardiogenic pulmonary edema was induced in C57BL/6J male mice by an increase in heart rate with continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/h) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg LY374388, a prodrug of LY329722 that inhibits sPLA2 activity, or vehicle was administered. The ISP infusion after myocardial infarction induced interstitial and alveolar edema on lung histology. Furthermore, it increased the lung-to-body weight ratio, pulmonary vascular permeability evaluated by the Evans blue extravasation method, lung activity of sPLA2, and lung content of thromboxane A2 and leukotriene B4. These changes were significantly attenuated by LY374388 treatment. In Kaplan-Meier analysis, the survival rate during the ISP infusion after myocardial infarction was significantly higher in LY374388- than in vehicle-treated mice. Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. In conclusion, inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema.

Comparative study of bezafibrate and pravastatin in patients with coronary artery disease and high levels of remnant lipoprotein.

BACKGROUND: Remnant lipoproteinemia is a strong risk factor for cardiovascular (CV) diseases. This study examined which of 2 common lipid-lowering drugs (fibrates and statins) is more effective in patients with remnant lipoproteinemia and if lowering remnant lipoprotein levels can reduce CV risk. METHODS AND RESULTS: Remnant lipoprotein levels were measured by an immunoseparation method (remnant-like lipoprotein particles cholesterol: RLP-C) in 274 patients with coronary artery disease and high RLP-C levels (>or=5.0 mg/dl). They were randomly assigned to receive bezafibrate (200-400 mg/day) or pravastatin (10-20 mg/day), and were prospectively followed-up for 1 year or until the occurrence of CV events. Complete follow-up data were obtained in 180 patients. RLP-C levels at 1 year of treatment were reduced more by bezafibrate than pravastatin (37% and 25% from baseline, respectively). During follow-up, bezafibrate-treated patients had 3 CV events, compared with 12 events in pravastatin-treated patients (P<0.01). In multivariate logistic regression analysis, a decrease in RLP-C level was significantly associated with a reduction in CV events after adjustment for treatment group and changes in levels of other lipids. CONCLUSIONS: Bezafibrate therapy decreased RLP-C levels to a greater extent than pravastatin and a decrease in RLP-C level may be associated with a reduction in CV events in patients with high RLP-C levels.

Inhibition of secretory phospholipase A2 activity attenuates lipopolysaccharide-induced acute lung injury in a mouse model.

This study evaluated the hypothesis that LY374388, an inhibitor of secretory phospholipase A(2) (sPLA(2)) activity, may exert a protective effect on lipopolysaccharide (LPS)-induced acute lung injury in male C57BL/6J mice. Intratracheal administration of LPS increased histopathological changes in lung tissue, lung wet to dry ratios, and the bronchoalveolar lavage fluid levels of neutrophil numbers, sPLA(2) activity, leukotriene B(4), and thromboxane B(2). However, a simultaneous intraperitoneal treatment with LY374388 significantly attenuated these LPS-induced changes. Thus, inhibition of sPLA(2) activity significantly attenuated the acute lung injury induced by LPS. sPLA(2) played an important role in the pathogenesis of LPS-induced acute lung injury in mice.

Nine-year trend of oral anticoagulant use in patients with embolic stroke due to nonvalvular atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly used as an alternative to warfarin in patients with nonvalvular atrial fibrillation (NVAF). However, whether there is sufficient prescription of oral anticoagulants (OACs) to decrease the incidence of embolic stroke remains unclear. METHODS AND RESULTS: We conducted a retrospective observational study of patients hospitalized with ischemic stroke between January 1, 2010 and December 31, 2018. During the 8 years, the annual incidence ratio of embolic stroke to all ischemic strokes did not decrease over time (21-33%) except for that in 2018. The proportion of OAC users did not also change over time (from 23% to 45% [overall 31%], P = .78). Among the OAC users, 19% patients were warfarin users, and 12% patients were DOAC users. In 73% of warfarin users, prothrombin time was subtherapeutic, whereas in 60% of DOAC users, the dose was adequately prescribed. OACs were prescribed more often in patients with high CHADS2 score than in those with low score (P = .01). The number of patients who had no medical history of a doctor visit before admission increased significantly in the recent period of 2015-2018 (22% vs 8% in the previous period of 2010-2014) (P = .01). CONCLUSIONS: The incidence of embolic stroke patients without OACs did not decrease over time, and OACs in patients with NVAF have not been sufficient, even in DOAC era. In recent years, the incidence of undiagnosed AF has increased. To prevent embolic stroke, a correct AF diagnosis beforehand is important.

Reduction in myocardial ischemia/reperfusion injury in group X secretory phospholipase A2-deficient mice.

BACKGROUND: Group X secretory phospholipase A(2) (sPLA(2)-X) has the most potent hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic acid among several types of sPLA(2). sPLA(2)-X is expressed in neutrophils, but its pathogenic role remains unclear. METHODS AND RESULTS: We generated mice that lack sPLA(2)-X and studied their response to myocardial ischemia/reperfusion. The sPLA(2)-X(-/-) mice had a significant reduction in myocardial infarct size and a decrease in myocardial myeloperoxidase activity compared with sPLA(2)-X(+/+) mice. Myocardial infarct size was also significantly reduced in lethally irradiated sPLA(2)-X(+/+) mice reconstituted with sPLA(2)-X(-/-) bone marrow compared with sPLA(2)-X(+/+) bone marrow. The extent of myocardial ischemia/reperfusion injury was comparable between sPLA(2)-X(-/-) and sPLA(2)-X(+/+) mice in Langendorff experiments using isolated hearts and blood-free perfusion buffer, supporting a potential role of sPLA(2)-X in blood in myocardial ischemia/reperfusion injury. In the infarcted myocardium of sPLA(2)-X(+/+) mice, sPLA(2)-X was released from neutrophils but not myocardial tissues and platelets and was undetectable in the peripheral serum. The sPLA(2)-X(-/-) mice had lower accumulation of neutrophils in ischemic myocardium, and the isolated sPLA(2)-X(-/-) neutrophils had lower release of arachidonic acid and attenuated cytotoxic activities including respiratory burst compared with sPLA(2)-X(+/+) neutrophils. The attenuated functions of sPLA(2)-X(-/-) neutrophils were reversible by the exogenous addition of sPLA(2)-X protein. Furthermore, administration of a sPLA(2) inhibitor reduced myocardial infarct size and suppressed the cytotoxic activity of sPLA(2)-X(+/+) neutrophils. CONCLUSIONS: Myocardial ischemia/reperfusion injury was attenuated in sPLA(2)-X(-/-) mice partly through the suppression of neutrophil cytotoxic activities.

Measurement of the platelet retention rate in a column of collagen-coated beads is useful for the assessment of efficacy of antiplatelet therapy.

INTRODUCTION: A simple, validated method to measure platelet function is unavailable for bedside use. Measurement of platelet retention rate using a column of collagen-coated beads and whole blood is a new, simple assay that reflects platelet aggregation. This study was aimed to examine the utility of this assay to assess efficacy of antiplatelet drug therapy. METHODS: Citrated whole blood (1.5 ml) in a syringe was passed through a polyvinyl tube packed with collagen-coated beads for 40 seconds using a syringe pump. Platelet retention rate in the column was calculated from platelet counts in blood before and after passage. An increase in the retention rate reflects an increase in platelet activity. This new platelet retention assay and the traditional optical aggregometry assay were performed in 331 patients with stable coronary artery disease (CAD). RESULTS: The retention rate was significantly reduced in patients taking dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine) compared with aspirin alone. There was a significant linear correlation between the platelet retention rate and platelet aggregability measured by the traditional method (r=0.44, p<0.001). In multivariate Cox proportional hazards analysis, higher platelet retention rate was an independent predictor of future cardiovascular events in patients on dual antiplatelet therapy (hazard ratio 3.9, 95% CI 1.6 to 9.5, p=0.003). CONCLUSIONS: Measurement of the platelet retention rate in a column of collagen-coated beads may be useful for monitoring the efficacy of antiplatelet drug therapy in patients with CAD.

[A case of multicentric Castleman's disease with metachronous pulmonary and nephric (renal) involvement].

A 52-year-old woman was referred to our hospital due to cough and sputum in January, 1996. Chest CT scans showed multiple hilar and mediastinal lymphadenopathy and laboratory tests revealed anemia, strong inflammatory reaction, polyclonal hyperimmunoglobulinemia, and an elevated interleukin-6 level. Video-assisted thoracoscopic lung biopsy revealed lymphocytic and plasmacytic infiltration around the bronchovascular band, suggesting a diagnosis of Castleman's disease, and so we began to administer steroids. Although her pulmonary symptoms improved, anemia and hyperimmunoglobulinemia continued. In 2001, her feeling of malaise worsened and gallium scintigraphy revealed new accumulation in her kidneys. Renal biopsy revealed lymphocytic and plasmacytic infiltration mimicking her prior pulmonary involvement. We therefore diagnosed multicentric Castleman's disease with renal involvement. Case in which lymphocytes and plasmacytes infiltrated both the lungs and kidneys metachronously are unusual. We discuss it in relation to the pertinent literature.

[A case of lymphangioleiomyomatosis found due to chylous ascites, pleural effusion and pelvic lymphadenopathy].

We report a case of lymphangioleiomyomatosis, complaining initially of abdominal distension due to massive chylous ascites. The patient was a 28-year-old woman in whom abdominal ultrasound had strongly suggested the existence of both pelvic lymphadenopathy and massive ascites, the latter subsequently turning out to be chylous. Pelvic lymph node biopsy yielded a diagnosis of lymphangioleiomyomatosis. High-resolution computed tomography (HRCT) of the chest showed no remarkable findings except for very few cystic changes in the lung parenchyma. Pulmonary function had remained normal except for a temporary constrictive pattern when chylous pleural effusion developed. No airflow obstruction was detected on pulmonary function tests. Although lymphangioleiomyomatosis is often associated with pulmonary symptoms, we should bear in mind the possibility of lymphangioleiomyomatosis even in the absence of such symptoms when facing any woman of child-bearing age with abdominal chylous ascites of unknown etiology.

Bronchodilator Effect of Tiotropium via Respimat®Administered with a Spacer in Patients with Chronic Obstructive Pulmonary Disease (COPD).

Objective Among elderly patients with chronic obstructive pulmonary disease (COPD), there are some patients who cannot inhale tiotropium via Respimat® due to poor hand-lung coordination. This study aimed to examine whether or not tiotropium inhalation therapy using Respimat® with a spacer increased the forced expiratory volume in 1 s (FEV1) in patients with COPD. Methods A randomized, crossover, single-center study was conducted in 18 patients with stable COPD. Tiotropium (5 µg) via Respimat® with or without a spacer (AeroChamber®) was administered for 2 weeks. Following a 2-week washout period using a transdermal tulobuterol patch (2 mg per day), participants were then crossed over to the other inhalation therapy with respect to spacer use. The trough FEV1 was measured at every visit using a spirometer. A questionnaire regarding inhalation therapy was administered to patients at the final visit. Results The administration of tiotropium via Respimat® both with and without a spacer significantly increased the trough FEV1 from baseline during each treatment period, with mean differences of 115.0±169.6 mL and 92.8±128.1 mL, respectively. There was no significant difference in the change in the trough FEV1 between the 2 procedures (p=0.66). A total of 86% of patients reported that inhalation using a spacer was not difficult, and more than half also rated both the usage and maintenance of the AeroChamber® as easy. Conclusion Tiotropium inhalation therapy administered via Respimat® using a spacer exerted a bronchodilatory effect similar to that observed with tiotropium Respimat® alone.

Predictors of chronic pulmonary vein reconnections after contact force-guided ablation: importance of completing electrical isolation with circumferential lines and creating sufficient ablation lesion densities.

PURPOSE: We aimed to identify the predictors of chronic pulmonary vein reconnections (CPVRs) after contact force (CF)-guided circumferential PV isolation (CPVI) of atrial fibrillation (AF). METHODS: Forty-nine consecutive patients undergoing second ablation procedures for recurrent AF after CF-guided ablation were retrospectively studied. The CPVI was performed by point-by-point ablation with a target CF of 15-20 g. The incidence of CPVRs was evaluated along the right- and left-sided anterior and posterior CPVI regions (Ant-RPVs, Post-RPVs, Ant-LPVs, and Post-LPVs). RESULTS: CPVRs were observed in 30.6, 22.4, 20.4, and 32.7 % of patients along the Ant-RPVs, Post-RPVs, Ant-LPVs, and Post-LPVs, respectively (P = 0.436). In the multivariate logistic analyses, completing a left atrium-PV conduction block with touch-up ablation inside the initially estimated CPVI lines (Ant-RPVs, Post-RPVs, Ant-LPVs, Post-LPVs; odds ratio [OR] 5.747, 15.000, 207.619, 7.940; P = 0.032, 0.004, 0.034, 0.021) and region length (Post-LPVs; OR 3.183, P = 0.027) were positive predictors of CPVRs, while the mean CF (Ant-RPVs; OR 0.861, P = 0.045) and number of radiofrequency applications per unit length (Ant-LPVs, Post-LPVs; OR 0.038, 0.122; P = 0.034, 0.029) were negative predictors. At optimal cutoffs of 5.8 cm for the region length, 14.2 g for the mean CF, and 1.97/cm (Ant-LPVs) and 2.01/cm (Post-LPVs) for the radiofrequency application density, the sensitivity and specificity were 93.8 and 63.6 %, 60.0 and 76.5 %, 90.0 and 64.1 %, and 75.0 and 63.6 %, respectively. CONCLUSIONS: Completing PVI with circumferential lines without touch-up ablation and creating a sufficient density of radiofrequency ablation lesions on the lines with a sufficient CF may be necessary to prevent CPVRs after a CF-guided CPVI.

Manifestation of latent left ventricular outflow tract obstruction caused by acute myocardial infarction: An important complication of acute myocardial infarction.

BACKGROUND: Although transient left ventricular outflow tract (LVOT) obstruction is reported as a complication with acute myocardial infarction (AMI), the mechanisms and features of LVOT obstruction in AMI are unclear. METHODS AND RESULTS: Herein, we present two cases of transient LVOT obstruction with anteroseptal AMI. The features of these two cases were one-vessel disease (1-VD) of the left anterior descending artery (LAD) and maintenance of blood flow to the major septal branch (SB). Moreover, LVOT obstruction was revealed after dobutamine infusion in the chronic phase and the aorto-septal angle was low in these two cases, meaning that latent LVOT obstruction was due to sigmoid-shaped septum. CONCLUSIONS: Latent LVOT obstruction would be manifested in the acute phase of AMI. 1-VD of LAD and the maintenance of major SB blood flow are important factors with respect to the manifestation of latent LVOT obstruction.

Primary percutaneous coronary intervention and bleeding risk in the era of drug-eluting stent: a long-term cohort study.

Data of long-term efficacy and safety including bleeding risk associated with antithrombotic regimens after primary percutaneous coronary intervention (PCI) using first-generation drug-eluting stent (1st DES) are scarce. Consecutive 422 patients with ST-elevation myocardial infarction (STEMI) underwent primary PCI with DES (285 patients), bare metal stent (BMS, 58 patients) or balloon angioplasty (BA 79 patients). At a median follow-up of 44 months, major cardiovascular events were significantly lower for 1st DES compared with BMS and BA (11.9 vs. 25.9 vs. 16.5 %, p = 0.027). Cardiac death, recurrent myocardial infarction and target lesion revascularization (TLR), differed among the groups (DES 8.8 %; BMS 13.8 %; BA 17.7 %; p = 0.019), although the superiority of DES subsided beyond 1 year by increased late TLRs. Major bleedings were not higher in DES than in BMS and BA (4.6 vs. 6.9 vs. 1.5 %, p = 0.252). Multivariate logistic regression analysis revealed that both dual antiplatelet therapy (DAPT) >24 months and indefinite oral anticoagulation (OAC) were associated with a major bleeding. The risk was even greater with triple antithrombotic therapy (odds ratio 19.5; 95 % confidence interval 3.73-102.07; p < 0.0001). 1st DES showed favorable overall long-term clinical outcome in STEMI, with an inherent limitation of an increased risk of late TLR. Prolonged DAPT and OAC synergistically increase the risk of major bleeding after primary PCI.