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Background Although an “obesity paradox” exists in patients after myocardial infarction, the association between obesity and the risk of sudden cardiac death (SCD) is limited. The aim of this study was to determine whether obesity is associated with an increased risk of SCD in Japanese survivors of acute myocardial infarction. Methods and Results Pooled data from 2 cohort studies in Japan, JCAD (Japanese Coronary Artery Disease) study and the Heart Institute of Japan Acute Myocardial Infarction‐II (HIJAMI‐II) registry, comprising of 6216 patients (mean age 65±11 years, 75.2% male) with acute myocardial infarction who were discharged alive, were studied. The patients were categorized into the following body mass index (BMI) groups at baseline according to the World Health Organization classification for Asian populations: BMI

Human cells and tissue products belong to a relatively new class of medical products. Therefore, limited information is available on the classification and premarket evaluation of human cells and tissue products in the United States (US), the European Union (EU), and Japan. In this study, the definition, legislation, and approval system of these products were surveyed. A total of nine autologous human cells and tissue products approved until October 2013 were collected. The definitions of human cells and tissue products were compatible among the US, the EU and Japan. The products were classified as human cells, tissue, and cellular and tissue-based products (HCT/Ps) in the US, advanced therapy medicinal products (ATMPs) in the EU, and cell/tissue-engineered products in Japan. These products were categorized as biologics and medical device in the US and Japan, and drug in the EU. The issuance of new guidance induced regulatory impact for manufacturer, especially in the US. These products are subjected to the accelerated approval of biological product, the humanitarian device exemption approval, the premarket application approval, the biologics license application approval, and new drug application approval with specific targeting of postapproval registry or surveillance. Of nine autologous human cells and tissue products, four products had been evaluated using clinical experiences or open clinical trials with small subjects, although the rests of products had been evaluated using comparative clinical trials with control treatment. Our survey suggests that autologous human cells and tissue products would need postmarket-oriented evaluation rather than premarket-oriented evaluation for doctors and patients.

Background: Nifekalant, a first-line drug for the treatment of ventricular tachycardia/ventricular fibrillation (VT/VF) in Japan, has been known to prolong the QT interval; however, the incidence of excess QT/QTc prolongation and subsequent torsades de pointes (TdP) has not yet been reported. Methods: The QT/QTc interval and occurrence of TdP during nifekalant therapy were evaluated in 1402 emergency patients with VT/VF. Results: Thirty-five cases (2.5%) of QT/QTc prolongation and 54 cases (3.9%) of TdP were reported. High nifekalant doses and long QTc intervals were associated with frequent TdP. The incidence of TdP was 1.4% for QTc intervals

Risk stratification of lethal arrhythmias is important for the management of ischemic heart disease. Recently, we developed a novel 187-channel signal-averaged vector-projected high-resolution electrocardiograph (187-ch SAVP-ECG) with a Mason–Likar lead system with 10 electrodes. The purpose of this study was to examine the feasibility of a noninvasive evaluation of the spatial distribution of high-frequency late potentials (HFLPs) in patients with myocardial infarction (MI) by using the 187-ch SAVP-ECG. Sixty-four MI patients (7 women and 57 men), between the age of 39 and 84 years (mean 67.7±9.7 years), with positive ventricular late potentials defined by an X, Y, Z-lead ECG were studied. The integrated ventricular 187-ch SAVP-ECG could identify the area of HFLPs that was projected virtually by mathematically calculated 187 electrograms on the body surface in all patients, and differentiate the locations of MI. The 187-ch SAVP-ECG can be a practical and noninvasive examination tool for identifying the location of infarction areas and possible arrhythmogenic substrates with slow conduction properties in patients with MI.

Introduction: Amiodarone infusion has been recommended for life-threatening ventricular arrhythmias. However its effectiveness in Japanese patients has not yet been determined. Methods: This was an uncontrolled, open-label trial involving patients with hemodynamically unstable ventricular tachycardia (VT) or ventricular fibrillation (VF). Intravenous amiodarone was delivered as a 125 mg bolus followed by infusion of 50 mg/h for 6 hours, then 25 mg/h for 42 hours. The primary endpoint for efficacy was the proportion of patients free from hemodynamically unstable VT/VF at 48-hour. Secondary endpoints included: event frequency; proportion of patients event-free, treatment outcome, and safety. Results: Forty-seven patients were enrolled. Forty-one patients were evaluated for efficacy and safety parameters were assessed for all 47 patients. The proportion of patients free from hemodynamically unstable VT/VF was 53.9%; the proportion of patients free from hemodynamically unstable VT/VF relapse or whose treatment was discontinued was 48.8%. Eight patients died; all deaths were judged, by the investigator, as being unrelated to amiodarone. No cases of torsades de pointes were reported. Mild abnormal thyroid function was noted in one patient. No cases of interstitial lung disease or pulmonary fibrosis were observed. Conclusion: Amiodarone infusion provides a useful tool in preventing acute relapse of lifethreatening ventricular arrhythmias in Japanese patients.

In a new drug development, regulatory authorities recommend the “thorough QT/QTc study”, in which the use of a positive control group was recommended for evaluating assay sensitivity that allows the detection of a QT/QTc interval prolongation about 5 msec. The effects of postural change on the QT/QTc intervals were examined to determine its potential usefulness as a nonpharmacological positive control. Standard 12-lead electrocardiograms of 72 healthy male subjects (mean age: 22.6 ± 2.0 years) were recorded in the morning and evening in 6 positions (supine, 30-degree semisitting, standing, supine, 90-degree sitting, and standing). The QT-RR relationships during postural changes seemed to be similar in the morning and the evening. The QTc interval calculated by the Fridericia's or Framingham's formula shortened in the sitting (7 to 10 msec) and the standing position (11 to 14 msec) compared to that in the supine position. On the other hand, the QTc interval calculated by the Bazett's formula prolonged by nearly 4 msec in the sitting position and by nearly 9 msec in the standing position. The results suggest that the difference in QTc interval during postural change, especially from supine to sitting position, could be useful as a nonpharmacological positive control.

Background: Anxiety is often present in patients with depression. The aim of this study was to evaluate the impact of clustered depression and anxiety on mortality and rehospitalization in hospitalized patients with heart failure (HF). Methods: A total of 221 hospitalized patients with HF, who completed the questionnaires, were analyzed in this prospective study (mean age 62 ± 13 years; 28% female). One-third patients had implanted cardiac devices. Depression was defined as a Zung Self-Rating Depression Scale index score of ≥ 60 and anxiety was defined as a State-Trait Anxiety Inventory score of ≥ 40 (male) or ≥ 42 (female). The primary outcome was the composite of death from any cause or rehospitalization due to worsened HF and refractory arrhythmia. Results: Of the 221 HF patients, 29 (13%) had depression alone, 80 (36%) had anxiety alone, and 46 patients (21%) had both depression and anxiety. During an average follow-up of 41 ± 21 months, patients with depression alone and those with clustered depression and anxiety were at an increased risk of the primary outcome [hazard ratio (HR) 2.24, 95% confidence interval (Cl): 1.17 - 4.28, p = 0.01 and HR 2.75, 95% CI: 1.51 - 4.99, p = 0.01, respectively] compared to patients with no symptoms. Multivariate analysis after adjusting for age, gender, New York Heart Association functional class, B-type natriuretic peptide, device implantation, renal dysfunction, and left ventricular dysfunction showed clustered depression and anxiety, but not depression alone or anxiety alone, was an independent predictor of the primary outcome (HR 1.96, 95% CI: 1.00 - 3.27, p = 0.04). Conclusions: Our results showed that clustered depression and anxiety were associated with worse outcomes in patients with HF. [ABSTRACT FROM AUTHOR]

Abstract Purpose  In patients with acute decompensated heart failure (ADHF) and left ventricular systolic dysfunction (LVSD), the role of initial vasodilator therapy remains uncertain. The present study aimed to evaluate the acute efficacy of initial carperitide therapy and to predict its response in ADHF patients with LVSD. Methods  Twenty-four consecutive patients with ADHF and LVSD were enrolled. Inclusion criteria were a left ventricular ejection fraction  90 mm Hg, and pulmonary capillary wedge pressure ≥18 mm Hg at baseline. Hemodynamic parameters were evaluated by right heart catheterization before and after carperitide infusion. Responders were defined as a ≥30% reduction of pulmonary capillary wedge pressure (PCWP) or a decrease to Results  Seventeen (71%) of the 24 patients were responders for initial carperitide therapy. The responders had significantly higher systolic BP and cardiac index at baseline compared with nonresponders. The area under the curve (AUC) for systolic BP was 0.93 and a cut-off value of 120 mm Hg had a sensitivity of 94% and specificity of 86% for predicting the efficacy of carperitide. The AUC for the cardiac index was 0.88 and a cut-off value of 2.30 L/min/m2 had a sensitivity of 65% and a specificity of 100% for predicting the response to carperitide. Conclusions  The initial use of carperitide therapy safely reduces PCWP in ADHF patients with LVSD and baseline systolic BP may be useful for predicting the response to initial carperitide therapy for ADHF with LVSD. [ABSTRACT FROM AUTHOR]

Abstract Background  The lack of any randomized controlled trials demonstrating a beneficial effect of nitrates for the secondary prevention of coronary artery disease leads to a negative recommendation in current practice guidelines. The aim of the present study was to examine the efficacy of nitrate therapy for the treatment of acute myocardial infarction (AMI) in the contemporary revascularization era. Methods and results  Of 2,736 consecutive patients with AMI (1,677 on nitrate therapy and 1,059 control patients not receiving nitrates), 1,766 patients were matched according to a propensity score (883 receiving nitrates and 883 control subjects). Before propensity score matching, the patients treated with nitrates were significantly older, had a higher Killip class, and underwent less aggressive revascularization and less modern pharmacotherapy compared with the patients who were not given nitrates. A total of 117 patients (11.0%) died in the control group and 317 patients (18.9%) in the nitrate group (hazard ratio, 1.70; 95% CI, 1.38–2.10; P P = 0.678). The 1-, 3- and 5-year cumulative mortality rates (Kaplan–Meier method) were respectively 4.5%, 9.8%, and 14.1% in the control group versus 5.2%, 9.8%, and 14.8% in the nitrate group. There were also no statistical or clinical differences between the two matched groups with regard to the other endpoints assessed. Conclusions  Our results suggest that nitrate therapy does not increase mortality and cardiac events in AMI patients. Our results differ from those of previous observational studies, suggesting that new prospective randomized clinical trials are needed in the current revascularization era. [ABSTRACT FROM AUTHOR]

1. Human ABCA8, a new member of the ATP binding cassette (ABC) transporter family, transports certain lipophilic drugs, such as digoxin. To investigate the roles of this transporter, we cloned a mouse homologue of ABCA8, from a mouse heart cDNA library, named ABCA8a. 2. The deduced mouse ABCA8a protein is 66% identical with that of human ABCA8 and possesses features common to the ABC superfamily. It was found that ABCA8a was mainly expressed in the liver and heart, similar to human ABCA8. 3. We further evaluated the effect of acute digoxin (a substrate for ABCA8) intoxication on the mRNA expression of ABCA8 using northern blotting with a 3′ non-coding region as a probe to avoid cross-hybridization with other ABCA genes. 4. Following acute digoxin infusion, the mRNA expression of ABCA8 was significantly reduced in the liver 12–24 h after injection (14.7% of vehicle treatment), but not in the heart and kidney. 5. Real-time quantitative polymerase chain reaction analysis confirmed the reduction in ABCA8a mRNA. Similar reductions in ABCA5, ABCA7, ABCA8b and ABCA9 mRNA were also observed. A comparable amount of digitoxin did not affect ABCA8a mRNA expression in the liver. 6. The results suggest that ABCA8 may play a role in digoxin metabolism in the liver. [ABSTRACT FROM AUTHOR]

The phenotypic expression of cardiomyopathy is greatly influenced by extrinsic factors other than intrinsic genetic defects, such as environmental stress. Exercise is assumed to be an important extrinsic factor, since sudden death is sometimes seen during exercise in young patients with hypertrophic cardiomyopathy (HCM). However, the long-term effects of mild exercise on phenotypic expression in cardiomyopathy remain unclear. To evaluate the effects of exercise performed during infancy or adolescence in cardiomyopathic patients, cardiomyopathic Syrian hamsters (BIO14.6) were subjected to swimming. BIO14.6 and age-matched congenic normal hamsters (CN) as controls were divided into three groups: sedentary (Sed), and trained during infancy (Inf) and during adolescence (Ado). Histological and biochemical analysis of 41-week-old hamsters revealed that (1) the relative level of β-myosin heavy chain mRNA was significantly lower in the Inf group than in the Sed and Ado groups of BIO14.6. The level in the Inf group of BIO14.6 was compatible with that in the age-matched Sed group of the CN strain; (2) in BIO14.6, degenerative mitochondrial change in the cardiomyocytes was not seen in the Inf group while it was common in the Sed and Ado groups; (3) calcineurin phosphatase activity in the swimming group in 10-week-old CN was significantly higher than that of the age-matched sedentary group, and was as much as that of the swimming and sedentary groups in 10- and 41-week-old BIO14.6. [ABSTRACT FROM AUTHOR]