Koichiro Yoshioka

Regional sympathetic denervation detected by iodine 123 metaiodobenzylguanidine in non-Q-wave myocardial infarction and unstable angina.

Previous studies have revealed that the sympathetic nervous system is more vulnerable to ischemia than the myocardium itself. Thus our study was undertaken to detect denervated myocardium in non-Q-wave myocardial infarction (MI) and unstable angina with iodine 123 metaiodobenzylguanidine (123I-MIBG), which can delineate myocardial sympathetic innervation. Eight patients with non-Q-wave MI and 12 with unstable angina were studied. Sequential 123I-MIBG and thallium-201 chloride (201TlCl) imaging and single-photon emission computed tomography (SPECT) were performed at rest 24 +/- 12 days after the last ischemic attack. Myocardial perfusion defect was not detected by 201TlCl in 4 of 8 patients with non-Q-wave MI, whereas 123I-MIBG SPECT imaging revealed defects corresponding to myocardial ischemic areas predicted by coronary angiography in all 8 patients. 123I-MIBG imaging revealed defects in 7 of 12 patients with unstable angina corresponding to coronary angiographic findings, whereas no myocardial perfusion defect was detected by 201TlCl imaging in any of them. In conclusion, 123I-MIBG SPECT is a sensitive method for detecting myocardium exposed to transient ischemia that cannot be detected by 201TlCl imaging.

Year-long upregulation of connexin43 in rabbit hearts by heavy ion irradiation

A previous study from our laboratory has shown that a single targeted heavy ion irradiation (THIR; 15 Gy) to rabbit hearts increases connexin43 (Cx43) expression for 2 wk in association with an improvement of conduction, a decrease of the spatial inhomogeneity of repolarization, and a reduction of vulnerability to ventricular arrhythmias after myocardial infarction. This study investigated the time- and dose-dependent effects of THIR (5-15 Gy) on Cx43 expression in normal rabbit hearts (n = 45). Five rabbits without THIR were used as controls. A significant upregulation of Cx43 protein and mRNA in the ventricular myocardium was recognized by immunohistochemistry, Western blotting, and real-time PCR from 2 wk up to 1 yr after a single THIR at 15 Gy. THIR > or =10 Gy caused a significant dose-dependent increase of Cx43 protein and mRNA 2 wk after THIR. Anterior, lateral, and posterior free wall of the left ventricle, interventricular septum, and right ventricular free wall were affected similarly by THIR in terms of Cx43 upregulation. The radiation-induced increase of immunolabeled Cx43 was observed not only at the intercalated disk region but also at the lateral surface of ventricular myocytes. The increase of immunoreactive Cx43 protein was predominant in the membrane fraction insoluble in Triton X-100, that is the Cx43 in the sarcolemma. In vivo examinations of the rabbits 1 yr after THIR (15 Gy) revealed no significant changes in ECGs and echocardiograms (left ventricular dimensions, contractility, and diastolic function), indicating no apparent late radiation injury. A single application of THIR causes upregulation and altered cellular distribution of Cx43 in the ventricles lasting for at least 1 yr. This long-lasting remodeling effect on gap junctions may open the pathway to novel therapy against life threatening ventricular arrhythmias in structural heart disease.

Nifekalant Hydrochloride and Amiodarone Hydrochloride Result in Similar Improvements for 24-Hour Survival in Cardiopulmonary Arrest Patients: The SOS-KANTO 2012 Study.

Background: Amiodarone (AMD), nifekalant (NIF), and lidocaine (LID) hydrochlorides are widely used for ventricular tachycardia/fibrillation (VT/VF). This study retrospectively investigated the NIF potency and the differential effects of 2 initial AMD doses (⩽150 mg or 300 mg) in the Japanese SOS-KANTO 2012 study population. Methods and Results: From 16,164 out-of-hospital cardiac arrest cases, 500 adult patients using a single antiarrhythmic drug for shock-resistant VT/VF were enrolled and categorized into 4 groups (73 LID, 47 NIF, 173 AMD-⩽150, and 207 AMD-300). Multivariate analyses evaluated the outcomes of NIF, AMD-⩽150, or AMD-300 groups versus LID group. Odds ratios (ORs) for survival to admission were 3.21 [95% confidence interval (CI): 1.38–7.44, P < 0.01] in NIF and 3.09 (95% CI: 1.55–6.16, P < 0.01) in AMD-⩽150 groups and significantly higher than those of the LID group. However, the OR was 1.78 (95% CI: 0.90–3.51, P = 0.10) in AMD-300 group and was not significant than LID group. ORs for 24-hour survival were 6.68 in NIF, 4.86 in AMD-⩽150, and 2.97 in AMD-300, being significantly higher in these groups. Conclusions: NIF and AMD result in similar improvements for 24-hour survival in cardiopulmonary arrest patients, and this suggest the necessity of a randomized control study.

Atypical Carcinoid Tumor of the Lung, Associated with Giant‐cell Transformation in Bone Metastasis

A case of neuroendocrine lung tumor located beneath the pleura in a 71 year old woman is reported. At autopsy, the tumor was found to have metastasized to the bones and liver without involving the hilar lymph nodes. Histological‐ly, the tumor cells at the primary site and in the liver metastasis exhibited a carcinoid‐like organoid structure, whereas pleomorphic giant cells were noted in the bone metastasis. The argyrophilic tumor cells were immuno‐reactive for neuron specific enolase, chromogranin A, serotonin, calcitonin, calcitonin gene‐related peptide, gas‐trin‐releasing peptide, neuropeptide Y, gastrin, pancreatic polypeptide, glicentin, the alpha subunit of human cho‐rionic gonadotropin, keratin, epithelial membrane antigen, Leu M1 and carcinoembryonic antigen. Electron microscopy revealed abundant neurosecretory granules in the cytoplasm. This was considered to be a rare case of neuroendocrine lung tumor showing carcinoid like histology at the primary site and large‐cell transformation in bone metastasis.

Evaluation of a nine-lead Holter monitor for identifying and localizing ischemia and coronary artery disease detected by quantitative thallium-201 tomography

We devised a nine-lead Holter monitor system with a lead-switching technique to record electrocardiograms from multiple sites in the anterior and the posterior or lateral chest. Leads CM1 to CM6, high lateral (HL), low lateral (LL), and low posterior chest (LB) were used. The sensitivity, specificity, and predictive accuracy of this system for identifying specific regions of myocardial ischemia and coronary artery disease were investigated in 130 patients with coronary artery disease. Anterolateral leads (CM4 to CM6, HL, and LL) showed high sensitivity for detecting anterior and lateral ischemia (69% to 100%) but low specificity (4% to 44%) compared with tomographic results. The specificity of these leads for identifying single-vessel disease was low (6% to 47%) although some leads showed high sensitivity (69% to 100%). In contrast, the LB lead exhibited high sensitivity and specificity for detecting inferior ischemia (70% and 95%, respectively) and right coronary artery (RCA) disease (74% and 93%, respectively). Consequently, ST depressions in the LB lead (anode) are specific for identifying inferior ischemia and RCA disease, whereas those in the anterior and lateral chest leads do not identify the ischemic region or the obstructed coronary artery.

Circadian Distribution of Paroxysmal Atrial Fibrillation in Patients with and without Structural Heart Disease in Untreated State

Background: This study aimed to compare the circadian distribution of the onset, maintenance and termination of paroxysmal atrial fibrillation (PAF) between structural and non‐structural heart diseases (SHD and NSHD, respectively) in the untreated state.

Evaluation of a newly devised three-lead Holter recording during treadmill testing in the diagnosis of ischemic ST changes

Sixty-five patients (54 men, 11 women) with angina pectoris were studied using a technique for recording a 3-lead electrocardiogram without increasing the number of channels and electrodes in the commercial 2-channel Holter recorder. In 52 of the 65 patients, simultaneous ECGs with both the 3-lead Holter method and the conventional 12-lead system during treadmill exercise testing were performed. The results of the two systems in detecting significant ST depressions were consistent in 51 of 52 patients (98%). Twenty-seven of the 32 patients with significant coronary stenosis showed ST depressions during exercise both in the 3-lead Holter and the 12-lead ECG systems. There were cases in which ST depressions were confined only to the CM2 lead (n = 1), the CM5 lead (n = 18) or the CMf lead (n = 3). This indicates that at least three leads are needed in the Holter system for the detection of certain ST changes. The sensitivity of the Holter system during exercise in detecting significant coronary artery disease was the same as that of the 12-lead system (84%). Two of the total 65 patients had variant angina at night. No ST changes in the CM5 lead were observed in either case. Thus, the 3-lead Holter monitoring technique is as accurate as the 12-lead system for the detection of ischemic ST depressions associated with coronary stenosis and is unlikely no miss the signs of variant angina. In addition, this technique is expandable since it can continuously switch between leads using the same channel.

Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease.

The efficacies and side effects of disopyramide and mexiletine used alone and in combination were assessed in 29 patients with chronic ventricular arrhythmias. In combination therapy, one half or two thirds of the conventional doses of each drug were administered. Each patient underwent Holter electrocardiographic monitoring during 4 different periods: baseline, disopyramide alone, mexiletine alone and combination of the two drugs. The mean baseline number of ventricular premature complex per hour was 783 +/- 521 (mean +/- SD), which was significantly reduced with all three therapies. Disopyramide alone significantly reduced the ventricular premature complex frequency in patients with organic heart disease (P less than 0.05), but did not significantly reduce the ventricular premature complex frequency in patients with no apparent heart disease. In contrast, mexiletine alone significantly decreased the ventricular premature complex frequency in no apparent heart disease patients (P less than 0.05), but did not significantly reduce the ventricular premature complex frequency in organic heart disease patients. With disopyramide alone, patients having a significant reduction in ventricular premature complexes (greater than or equal to 83% reduction in ventricular premature complexes) or elimination of ventricular tachycardias tended to be more frequently found in organic heart disease than in no apparent heart disease. The opposite was observed with mexiletine alone. QTc interval with disopyramide alone was significantly prolonged, and the prematurity index of ventricular premature complexes was significantly lowered as compared to mexiletine alone or combination therapy (P less than 0.01 for disopyramide versus mexiletine; P less than 0.05 for disopyramide versus combination therapy). During combination therapy, no patients withdrew from the study due to side effects. However, 3 patients receiving single drug therapy withdrew from the study due to severe side effects. Consequently, disopyramide is suggested to be more effective on ventricular premature complexes in organic heart disease than in no apparent heart disease patients, whereas the opposite was true for mexiletine. A combination of disopyramide and mexiletine in smaller doses may provide almost the same or enhanced antiarrhythmic effects, no aggravation of electrocardiographical parameters and less incidence of side effects when compared to the conventional dose of each drug alone.

Does Antiarrhythmic Drug during Cardiopulmonary Resuscitation Improve the One-month Survival: The SOS-KANTO 2012 Study

Background: Antiarrhythmic drugs (AAD) are often used for fatal ventricular arrhythmias during cardiopulmonary resuscitation (CPR). However, the efficacy of initial AAD administration during CPR in improving long-term prognosis remains unknown. This study retrospectively evaluated the effect of AAD administration during CPR on 1-month prognosis in the SOS-KANTO 2012 study population. Methods and Results: Of the 16,164 out-of-hospital cardiac arrest cases, 1350 shock-refractory patients were included: 747 patients not administered AAD and 603 patients administered AAD. Statistical adjustment for potential selection bias was performed using propensity score matching, yielding 1162 patients of whom 792 patients were matched (396 pairs). The primary outcome was 1-month survival. The secondary outcome was the proportion of patients with favorable neurological outcome at 1 month. Logistic regression with propensity scoring demonstrated an odds ratio (OR) for 1-month survival in the AAD group of 1.92 (P < 0.01), whereas the OR for favorable neurological outcome at 1 month was 1.44 (P = 0.26). Conclusions: Significantly greater 1-month survival was observed in the AAD group compared with the non-AAD group. However, the effect of ADD on the likelihood of a favorable neurological outcome remains unclear. The findings of the present study may indicate a requirement for future randomized controlled trials evaluating the effect of ADD administration during CPR on long-term prognosis.

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension

BACKGROUND Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODSANDRESULTS Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P<0.0001). 6MWD increased from 427±128 to 494±116 m (P<0.0001). WHO functional class improved in 13 patients (46.4%) and was maintained in 15 patients (53.6%), and NT-pro-BNP was reduced by 18% (P<0.0001). The favorable treatment effect on PVR was apparent regardless of concomitant therapy for PAH. CONCLUSIONS Macitentan was efficacious and well tolerated and improved the hemodynamic parameters, exercise capacity, symptoms, and clinical biomarkers in Japanese PAH patients. Macitentan can be a valuable therapeutic option for Japanese patients with PAH. ( TRIAL REGISTRATION JAPIC Clinical Trials Information [JapicCTI-121986].) (Circ J 2016; 80: 1478-1483).