Reversal Rate of Clustering of Cardiovascular Disease Risk Factors of Metabolic Syndrome in the General Population: The Niigata Preventive Medicine Study

The reversal rate from clustering of cardiovascular disease (CVD) risk factors—components of the metabolic syndrome (MetS) is not known. Methods and Results. Among 35,534 subjects who received the annual health examinations at the NiigataHealth Foundation (Niigata, Japan), 4,911 subjects had clustering of 3 or more of the following CVD risk factors: (1) body mass index (BMI) ≥25 Kg/m2, (2) blood pressure ≥130 mm Hg in systolic and/or ≥85 mm Hg in diastolic, (3) triglycerides ≥150 mg/dL, (4) high-density lipoprotein cholesterol ≤40 mg/dL in men, ≤50 mg/dL in women, and (5) fasting blood glucose ≥100 mg/dL. After 5 years 1,929 subjects had a reversal of clustering (39.4%). A reversal occurred more often in males. The subjects with a reversal of clustering had milder level of each risk factor and a smaller number of risk factors, while BMI was associated with the least chance of a reversal. Conclusion. We concluded that a reversal of clustering CVD risk factors is possible in 4/10 subjects over a 5-year period by habitual or medical interventions. Gender and each CVD risk factor affected the reversal rate adversely, and BMI was associated with the least chance of a reversal

Risk factors for the first and second inappropriate implantable cardioverter-defibrillator therapy

Introduction: Various risk factors for the first inappropriate implantable cardioverter-defibrillator (ICD) therapy event have been reported, including a history of atrial fibrillation/atrial flutter (AF/AFL), younger age, and multiple zones. Nonetheless, which factors are concordant with real-world data has not been clarified, and risk factors for the second inappropriate ICD therapy event have not been well examined. This study aimed to clarify the risk factors for the first and second inappropriate ICD therapy events. Methods: We conducted a post-hoc secondary analysis of data from a multicenter, prospective observational study (the Nippon Storm Study) designed to clarify the risk factors for electrical storm. Results: The analysis included data from 1549 patients who received ICD or cardiac resynchronization therapy with defibrillator (CRT-D). Over a median follow-up of 28 months, 293 inappropriate ICD therapy events occurred in 153 (10.0%) patients. On multivariate Cox regression analysis, the risk factors for the first inappropriate ICD therapy event were younger age (hazard ratio [HR], 0.986; p = 0.028), AF/AFL (HR, 2.324; p = 0.002), ICD without CRT implantation (HR, 2.377; p = 0.004), and multiple zones (HR, 1.852; p = 0.010). "No-intervention" after the first inappropriate ICD therapy event was the sole risk factor for the second inappropriate ICD therapy event. Conclusions: Risk factors for the first inappropriate ICD therapy event were similar to those previously reported. Immediate intervention after the first inappropriate ICD therapy event could reduce the risk of the second inappropriate event

Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect

AbstractWe identified a novel mutation Ala178fs/105 missing S3–S6 and C-terminus portions of KCNQ1 channel. Ala178fs/105-KCNQ1 expressed in COS-7 cells demonstrated no current expression. Co-expression with wild-type (WT) revealed a dominant-negative effect, which suggests the formation of hetero-multimer by mutant and WT. Confocal laser microscopy displayed intracellular retention of Ala178fs/105-KCNQ1 protein. Co-expression of the mutant and WT also increased intracellular retention of channel protein compared to WT alone. Our findings suggest a novel mechanism for LQT1 that the truncated S1–S2 KCNQ1 mutant forms hetero-multimer and cause a dominant-negative effect due to trafficking defect

Noninvasive Tracking of Donor Cell Homing by Near-Infrared Fluorescence Imaging Shortly after Bone Marrow Transplantation

BACKGROUND: Many diseases associated with bone marrow transplantation (BMT) are caused by transplanted hematopoietic cells, and the onset of these diseases occurs after homing of donor cells in the initial phase after BMT. Noninvasive observation of donor cell homing shortly after transplantation is potentially valuable for improving therapeutic outcomes of BMT by diagnosing the early stages of these diseases. METHODOLOGY/PRINCIPAL FINDINGS: Freshly harvested near-infrared fluorescence-labeled cells were noninvasively observed for 24 h after BMT using a photon counting device to track their homing process. In a congenic BMT model, the homing of Alexa Fluor 750-labeled donor cells in the tibia was detected less than 1 h after BMT. In addition, subsequent cell distribution in an intraBM BMT model was successfully monitored for the first time using this method. In the allogeneic BMT model, T-cell depletion decreased the near-infrared fluorescence (NIRF) signals of the reticuloendothelial system. CONCLUSIONS/SIGNIFICANCE: This approach in several murine BMT models revealed that the transplanted cells homed within 24 h after transplantation. NIRF labeling is useful for tracking transplanted cells in the initial phase after BMT, and this approach can contribute to in vivo studies aimed at improving the therapeutic outcomes of BMT

Electrical Storm in Idiopathic Ventricular Fibrillation Is Associated With Early Repolarization

ObjectivesThis study sought to characterize patients with idiopathic ventricular fibrillation (IVF) who develop electrical storms.BackgroundSome IVF patients develop ventricular fibrillation (VF) storms, but the characteristics of these patients are poorly known.MethodsNinety-one IVF patients (86% male) were selected after the exclusion of structural heart diseases, primary electrical diseases, and coronary spasm. Electrocardiogram features were compared between the patients with and without electrical storms. A VF storm was defined as VF occurring ≥3 times in 24 h and J waves >0.1 mV above the isoelectric line in contiguous leads.ResultsFourteen (15.4%) patients had VF storms occurring out-of-hospital at night or in the early morning. J waves were more closely associated with VF storms compared to patients without VF storms: 92.9% versus 36.4% (p < 0.0001). VF storms were controlled by intravenous isoproterenol, which attenuated the J-wave amplitude. After the subsidence of VF storms, the J waves decreased to the nondiagnostic level during the entire follow-up period. Implantable cardioverter-defibrillator therapy was administered to all patients during follow-up. Quinidine therapy was limited, but the patients on disopyramide (n = 3), bepridil (n = 1), or isoprenaline (n = 1) were free from VF recurrence, while VF recurred in 5 of the 9 patients who were not given antiarrhythmic drugs.ConclusionsThe VF storms in the IVF patients were highly associated with J waves that showed augmentation prior to the VF onset. Isoproterenol was effective in controlling VF and attenuated the J waves, which diminished to below the diagnostic level during follow-up. VF recurred in patients followed up without antiarrhythmic agents

Role of Differential Signaling Pathways and Oxidative Stress in Diabetic Cardiomyopathy

Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy

Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan

金沢大学大学院医学系研究科We determined the alleles of five polymorphic molecules including HA-1 and four adhesion molecules for 106 patients transplanted with HLA-identical stem cell grafts and investigated the association of mismatches as correlates of relapse and graft-versus-host disease (GVHD). All 106 recipients underwent stem cell transplantation (SCT) after myeloablative conditioning between 1985 and 2002. Risk status of disease at SCT was standard (n = 63) and high (n = 42). After SCT, 36, 49 and 33 developed acute GVHD, chronic GVHD and relapsed, respectively. Our patients relapsed at rates of 16.7 and 38.6% with one or more and without incompatibilities (P = 0.013). The relapse rates of patients with CD62L, CD31 codon 563, CD31 codon 125, HA-1 and CD49b incompatibilities were 5.9, 11.8, 15.4, 16.0 and 33.3%, respectively. The frequency of acute GVHD did not differ regardless of incompatibilities. In standard-risk group, the accumulated relapse rates of 19 and 44 patients with and without minor histocompatibility antigen incompatibility were 22% and unexpectedly 66%, respectively (P = 0.02). The probability of 12-year survival was 88% in the former and 66% in the latter patients (P = 0.03). Our data suggest that incompatibility of CD62L, CD31 codon 563 and CD31 codon 125 contributes to a graft-versus-leukemia effect rather than to GVHD, resulting in prolonged survival after HLA-identical SCT

Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome Multicenter study in Japan

AbstractObjectivesWe sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1channel in the LQT1 form of congenital long QT syndrome (LQTS).BackgroundThe LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms.MethodsSixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes.ResultsPatients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005).ConclusionsIn this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations