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Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC., Methods and Results: We recruited children with left ventricular noncompaction from Japanese multi-institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy-associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0-6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate ( P =0.0009)., Conclusions: Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease-causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality-related cardiac phenotypes.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes., Methods: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values., Results: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight., Conclusions: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120., (© 2024. The Author(s).)

Background: Left ventricular noncompaction (LVNC) is morphologically characterized by numerous prominent trabeculations and a severely thickened, two-layered myocardium. The fetal onset of LVNC has rarely been described., Methods and results: We conducted nationwide retrospective surveys on fetal cardiomyopathy (CM) in Japan from 2010 to 2016, from which 38 fetal patients with CM were enrolled, including 16 patients with LVNC. The rate of diagnostic concordance was 56.3% between fetal and postnatal visits in LVNC patients. The increase in the ratio of noncompacted to compacted (N/C) myocardium was time-dependent throughout the fetal period till birth (LV lateral: 1.6±0.1 to 2.8±0.2; LV apex: 2.0±0.1 to 3.2±0.2). Of all fetuses, 16 (42.1%) died or underwent heart transplantation (HT), with 3 intrauterine deaths. Lower fetal cardiovascular profile score (odds ratio, 26.9; P=0.0266) was a risk factor for death or HT. N/C ratio ≥1.6 at the apex at the first visit was a significant predictor of LVNC (odds ratio, 47.8; P=0.0113)., Conclusions: This is the first study to reveal the etiology of fetal CM based on results from a nationwide survey in Japan, highlighting the difficulty of diagnosing LVNC in fetal patients. To better understand and manage fetal CM, novel diagnostic criteria of LVNC in fetus should be established.

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort., Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing., Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure., Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

Background: The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries)., Patients and Methods: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m 2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m 2 of oxaliplatin on day 1 and 80 mg/m 2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS)., Results: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05)., Conclusion: As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular noncompaction (LVNC) is a primary cardiomyopathy with heterogeneous genetic origins. The aim of this study was to elucidate the role of sarcomere gene variants in the pathogenesis and prognosis of LVNC., Methods and Results: We screened 82 Japanese patients (0-35 years old), with a diagnosis of LVNC, for mutations in seven genes encoding sarcomere proteins, by direct DNA sequencing. We identified variants in a significant proportion of cases (27%), which were associated with poor prognosis (p = 0.012), particularly variants in TPM1, TNNC1, and ACTC1 (p = 0.012). To elucidate the pathological role, we developed and studied human-induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p.Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Microarray analysis indicated that the TPM1 mutation resulted in the down-regulation of the expression of numerous genes involved in heart development, and positive regulation of cellular process, especially the calcium signaling pathway., Conclusions: Sarcomere genes are implicated as genetic triggers in the development of LVNC, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.

The risk of complication of polycythemia vera (PV) and essential thrombocythemia (ET) by thrombosis in Japanese patients is clearly lower than in western populations, suggesting that genetic background such as race may influence the clinical features. This study aimed to clarify the relationship between genetic mutations and haplotypes and clinical features in Japanese patients with PV and ET. Clinical features were assessed prospectively among 74 PV and 303 ET patients. There were no clinical differences, including JAK2V617F allele burden, between PV patients harboring the various genetic mutations. However, CALR mutation-positive ET patients had a significantly lower WBC count, Hb value, Ht value, and neutrophil alkaline phosphatase score (NAP), and significantly more platelets, relative to JAK2V617F-positive ET patients and ET patients with no mutations. Compared to normal controls, the frequency of the JAK246/1 haplotype was significantly higher among patients with JAK2V617F, JAK2Ex12del, or MPL mutations, whereas no significant difference was found among CALR mutation-positive patients. CALR mutation-positive patients had a lower incidence of thrombosis relative to JAK2V617F-positive patients. Our findings suggest that JAK2V617F-positive ET patients and CALR mutation-positive patients have different mechanisms of occurrence and clinical features of ET, suggesting the potential need for therapy stratification in the future., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: J waves can be observed in individuals of the general population, but electrocardiographic characteristics are poorly understood., Objective: The purpose of this study was to examine the J-wave dynamicity in a general patient population., Methods: The responses of J waves (>0.1 mV above the isoelectric line in 2 contiguous leads) to varying RR intervals were analyzed. Patients with aborted sudden cardiac death, documented ventricular fibrillation, or a family history of sudden cardiac death were excluded. The J-wave amplitude was measured at baseline, in beats with short RR intervals in conducted atrial premature beats (APBs) or atrial stimulation during the electrophysiology study, and in the beats next to APBs with prolonged RR intervals., Results: Mainly notched J waves were identified in 94 of 701 (24.5%) general patients (13.4%), and APBs were present in 23 of 94 (24.5%) patients. The mean baseline amplitude of J waves was 0.20 ± 0.06 mV at the baseline RR interval of 853 ± 152 ms, 0.25 ± 0.11 mV at the RR interval in the conducted APB of 545 ± 133 ms (P = .0018), and 0.19 ± 0.08 mV at the RR interval of 1146 ± 314 ms (P = .3102). The clinical characteristics were not different between patients with and without tachycardia-dependent augmentation of J waves. Augmentation of J waves was confirmed by the electrophysiology study: 0.28 ± 0.12 mV vs 0.42 ± 0.11 mV at baseline and in the beats of atrial stimulation, respectively (P = .0001). However, no bradycardia-dependent augmentation (>0.05 mV) was observed. Such tachycardia-dependent augmentation can represent depolarization abnormality rather than repolarization abnormality., Conclusion: J waves in a general patient population were augmented at shorter RR intervals, but not at prolonged RR intervals. Mechanistically, conduction delay is most likely responsible for this., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

As there is a risk of MTCT of HTLV-1, the HSGP HTLV-1 MTCT was organized in 2011. To determine how many pregnant women are infected with HTLV-1 in Hokkaido, which is the northernmost and the second largest island in Japan with a population of 5,467,000 and 39,392 newborns in 2011, the HSGP HTLV-1 MTCT asked all facilities that may care for pregnant women in Hokkaido in July 2013 to provide information on the number of pregnant women who underwent screening for anti-HTLV-1 antibody using particle agglutination or chemiluminescent enzyme immunoassay, and the numbers of those with positive, equivocal, and negative test results in the screening and confirmation tests using western blotting or PCR methods in 2012, respectively. A total of 111 facilities participated in this study and provided information on 33,617 pregnant women who underwent screening in 2012, corresponding to approximately 85% of all pregnant women who gave birth in Hokkaido in 2012. Of 81 candidates for a confirmation test because of positive (n = 77) or equivocal (n = 4) results on screening, 63 (78%) underwent the confirmation test and, finally, 34 (0.1%) and 33,563 (99.8%) women were judged to be HTLV-1 carriers and non-carriers, respectively. It was concluded that the prevalence rate of HTLV-1 carriers was low, one per 1000 pregnant women in Hokkaido. Approximately 40 infants are born yearly to mothers infected with HTLV-1 in Hokkaido., (© 2014 The Societies and Wiley Publishing Asia Pty Ltd.)

Controversies concerning the association between obesity and acute myocardial infarction (AMI) are still ongoing in Japan. We investigated the association between obesity defined by body mass index of 25 kg/m(2) or higher and AMI by a case-control study using data from 1199 AMI cases and 4056 apparently healthy controls. The analysis was performed in age- and sex-matched samples of 621 case-control pairs younger than 80 years and in crude samples aged 40-79 years divided into 10-year age groups. Prevalence of obesity, diabetes, current smoking, hypertension, and hypercholesterolemia were compared between cases and controls, and a multivariable odds ratio (OR) of AMI was calculated for each risk factor in various age groups. The OR (95 % confidence interval (CI)) of AMI for obesity was 1.63 (1.23-2.17), P = 0.0008 in men younger than 80 years; 2.65 (1.41-5.00), P = 0.0025 in women younger than 80 years; 2.23 (1.46-3.41), P = 0.0002 in men aged 59 years or younger; 1.34 (0.90-2.01), P = 0.1510 in men aged 60-79 years; and 2.98 (1.56-5.71), P = 0.0010 in women aged 60-79 years using paired samples. The OR (95 % CI) of AMI for obesity was 4.92 (2.53-9.58), P < 0.0001 in men aged 40-49 years; 1.54 (1.07-2.21), P = 0.0197 in men aged 50-59 years; 1.07 (0.69-1.66), P = 0.7717 in men aged 60-69 years; 2.24 (1.20-4.20), P = 0.0118 in men aged 70-79 years; 2.48 (1.12-5.48), P = 0.0245 in women aged 60-69 years; and 3.05 (1.46-6.37), P = 0.0029 in women aged 70-79 years using crude samples. The association between obesity and AMI was age- and gender-dependent in a Japanese population.

Aims: The prevalence, clinical significance, and pathogenesis of J-waves were studied in the patients with an ST-elevation myocardial infarction (MI) after percutaneous coronary intervention (PCI)., Methods and Results: One hundred and fifty-two consecutive patients with an acute ST-elevation MI were included. The mean age was 68.6 ± 13.5 years, and 78.3% of the patients were male. Following successful PCI, 12-lead electrocardiograms (ECGs) were monitored, and J-waves were measured 1 week after the MI and analysed in relation to the location of the MI and arrhythmias. Clinical and ECG parameters were compared between the groups with and without J-waves. The rate dependency of the J-wave amplitude was analysed in the conducted atrial premature beats (APBs). J-waves were present in 60.5% (≥0.1 mV) or 48.9% (≥0.2 mV) of the 152 patients. The J-waves were more often located in the inferior leads and more frequently in an inferior MI. The presence of J-waves was associated with ventricular arrhythmias, including ventricular fibrillation. The J-wave amplitude increased in the conducted APB, mechanistically suggesting a phase 3 block., Conclusion: Many patients in the early recovery phase after an acute MI had J-waves. This ECG phenomenon was associated with an increased incidence of ventricular arrhythmias. The tachycardia-dependent augmentation of the J-wave amplitude suggested a mechanistic role of conduction delay.

Background and Purpose: Some de- and re-polarization patterns can reflect an increased risk of ventricular tachyarrhythmias. We studied whether some electrocardiographic (ECG) patterns are able to predict the development of ventricular fibrillation (VF) during acute myocardial infarction (MI)., Methods: We compared the patterns of ST-T segment of 78 patients who developed VF during acute MI (patient with VF) vs 170 comparable patients with acute MI but with no VF complications., Results: Of the VF group, 47 developed out-of-hospital VF and 31 developed VF after their admission to the hospital. A steep downsloping ST segment toward a negative T wave with or without a short, flat, or rising portion at the initial portion was observed in 69.2% of the 78 patients: 61.3% in patients with pre-VF and 74.5% in patients with post-VF, vs 9.4% of patients who did not develop VF (P < .0001). In 90.6% of the latter, a typical upward-concave or convex "ischemic" pattern of the ST segment was observed. Thus, the characteristic ST-T patterns were highly associated with VF with a specificity greater than 90%., Conclusions: A steep downsloping ST segment may characterize the ECGs of patients who develop VF during acute MI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear., Methods and Results: This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels., Conclusions: We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

Background: On October 23, 2004, a major earthquake, which registered 6.8 on the Richter scale, occurred in Niigata Prefecture in Japan. Emotional stress is important as a trigger of transient left ventricular apical ballooning (so-called 'Takotsubo' cardiomyopathy), but its incidence and clinical profile immediately after a natural disaster have not been fully elucidated., Methods and Results: 'Takotsubo' cardiomyopathy was diagnosed in 16 patients (1 man, 15 women, mean age 71.5 years) within 1 month after the earthquake. Of them, 13 (81%) lived in areas where the Japan Meteorological Agency seismic intensity scale registered 6 or above, and 11 (69%) developed symptoms on the day of the earthquake. The incidence of 'Takotsubo' cardiomyopathy 1 month after the earthquake was approximately 24-fold higher near the epicenter than that before the earthquake., Conclusion: 'Takotsubo' cardiomyopathy can occur on the day of the earthquake in elderly women living near the epicenter.

The frequency of myocarditis and the prognosis for patients remains uncertain and, moreover, the clinical classification of myocarditis is controversial. From 1985 to 2000, 71 adult patients with clinically suspected myocarditis were admitted to 11 cardiovascular centers. Of these, 48 cases had histology proven myocarditis: 41 cases of lymphocytic myocarditis, 6 of giant cell myocarditis and 1 of eosinophilic myocarditis. Myocarditis was classified as acute (30 cases) or chronic (18 cases) according to the onset of the disease, and acute myocarditis was further categorized into common or fulminant type depending on whether or not patients required mechanical circulatory support in the management of heart failure (9 and 21 cases, respectively). Chronic myocarditis was divided into 3 subgroups: a persistent type lasting over 3 months after distinct onset (3 cases), a recurrent type (2 cases) and a latent form (13 cases). The early mortality of these 5 subtypes of myocarditis were acute common 22%, acute fluminant 43%, chronic persistent 33%, chronic recurrent 50%, and chronic latent 38%. The overall early mortality of all patients with myocarditis was 38% in spite of aggressive treatment during hospitalization. On the other hand, the long-term prognosis of patients with myocarditis was favorable; only 4 cases, who survived the active phase, died in the late phase: 1 had fulminant myocarditis and the other 3 had the chronic latent form. Thus, the early mortality of patients with myocarditis was very high regardless of the subtype, but if patients can survive the active phase, they have a favorable prognosis except with the chronic latent form.