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Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.

Background: Because adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts (CFs) synthesize extracellular matrix after myocardial infarction (MI) to form fibrosis, leading to cardiac dysfunction and heart failure. Therapies that can regenerate the myocardium and reverse fibrosis in chronic MI are lacking. The overexpression of cardiac transcription factors, including Mef2c/Gata4/Tbx5/Hand2 (MGTH), can directly reprogram CFs into induced cardiomyocytes (iCMs) and improve cardiac function under acute MI. However, the ability of in vivo cardiac reprogramming to repair chronic MI with established scars is undetermined. Methods: We generated a novel Tcf21 iCre /reporter/MGTH2A transgenic mouse system in which tamoxifen treatment could induce both MGTH and reporter expression in the resident CFs for cardiac reprogramming and fibroblast lineage tracing. We first tested the efficacy of this transgenic system in vitro and in vivo for acute MI. Next, we analyzed in vivo cardiac reprogramming and fusion events under chronic MI using Tcf21 iCre /Tomato/MGTH2A and Tcf21 iCre /mTmG/MGTH2A mice, respectively. Microarray and single-cell RNA sequencing were performed to determine the mechanism of cardiac repair by in vivo reprogramming. Results: We confirmed the efficacy of transgenic in vitro and in vivo cardiac reprogramming for acute MI. In chronic MI, in vivo cardiac reprogramming converted ≈2% of resident CFs into iCMs, in which a majority of iCMs were generated by means of bona fide cardiac reprogramming rather than by fusion with cardiomyocytes. Cardiac reprogramming significantly improved myocardial contraction and reduced fibrosis in chronic MI. Microarray analyses revealed that the overexpression of MGTH activated cardiac program and concomitantly suppressed fibroblast and inflammatory signatures in chronic MI. Single-cell RNA sequencing demonstrated that resident CFs consisted of 7 subclusters, in which the profibrotic CF population increased under chronic MI. Cardiac reprogramming suppressed fibroblastic gene expression in chronic MI by means of conversion of profibrotic CFs to a quiescent antifibrotic state. MGTH overexpression induced antifibrotic effects partly by suppression of Meox1, a central regulator of fibroblast activation. Conclusions: These results demonstrate that cardiac reprogramming could repair chronic MI by means of myocardial regeneration and reduction of fibrosis. These findings present opportunities for the development of new therapies for chronic MI and heart failure.

While right ventricular (RV) involvement is commonly observed in patients with cardiac sarcoidosis (CS), the utility of strain imaging to detect RV involvement is unclear. We aimed to investigate the association between RV free wall longitudinal strain (RVFWLS) and cardiovascular events in patients with CS.We studied 51 patients with CS who were diagnosed between 2012 and 2020. All patients underwent comprehensive echocardiographic evaluation, and RVFWLS was assessed using 2-dimensional speckle tracking echocardiography. The primary outcome was major adverse cardiovascular events (MACEs).During a median follow-up duration of 548 days, 11 patients exhibited MACEs. In the univariable Cox proportional hazards model, the baseline RVFWLS was associated with MACEs (hazard ratio: 1.29, p = 0.008). The addition of RVFWLS to the conventional echocardiographic parameters exhibited a significant incremental value associated with MACEs. Patients with reduced RVFWLS showed a higher prevalence of late gadolinium enhancement on cardiac magnetic resonance imaging in RV wall (p = 0.02) and trends toward higher prevalence of fluorodeoxyglucose uptake in RV (p = 0.06). A serial echocardiographic evaluation revealed that patients with events showed a worsening in RVFWLS, while others showed a trend toward improvement.Impaired RVFWLS at baseline was associated with MACEs in patients with CS. RVFWLS could be an important surrogate of disease activity and prognosis by detecting active RV involvement in CS.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

To investigate the relationship between periprocedural myocardial injury (PMI) and plaque characteristics detected by multidetector computed tomography (MDCT) and cardiac magnetic resonance imaging (CMR).This observational retrospective study, between July 2012 and October 2019, included chronic coronary syndrome patients undergoing elective percutaneous coronary intervention (PCI) after MDCT and CMR. High-intensity plaque (HIP) on non-contrast T1-weighted imaging was defined as a coronary plaque-to-myocardium signal intensity ratio of ≥ 1.4. High-risk plaque (HRP) in MDCT displayed ≥ 2 features: positive remodeling, low-attenuation plaque, spotty calcification, and napkin-ring sign. PMI was defined as an increase in cardiac troponin T levels5 times the upper normal limit at 24 h after PCI.Ninety-five target lesions in 76 patients (mean age ± standard deviation, 67 years ± 9; 62 males [82%]) were included. Twenty-one patients (24 lesions) were assigned to the PMI group, while 55 patients (71 lesions) to the non-PMI group. Presence of HRP characteristics on MDCT and HIP on CMR was significantly higher in the PMI group. Multivariate logistic regression analysis showed that HRP in MDCT and HIP in CMR were significant independent predictors of PMI. Target lesions with HRP on MDCT and HIP on CMR were significantly more likely to develop PMI. In 141 plaques with ≥ 50% stenosis (76 patients), patients with PMI had significantly more frequent HRP in MDCT and HIP in CMR in target and non-target lesions.MDCT and CMR can play an important role in the detection of high-risk lesions for PMI following elective PCI.• Multivariate logistic regression analysis showed that high-risk plaque on MDCT and high-intensity plaque on MRI were significant independent predictors of periprocedural myocardial injury (PMI). • Target lesions with high-risk plaque on MDCT and high-intensity plaque on CMR were significantly more likely to develop PMI. • In 141 plaques with ≥ 50% stenosis, patients with PMI were significantly more likely to have high-risk plaques on MDCT and high-intensity plaque on CMR in target and non-target lesions.

Specific pacing methods to unmask the existence of the dual atrioventricular (AV) nodal pathway in patients with dual AV nodal non-reentrant tachycardia remain to be established.This study aimed to determine the electrophysiological characteristics of dual AV nodal non-reentrant tachycardia by its responses to specific pacing methods.Five patients diagnosed as having dual AV nodal non-reentrant tachycardia were retrospectively investigated.Atrial pacing could not induce the clinical tachycardia as continuous double firing in any of the 5 patients, but did induce sudden prolongation of the A-H interval as the linking phenomenon in 1 patient. A single atrial extrastimulation after sinus excitations was performed without interruption of double firing in 1 patient, and it induced the double ventricular response phenomenon within the limited range of the extrastimulus intervals. The pacing method of AV simultaneous basic pacing preceding atrial programmed extrastimulation did not allow interruptions of double firing during the basic drive trains and induced the double ventricular response phenomenon within the limited range of the extrastimulus intervals in all 5 patients, even in 1 patient without inducibility of the clinical tachycardia in the catheterization laboratory. The double ventricular response phenomenon within the limited range of the extrastimulus intervals may be based on the existence of the dual AV nodal pathway with concealed retrograde penetration.The AV simultaneous basic pacing preceding atrial programmed extrastimulation method consistently and reproducibly unmasked the existence of the dual AV nodal pathway as the double ventricular response phenomenon in patients with dual AV nodal non-reentrant tachycardia.

Perioperative atrial fibrillation is a common postoperative complication. Adverse consequences associated with POAF include hemodynamic instability, increased risk of stroke, extended hospital stays, and increased mortality.To determine the risk factors for POAF and to investigate the outcomes of POAF for patients with cancer, a systematic search of the PubMed and Cochrane Library databases was conducted from inception of the study to 1 September 2021. The inclusion criteria specified studies reporting the prevalence of POAF among patients with cancer. The study excluded articles not written in English, review articles, case reports, letters, commentaries, systematic reviews, meta-analyses, and conference abstracts.The search identified 49 studies with 201,081 patients, and the pooled prevalence of POAF was 13.5% (95% confidence interval [CI], 11.6-15.7%). Meta-analyses showed that the incidence of POAF among patients with cancer was associated with age (mean difference [MD], 4.31; 95%CI, 3.16-5.47), male sex (odds ratio [OR], 1.39; 95% CI, 1.19-1.62), chronic obstructive pulmonary disease (OR, 2.47; 95% CI, 1.71-3.56), hypertension (OR, 1.47; 95% CI, 1.23-1.75), intraoperative blood transfusion (OR, 4.58; 95% CI, 2.31-9.10), and open surgery (OR, 1.51; 95% CI, 1.26-1.81). Patients with POAF had significantly higher in-hospital mortality (OR, 4.25; 95% CI, 2.79-6.45), longer hospital stays (MD, 3.07; 95% CI, 1.63-4.51), and higher incidences of pneumonia (OR, 3.32; 95% CI, 2.85-3.86), stroke (OR, 6.57; 95% CI, 1.56-26.00), and myocardial infarction (OR, 3.00; 95% CI, 1.45-6.20) than those without POAF.For patients with cancer, POAF is associated with an increased burden of comorbidities and worse outcomes.

Pulmonary arterial hypertension (PAH) is characterized by abnormal outgrowth of pulmonary artery smooth muscle cells (PASMCs) of the media. Abundant expression of endothelin-1 (ET-1) and activated p38 mitogen-activated protein kinase (p38MAPK) has been observed in PAH patients. p38MAPK has been implicated in cell proliferation. An unspecified disturbance in bone morphogenetic protein (BMP) signaling may be involved in the development of PAH. Type I receptors (BMPR1A and BMPR1B) and type II receptor (BMPR2) transduce signals via two distinct pathways, i.e., canonical and non-canonical pathways, activating Smad1/5/8 and p38MAPK, respectively. BMPR1B expression was previously reported to be enhanced in the PASMCs of patients with idiopathic PAH. BMP15 binds specifically to BMPR1B. We assessed the effects of ET-1 on BMP receptor expression and cell proliferation. BMP2 increased BMPR1B expression in human PASMCs after pretreatment with ET-1 in vitro. Although BMP2 alone did not affect PASMC proliferation, BMP2 treatment after ET-1 pretreatment significantly accelerated PASMC proliferation. PH-797804, a selective p38MAPK inhibitor, abrogated this proliferation. Similarly, after ET-1 pretreatment, BMP15 significantly accelerated the proliferation of PASMCs, whereas stimulation with BMP15 alone did not. In conclusion, in PASMCs, ET-1 exposure under pathological conditions alters BMP signaling to activate p38MAPK, resulting in cell proliferation.

Left-ventricular (LV) global longitudinal strain (GLS) has been reported to be a robust and sensitive marker of chemotherapy-induced cardiac damage. Image quality is paramount for accurate GLS measurements. In real-world cardio-oncology settings, the incidence of suboptimal echocardiography quality and its significance in clinical decision-making have not been well investigated. This prospective study examined the incidence and impact of suboptimal echocardiographic image quality on detecting subtle myocardial damage by chemotherapy.Seventy-seven consecutive patients with breast cancer (age, 52 ± 12 years, 76 women, 33 with left-sided breast cancer) were included in this study. Echocardiography was performed at 3-month intervals 1 year before and after chemotherapy initiation. We classified the image quality of each echocardiographic acquisition into three groups: optimal, suboptimal, or inadequate for speckle tracking.Among the 376 examinations obtained during the cardiac monitoring, the image quality in 194 (52%) was optimal, suboptimal in 159 (42%), and inadequate in 23 (6%). The interobserver reproducibility was 0.91 in the optimal and 0.21 in the suboptimal group. In contrast, the optimal group showed progressive impairment in both GLS (p = 0.001) and LV ejection fraction (LVEF) (p 0.001) during follow-up, and the suboptimal group showed a progressive decrease in LVEF (p = 0.006), but not in GLS (p = 0.13). Left-sided mammotomy and/or reconstruction surgery and high body mass index were significant determinants of suboptimal image quality.Even in cases of minor image quality impairment, the physician should assess GLS carefully to avoid errors in crucial clinical decision-making.

Cardiovascular diseases are a common cause of death worldwide. Adult cardiomyocytes have limited regenerative capacity after injury, and there is growing interest in cardiac regeneration as a new therapeutic strategy. There are several limitations of induced pluripotent stem cell-based transplantation therapy with respect to efficiency and risks of tumorigenesis. Direct reprogramming enables the conversion of terminally differentiated cells into target cell types using defined factors. In most cardiac diseases, activated fibroblasts proliferate in the damaged heart and contribute to the progression of heart failure. In vivo cardiac reprogramming, in which resident cardiac fibroblasts are converted into cardiomyocytes in situ, is expected to become a new cardiac regenerative therapy. Indeed, we and other groups have demonstrated that in vivo reprogramming improves cardiac function and reduces fibrosis after myocardial infarction. In this review, we summarize recent discoveries and developments related to in vivo reprogramming. In addition, issues that need to be resolved for clinical application are described.

BACKGROUND Left atrial (LA) global strain has been studied as an early marker of LA dysfunction, followed by LA dilatation. Recently, a novel dedicated software for LA 3-dimensional speckle tracking echocardiography (LA-3DSTE) has allowed us to assess anatomy-based six-segmental LA deformation. This study aimed to assess the accuracy of LA-3DSTE software in measuring LA volume and to reveal the characteristics of regional LA reservoir strain. METHODS Fifty patients with paroxysmal atrial fibrillation who underwent computed tomography (CT) and 3D-STE were enrolled. The LA volumes obtained by 3D-STE and CT were compared, and regional LA strain was analyzed. Six LA segments (anterior, septal, inferior, lateral, roof, and posterior) were determined on the basis of LA anatomy. RESULTS In 50 patients (mean age, 64 years; 62% male), the 3D-STE-derived LA volume index (LAVI) showed good correlation with the CT-derived index, (r = 0.78, p < 0.001) with an underestimate bias of 10.5 ± 11.0 ml/m2 (p < 0.001). The lateral LA strain was negatively correlated with LAVI and emptying fraction, while the anterior and septal strains were not. In the 1st quantile LA volume group, the segmental LA strain was heterogeneous, that is, the lateral and inferior strains were greater than the anterior strain. While in the 3rd quantile LA volume group, the lateral and inferior strains were decreased, and there was no regional difference. CONCLUSION LA volume obtained by 3D-STE and CT showed a good correlation. LA segmental analysis by 3D-STE enables early identification of how LA dysfunction affects lateral and inferior LA strains, consistent with anatomical features.

Amiodarone and its main metabolite, desethylamiodarone, are highly distributed to serum lipoproteins such as very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and desethylamiodarone with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and desethylamiodarone were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration-to-dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs = 0.541, P < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, P < 0.001). No correlation was found between the C/D ratio of desethylamiodarone and serum triglyceride levels (rs = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, P < 0.001). In hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high-density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum desethylamiodarone, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs = 0.572, P < 0.001) and was higher in hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in hypertriglyceridemic state through the increased lipoproteins-binding and decreased metabolism of amiodarone.

Brain or B-type natriuretic peptide (BNP) is an objective marker to diagnose the presence of heart failure (HF) and assess its severity. However, the determinants of serum BNP level in elderly patients with severe aortic valve stenosis (AS) referred for transcatheter aortic valve implantation (TAVI) have not been well investigated.We prospectively studied 106 AS patients who underwent TAVI. Cardiac catheterization, transesophageal echocardiography, and blood collection for plasma BNP level measurements were performed simultaneously just before the TAVI procedures.Ninety-nine patients (83.9±5.0 years, 33% male) were studied. The natural logarithm of BNP (lnBNP) level was 5.4±0.9 pg/mL. Significant correlations with lnBNP level were observed in: 1) the history of syncope, prior HF medication, and New York Heart Association class III or IV (R=0.255, p=0.011) (R=0.210, p=0.037) (R=0.402, p0.001), 2) albumin and hemoglobin level (R=-0.289, p=0.004) (R=0.263, p=0.009), 3) Left ventricular (LV) ejection fraction and global longitudinal strain (LVGLS) (R=-0.338, p0.001) (R=0.447, p0.001), 4) LV end-diastolic volume index (EDVI), LV mass index, and left atrial volume index (R=0.280, p=0.005) (R=0.366, p0.001) (R=0.337, p0.001), 5) the catheter-measured pressure gradient across the aortic valve (AVPG) (R=0.365, p0.001). Note that LV wall stress was not significantly correlated with lnBNP level. LVGLS, AVPG, hemoglobin level, and LVEDVI were independently correlated with ln BNP level (R=0.652, LVGLS; β=0.395, p0.006, AVPG; β=0.291, p=0.001, hemoglobin level; β=-0.216, p=0.011, and LVEDVI; β=0.203, p=0.016, respectively).In severe AS patients candidate for TAVI, multiple factors, including the severities of AS and HF conditions and subclinical LV dysfunction determined by LVGLS affects plasma BNP level.

Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is a targeted drug used for the treatment of non-small cell lung cancer (NSCLC). Erlotinib is considered relatively safe and generally well-tolerated, with rarely reported cardiac side effects. Herein, we report a case of cardiomyopathy that developed during erlotinib treatment for NSCLC. Two months after erlotinib initiation, our 70 year-old female patient complained of progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating erlotinib-induced cardiomyopathy. We believed that continued administration of erlotinib would exacerbate her heart failure, while treatment of the heart failure with intensive monitoring would allow the administration of erlotinib to be continued. This case report highlights the potential cardiotoxic effects of erlotinib and suggests the need for close clinical and echocardiographic follow-up of patients receiving erlotinib.

Historically, a right bundle branch block has been considered a benign finding in asymptomatic individuals. However, this conclusion is based on a few old studies with small sample sizes. We examined the association between a complete right bundle branch block (CRBBB) and subsequent cardiovascular mortality in the general population in Japan. In this large community-based cohort study, data of 90,022 individuals (mean age, 58.5 ± 10.2 years; 66.2% women) who participated in annual community-based health check-ups were assessed. Subjects were followed up from 1993 to the end of 2016. Cox proportional hazards’ models and log-rank tests were used for the data analysis. CRBBB was documented in 1,344 participants (1.5%). Among all included participants, CRBBB was associated with an increased risk of cardiovascular mortality after adjustment for all potential confounders (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.06–1.38). The increased risk of cardiovascular mortality was particularly evident in women aged

Elevated central venous pressure (CVP) in heart failure causes renal congestion, which deteriorates prognosis. Sodium glucose co-transporter 2 inhibitor (SGLT2-i) improves kidney function and heart failure prognosis; however, it is unknown whether they affect renal congestion. This study investigated the effect of SGLT2-i on the kidney and left ventricle using model rats with hypertensive heart failure.Methods and Results: Eight rats were fed a 0.3% low-salt diet (n=7), and 24 rats were fed an 8% high-salt diet, and they were divided into 3 groups of untreated (n=6), SGLT2-i (canagliflozin; n=6), and loop diuretic (furosemide; n=5) groups after 11 weeks of age. At 18 weeks of age, CVP and renal intramedullary pressure (RMP) were monitored directly by catheterization. We performed contrast-enhanced ultrasonography to evaluate intrarenal perfusion. In all high-salt fed groups, systolic blood pressure was elevated (P=0.287). The left ventricular ejection fraction did not differ among high-salt groups. Although CVP decreased in both the furosemide (P=0.032) and the canagliflozin groups (P=0.030), RMP reduction (P=0.003) and preserved renal medulla perfusion were only observed in the canagliflozin group (P=0.001). Histological analysis showed less cast formation in the intrarenal tubule (P=0.032), left ventricle fibrosis (P0.001), and myocyte thickness (P0.001) in the canagliflozin group than in the control group.These results suggest that SGLT2-i causes renal decongestion and prevents left ventricular hypertrophy, fibrosis, and dysfunction.

Objectives This study sought to demonstrate a new type of verapamil-sensitive fascicular ventricular tachycardia (VT) with a reverse circuit. Background Left posterior fascicular ventricular tachycardia (LPFVT) is the most common form of verapamil-sensitive fascicular VT. Reverse-type LPFVT has not been reported. Methods We searched for a reverse-type LPFVT among 242 patients with verapamil-sensitive VT from February 2006 to September 2019. Results Three patients had a reverse-type LPFVT (cycle lengths: 340, 360, and 340 ms). QRS configuration during VT was narrow (140, 150, and 140 ms) and exhibited rSr’ morphology in V1 with an early precordial transition and inferior axis. Two of 3 patients had common-type LPFVT. During reverse-type LPFVT, the earliest ventricular activation was the left superior middle septum. Fragmented Purkinje potentials (P1) buried within the local ventricular electrogram were recorded with an activation sequence from the apex to the base and were linked to the subsequent left ventricular septal activation. After radiofrequency catheter ablation at P1 during LPFVT, the reverse-type LPFVT also became noninducible. In 1 patient with only the reverse-type LPFVT, radiofrequency catheter ablation at the earliest LV activation site suppressed VT. These findings suggest that this new type of verapamil-sensitive fascicular VT shares a re-entrant circuit with a reverse direction of common LPFVT with an intramural exit site at the superior middle septum. Conclusions Reverse-type LPFVT can occur. If common LPFVT exists, diastolic P1 during LPFVT can be a common target of ablation. If only reverse-LPFVT is inducible, the earliest ventricular activation site can be a target.

Background RE-CIRCUIT (NCT02348723) and ABRIDGE-J (UMIN000013129) are recently published randomized clinical trials showing that anticoagulation therapy with dabigatran during the periprocedural period of catheter ablation (CA) for atrial fibrillation (AF) was associated with fewer complications. However, the dabigatran administration protocols were different (uninterrupted in RE-CIRCUIT and minimally interrupted in ABRIDGE-J). The aim of this present study was to clarify the optimal interruption time of dabigatran Oral administration to Ablation (O-A time). Methods We conducted an integrated analysis of the 2 prospective trials. The endpoint of the study was the incidence of major bleeding events during and up to 8 weeks after CA across participants with different O-A times. Results The 535 patients in the dabigatran groups of the 2 trials were divided into 3 groups based on their O-A times ( 24 h, n = 86). Major bleeding events occurred in 5 patients (1.9%) in the 24 h group; however, no major bleeding events occurred in the 8–24 h group (3 group-comparison, p = 0.026). No thromboembolic complication was observed in any of the 3 O-A time groups. Conclusion In patients undergoing CA for AF using dabigatran as a periprocedural anticoagulant, an O-A time of 8–24 h was associated with no bleeding complications. These data suggest that an O-A time of 8–24 h may be an appropriate option, especially in a low thromboembolic-risk patient.

Radiofrequency catheter ablation (RFCA) is the primary choice for treating patients with an accessory pathway and atrioventricular re-entrant tachycardia. However, using RFCA to treat a right-sided accessory pathway in a patient with Ebstein anomaly can be difficult owing to challenges in locating the electrophysiological atrioventricular groove. We report a case of atrioventricular re-entrant tachycardia in a patient with Ebstein anomaly and a right-sided accessory pathway that was successfully treated using RFCA and 3-dimensional (3D) high-density mapping. RFCA and 3D mapping may be useful in the management of such cases and may aid in improving prognoses of patients.

Electrocardiogram (ECG) findings showing ST-segment depression in a wide range of leads and ST-segment elevation in aVR are found in patients with acute coronary syndrome with multivessel coronary lesions and left main trunk lesions. A 64-year-old man with a history of eosinophilic granulomatosis presented with chest pain and dyspnea. Although an ECG showed the above findings, he was diagnosed with acute severe aortic regurgitation (AR) complicating aortic root dissection and successfully underwent urgent Bentall operation. These ECG findings indicated that acute severe AR caused subendocardial ischemia.

Electron microscopy enables a finely detailed analysis of ultra-structural features, and hence, it generally has an added diagnostic value to light microscopy alone. However, no studies have verified the additional diagnostic value of electron microscopic examination in patients with suspected non-ischemic cardiomyopathy.A total of 294 consecutive patients with non-ischemic cardiomyopathy who underwent endomyocardial biopsy were prospectively enrolled. Patients were divided into three groups according to left ventricular morphology assessed using echocardiography. Myocardial specimens were collected from the right ventricular septum and examined by light microscopy. Electron microscopy was performed subsequently to evaluate the additional diagnostic value.Altogether, 294 patients were analyzed, including 160 (55 %), 96 (33 %), and 35 (12 %) patients who were diagnosed with primary, secondary, and unclassified cardiomyopathy, respectively. In patients with dilated cardiomyopathy-like morphology, the detection rate of disease-specific histological findings was relatively low compared to that in patients with other cardiac morphologies. The additional diagnostic value of electron microscopy was observed in eight patients, including five with Fabry disease, one with cardiac amyloidosis, one with mitochondrial cardiomyopathy, and one with triglyceride deposit cardiomyovasculopathy. Among the 18 cardiac amyloidosis cases, electron microscopy detected amyloid fibrils in all patients, whereas light microscopy could not detect amyloid deposition in 1 patient. Among one of five patients with Fabry disease, light microscopy did not show obvious vacuolated cardiomyocytes, but zebra bodies were detected by electron microscopy, leading to the diagnosis of cardiac Fabry disease. The diagnostic value of electron microscopic examination in patients with cardiac sarcoidosis was not observed.The additional diagnostic value of electron microscopy was observed in patients with secondary cardiomyopathy, in whom light microscopy did not show disease-specific histological findings. Electron microscopy should be performed in cases where secondary cardiomyopathy is strongly suspected with no disease-specific findings by light microscopy.

We herein report three patients with cardiac angiosarcoma who were directly admitted to the intensive-care unit for hemodynamic instability with circulatory collapse. Using a multidisciplinary cardio-oncologic approach, we diagnosed their condition as angiosarcoma by an invasive biopsy and urgently started weekly paclitaxel administration despite their poor performance status. Their vital signs were soon stabilized, leading to the patients’ discharge from the hospital. Although no treatment guidelines for cardiac angiosarcoma have been established, chemotherapy with paclitaxel can be an option for cases presenting with hemodynamic instability.

Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.

BACKGROUND The relationship between the characteristics of tissue protrusion detected by using optical coherence tomography (OCT) and the findings of coronary angioscopy (CAS) immediately after stent implantation were evaluated.Methods and Results:A total of 186 patients (192 stents) underwent OCT before and after stenting and were observed by using CAS immediately after stenting and at the chronic phase. Patients were assigned to irregular protrusion, smooth protrusion, and disrupted fibrous tissue protrusion groups according to OCT findings. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured before and after stent implantation. The grade of yellow color (YC) and neointimal coverage (NC), and incidence of thrombus in the stented segment were evaluated by using CAS. After stent implantation, maximum YC grade (smooth, 0.64±0.80; disrupted fibrous tissue, 0.50±0.77; irregular, 1.50±1.09; P

Background The new guideline (NG) published by the Japanese Circulation Society (JCS) places emphasis on previous arrhythmic syncope and inducibility of ventricular fibrillation (VF) by ≤2 extrastimuli during programmed electrical stimulation (PES) for deciding the indication of an implantable cardioverter-defibrillator in patients with Brugada syndrome (BrS). This study evaluated the usefulness of the NG and compared it with the former guideline (FG) for risk stratification of patients with BrS.Methods and Results:This was a multicenter (7 Japanese hospitals) retrospective study involving 234 patients with BrS who underwent PES at baseline (226 males; mean age at diagnosis: 44.9±13.4 years). At diagnosis, 46 patients (20%) had previous VF, 100 patients (43%) had previous syncope, and 88 patients (37%) were asymptomatic. We evaluated the difference in the incidence of VF in each indication according to the new and FGs. During the follow-up period (mean: 6.9±5.2 years), the incidence of VF was higher in patients with Class IIa indication according to the NG (NG: 16/45 patients [35.6%] vs. FG: 16/104 patients [15.4%]), while the incidence of VF in patients with other than class I or IIa indication was similarly low in both guidelines (NG: 2/143 patients [1.4%] vs. FG: 2/84 patients [2.4%]). Conclusions This study validated the usefulness of the NG for risk stratification of BrS patients.

Catheter ablation is a therapeutic option to suppress ventricular tachycardia (VT) in the setting of dilated-phase hypertrophic cardiomyopathy (DHCM). However, the characteristics of the arrhythmogenic substrate and the ablation outcome are not fully illustrated.A total of 23 ablation procedures for drug-refractory sustained monomorphic VTs in 13 DHCM patients (60 ± 11 years, one female, the left ventricular [LV] ejection fraction 39% ± 9%, the LV mass index 156 ± 39 g/mTwo patients underwent ablation of sustained monomorphic VT that was not scar-mediated tachycardia. Of the remaining 11 patients, eight (73%) patients had VT substrate in the basal regions, most frequently at the epicardial and/or intramural basal antero-septum. None of the patients had VT substrate located at the LV inferolateral region. Ablation at the right ventricular septum and the aortic cusps was done in four and five patients, respectively. Other approaches including bipolar and chemical ablations, were done in three and two patients, respectively. Six (55%) out of 11 patients (two patients lost follow-up) had VT recurrence. All the six patients had basal substrate. However, anti-tachycardia pacing was sufficient for VT termination except in one patient.Catheter ablation of VT in patients with DHCM is challenging because of the predominant basal anteroseptal epicardial/intramural location of arrhythmogenic substrate. An ablation approach from multiple sites and/or adjunctive interventional techniques are often required.

Background and Purpose: Isorhamnetin, a natural flavonoid, has strong antioxidant and anti-fibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). This study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Experimental Approach: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII-and isorhamnetin-treated groups. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Key Results: Isorhamnetin decreased AF inducibility compared to the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. Conclusion and Implications: The findings of this study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling via modulating CaMKII-RyR2 and TRPC-mediated MAPK pathways, highlighting its potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Identifying the optimal atrioventricular (AV) or interventricular (VV) delay is beneficial for patients using cardiac resynchronization therapy (CRT) devices. Ultrasonic echocardiography (UCG) has been the most commonly used method; however, it requires high technical knowledge. Impedance cardiography (ICG) can calculate stroke volume by measuring changes in transthoracic electric impedance. This study sought to assess the clinical utility of ICG in comparison with that of UCG for the optimization of CRT devices.Patients who underwent CRT device implantation were retrospectively analyzed. One week after implantation, optimization of AV delay (AVD) was performed in every patient with ICG (AVD-ICG) and UCG (AVD-UCG). VV delay (VVD) was then determined according to the optimal AVD using these two methods.Forty-two patients were enrolled. Average AVD-ICG was significantly shorter than AVD-UCG (128 ± 49 versus 146 ± 41 milliseconds, P = 0.018). Five patients (12%) had the same optimized AVD with two methods, and the difference between AVD-ICG and AVD-UCG was ≤ 20 milliseconds in 19 patients (45%). In the multivariate analysis, the presence of postoperative mitral regurgitation (MR) was an independent predictor of AVD-ICG/AVD-UCG mismatch, defined as a difference over 20 milliseconds (odds ratio = 10.71; 95% confidence interval = 1.72 to 66.72; P = 0.018). The results of optimized VVD were similar using both methods.ICG might be a promising tool for the rapid optimization of CRT devices. However, in patients with moderate-to-severe MR, ICG may not be able to optimize AVD.

Summary Direct cardiac reprogramming holds great potential for regenerative medicine. However, it remains inefficient, and induced cardiomyocytes (iCMs) generated in vitro are less mature than those in vivo, suggesting that undefined extrinsic factors may regulate cardiac reprogramming. Previous in vitro studies mainly used hard polystyrene dishes, yet the effect of substrate rigidity on cardiac reprogramming remains unclear. Thus, we developed a Matrigel-based hydrogel culture system to determine the roles of matrix stiffness and mechanotransduction in cardiac reprogramming. We found that soft matrix comparable with native myocardium promoted the efficiency and quality of cardiac reprogramming. Mechanistically, soft matrix enhanced cardiac reprogramming via inhibition of integrin, Rho/ROCK, actomyosin, and YAP/TAZ signaling and suppression of fibroblast programs, which were activated on rigid substrates. Soft substrate further enhanced cardiac reprogramming with Sendai virus vectors via YAP/TAZ suppression, increasing the reprogramming efficiency up to ∼15%. Thus, mechanotransduction could provide new targets for improving cardiac reprogramming., Graphical Abstract, Highlights • Hydrogel culture reveals the role of mechanotransduction in cardiac reprogramming • Soft ECM comparable with native myocardium promotes cardiac reprogramming • Soft ECM promotes cardiac reprogramming via YAP/TAZ/fibroblast signaling inhibition • Soft ECM promotes Sendai virus vector-mediated cardiac reprogramming, In this article, Ieda and colleagues showed that a soft matrix, which is comparable with native myocardium, efficiently promoted cardiac reprogramming. This soft matrix enhanced cardiac reprogramming via inhibition of integrin, Rho/ROCK, actomyosin, and YAP/TAZ signaling and subsequent suppression of fibroblast programs, which were activated on conventional rigid substrates, thus demonstrating that mechanotransduction plays a critical role in cardiac reprogramming.

Background Interruption in Doppler intrarenal venous flow (IRVF) has been used in assessing renal congestion and in the prediction of prognosis of cardiovascular diseases. However, there is a paucity of pathophysiological knowledge, so we aimed to clarify the determinants of IRVF interruption.Methods and Results:Intrarenal Doppler studies were performed within 24 h before right-side catheterization studies. The interruption in IRVF in 73 patients was divided into a continuous pattern, and 4 discontinuous types based on the timing of interruption. Type 1, with an interruption in early systole, was associated with a-wave elevation of right atrial pressure (RAP). Type 2, with an interruption in early diastole, was associated with v-wave elevation, tricuspid regurgitation (TR), and right ventricular dysfunction. Both Type 1 and 2 were observed even in the normal range of mean RAP. Type 3, with an interruption throughout systole, was observed in advanced right heart failure patients with markedly elevated RAP, particularly elevated x-descend and atrial fibrillation. Finally, Type 4, with limited flow at systole, was observed in 2 of the patients with pulmonary arterial hypertension. Conclusions IRVF interruption was closely related to RAP elevation at each specific point of the cardiac cycle rather than to mean RAP levels, suggesting that the characteristics of IRVF mirror right-sided heart hemodynamics, not mean RAP.

Background Ablation of the pulmonary vein (PV) carina is occasionally required for PV isolation (PVI). Marshall bundle and epicardial connections between the right-sided PV (RtPV) carina and right atrium (RA) may be one of the mechanisms that necessitates carina ablation. Objective We sought to clarify anatomical characteristics predictive of the necessity of carina ablation. Methods Forty-five consecutive patients undergoing radiofrequency catheter ablation of atrial fibrillation were prospectively included in this study. Left atrial (LA) and PV size and morphology, and interatrial distance in the posterior aspect, were measured on cardiac computed tomography (CT) images. Results For right-sided PVI, the patients were divided into 2 groups based on the necessity of RtPV carina ablation, Carina-ABL group (n = 21) and Non-Carina-ABL group (n = 24). The distance between the anterior portion of the RtPV carina and RA was shorter in the Carina-ABL group vs in the Non-Carina-ABL group (7.7 ± 1.7 mm/m2 vs 9.5 ± 2.3 mm/m2; P = .005), whereas other anatomical parameters (LA and RA volumes, right inferior PV angle, and ostial diameters of the RtPVs) did not differ between the groups. For left-sided PVI, the ostial diameter and circumference of the left superior PV were smaller in the Carina-ABL group (n = 13) vs the Non-Carina-ABL group (n = 32) (8.6 ± 2.1 mm/m2 vs 7.3 ± 1.5 mm/m2; P = .044, and 34.9 ± 6.0 mm/m2 vs 30.1 ± 5.1 mm/m2; P = .017, respectively). Conclusions A shorter interatrial distance for right-sided PVI and a smaller PV ostium for left-sided PVI were associated with the necessity of additional carina ablation. The presence and location of the epicardial fibers may be affected by the atrial and PV geometry.