Search

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.

Herein we describe the structure–property relationships of three biazulene isomers (2,6′-biazulene (BAz1), 2,2′-biazulene (BAz2), and 6,6′-biazulene (BAz3)). The unimolecular planarities of these m...

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.

Dilated cardiomyopathy (DCM) remains among the most refractory heart diseases because of its complicated pathogenesis, and the key molecules that cause it remain unclear.To elucidate the molecules and upstream pathways critical for DCM pathogenesis, we performed meta-analysis and co-expression analysis of RNA-sequencing (RNA-seq) datasets from publicly available databases. We analyzed three RNA-seq datasets containing comparisons of RNA expression in left ventricles between healthy controls and DCM patients. We extracted differentially expressed genes (DEGs) and clarified upstream regulators of cardiovascular disease-related DEGs by Ingenuity Pathway Analysis (IPA). Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) analysis were also used to identify the hub gene candidates strongly associated with DCM.In total, 406 samples (184 healthy, 222 DCM) were used in this study. Overall, 391 DEGs [absolute fold change (FC) ≥ 1.5; P 0.01], including 221 upregulated and 170 downregulated ones in DCM, were extracted. Seven common hub genes (LUM, COL1A2, CXCL10, FMOD, COL3A1, ADAMTS4, MRC1) were finally screened. IPA showed several upstream transcriptional regulators, including activating (NFKBIA, TP73, CALR, NFKB1, KLF4) and inhibiting (CEBPA, PPARGC1A) ones. We further validated increased expression of several common hub genes in the transverse aortic constriction-induced heart failure model.In conclusion, meta-analysis and WGCNA using RNA-seq databases of DCM patients identified seven hub genes and seven upstream transcriptional regulators.

Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). However, the effects of the xanthine oxidase (XO) inhibition for AF remain to be fully elucidated. We investigated the effects of a novel XO inhibitor febuxostat on AF compared with allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed either low-salt (LS) (0.3% NaCl) or high-salt (HS) (8% NaCl) diet. After 4 weeks of diet, HS diet rats were divided into three groups: orally administered to vehicle (HS-C), febuxostat (5 mg/kg/day) (HS-F), or allopurinol (50 mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure (SBP) was significantly higher in HS-C than LS, and it was slightly but significantly decreased by treatment with each XO inhibitor. AF duration was significantly prolonged in HS-C compared with LS, and significantly suppressed in both HS-F and HS-A (LS; 5.8 ± 3.5 s, HS-C; 33.9 ± 23.7 s, HS-F; 15.0 ± 14.1 s, HS-A; 20.1 ± 11.9 s: P

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented, however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.

Background: Isorhamnetin (ISO), a natural flavonoid compound, has been shown to have strong antioxidant and antifibrotic effects in vivo and in vitro; however, no report has been shown on the effect of ISO on arrhythmic disorders. This study aimed to investigate the effect of ISO on angiotensin-II (Ag-II) induced atrial fibrillation (AF) in mice. Methods: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned in 3 groups as follows: control group (Cont), Ag-II group treated with Ag-II and Ag-II & ISO group treated with Ag-II and ISO. Ag-II (1000 ng/kg/min) was continuously administered using an implantable osmotic pump for 2 weeks, and ISO (5 mg/kg) was administered intraperitoneally one week before starting Ag-II administration. We performed AF induction and electrophysiologic study via transvenous electrode catheter and Ca 2+ imaging with isolated cardiomyocyte. We also assessed the gene expression levels of AF-related molecules, and histological examination of atrial fibrosis. Results: Compared with Cont, AF inducibility was dramatically increased by Ag-II and significantly decreased by ISO. AF duration was also remarkably prolonged by Ag-II and significantly reduced by ISO. Atrial effective refractory period (A-ERP) (BCL=150msec) was reduced by Ag-II and recovered by ISO. Incidences of diastolic intracellular Ca 2+ abnormal activities (sarcoplasmic reticulum [SR] Ca 2+ leakage) was observed in Ag-II group; however, ISO treatment eliminated these abnormalities. Ag-II induced elevated expression of fibrosis-related molecules (Col1a1, Tgfb1 and Tgfb2) and Ca 2+ -handling related molecules (Camk2 and Ryr2), those were partially normalized by ISO. Histological examination revealed that cell size and the fibrosis ratio were increased by Ag-II, and significantly attenuated by ISO. Conclusion: These results suggest that ISO prevented against Ag-II induced AF vulnerability through both electrophysiological and structural reverse remodeling.

Background Recent Cochrane Systematic Review suggested that the participation in cardiac rehabilitation is associated with approximately 20% lower cardiovascular mortality and morbidity. Exercise therapy is the key component of cardiac rehabilitation programs. In recent years, innovative technologies have been introduced into the field of rehabilitation, and a typical example is the wearable cyborg Hybrid Assistive Limb (HAL). The wearable cyborg HAL provides motion assistance based on detection of bioelectrical signals on the skin surface when muscle forces are generated. The lumbar-type HAL is expected to expand the therapeutic options for severe cardiac patients who have difficulty in performing usual cardiac rehabilitation programs, such as bicycle pedaling or walking. Purpose We aim to compare the efficacy of exercise therapy performed with motion assistance from a lumbar-type HAL versus conventional training (sit-to-stand exercise without HAL) in patients with chronic heart failure. Methods This clinical trial is a randomized, non-blinded, and controlled study. Twenty-eight heart failure patients (73.1±13.8 years) who have difficulty in walking at the usual walking speed of healthy subjects were randomly assigned to 2 groups (HAL group or control group) with a 1:1 allocation ratio and performed sit-to stand exercise either with HAL or without HAL for 5 to 30 minutes once a day, and 6 to 10 days during the study period. The brain natriuretic peptide (BNP), isometric knee extensor strength, standing ability (30-seconds chair-stand test: CS-30), short physical performance battery (SPPB) and 6-minute walking distance (6MWD) were measured before and after the completion of cardiac rehabilitation. Cardiac events such as death, re-hospitalization, myocardial infarction and worsening of angina pectoris and heart failure during 1 year after discharge were evaluated. Results There was no significant difference in the number of days of exercise therapy between the two groups. BNP, SPPB and 6MWD were improved in both groups. In the HAL group, the isometric knee extensor strength (0.29±0.11 vs 0.35±0.11 kgf/kg, p=0.003) significantly improved and CS-30 (5.5±5.1 vs 8.2±5.3, p=0.054) tended to improve. However, in the control group, either the isometric knee extensor strength (0.35±0.11 vs 0.36±0.14 kgf/kg, p=0.424) or CS-30 (6.0±4.3 vs 9.2±6.2, p=0.075) did not significantly change. HAL group showed significantly more improvement in the isometric knee extensor strength than control group (p=0.045). Cardiac events occurred in 20% in the HAL group and 43% in the control group. Conclusion The improvement in isometric knee extensor strength with the assistance from lumbar-type HAL suggests that exercise therapy using this device may be useful in chronic heart failure patients with flail or sarcopenia, a strong poor prognostic factor in these patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (JSPS KAKENHI grant number JP17K09485) and funded by the ImPACT Program of the Council for Science, Technology and Innovation (Cabinet Office, Government of Japan) (grant number 2017-PM05-03-01).

Macrophages are fundamental components of inflammation in post‐myocardial infarction (MI) and contribute to adverse cardiac remodelling and heart failure. However, the regulatory mechanisms in macrophage activation have not been fully elucidated. Previous studies showed that myeloid‐associated immunoglobulin–like receptor II (MAIR‐II) is involved in inflammatory responses in macrophages. However, its role in MI is unknown. Thus, this study aimed to determine a novel role and mechanism of MAIR‐II in MI. We first identified that MAIR‐II–positive myeloid cells were abundant from post‐MI days 3 to 5 in infarcted hearts of C57BL/6J (WT) mice induced by permanent left coronary artery ligation. Compared to WT, MAIR‐II–deficient (Cd300c2 −/−) mice had longer survival, ameliorated cardiac remodelling, improved cardiac function and smaller infarct sizes. Moreover, we detected lower pro‐inflammatory cytokine and fibrotic gene expressions in Cd300c2 −/−‐infarcted hearts. These mice also had less infiltrating pro‐inflammatory macrophages following MI. To elucidate a novel molecular mechanism of MAIR‐II, we considered macrophage activation by Toll‐like receptor (TLR) 9–mediated inflammation. In vitro, we observed that Cd300c2 −/− bone marrow–derived macrophages stimulated by a TLR9 agonist expressed less pro‐inflammatory cytokines compared to WT. In conclusion, MAIR‐II may enhance inflammation via TLR9‐mediated macrophage activation in MI, leading to adverse cardiac remodelling and poor prognosis.

Background Most recent consensus conference report recommends Implantable Cardioverter Defibrillator (ICD) implantation for asymptomatic Brugada patients with spontaneous or fever-induced type-1 ECG (A-BrS) and inducible ventricular tachyarrhythmias (VTs) by up to two extrastimuli as class IIb indication. However, the validity of the inducible VTs by up to two extrastimuli in A-BrS is still unknown. Purpose To evaluate the validity of the inducibility by up to two extrastimuli in A-BrS in a large Japanese cohort of BrS (The Japan Idiopathic Ventricular Fibrillation Study [J-IVFS]). Methods A total of 193 consecutive A-BrS patients performed programmed electrical stimulation (PES) with non-aggressive uniform protocol (mean age 50±13 years, 180 males) were enrolled. PES protocol was using 2 basic pacing cycles and the order of introduction of up to 2 ventricular extra-stimuli from right ventricular apex [RVA] first, then right ventricular outflow tract [RVOT], 3 ventricular extra-stimuli from RVA then RVOT down to the minimum of 200ms. Clinical outcomes during the follow-up period were compared between A-BrS patients with and without inducible VTs by up to two extrastimuli. Results Thirty-five A-BrS (18%) had inducible VTs by up to two extrastimuli. During a mean follow-up period of 101±48 months, 7 A-BrS experienced cardiac events (sudden cardiac death [SCD] or VTs, 0.4%/yr). None of the 7 A-BrS had inducible VTs by up to two extrastimuli. The incidences of cardiac events tended to be higher in A-BrS without inducible VTs by up to two extrastimuli than in those with inducible VTs (p=0.10), as determined by the Kaplan-Meier method. In the A-BrS, the annual incidences of cardiac events in A-BrS with family history of SCD, inferolateral J wave, wide QRS duration >90msec in lead V2, or inducible VT/VF by 3 extrastimuli were 0.7, 0.7, 0.6, and 0.3%/yr, respectively. Conclusions Our large-scaled multicentre study with long-term follow-up revealed the inducibility of ventricular tachyarrhythmias by up to two extrastimuli does not predict future cardiac events in A-BrS, even using non-aggressive uniform protocol. Rather, other parameters such as family history of SCD or inferolateral J wave might be helpful for risk assessment in A-BrS.

Background: Risk stratification in patients with Brugada Syndrome (BS) without aborted Sudden Death (SD) and/or documented Ventricular Fibrillation (VF) has not been clearly determined. The prognostic value of a J-wave and ST-segment morphology after the J-wave (ST) in inferolateral leads in Brugada Syndrome (BS) is still unknown. Purpose To evaluate the prognostic value of a J-wave and ST in a large Japanese cohort of BS without aborted SD and/or documented VF. Methods: A total of 376 consecutive BS patients without aborted SD and/or documented VF (mean age 53±14 years, 248 males) were enrolled. Clinical and ECG characteristics, including the presence and location of leads showing a J wave, ST-segment, and clinical outcomes, were evaluated in patients with syncope without documented VF (N = 109), and subjects without symptoms (N = 267). Results: The incidence of J wave at inferior and/or lateral leads was 39 cases (10%). The prevalence of J wave between the 2 groups was not different. The incidence of cardiac events (SD or VF) during a mean follow-up period of 51±31 months was significantly higher in patients with symptoms, QRS duration in lead V2 > 90 ms, horizontal ST-segment after J wave, and the combination of a J wave in both inferior and lateral leads with horizontal ST-segment after the J wave, as determined by univariate analysis. J wave in both inferior and lateral leads tended to be associated with cardiac events. The combination of a J wave in both inferior and lateral leads with horizontal ST-segment after the J wave yielded a higher hazard ratio (5.08) than that of each parameter individually (2.71 and 3.24, respectively). Multivariate analysis revealed that symptoms, QRS duration in lead V2 > 90 ms, and the combination of a J wave in both inferior and lateral leads with horizontal ST-segment after J wave were significantly associated with cardiac events. Conclusion: Presence of a J wave in multiple leads and horizontal ST-segments after the J wave may indicate a highly arrhythmogenic substrate in BS patients without aborted SD and/or documented VF.

Background: Reentrant atrial tachycardia involving interatrial septum is associated with higher likelihood of recurrence. We assessd the procedural characteristics and clinical outcomes of catheter ablation for macro-reentrant atrial tachycardia involving interatrial septum (septal AT). Methods: The consecutive 49 patients with atrial tachycardia which was directly terminated during ablation were divided into 3 groups, based on the mechanism; septal AT, macro-reentrant AT which does not involve interatrial septum within the circuit (non-septal AT), or focal AT. Results: Clinical AT was septal AT in 9, non-septal AT in 21, and focal AT in 19 patients. Prevalence of underlying structural heart disease was the highest in patients with septal AT (78 vs 40 vs 7%, p

Background: We recently showed that the presence of early repolarization (ER) increases the risk of ventricular fibrillation (VF) occurrences in the early phase of acute myocardial infarction (AMI). However, clinical characteristics of VF occurrence in the early phase of AMI between patients with and without ER were still unknown. Methods: This study included 220 consecutive patients with AMI (69±11 years; 57 females) in whom 12-lead ECGs before the AMI onset could be evaluated. The patients were classified based on the VF occurrence 0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching. Results: Twenty-one patients experienced an episode of VF