Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.

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.

Electrical, structural, and autonomic atrial remodeling underlies atrial fibrillation in inflammatory atrial cardiomyopathy.

Background: There is growing evidence indicating a close relationship between inflammation and atrial fibrillation (AF). Although underlying inflammatory atrial cardiomyopathy may contribute to the development of AF, the arrhythmogenic remodeling caused by atrial inflammation has not been elucidated in detail. Herein, we examined electrical, structural, and autonomic changes in the atria in a mouse model of autoimmune myocarditis. Methods: BALB/c mice were immunized with cardiac myosin peptide (MyHC-α614-629) conjugated with complete Freund's adjuvant on days 0 and 7. Susceptibility to AF was assessed using right-atrial burst pacing. Results: The mice immunized with MyHC-α614-629 showed an inflammatory atrial cardiomyopathy phenotype, with enlarged atria; a high degree of inflammatory cell infiltration primarily consisting of CD4+ T cells, CD8+ T cells, Ly6GlowCD11b+ macrophages, and CD11c+ dendritic cells; and severe interstitial fibrosis with collagen deposition. These mice demonstrated significantly enhanced susceptibility to AF, as indicated by their increased AF induction rate and duration. In addition, the expression of potassium channels (Kcnh2, Kcnd3, and Kcnj2) and calcium handling-associated genes (Cacna1c, Camk2, Ryr2, and Atp2a2) was downregulated. Connexin 40 expression was significantly downregulated, leading to frequent lateralization to the inflamed atrium. Sympathetic and parasympathetic innervation and neurotrophin expression (nerve growth factor and brain-derived neurotrophic factor) were upregulated in the inflamed atria. Conclusion: Inflammatory atrial cardiomyopathy promotes susceptibility to AF via arrhythmogenic electrical, structural, and autonomic remodeling of the atria.

Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function.

Insomnia is one of the most common sleep problems with an estimated prevalence of 10%-15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.

Efficacy of Endocardial Ablation of Drug-Resistant Ventricular Fibrillation in Brugada Syndrome: Long-Term Outcome.

Background Both endocardial trigger elimination and epicardial substrate modification are effective in treating ventricular fibrillation (VF) in Brugada syndrome. However, the primary approach and the characteristics of patients who respond to endocardial ablation remain unknown. Methods Among 123 symptomatic Brugada syndrome patients (VF, 63%; syncope, 37%), ablation was performed in 21 VF/electrical storm patients, the majority of whom were resistant to antiarrhythmic drugs. Results Careful endocardial mapping revealed that 81% of the patients had no specific findings, whereas 19% of the patients, who experienced the most frequent VF episodes with notching of the QRS in lead V1, had delayed low-voltage fractionated endocardial electrograms. Ablation of VF triggers followed by endocardial substrate modification was performed in the right ventricular outflow tract in 85% of the cases and in the right ventricle in 15%. VF triggers could not be completely eliminated in 1 patient and VF became noninducible in 14 (88%) patients among 16 patients who underwent VF induction with normalization of Brugada-type ECG in 3. During follow-up (56.14±36.95 months), VF recurrence was observed in 7 patients. Importantly, all patients who had nothing of QRS in lead V1 did not respond to endocardial ablation despite presence of VF-triggering ectopic beats during ablation. Conclusions With careful documentation of VF-triggering ectopic beats and detailed endocardial mapping, endocardial VF trigger elimination followed by endocardial substrate modification has an excellent long-term outcome, whereas presence of QRS notching in lead V1 was associated with high VF recurrence suggesting epicardial substrate ablation as effective initial approach.

Radiofrequency Catheter Ablation of Ventricular Tachycardia in Patients With Hypertrophic Cardiomyopathy and Apical Aneurysm.

OBJECTIVES: This study evaluated the characteristics and results of radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) in patients with hypertrophic cardiomyopathy (HCM) and left ventricular apical aneurysm (AA). BACKGROUND: Monomorphic VT in patients with HCM and left ventricular AA has been reported. However, outcome data of RFCA are insufficient. METHODS: Fifteen patients with HCM and AA who underwent RFCA for VT at 5 different institutions were included in this study. The data were evaluated retrospectively. RESULTS: Endocardial voltage mapping showed a low-voltage area (LVA), and late potential in the AA was recorded in 12 patients (80%). Although epicardial or intramural origin of VT was suspected in 7 patients, endocardial RFCA successfully suppressed the VT at the LVA border (n = 10) or within the LVA (n = 2). In 2 of 3 patients without LVA at the endocardial site, linear RFCA at the anterior wall of the aneurysmal neck side was successful. In the remaining patient, endocardial RFCA of AA was not effective, and epicardial RFCA site was needed. In all patients, clinical VT became noninducible after RFCA. VT recurrence was observed in 2 patients (13.3%) during the 12-month follow-up period. One patient underwent a second endocardial RFCA, and no VT recurrence was noted. In the other patient, VT recurred 3 months after RFCA and was successfully terminated by antitachycardia pacing of the implantable cardioverter-defibrillator. CONCLUSIONS: In patients with HCM and AA, endocardial RFCA of AA effectively suppressed monomorphic VT which was related to AA and resulted in satisfactory outcomes.

New Substrate-Guided Method of Predicting Slow Conducting Isthmuses of Ventricular Tachycardia: Preliminary Analysis to the Combined Use of Voltage Limit Adjustment and Fast-Fourier Transform Analysis.

BACKGROUND: Several conducting channels of ventricular tachycardia (VT) can be identified using voltage limit adjustment (VLA) of substrate mapping. However, the sensitivity or specificity to predict a VT isthmus is not high by using VLA alone. This study aimed to evaluate the efficacy of the combined use of VLA and fast-Fourier transform analysis to predict VT isthmuses. METHODS AND RESULTS: VLA and fast-Fourier transform analyses of local ventricular bipolar electrograms during sinus rhythm were performed in 9 postinfarction patients who underwent catheter ablation for a total of 13 monomorphic VTs. Relatively higher voltage areas on an electroanatomical map were defined as high voltage channels (HVCs), and relatively higher fast-Fourier transform areas were defined as high-frequency channels (HFCs). HVCs were classified into full or partial HVCs (the entire or >30% of HVC can be detectable, respectively). Twelve full HVCs were identified in 7 of 9 patients. HFCs were located on 7 of 12 full HVCs. Five VT isthmuses (71%) were included in the 7 full HVC+/HFC+ sites, whereas no VT isthmus was found in the 5 full HVC+/HFC- sites. HFCs were identical to 9 of 16 partial HVCs. Eight VT isthmuses (89%) were included in the 9 partial HVC+/HFC+ sites, whereas no VT isthmus was found in the 7 partial HVC+/HFC- sites. All HVC+/HFC+ sites predicted VT isthmus with a sensitivity of 100% and a specificity of 80%. CONCLUSIONS: Combined use of VLA and fast-Fourier transform analysis may be a useful method to detect VT isthmuses.

Epicardial catheter ablation of ventricular tachycardia in no entry left ventricle: mechanical aortic and mitral valves.

BACKGROUND: In patients with mechanical aortic and mitral valves and left ventricular tachycardia, catheter ablation may be prevented by limited access to the left ventricle. METHODS AND RESULTS: In our series of 6 patients, 2 patients underwent direct surgical ablation and 4 underwent epicardial catheter ablation via a pericardial window. All patients had abnormal low voltage areas with fractionated or delayed isolated potentials on the apical epicardium. Most of the ventricular tachycardias were targeted by pace mapping. Sites with a good pace match or abnormal electrograms were ablated using an irrigated radiofrequency ablation catheter. A microscopic pathological evaluation of the resected tissue from 2 of the open-heart ablation patients revealed dense fibrosis on the epicardium compared with the endocardium, supporting the feasibility of an epicardial ablation for the ventricular tachycardia. CONCLUSIONS: Epicardial catheter ablation of ventricular tachycardia is a potentially useful therapy in patients who have mechanical aortic and mitral valves.

Electrocardiographic determinants of the polymorphic QRS morphology in idiopathic right ventricular outflow tract tachycardia.

INTRODUCTION: Premature ventricular contractions (PVCs) arising from the right ventricular outflow tract (RVOT) can trigger polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF) in patients with no structural heart disease. We aimed to clarify the ECG determinants of the polymorphic QRS morphology in idiopathic RVOT PVT/VF. METHODS AND RESULTS: The ECG parameters were compared between 18 patients with idiopathic PVT/VF (PVT-group) and 21 with monomorphic VT arising from the RVOT (MVT-group). The coupling interval (CI) of the first VT beat was comparable between the 2 groups. However, the prematurity index (PI) of the first VT beat was smaller in the PVT-group than in the MVT-group (P < 0.001). Furthermore, the QT index, defined as the ratio of the CI to the QT interval of the preceding sinus complex, was also smaller for the PVT/VF in the PVT-group than that for the VT in the MVT-group (P < 0.01). In the PVT-group, the CI of the first VT beat was comparable between that of VT and isolated PVCs, but the PI of the first VT beat was shorter for VT than isolated PVCs (P < 0.05). The PI was the only independent determinant of the polymorphic QRS morphology (odd ratio = 2.198; 95% confidence interval = 1.321-3.659; P = 0.002). CONCLUSION: The smaller PIs of the first VT beat may result in a polymorphic QRS morphology.