Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARα/LACC1/NF-κB signaling pathway.

BACKGROUND: Autoimmune myocarditis, with increasing incidence and limited therapeutic strategies, is in urgent need to explore its underlying mechanisms and effective drugs. Pyroptosis is a programmed cell death that may contribute to the pathogenesis of myocarditis. Nonetheless, no direct evidence validated the role of pyroptosis in autoimmune myocarditis. Lupeol (Lup), a pentacyclic triterpene, possesses various biological activities such as antidiabetic properties. However, the effects of Lup on autoimmune myocarditis and pyroptosis remain unelucidated. PURPOSE: This study aimed to reveal the role of pyroptosis in autoimmune myocarditis and explore the protective effects of Lup, and its engaged mechanisms. METHODS: The experimental autoimmune myocarditis (EAM) mouse model was established by immunization with a fragment of cardiac myosin in Balb/c mice. Lup and MCC950 were administered after EAM induction. The protective effects were assessed by inflammation score, cardiac injury, chronic fibrosis, and cardiac function. Mechanistically, the effects of Lup on the M1 polarization and pyroptosis of macrophages were evaluated. Transcriptome sequencing and molecular docking were subsequently employed, and the underlying mechanisms of Lup were further explored in vitro with small interfering RNA and adenovirus. RESULTS: Administration of Lup and MCC950 alleviated EAM progression. Western blotting and immunofluorescence staining identified macrophages as the primary cells undergoing pyroptosis. Lup inhibited the expression of pyroptosis-associated proteins in macrophages during EAM in a dose-dependent manner. Furthermore, Lup suppressed pyroptosis in both bone marrow-derived macrophages (BMDMs) and THP-1-derived macrophages in vitro. In addition, Lup inhibited the M1 polarization of macrophages both in vivo and in vitro. Mechanistically, the protective effects of Lup were demonstrated via the suppression of the nuclear factor-κΒ (NF-κB) signaling pathway. Transcriptome sequencing and molecular docking revealed the potential involvement of peroxisome proliferator-associated receptor α (PPARα). Subsequently, we demonstrated that Lup activated PPARα to reduce the expression level of LACC1, thereby inhibiting the NF-κB pathway and pyroptosis. CONCLUSION: Our findings indicated the crucial role of macrophage pyroptosis in the pathogenesis of EAM. Lup ameliorated EAM by inhibiting the M1 polarization and pyroptosis of macrophages through the PPARα/LACC1/NF-κB signaling pathway. Thus, our results provided a novel therapeutic target and agent for myocarditis.

Delayed efficacy of radiofrequency catheter ablation on ventricular arrhythmias originating from the left ventricular anterobasal wall.

BACKGROUND: Ventricular arrhythmias (VAs) originating from the left ventricular anterobasal wall (LV-ABW) may represent a therapeutic challenge. OBJECTIVE: The purpose of this study was to investigate the delayed efficacy of radiofrequency catheter (RFCA) ablation without an epicardial approach on VAs originating from the LV-ABW. METHODS: Eighty patients (mean age 46.9 ± 14.9 years; 47 male) with VAs originating from the LV-ABW were enrolled. After systematic mapping of the right ventricular outflow tract, aortic root, adjacent LV endocardium, and coronary venous system, 3-4 ablation attempts were made at the earliest activation sites and/or best pace-mapping sites. Delayed efficacy was evaluated in patients with acute failure. RESULTS: During mean follow-up of 23.8 ± 21.9 months (range 3-72 months), complete elimination of all VAs was achieved in 47 patients (59%) and partial success in 19 (24%), for an overall success rate of 83%. In 25 of 37 patients (68%) with acute failure, VAs were eliminated or significantly reduced (>80% VA burden) by the delayed effect of RFCA during follow-up. Logistic regression analysis revealed that response time to ablation was a predictor of occurrence of delayed efficacy. No complications occurred during follow-up. CONCLUSION: Instead of extensive ablation, waiting for delayed efficacy of RFCA may be a reasonable choice for patients with VAs arising from the LV-ABW.

Impact of Alcohol Consumption on Substrate Remodeling and Ablation Outcome of Paroxysmal Atrial Fibrillation.

BACKGROUND: The effect of alcohol consumption on substrate remodeling and ablation outcome of paroxysmal atrial fibrillation (PAF) remains unknown. METHODS AND RESULTS: We performed circumferential pulmonary vein isolation (CPVI) and voltage mapping of left atrium (LA) during sinus rhythm in 122 consecutive patients with symptomatic PAF (age, 55.4±9.4 years; 73.8% men). Low-voltage zones (LVZs) were semiquantitatively estimated and presented as low-voltage index (LVI). Each patient's daily alcohol consumption history was recorded at baseline and classified into alcohol abstainers, moderate drinkers, and heavy drinkers based on the National Institute on Alcohol Abuse and Alcoholism definition. Follow-up was ≥12 months for AF recurrence. Alcohol abstainers and moderate and heavy drinkers were 70 (57.4%), 13 (10.6%), and 39 (32.0%), respectively. In total, LVZs were observed in 44 patients (36.1%). Daily alcohol consumption independently predicted presence of LVZs (odds ratio [OR], 1.097; 95% confidence interval [CI], 1.001-1.203; P=0.047). During mean follow-up of 20.9±5.9 months, 40 patients (35.1%) experienced AF recurrence. Success rate was 81.3%, 69.2%, and 35.1% in alcohol abstainers, moderate drinkers, and heavy drinkers, respectively (overall log rank, P<0.001). Multivariate analysis showed that both alcohol consumption and LVI were independent predictors of AF recurrence (hazard ratio [HR], 1.579; 95% CI, 1.085-2.298; P=0.017; HR, 2.188; 95% CI, 1.582-3.026; P<0.001, respectively). Furthermore, mediation analysis revealed that LVZs acted as a partial mediator in effect of alcohol consumption on AF ablation outcomes. CONCLUSIONS: Daily alcohol consumption was associated with atrial remodelling, and heavy drinkers have substantial risk for AF recurrence after CPVI.