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Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real‐time quantitative RT‐PCR (qRT‐PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib‐treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28‐day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib‐induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT‐dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib‐treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib‐promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib‐stimulated proinflammatory signaling (TNF‐α/IL‐1β/IL‐6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib‐promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) is a recognized risk factor for atrial fibrillation (AF), yet the precise molecular and electrophysiological mechanisms behind SD-induced AF are unclear. This study explores the electrical and structural changes that contribute to AF in chronic partial SD. We induced chronic partial SD in Wistar rats using a modified multiple-platform method. Echocardiography demonstrated impaired systolic and diastolic function in the left ventricle (LV) of the SD rats. The SD rats exhibited an elevated heart rate and a higher low-frequency to high-frequency ratio in a heart-rate variability analysis. Rapid transesophageal atrial pacing led to a higher incidence of AF and longer mean AF durations in the SD rats. Conventional microelectrode recordings showed accelerated pulmonary vein (PV) spontaneous activity in SD rats, along with a heightened occurrence of delayed after-depolarizations in the PV and left atrium (LA) induced by tachypacing and isoproterenol. A Western blot analysis showed reduced expression of G protein-coupled receptor kinase 2 (GRK2) in the LA of the SD rats. Chronic partial SD impairs LV function, promotes AF genesis, and increases PV and LA arrhythmogenesis, potentially attributed to sympathetic overactivity and reduced GRK2 expression. Targeting GRK2 signaling may offer promising therapeutic avenues for managing chronic partial SD-induced AF. Future investigations are mandatory to investigate the dose–response relationship between SD and AF genesis. [ABSTRACT FROM AUTHOR]

Background: Metabolic stress predisposes to ventricular arrhythmias and sudden cardiac death. Right ventricular outflow tract (RVOT) is the common origin of ventricular arrhythmias. Adenosine monophosphate‐regulated protein kinase (AMPK) activation is an important compensatory mechanism for cardiac remodeling during metabolic stress. Objectives: The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca2+) regulation, and RVOT arrhythmogenesis or not. Methods: Conventional microelectrodes were used to record electrical activity before and after compound C (10 µM, an AMPK inhibitor) in isoproterenol (1 µM)‐treated rabbit RVOT tissue preparations under electrical pacing. Whole‐cell patch‐clamp and confocal microscopic examinations were performed in baseline and compound C‐treated rabbit RVOT cardiomyocytes to investigate ionic currents and intracellular Ca2+ transients in isolated rabbit RVOT cardiomyocytes. Results: Compound C decreased RVOT contractility, and reversed isoproterenol increased RVOT contractility. Compound C decreased the incidence, rate, and duration of isoproterenol‐induced RVOT burst firing under rapid pacing. Compared to baseline, compound C‐treated RVOT cardiomyocytes had a longer action potential duration, smaller intracellular Ca2+ transients, late sodium (Na+), peak L‐type Ca2+ current density, Na+‐Ca2+ exchanger, transient outward potassium (K+) current, and rapid and slow delayed rectifier K+ currents. Conclusion: AMPK inhibition modulates RVOT electrophysiological characteristics and Ca2+ homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias. [ABSTRACT FROM AUTHOR]