While recent advances clarified the molecular and cellular modes of action of antiarrhythmic drugs (AADs), their link to suppression of dynamical arrhythmia mechanisms remains only partially understood. The current classifications of AADs (Classes I, III, and IV) rely on blocking peak Na, K and L-type calcium currents (I), with Class II with dominant beta receptor blocking activity and Class V including drugs with diverse classes of actions. The discovery that the calcium and redox sensor, cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) enhances both the late Na (I) and the late I in patients at high risk of VT/VF provided a new and a rational AAD target. Pathological rise of either or both of I and late I are demonstrated to promote cellular early afterdepolarizations (EADs) and EAD-mediated triggered activity that can initiate VT/VF in remodeled hearts. Selective inhibition of the I without affecting their peak transients with the highly specific prototype drug, GS-967 suppresses these EAD-mediated VT/VFs. As in the case of I, selective inhibition of the late I without affecting its peak with the prototype drug, roscovitine suppressed oxidative EAD-mediated VT/VF. These findings indicate that specific blockers of the late inward currents without affecting their peaks (gating modifiers), offer a new and effective AAD class action i.e., "Class VI." The development of safe drugs with selective Class VI actions provides a rational and effective approach to treat VT/VF particularly in cardiac conditions associated with enhanced CaMKII activity such as heart failure.
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http://dx.doi.org/10.3389/fphar.2017.00036 | DOI Listing |
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Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, Guangzhou, China.
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School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
China witnessed an Omicron COVID-19 outbreak at the end of 2022. During this period, medical crowding and enormous pressure on the healthcare systems occurred, which might result in the occurrence of occupational burnout among healthcare workers (HCWs). This study aims to investigate the prevalence of occupational burnout and associated mental conditions, such as depressive symptoms, anxiety, PTSD symptoms, perceived social support, resilience, and mindfulness among HCWs of the Chinese mainland during the Omicron COVID-19 outbreak, and to explore the potential risk and protective factors influencing occupational burnout of HCWs.
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January 2025
Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
Hepatocellular carcinoma (HCC) is a predominant cause of cancer-related mortality globally, noted for its propensity towards late-stage diagnosis and scarcity of effective treatment modalities. The process of metabolic reprogramming, with a specific emphasis on lipid metabolism, is instrumental in the progression of HCC. Nevertheless, the precise mechanisms through which lipid metabolism impacts HCC and its viability as a therapeutic target have yet to be fully elucidated.
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January 2025
Laboratory for Biological Geochemistry, School of Architecture, Civil and Environmental Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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