Rahul Singhal1, Shih-Lin Chang2, Eric Chong1, Ya-Wen Hsiao1, Shuen-Hsin Liu3, Yung-Nan Tsai1, Chiao-Po Hsu4, Yenn-Jiang Lin2, Li-Wei Lo2, Trung Le Ha1, Yao-Chang Chen5, Yi-Jen Chen6, Chuen-Wang Chiou7, Shih-Ann Chen8. 1. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 2. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine and Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. 3. Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan. 4. Institute of Clinical Medicine and Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. 5. Department of Biomedical Engineering, National Defence Medical Centre, Taipei, Taiwan. 6. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. 7. Institute of Clinical Medicine and Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. Electronic address: cwchiou@isca.vghks.gov.tw. 8. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine and Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: epsachen@ms41.hinet.net.
Abstract
BACKGROUND: This study aimed to investigate the mechanism by which colchicine suppresses atrial fibrillation (AF) in a rabbit heart failure (HF) model. METHODS AND RESULTS: HF was induced by coronary ligation. Using the Langendorff perfusion system, monophasic action potentials were recorded in the left atrial appendage (LAA) of normal rabbits (n=6) and HF rabbits (n=6) treated with colchicine (100 μM) followed by colchicine (100 μM) plus paclitaxel (5 μM). Collagen content and mRNA and protein expression of ion channels through the PI3K/AKT/eNOS signaling pathway were evaluated in LAA of normal rabbits (n=6) and HF rabbits treated with vehicle (n=6) or colchicine (n=6) intraperitoneal injection for 2 days. Colchicine decreased action potential duration (74.1±2.6 vs 91.8±3.3 ms, P<0.001), effective refractory period, and maximum slope of the restitution curve in HF LAA. However, these effects were reversed by paclitaxel. The incidence of early afterdepolarizations, delayed afterdepolarizations, and AF inducibility was significantly lower after colchicine perfusion than at baseline or after colchicine plus paclitaxel perfusion. Cardiac function increased and LA fibrosis decreased after colchicine treatment. mRNA and protein expression of Kir2.1, Kv1.4, Kv1.5, Kv7.1, Cav1.2, and SERCA2a were upregulated after colchicine treatment, as was mRNA expression of PI3K, AKT, and eNOS. CONCLUSION: Colchicine regulates ion channel gene expression and activates the PI3K/AKT/eNOS signaling pathway in HF rabbits, which may reverse atrial remodeling and suppress AF.
BACKGROUND: This study aimed to investigate the mechanism by which colchicine suppresses atrial fibrillation (AF) in a rabbit heart failure (HF) model. METHODS AND RESULTS: HF was induced by coronary ligation. Using the Langendorff perfusion system, monophasic action potentials were recorded in the left atrial appendage (LAA) of normal rabbits (n=6) and HF rabbits (n=6) treated with colchicine (100 μM) followed by colchicine (100 μM) plus paclitaxel (5 μM). Collagen content and mRNA and protein expression of ion channels through the PI3K/AKT/eNOS signaling pathway were evaluated in LAA of normal rabbits (n=6) and HF rabbits treated with vehicle (n=6) or colchicine (n=6) intraperitoneal injection for 2 days. Colchicine decreased action potential duration (74.1±2.6 vs 91.8±3.3 ms, P<0.001), effective refractory period, and maximum slope of the restitution curve in HF LAA. However, these effects were reversed by paclitaxel. The incidence of early afterdepolarizations, delayed afterdepolarizations, and AF inducibility was significantly lower after colchicine perfusion than at baseline or after colchicine plus paclitaxel perfusion. Cardiac function increased and LA fibrosis decreased after colchicine treatment. mRNA and protein expression of Kir2.1, Kv1.4, Kv1.5, Kv7.1, Cav1.2, and SERCA2a were upregulated after colchicine treatment, as was mRNA expression of PI3K, AKT, and eNOS. CONCLUSION:Colchicine regulates ion channel gene expression and activates the PI3K/AKT/eNOS signaling pathway in HF rabbits, which may reverse atrial remodeling and suppress AF.
Authors: Larissa Fabritz; Eduard Guasch; Charalambos Antoniades; Isabel Bardinet; Gerlinde Benninger; Tim R Betts; Eva Brand; Günter Breithardt; Gabriela Bucklar-Suchankova; A John Camm; David Cartlidge; Barbara Casadei; Winnie W L Chua; Harry J G M Crijns; Jon Deeks; Stéphane Hatem; Françoise Hidden-Lucet; Stefan Kääb; Nikos Maniadakis; Stephan Martin; Lluis Mont; Holger Reinecke; Moritz F Sinner; Ulrich Schotten; Taunton Southwood; Monika Stoll; Panos Vardas; Reza Wakili; Andy West; André Ziegler; Paulus Kirchhof Journal: Nat Rev Cardiol Date: 2015-12-24 Impact factor: 32.419