Dechun Yin1, Mu Chen2, Na Yang3, Adonis Z Wu4, Dongzhu Xu5, Wei-Chung Tsai6, Yuan Yuan7, Zhipeng Tian8, Yi-Hsin Chan9, Changyu Shen10, Zhenhui Chen11, Shien-Fong Lin12, James N Weiss13, Peng-Sheng Chen11, Thomas H Everett14. 1. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China. 2. Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 3. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Gynecological and Obstetric Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin, China. 4. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan. 5. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 6. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. 7. Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 8. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, China. 9. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan. 10. Richard and Susan Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 11. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. 12. Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan. 13. Departments of Medicine and Physiology, University of California, Los Angeles, California. 14. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: theveret@iu.edu.
Abstract
BACKGROUND: Apamin-sensitive small conductance calcium-activated K current (IKAS) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM). OBJECTIVE: The purpose of this study was to determine the role of IKAS in long-term CM. METHODS: CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD80) was determined during right atrial pacing. Ventricular stability was tested before and after IKAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. RESULTS: There were no significant differences in either echocardiographic parameters or fibrosis levels between groups. Apamin induced more APD80 prolongation in CM than in normal ventricles (mean [95% confidence interval]: 9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%]; P <.001). Apamin significantly lengthened APD80 in the CM model at late activation sites, indicating significant IKAS up-regulation at those sites. The CM model also had altered Ca2+ handling, with the 50% Ca2+ transient duration and amplitude increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased ventricular fibrillation (VF) inducibility (paced vs control: 33/40 (82.5%) vs 7/20 (35%); P <.001) and longer VF durations (124 vs 26 seconds; P <.001). CONCLUSION: Chronic ventricular pacing increases Ca2+ transients at late activation sites, which activates IKAS to maintain repolarization reserve. IKAS blockade increases VF vulnerability in chronically paced rabbit ventricles.
BACKGROUND: Apamin-sensitive small conductance calcium-activated K current (IKAS) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM). OBJECTIVE: The purpose of this study was to determine the role of IKAS in long-term CM. METHODS: CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD80) was determined during right atrial pacing. Ventricular stability was tested before and after IKAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. RESULTS: There were no significant differences in either echocardiographic parameters or fibrosis levels between groups. Apamin induced more APD80 prolongation in CM than in normal ventricles (mean [95% confidence interval]: 9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%]; P <.001). Apamin significantly lengthened APD80 in the CM model at late activation sites, indicating significant IKAS up-regulation at those sites. The CM model also had altered Ca2+ handling, with the 50% Ca2+ transient duration and amplitude increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased ventricular fibrillation (VF) inducibility (paced vs control: 33/40 (82.5%) vs 7/20 (35%); P <.001) and longer VF durations (124 vs 26 seconds; P <.001). CONCLUSION: Chronic ventricular pacing increases Ca2+ transients at late activation sites, which activates IKAS to maintain repolarization reserve. IKAS blockade increases VF vulnerability in chronically paced rabbit ventricles.
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