Aus dem Universitäts-Herzzentrum Freiburg-Bad Krozingen Klinik für Kardiologie und Angiologie II Abteilung für Rhythmologie Extent and Spatial Distribution of Left Atrial Arrhythmogenic Sites, Late Gadolinium Enhancement at MRI and Low Voltage Areas in Patients with Persistent Atrial Fibrillation – Comparison of Imaging vs. Electrical Parameters of Fibrosis and Arrhythmogenesis I N A U G U R A L – D I S S E R T A T I O N zur Erlangung des Medizinischen Doktorgrades der Medizinischen Fakultät der Albert-Ludwigs-Universität Freiburg im Breisgau Vorgelegt 2018 von Juan Chen geboren in Hubei, V.R. China Dekan: Professor Dr. Norbert Südkamp 1. Gutachter: Professor Dr. med. Thomas Arentz 2. Gutachter: Professor Dr. med. Peter Kohl Jahr der Promotion: 2019 Widmung An dieser Stelle möchte ich mich bei allen Beteiligten herzlich bedanken, ohne deren Beitrag diese Arbeit unmöglich gewesen wäre: Prof. Dr. Thomas Arentz, Chefarzt der Abteilung Rhythmologie am Universitäts-Herzzentrum Freiburg-Bad Krozingen für die Möglichkeit der Anfertigung dieser Doktorarbeit in seiner Abteilung, der Überlassung des Themas und der Betreuung der Arbeit sowie für das entgegengebrachte Vertrauen. Dr. Amir Jadidi, für seine Begeisterung und kompetente Betreuung und Unterstützung, für seine reichlichen Ideen und die Einführung in das wissenschaftliche Arbeiten, für die sorgfältigen Korrekturen und vor allem das freundliche und angenehme Arbeitsklima. Dr. Zoraida Moreno Weidmann, für ihre großzügige Unterstützung meiner Forschungsarbeit sowie die statistische Auswertung und die konstruktiven Vorschläge und die Hilfe durch mein Leben. Dr. Bjoern Mueller-Edenborn, für die Korrekturen und statistischen Auswertung und freundliche Hilfe. Meine Familie danke ich für die Motivation, sowohl in der Durchführung als auch in jedem Aspekt des Lebens. I Table of Contents 1. INTRODUCTION ............................................................................................................ 1 1.1 History of Atrial Fibrillation ............................................................................................. 1 1.2 Definition of Atrial Fibrillation ......................................................................................... 3 1.3 Incidence and Prevalence of Atrial Fibrillation ................................................................. 4 1.4 The Electrophysiological Mechanism of Atrial Fibrillation – Three Distinct Hypothesis: Multiple Wavelets, Localized Rotational Sources (Rotors) and Focal Triggers ........................ 4 1.4.1 Focal or Localized Reentrant Circuits Develop within Pulmonary Veins and Their Antral Areas and Constitute the Arrhythmogenic Sources of Human Paroxysmal Atrial Fibrillation .......................................................................................................................... 6 1.4.2 Non-Pulmonary Vein Arrhythmogenic Sources with Rotational or Focal Activity Originate from the Atrial Body and Maintain Persistent Atrial Fibrillation .......................... 6 1.4.3 Role of Arrhythmogenic Atrial Substrate for Development of Persistent Atrial Fibrillation .......................................................................................................................... 8 1.5 Reversibility of Arrhythmogenic Left atrial Substrate by Treatment of Cardiovascular Risk Factors and Reduction of Left Atrial Hypertension / Stretch ................................................. 10 1.6 Management of Atrial Fibrillation ................................................................................... 12 1.6.1 Antiarrhythmic Drug Therapy .................................................................................. 12 1.6.2 Catheter Ablation Strategy ....................................................................................... 13 1.7 Atrial Substrate Detection Techniques............................................................................. 17 1.7.1 Delayed Gadolinium Enhancement Magnetic Resonance Imaging for Detection of Atrial Substrate ................................................................................................................. 17 1.7.2 Electroanatomic Voltage Mapping ............................................................................ 18 1.8 Correlation between CFAE, Atrial Delayed Enhanced Areas at MRI and Low Voltage Substrate .............................................................................................................................. 20 1.9 Summary ........................................................................................................................ 21 2. MATERIALS AND METHODS .................................................................................... 22 2.1 Patients ........................................................................................................................... 22 2. 2 Magnetic Resonance Imaging ........................................................................................ 22 2.3 Electrophysiological mapping ........................................................................................ 24 II 2.4 Statistical Analyses ......................................................................................................... 29 3. RESULTS ........................................................................................................................ 29 3.1 Patient Characteristics .................................................................................................... 29 3.2 Left Atrial High-density Mapping ................................................................................... 29 3.3 LA Size, Extent of Delayed Enhanced Areas, Low Voltage Areas and Arrhythmogenic Sites ..................................................................................................................................... 31 3.4 Regional Distribution of Delayed Enhanced Areas and Low Voltage Areas ..................... 32 3.5 Correlation of Delayed Enhanced Areas and Low Voltage Areas ..................................... 34 3.6 Relationship of Arrhythmogenic Sites to Delayed Enhanced Areas and Low Voltage Areas ............................................................................................................................................. 36 3.7 Electrogram Characteristics of Arrhythmogenic Sites ..................................................... 37 4. DISCUSSION ................................................................................................................. 39 4.1 The Main Findings of Our Study .................................................................................... 39 4.2 Atrial Voltage Mapping for Identification of Arrhythmogenic Substrate .......................... 40 4.3 The Spatial Distribution of Dense/Patchy DE and of Atrial Low Voltage Areas in AF ..... 42 4.3.1 Differences in the Extent of Substrate Detection in DE-MRI and Voltage Mapping .. 42 4.3.2 Potential Causes for Mismatch between MRI and Voltage Mapping for Identification of Fibro-fatty Arrhythmogenic Atrial Substrate ................................................................. 43 4.4 Electrophysiological Criteria to Localize Sources of AF: Electrogram Voltage and Duration at Atrial Areas with Continuous or Rotational Activity ........................................... 44 4.5 Implication for Catheter Ablation ................................................................................... 46 4.6 Limitations ..................................................................................................................... 47 4.7 Summary ........................................................................................................................ 47 5. ZUSAMMENFASSUNG / ABSTRACT......................................................................... 48 6. REFERENCES ............................................................................................................... 50 7. PUBLICATION .............................................................................................................. 59 III 8. ANHANG ........................................................................................................................ 60 EIDESSTATTLICHE VERSICHERUNG ............................................................................... I ERKLÄRUNG ZUM EIGENANTEIL .................................................................................. II ACKNOWLEDGEMENTS .................................................................................................. III IV Abbreviations 3D three-dimensional AAD antiarrhythmic drug AF atrial fibrillation CA continuous activity CFAE complex fractionated atrial electrogram CL cycle length CPAP continuous positive airway pressure CS coronary sinus CT computer tomography CV conduction velocity DE delayed enhancement EAS electroanatomic system EAVM electroanatomical voltage mapping ECG electrocardiogram/electrocardiography EGM electrogram FIRM focal impulse and rotor modulation IIR MRI image intensity ratio IVSDD interventricular septum diastolic diameter LA left atrium LAA left atrial appendage LAD left atrial diameter LGE late gadolinium enhancement V LIPV left inferior pulmonary vein LSPV left superior pulmonary vein LVA low voltage area LVEDD left ventricular end-diastolic diameter LVEF left ventricular ejection fraction LVESD left ventricular end-systolic diameter MRI magnetic resonance imaging PA prolonged activity PV pulmonary vein PVI pulmonary