Characterization of the electrophysiological substrate in patients with atrial fibrillation - Role of the restitution of atrial conduction velocity and of the voltage for the development of atrial fibrillation

• Applicants: Professor Dr. Olaf Dössel; Privatdozent Dr. Amir Jadidi; Professor Dr. Peter Kohl, since 2/2021; Professor Dr. Claus Schmitt
• Subject Area: Medical Physics, Biomedical Technology ; Cardiology, Angiology
• Term: from 2011 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 183027722

Final Report Abstract

According to current guidelines, the classification of atrial fibrillation (AF) is (1) first diagnosed, (2) paroxysmal, (3) persistent, (4) long-standing persistent, and (5) permanent. This is a symptom-based clinical classification. Recent studies suggest that this classification does inadequately define transitions and does not correlate with the actual AF burden - and thus with the actual progression of the disease process. Nevertheless, this classification dominates clinical practice and plays an essential role in individual therapy planning (rhythm vs. rate control). However, since the success rates of interventional or drug therapy depend on the individual disease stage, a classification correlating with the severity of electrophysiological remodeling would be important to improve the currently limited AF therapy success rates. In this project, an individualized characterization of the heterogeneous tissue substrate in AF was performed. For this purpose, invasively acquired data on the effective refractory period (ERP) of the atrial tissue as well as the heart rate dependence (restitution) of propagation velocity and signal amplitude (voltage) were assimilated using novel methods that allow for optimal estimation of parameters that cannot be measured directly by using mechanistic computer models. Atrial measurement data and routine clinical parameters were acquired in 42 AF patients and processed using newly developed tailored open source software. Atrial propagation velocity as well as its anisotropy could be determined more precisely and locally than before using newly developed simulation-based estimation methods. Cluster analysis of patient-specific ERP and restitution of signal amplitude and propagation velocity did not yield statistically robust classification of patients beyond established AF stages. By combining signal processing and computer modeling/simulation, we were for example able to identify electrogram characteristics of arrhythmogenic sources in the atrium, quantify local fibrosis content and local tissue ERP, provide an in silico test bed for ablation strategies, predict the likelihood of success of pulmonary vein isolation and the risk for AF-associated heart failure completely noninvasively by machine learning on the 12-lead ECG, and mechanistically underpin the pharmacological mode of action of novel TASK-1 antiarrhythmic agents. The developed methods, data, and findings were published in 16 peer-reviewed publications and 12 additional research outputs.

Publications

• CVAR-Seg: An Automated Signal Segmentation Pipeline for Conduction Velocity and Amplitude Restitution. GitHub.
  Nothstein, Mark; Luik, Armin; Jadidi, Amir; Sánchez, Jorge; Unger, Laura A.; Wülfers, Eike M.; Dössel, Olaf; Seemann, Gunnar; Schmitt, Claus & Loewe, Axel
  
• Effects of Fibroblasts coupling on the Electrophysiology of Cardiomyocytes from Different Regions of the Human Atrium: a Simulation Study. Computing in Cardiology Conference inC) (2017, 9, 14). Computing in Cardiology.
  Seemann, Gunnar; Loewe, Axel & Wülfers, Eike M.
  
• A Computational Framework to Benchmark Basket Catheter Guided Ablation in Atrial Fibrillation. Frontiers in Physiology, 9(2018, 9, 21).
  Alessandrini, Martino; Valinoti, Maddalena; Unger, Laura; Oesterlein, Tobias; Dössel, Olaf; Corsi, Cristiana; Loewe, Axel & Severi, Stefano
  
• FS: Assisted Living & Health. Biomedical Engineering / Biomedizinische Technik, 63(s1), 111-115.
  Nothstein M, Doessel O & Loewe A
  
• Influence of left atrial size on P-wave morphology: differential effects of dilation and hypertrophy. EP Europace, 20(suppl_3),iii36-iii44.
  Andlauer, Robin; Seemann, Gunnar; Baron, Lukas; Dössel, Olaf; Kohl, Peter; Platonov, Pyotr & Loewe, Axel
  
• Mathematical Modeling of Nonselective Channels: Estimating Ion Current Fractions and Their Impact on Pathological Simulations. Computing in Cardiology Conference inC) (2018, 12, 30). Computing in Cardiology.
  Moritz Wülfers, Eike; Kohl, Peter & Seemann, Gunnar
  
• 85. Jahrestagung der Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung vom 24. bis 27. April 2019 in Mannheim. Clinical Research in Cardiology, 108(S1), 1-1.
  Nothstein M, Luik A; Jadidi A, Wülfers E; Dössel O, Seemann G & Schmitt C, Loewe A
  
• Automated stimulus removal for the clinical S1-S2 pacing protocol. In 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2019
  Nothstein, M.; Luik, A.; Seemann, G.; Dössel, O. & Loewe, A.
  
• Genetic Ablation of TASK-1 (Tandem of P Domains in a Weak Inward Rectifying K + Channel–Related Acid-Sensitive K + Channel-1) (K 2P 3.1) K + Channels Suppresses Atrial Fibrillation and Prevents Electrical Remodeling. Circulation: Arrhythmia and Electrophysiology, 12(9).
  Schmidt, Constanze; Wiedmann, Felix; Beyersdorf, Christoph; Zhao, Zhihan; El-Battrawy, Ibrahim; Lan, Huan; Szabo, Gabor; Li, Xin; Lang, Siegfried; Korkmaz-Icöz, Sevil; Rapti, Kleopatra; Jungmann, Andreas; Ratte, Antonius; Müller, Oliver J.; Karck, Matthias; Seemann, Gunnar; Akin, Ibrahim; Borggrefe, Martin; Zhou, Xiao-Bo; ... & Thomas, Dierk
  
• Influence of Fibrotic Tissue Arrangement on Intracardiac Electrograms During Persistent Atrial Fibrillation. Computing in Cardiology Conference inC) (2019, 12, 30). Computing in Cardiology.
  Sánchez, Jorge; Nothstein, Mark; Unger, Laura; Saiz, Javier; Trénor Gomis, Beatriz; Doessel, Olaf & Loewe, Axel
  
• 86. Jahrestagung und Herztage 2020 der DGK Vom 14.- 17. Oktober 2020 in Berlin. Clinical Research in Cardiology, 109(S1), 1-1.
  Nothstein M, Luik A; Dössel O, Jadidi AS; Wülfers EM, Loewe A & Schmitt C, Seemann G
  
• Ein digitales Herz. Spektrum der Wissenschaft, 2020;20(10):44–48
  Loewe, A.
  
• Mapping and Removing the Ventricular Far Field Component in Unipolar Atrial Electrograms. IEEE Transactions on Biomedical Engineering, 67(10), 2905-2915.
  Frisch, Daniel; Oesterlein, Tobias G.; Unger, Laura A.; Lenis, Gustavo; Wakili, Reza; Schmitt, Claus; Luik, Armin; Dossel, Olaf & Loewe, Axel
  
• Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model. Journal of the American Heart Association, 9(10).
  Wiedmann, Felix; Beyersdorf, Christoph; Zhou, Xiaobo; Büscher, Antonius; Kraft, Manuel; Nietfeld, Jendrik; Walz, Teo Puig; Unger, Laura A.; Loewe, Axel; Schmack, Bastian; Ruhparwar, Arjang; Karck, Matthias; Thomas, Dierk; Borggrefe, Martin; Seemann, Gunnar; Katus, Hugo A. & Schmidt, Constanze
  
• Phase Singularities in Cardiac Patch Model with Non-conductive Fibrotic Area during Atrial Fibrillation. Computing in Cardiology Conference inC) (2020, 12, 30). Computing in Cardiology.
  Paggi de Almeida, Tiago; Nothstein, Mark; Li, Xin; Masè, Michela; Ravelli, Flavia; C. Soriano, Diogo; S. Bezerra, Arthur; S. Schlindwein, Fernando; Yoneyama, Takashi; Dössel, Olaf; André Ng, G. & Loewe, Axel
  
• Poster Session: Modelbased Personalised Medicine. Biomedical Engineering / Biomedizinische Technik, 65(s1), 255-263.
  Nothstein M, Müller-Edenborn B; Arentz T, Doessel O & Jadidi A, Loewe A
  
• Specific Electrogram Characteristics Identify the Extra-Pulmonary Vein Arrhythmogenic Sources of Persistent Atrial Fibrillation – Characterization of the Arrhythmogenic Electrogram Patterns During Atrial Fibrillation and Sinus Rhythm. Scientific Reports, 10(1).
  Jadidi, Amir; Nothstein, Mark; Chen, Juan; Lehrmann, Heiko; Dössel, Olaf; Allgeier, Jürgen; Trenk, Dietmar; Neumann, Franz-Josef; Loewe, Axel; Müller-Edenborn, Björn & Arentz, Thomas
  
• A Fully-Coupled Electro-Mechanical Whole-Heart Computational Model: Influence of Cardiac Contraction on the ECG. Frontiers in Physiology, 12(2021, 12, 16).
  Moss, Robin; Wülfers, Eike Moritz; Schuler, Steffen; Loewe, Axel & Seemann, Gunnar
  
• CVAR-Seg: An Automated Signal Segmentation Pipeline for Conduction Velocity and Amplitude Restitution. Frontiers in Physiology, 12(2021, 5, 24).
  Nothstein, Mark; Luik, Armin; Jadidi, Amir; Sánchez, Jorge; Unger, Laura A.; Wülfers, Eike M.; Dössel, Olaf; Seemann, Gunnar; Schmitt, Claus & Loewe, Axel
  
• Cycle length statistics during human atrial fibrillation reveal refractory properties of the underlying substrate: a combined in silico and clinical test of concept study. EP Europace, 23(Supplement_1),i133-i142.
  Unger, Laura A; Azzolin, Luca; Nothstein, Mark; Sánchez, Jorge; Luik, Armin; Seemann, Gunnar; Yeshwant, Srinath; Oesterlein, Tobias; Dössel, Olaf; Schmitt, Claus; Spector, Peter & Loewe, Axel
  
• Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology. Cells, 10(11), 2852.
  Sánchez, Jorge; Trenor, Beatriz; Saiz, Javier; Dössel, Olaf & Loewe, Axel
  
• Machine learning enables noninvasive prediction of atrial fibrillation driver location and acute pulmonary vein ablation success using the 12-lead ECG. Cardiovascular Digital Health Journal, 2(2), 126-136.
  Luongo, Giorgio; Azzolin, Luca; Schuler, Steffen; Rivolta, Massimo W.; Almeida, Tiago P.; Martínez, Juan P.; Soriano, Diogo C.; Luik, Armin; Müller-Edenborn, Björn; Jadidi, Amir; Dössel, Olaf; Sassi, Roberto; Laguna, Pablo & Loewe, Axel
  
• Novel insights into the electrophysiology of murine cardiac macrophages: relevance of voltage-gated potassium channels. Cardiovascular Research, 118(3), 798-813.
  Simon-Chica, Ana; Fernández, Marbely C; Wülfers, Eike M; Lother, Achim; Hilgendorf, Ingo; Seemann, Gunnar; Ravens, Ursula; Kohl, Peter & Schneider-Warme, Franziska
  
• Quantitative collagen assessment in right ventricular myectomies from patients with tetralogy of Fallot. EP Europace, 23(Supplement_1),i38-i47.
  Wülfers, Eike M; Greiner, Joachim; Giese, Max; Madl, Josef; Kroll, Johannes; Stiller, Brigitte; Kohl, Peter; Rog-Zielinska, Eva A & Fürniss, Hannah E
  
• Using Machine Learning to Characterize Atrial Fibrotic Substrate From Intracardiac Signals With a Hybrid in silico and in vivo Dataset. Frontiers in Physiology, 12(2021, 7, 5).
  Sánchez, Jorge; Luongo, Giorgio; Nothstein, Mark; Unger, Laura A.; Saiz, Javier; Trenor, Beatriz; Luik, Armin; Dössel, Olaf & Loewe, Axel
  
• A computational model of rabbit geometry and ECG: Optimizing ventricular activation sequence and APD distribution. PLOS ONE, 17(6),e0270559.
  Moss, Robin; Wülfers, Eike M.; Lewetag, Raphaela; Hornyik, Tibor; Perez-Feliz, Stefanie; Strohbach, Tim; Menza, Marius; Krafft, Axel; Odening, Katja E. & Seemann, Gunnar
  
• Editorial: Atrial Fibrillation: Technology for Diagnosis, Monitoring, and Treatment. Frontiers in Physiology, 13(2022, 2, 23).
  Berenfeld, Omer; Corino, Valentina D. A.; Loewe, Axel; Martínez, Juan Pablo & Rodriguez Matas, Jose F.
  
• Machine Learning Using a Single-Lead ECG to Identify Patients With Atrial Fibrillation-Induced Heart Failure. Frontiers in Cardiovascular Medicine, 9(2022, 2, 28).
  Luongo, Giorgio; Rees, Felix; Nairn, Deborah; Rivolta, Massimo W.; Dössel, Olaf; Sassi, Roberto; Ahlgrim, Christoph; Mayer, Louisa; Neumann, Franz-Josef; Arentz, Thomas; Jadidi, Amir; Loewe, Axel & Müller-Edenborn, Björn