Experimental and computational approach to understand regional heterogeneity and electro-mechanical interactions in the rabbit heart

• Applicants: Professor Dr. Peter Kohl, since 2/2021; Professorin Dr. Katja Elisabeth Odening
• Subject Area: Cardiology, Angiology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394630089

• Final Report Year: 2022

Final Report Abstract

Background. Pronounced electrical and mechanical heterogeneities exist in the healthy heart, enabling physiological cardiac function. This electro-mechanical (E-M) heterogeneity exists on all levels, from the cell to the whole heart, and it is driven by regional heterogeneities in ion channels. Alterations of physiological E- M heterogeneity have been identified in various "electrical" and "mechanical" cardiac diseases and can be causatively linked to arrhythmogenesis. The mechanisms driving the pathological heterogeneity and their role in arrhythmia formation are unclear. Electrical and mechanical processes interact in a bi-directional way via electro-mechanical (EMC) and mechano-electrical coupling (MEC), so that acute or chronic alterations of either will lead to consecutive changes of the other. This can be observed in long-QT syndrome (LQTS), which is considered a typical "electrical" disease, but demonstrates also mechanical abnormalities correlating with - and presumably altering - the individual arrhythmic risk. Rationale. As E-M remodelling occurs in the "chronically" diseased heart, it is difficult to dissect drivers of bidirectional E-M-E interactions. In this project, we have therefore 1) characterized E-M heterogeneities and interactions in healthy and "acute" drug-induced LQTS hearts (without remodelling) and 2) have investigated consequences of acute changes of electrics and/or mechanics on E-M-E crosstalk by using targeted interventions. Methods and Results. Using multi-channel ECG and tissue-phase mapping MRI in vivo, we could demonstrate that 1) electrical alterations (“acute” LQTS) cause changes in mechanical function (EMC), that 2) acute alterations in preload cause acute (and heterogenous) changes in QT duration (MEC), and that 3) these mechano-induced electrical changes are more pronounced in “acute” LQTS hearts with longer baseline QT. Similar E-M-E interactions were also investigated on the whole heart level with simultaneous Ca2+/voltage optical mapping combined with transmural ultrasound ex vivo in Langendorff-perfused hearts. Furthermore, we developed an in-silico model of the rabbit heart and torso (openly available). Using this model, we investigated, which different apico-basal and transmural heterogeneities could reproduce the experimentally measured T-wave shapes. Moreover, we assessed the impact of cardiac contraction on T-wave characteristics. We are currently investigating - both experimentally and computationally - potential drivers of this E-M-E crosstalk. Conclusion and Outlook: A thorough understanding of EMC and MEC in healthy and "acute LQTS" hearts will allow us to predict the role of E-M-E crosstalk as causative link between E-M heterogeneity and arrhythmogenesis also in more complex, chronic diseases with remodelled substrate - which will form a future target for our research.

Publications

• Computational modelling of rabbit and human cardiac electromechanics: from cell to heart to ECG
  R. Moss
  
• T-Wave Changes Due to Cardiac Deformation Are Dependent on the Temporal Relationship Between Repolarization and Diastolic Phase. Computing in Cardiology Conference (CinC). Computing in Cardiology.
  Moss, Robin; Moritz, Wülfers Eike & Seemann, Gunnar
  
• Electro-mechanical heterogeneity and electro-mechano-electrical interactions in healthy and drug-induced LQTS rabbit hearts. DGK Herbsttagung - Basic Science Meeting, Oktober 2019, Berlin. Poster
  R. Lewetag, T. Hornyik, S. Jacobi, R. Moss, C. Zgierski-Johnston, M. Menza, S. Perez-Feliz, C. Bode, G. Seemann & K.E. Odening
  
• Modeling Inspired Hypothesis to Loss of Capture in Mechanical Pacing of the Heart. 8th International Workshop Cardiac Mechano-Electric Coupling and Arrhythmias, September 2019, Freiburg. Poster
  R. Moss, E. M. Wülfers & G. Seemann
  
• T-Wave Changes Due to Cardiac Deformation Are Dependent on the Temporal Relationship Between Repolarization and Diastolic Phase. DGK Jahrestagung, April 2019, Mannheim. Poster
  R. Moss, E. M. Wülfers & G. Seemann
  
• A Fully-Coupled Electro-Mechanical Whole-Heart Computational Model: Influence of Cardiac Contraction on the ECG. Frontiers in Physiology, 12.
  Moss, Robin; Wülfers, Eike Moritz; Schuler, Steffen; Loewe, Axel & Seemann, Gunnar
  
• Differences in extent of mechano-induced QT- changes in SQTS, WT and LQTS rabbit models. ESC 2021, online Congress. ePoster
  S. Nimani, T. Hornyik, N. Alerni, R. Lewetag, L. Giammarino, S. Perez-Feliz, L. Matas, K.R. Moss, M. Zehender, M. Brunner, G. Seemann & K.E. Odening
  
• Electro-mechanical heterogeneity and electro-mechano-electrical interactions in healthy and drug-induced LQTS rabbit hearts. DGK Jahrestagung, April 2021, Mannheim. Vortrag
  R. Lewetag, T. Hornyik, S. Jacobi, R. Moss, C. Zgierski-Johnston, M. Menza, S. Perez-Feliz, C. Bode, G. Seemann & K.E. Odening
  
• 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
  
• Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond. European Heart Journal, 43(32), 3018-3028.
  Odening, Katja E.; van der Linde, Henk J.; Ackerman, Michael J.; Volders, Paul G. A. & ter Bekke, Rachel M. A.
  
• Elektro-mechanische und mechano-elektrische Interaktionen am gesunden und medikamentös-induzierten LQTS Kaninchen-Herz
  R. Lewetag