Seventh TRM Forum on Computer Simulation and Experimental Assessment of Cardiac Function: Creating the Basis for Tailored Therapies

Computer simulations have gained increasing importance for the understanding of cardiac arrhythmias and the development of new therapeutic solutions, overcoming some of the limitations encountered in clinical and experimental research. Progresses in computer models depend on continuous exchange of clinical and experimental data, both for model development and validation. Therefore, it is important that experts from these two fields communicate. Today, patient-specific models based on clinical imaging and electrophysiological data are becoming a reality. Such models could be used in the future for guiding individual clinical antiarrhythmic therapies. The challenge lies in how to translate these computer methods into clinically effective tools. To that end, since 1998 the Theo Rossi di Montelera (TRM) forum has brought together researchers with different expertise in computer modelling, experimental and clinical research. The seventh TRM forum was held in Lugano, Switzerland, on 1–3 December 2013, hosted by the Lausanne Heart group, the University of Lugano (USI) and the Cardiocentro Ticino (CCT). The theme was ‘Creating the Basis for Tailored Therapies’. The objective of the TRM forum is to facilitate the translation of basic science findings in computer modelling into the clinical field. The first day of the forum was therefore focused on ‘From computer to bedside: how predictive are computer models’ with the presentation of latest patient-specific computer models of the atria and ventricles and how they can be used to predict the effect of cardiac therapies. The second day followed the opposite pathway ‘From bedside to computer: how much data do we need?’ with the imaging tools need to build patient-specific models and how the measure of cardiac signals can help in arrhythmia diagnosis and treatment. Several patient-specific models were presented at the TRM forum. The first article by Gonzales et al.1 presents a three-dimensional (3D) model of human atria based on patient-derived imaging and electrophysiology and studied the contributions of fibrosis to the maintenance atrial fibrillation (AF) and possible mechanisms of termination. A second computer model of AF was presented by Matene et al.2 that includes time-varying acetylcholine concentration to investigate the modulation of atrial activity by the parasympathetic nervous system during an arrhythmia. Results showed that transient acetylcholine release can affect the AF transient dynamics and also act as an arrhythmia perpetuator by generating new wavelets that self-perpetuate. The effect of atrial tissue thickness was investigated in a bilayer model of human atria by Labarthe et al.3 This study showed that, while surface models have significant computational advantages over tissue models, they cannot fully capture propagation patterns seen in vivo, such as dissociation of activity between endo- and epicardium. The effect of the antiarrhythmic agents such as amiodarone and dronedarone on atrial electrophysiology was investigated using a computational model of human atria by Loewe et al.4 Results provided possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF. Franz et al.5 tested the hypothesis that amiodarone suppresses tachycardia induction better than ‘pure’ Class III antiarrhythmic drugs because amiodarone causes post-repolarization refractoriness in a study on 31 inducible patients. This resulted in the development of a revised action potential computer model to provide mechanistic insights. Several models of heart failure were also presented. Maleckar et al.6 performed simulations in canine ventricular myocyte models including experimental data both from healthy and failing myocytes. A patient-specific modelling of heart failure patients was presented by Potse et al.7 Predicted electrocardiogram (ECG) and catheter electrograms were compared with their clinically measured equivalents and the model parameters were tuned to optimize the match. The modelling of cardiac resynchronization therapy (CRT) for heart failure was also addressed. Huntjens et al.8 investigated in a computer model how the position of the left ventricular CRT lead relative to a scar affects the haemodynamic response in patients with dyssynchronous heart failure, suggesting that the optimal lead position is a compromise between a position distant from the scar and from the septum. Pathologically shortened cardiac action potentials are highly arrhythmogenic. Optogenetic tools could be used to restore normal action potential duration and provide a low-energy alternative to electrical stimulation for cardiac pacing and cardioversion. Karathanos et al.9 used computational simulations to show proof-of-concept for optogenetics-based treatment of arrhythmia. They characterized practical constraints (non-uniform light-sensitive cell distribution, light attenuation in tissue) that must be overcome before the proposed treatment approach could be translated to clinical applications. Today, one of the challenges in computer modelling lies in the difficulty to access relevant human cardiac electrophysiological data upon which to develop or validate models at all scales. In a review article, Holzem et al.10 presents multi-scale human heart physiology investigations studied over 300 human hearts. Burton et al.11 illustrated tools to quantitatively assess the cell-type distribution from large histology and magnetic resonance imaging-based datasets using rabbit hearts. The data provided aids for the further development of histoanatomically detailed models of cardiac structure and function. Finally, cardiac imaging is another important aspect of computer modelling. Caiani et al.12 proposed a nearly automated left ventricular 3D surface segmentation procedure for cardiac magnetic resonance images. A comparison to manual segmentation showed its accuracy, speed, and potential application in patient-specific finite-element modelling. One last aspect addressed during the forum was analysis of cardiac signals (ECG and electrograms) either for diagnosis or as an aid to therapy. Benson et al.13 presented an algorithm for identifying circuit core density and distribution during multi-wavelet reentry based upon high-resolution electrogram frequency mapping of AF. They validate their algorithm efficacy through a map-guided ablation trial. Platonov et al.14 present a review paper on the current state of knowledge regarding ECG-derived atrial fibrillatory cycle length as a value to monitor the progress of atrial ablation therapy. In a study by Corino et al.,15 the effect of drugs on atrioventricular node in patient with AF was studied non-invasively from ECG during metropol administration. The changes observed in 60 patients suggest that this non-invasive method might be used to assess drug effects in AF. van Oosterom16 compared the performance of two major source types involved in the imaging of the electric activity of the heart on the basic potential differences observed on the thorax. Kuklik et al.17 proposed a method for endo–epicardial mapping of AF based on a concept of maximized phase coherence. Finally, Cerutti et al.18 assessed the changes in systolic arterial pressure during tilt test in patients with persistent AF. Results showed that the alterations detected were not uniform in the population: irregularity increased only in those patients where systolic arterial pressure also increased. The articles included in this issue offer a wide view of cardiac function using approaches of computer simulation, experimentation and clinical observation, both going from computer to bedside and from bedside to computer. We hope that it will contribute to the current trend in translational medicine and ultimately to the development of patient-specific models for tailored cardiac therapies. Conflict of interest: N.V. is a full time employee of Medtronic Europe (Tolochenaz, Switzerland) A.A. Speaker fee, honoraria, consultant: Abbott, Biotronik GmBH, Bristol-Meyers-Squibb, Cordis BDS, DC_Device, EBR Systems, Impulse Dynamics, Medtronic, ResMed, Sorin Group, St. Jude Medical.

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