Atrial fibrillation (AF) inducibility, sustainability and response to pharmacological treatment of individual patients are expected to be determined by their ionic current properties, especially in structurally-healthy atria. Mechanisms underlying AF and optimal cardioversion are however still unclear. In this study, in-silico drug trials were conducted using a population of human structurally-healthy atria models to 1) identify key ionic current properties determining AF inducibility, maintenance and pharmacological cardioversion, and 2) compare the prognostic value for predicting individual AF cardioversion of ionic current properties and electrocardiogram (ECG) metrics. In the population of structurally-healthy atria, 477 AF episodes were induced in ionic current profiles with both steep action potential duration (APD) restitution (eliciting APD alternans), and high excitability (enabling propagation at fast rates that transformed alternans into discordant). High excitability also favored 211 sustained AF episodes, so its decrease, through prolonged refractoriness, explained pharmacological cardioversion. In-silico trials over 200 AF episodes, 100 ionic profiles and 10 antiarrhythmic compounds were consistent with previous clinical trials, and identified optimal treatments for individual electrophysiological properties of the atria. Algorithms trained on 211 simulated AF episodes exhibited >70% accuracy in predictions of cardioversion for individual treatments using either ionic current profiles or ECG metrics. In structurally-healthy atria, AF inducibility and sustainability are enabled by discordant alternans, under high excitability and steep restitution conditions. Successful pharmacological cardioversion is predicted with 70% accuracy from either ionic or ECG properties, and it is optimal for treatments maximizing refractoriness (thus reducing excitability) for the given ionic current profile of the atria.

The best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti‐arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+ current (IK1) and Na+/K+ pump (INaK) densities (IK1 0.11 ± 0.03 vs. 0.07 ± 0.03 S mF–1; INaK 0.68 ± 0.15 vs. 0.38 ± 26 S mF–1; sustained vs. un‐sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher IK1 (median density 0.12 ± 0.02 S mF–1) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L‐type Ca2+ current, ICaL, density 0.08 ± 0.03 S mF–1). This atrial refractoriness, modulated by ICaL and fast Na+ current (INa), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median ICaL density 0.13 ± 0.05 S mF–1). For short refractoriness, atria with high INa (median density 8.92 ± 2.59 S mF–1) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low INa (median density 5.33 ± 1.41 S mF–1). In silico drug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. imageKey points Atrial fibrillation (AF) maintenance is facilitated by small L‐type Ca2+ current (ICaL) and large inward rectifier K+ current (IK1) and Na+/K+ pump. In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher IK1 and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low ICaL) Vernakalant is effective in atria presenting long refractoriness (high ICaL). For short refractoriness, atria with fast Na+ current (INa) up‐regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low INa. The inward currents (ICaL and INa) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.

Background Personalisation of pharmacological treatment for atrial fibrillation (AF) is challenging. Pharmacological ionic current blockers such as digoxin or flecainide are commonly used, with caution given possible cardiotoxicity and proarrhythmia. Moreover, patients are stratified based on their associated heart disease rather than individual electrophysiological substrate, in part due to the inability for its non-invasive characterisation. Here we hypothesise that the ECG may contain information on key ionic currents regulating AF initiation and sustenance, and which would enable personalisation of pharmacological treatments to increase safety and efficacy. Purpose To identify clinical ECG markers that reflect dysregulation of key ionic currents for AF using modelling and simulation in populations of whole-atria models without structural heart disease. Methods Experimental data obtained from human AF and control patients was used to develop a virtual population of 200 whole-atria models (Figure, organ-level) with individual ionic profiles (Figure 1, bottom-left), including electrophysiological regional inhomogeneities (Figure 1, bottom-right). Modified-limb 12 lead ECGs were computed during sinus rhythm (Figure 1, body-surface-level) and biomarkers were quantified for the P and Ta-waves, such as duration, time-to-peak, decay, dispersion, amplitude and P-wave terminal force. Results Simulated modified-limb ECG consistently reproduced the clinical ECG observed in human subjects, with an apparent Ta-wave inversion in lead II (Figure 1, body-surface-level). The inward rectified K+ current (IK1), known to be critical for AF, was the only ionic current associated with Ta-wave duration, showing an inversely proportional relationship (236±48 vs. 466±53 ms, IK1 up-regulation vs. down-regulation in lead V5; median ± interquartile range; P<0.001). Elevated IK1 additionally yield Ta-wave inversion in lead V5 and a higher Ta-wave magnitude in lead II (0.15±0.03 vs. 0.07±0.04 mV, IK1 up-regulation vs. down-regulation; P<0.001). However, Ta-wave magnitude showed a predominant relationship with the Na+/K+ pump (INaK), especially in the precordial leads (0.17±0.13 vs. 0.07±0.04 mV, INaK up-regulation vs. down-regulation in V5; P<0.001). Thus, the up-regulation of both currents led to very short, high-amplitude Ta-waves. While elevated IK1 additionally increased the P-wave terminal force (1.58±0.37 vs. 1.31±0.33 mV ms, IK1 up-regulation vs. down-regulation; P<0.001), a higher increase was observed for decreased fast Na+ current (INa) (1.35±0.17 vs. 1.86±0.30 mV ms, INa up-regulation vs. down-regulation; P<0.001). Conclusion Ta-wave duration and amplitude are revealing of IK1 and INaK dysregulation, respectively, holding potential for improving cardiac safety and efficacy through a better stratification of AF patients for pharmacological treatment. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860974

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska- Curie grant agreement Introduction Although the effective refractory period (ERP) is one of the main electrophysiological properties governing atrial tachycardia (AT) maintenance, ERP personalization is rarely performed when creating patient-specific computer models of the atria to inform clinical decision making. State-of-the-art models usually do not consider physiological ERP gradients but assume a homogeneous ERP distribution. This assumption might have an influence on the ability to induce reentries in the model. Aim To evaluate the impact of incorporating clinical ERP measurements when creating in silico personalized models to predict vulnerability to atrial fibrillation (AF). Methods Clinical ERP measurements were obtained from three patients from multiple locations in the atria. The protocol for ERP identification consisted of trains of 7 S1 stimuli with a basic cycle length of 500ms followed by an S2 stimulus with a coupling interval between 300 and 200ms in decrements of 10ms until loss of capture. The atrial geometries from the electroanatomical mapping system were used to generate personalized atrial models. To reproduce patient-specific ERP, the established Courtemanche cellular model was gradually reparameterized from control conditions to a setup representing AF-induced remodeling. Three different approaches were studied: 1) a control scenario with no ERP personalization 2) a discrete split where each region had a single ERP value and 3) a continuous ERP distribution by interpolation of measured ERP data (Fig. 1). Arrhythmia vulnerability was assessed by virtual S1S2 pacing from different locations separated by 3cm. The number and location of inducing points and type of arrhythmia were determined for the three approaches. The mean conduction velocity was set to 0.7 m/s and the electrical propagation in the atria was modeled by the monodomain equation and solved with openCARP. Results Incorporating patient-specific ERP as a continuous distribution did not induce any reentrant activity. A summary of induced ATs is shown in Table 1. For patient A, AF was induced from 3 different locations with the control setup, whereas 9 ATs were induced with the regional method, of which 4 were AF and 5 macro reentries. For patient B, AF was induced from 1 point with the control setup; whereas with the regional approach, AF was induced at 4 points. For patient C, only one macro reentry was induced with the regional method. Conclusion Incorporation of patient-specific ERP values has an impact on the assessment of AF vulnerability. Furthermore, the type of personalization affects the likelihood of AF inducibility. The incorporation of more detailed ERP distributions may lead to a more accurate prediction of AF trigger points and could in the future inform patient-specific therapy planning. Larger cohorts need to follow to demonstrate the role of incorporating clinical patient-specific ERP values into personalized models for predicting AF vulnerability.

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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have proven to be crucial in pharmacological assessment. Nevertheless, their response to drugs when coupled forming a tissue is not fully understood. Thus, the aim of this study was to determine whether blocking L-type Ca +2 current ( "#$ ) in a hiPSC-CMs tissue could be considered as a potential antiarrhythmic procedure.To analyze the effects of "#$ block, the maximum conductance of "#$ ( "#$ ) was decreased (block conditions) and compared to control. In both situations, control and block, the tissue was stimulated following a cross-field protocol to generate re-entries. A phase analysis was performed and specific parameters, such as re-entry frequency ( '(()*'+ ), excitation wavelength, vulnerable window (VW), and cellular excitability, were evaluated.Induced re-entries, where "#$ was reduced by 70% showed a 6.9% and a 47.83% decrease in '(()*'+ and in the width of the VW, respectively. Our results suggest that blocking calcium channels could be considered as an antiarrhythmic strategy in a hiPSC-CMs tissue.

Cardiac alternans has been linked to arrhythmias, and certain conditions, such as fibrosis, can change the onset of alternans increasing the vulnerability to electrical instabilities. The study of the underlying mechanisms of beat-to-beat cellular fluctuations and, in particular, when fibroblasts interact with myocytes, could help to reduce the risk of reentrant activity.We investigated the origin of cellular alternans in myocytes coupled to fibroblasts using mathematical models. Differences in alternans development in relation to variability in ion transport pathways between individuals of a population of cells was the key to identify the parameters that can modulate cellular alternation.Repolarization alternans and Ca 2+ cycling alternans were concomitant in myocytes, but the latter was a better quantitative indicator due to marked alternating Ca 2+ transients. Despite the similar mechanisms inducing Ca 2+ alternans, the myocyte-fibroblast population was more prone to alternans than the population without fibroblast. Our findings suggest that Ca 2+ -related parameters regulate alternans formation because they occur due to an impaired Ca 2+ dynamics, a situation that is exacerbated by fibrosis.

Intracellular Ca 2+ is the main activator of myofilament contraction and the altered Ca 2+ handling observed in failing cells has been established as the leading cause of reduced inotropy in heart failure. Electrophysiological studies usually quantify Ca 2+ transients to estimate contractile effects. However, heart failure remodeling of myofilaments also occurs, modifying the correlation between Ca 2+ and force. The aim of this study was to analyze myofilament tension generated by action potentials in human heart failure. In a ventricular electromechanical we investigated cellular contraction force associated with intracellular Ca 2+ in heart failure by implementing the characteristic electrophysiological, -adrenergic, and mechanical changes. Despite the inotropic myofilament remodeling induced by heart failure, the maximal active tension in failing cells was one third of the force generated in normal cells. With isoproterenol, -adrenergic stimulation increased systolic Ca 2+ , which enhanced myofilament tension by up to 150%, but failing cells also showed a smaller contraction force compared to normal. We observed that contractility was very sensitive to changes in intracellular Ca 2+ , confirming that increasing Ca 2+ peak would improve contraction in heart failure.