Abstract:

Atrial fibrillation (AF) is one of the most commoncardiac diseases. However, a complete understanding of howto treat patients suffering from AF is still not achieved. Asthe isolation of the pulmonary veins in the left atrium (LA)is the standard treatment for AF, the role of the right atrium(RA) in AF is rarely considered. We investigated the impactof including the RA on arrhythmia vulnerability in silico. Wegenerated a dataset of five mono-atrial (LA) and five bi-atrialmodels with three different electrophysiological (EP) setupseach, regarding different states of AF-induced remodelling.For every model, a pacing protocol was run to induce reen-tries from a set of stimulation points. The average share ofinducing points across all EP setups was 0.0, 0.8 and 6.7 %for the mono-atrial scenario, 0.5, 27.3 and 37.9 % for the bi-atrial scenario. The increase in inducibility of LA stimula-tion points from mono- to bi-atrial scenario was 0.91 ± 2.03%,34.55 ± 14.9 % and 44.2 ± 14.9 %, respectively. In this study,the RA had a marked impact on the results of the vulnerabilityassessment that needs to be further investigated.

Abstract:

UNLABELLED: Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe COVID-19. Remdesivir is a prodrug of the nucleoside analogue GS-441524 which is converted into the active nucleotide triphosphate to disrupt viral genome of the conserved non-structural proteins (NSPs) and thus block viral replication. GS-441524 exerts a number of pharmacological advantages over Remdesivir: (1) it needs fewer conversions for bioactivation to nucleotide triphosphate; (2) it requires only nucleoside kinase, while Remdesivir requires several hepato-renal enzymes, for bioactivation; (3) it is a smaller molecule and has a potency for aerosol and oral administration; (4) it is less toxic allowing higher pulmonary concentrations; (5) it is easier to be synthesized. The current article will focus on the discussion of interactions between GS-441524 and NSPs of VOCs to suggest potential application of GS-441524 in breakthrough SARS-CoV-2 infections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44231-022-00021-4.

Abstract:

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-specifi c 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 and3) 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 setto 0.7 m/s and the electrical propagation in the atria was modeled by the monodomain equation and solved withopenCARP.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: The incorporation of patient-specifi c 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-specifi c therapy planning. Larger cohorts need to follow to demonstrate the role of incorporating clinical patient-specifi c ERP values into personalized models for predicting AF vulnerability.

Abstract:

Atrial fibrillation (AF) is the most common sus- tained arrhythmia posing a significant burden to patients and leading to an increased risk of stroke and heart failure. Additional ablation of areas of arrhythmogenic substrate in the atrial body detected by either late gadolinium enhance- ment magnetic resonance imaging (LGE-MRI) or electro- anatomical mapping (EAM) may increase the success rate of restoring and maintaining sinus rhythm compared to the stan- dard treatment procedure of pulmonary vein isolation (PVI). To evaluate if LGE-MRI and EAM identify equivalent sub- strate as potential ablation targets, we divided the left atrium (LA) into six clinically important regions in ten patients. Then, we computed the correlation between both modalities by ana- lyzing the regional extents of identified pathological tissue. In this regional analysis, we observed no correlation between late gadolinium enhancement (LGE) and low voltage areas (LVA), neither in any region nor with regard to the entire atrial surface (−0.3 < 𝑟 < 0.3). Instead, the regional extents identified as pathological tissue varied significantly between both modali- ties. An increased extent of LVA compared to LGE was ob- served in the septal wall of the LA (𝑎 ̃sept.,LVA = 19.63 % and 𝑎 ̃sept.,LGE = 3.94 %, with 𝑎 ̃ = median of the extent of patho- logical tissue in the corresponding region). In contrast, in the inferior and lateral wall, the extent of LGE was higher than the extent of LVA for most geometries (𝑎 ̃inf.,LGE = 27.22% and 𝑎 ̃lat.,LGE = 32.70 % compared to 𝑎 ̃inf .,LVA = 9.21 % and 𝑎 ̃lat.,LVA = 6.69 %). Since both modalities provided dis- crepant results regarding the detection of arrhythmogenic sub- strate using clinically established thresholds, further investiga- tions regarding their constraints need to be performed in order to use these modalities for patient stratification and treatment planning.