Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III CIBERCV Introduction Cardiac arrhythmias can originate as a consequence of the proarrhythmic effects of some therapeutical regenerative products. In vitro studies have demonstrated different levels of electrophysiological complexity but these models usually lack of direct translation into the clinical practice. Objective To develop an arrhythmia complexity evaluation method that enables to characterize electrophysiological complexity in translational scenarios. Methodology: To build a new evaluation method, frequency and rotor biomarkers from in vitro cell cultures presenting fibrillatory activity (N=15) were evaluated using optical mapping recordings (Rhod-2AM Ca2+ transient dye, 30-minute incubation, excited with green light). The patterns observed at in vitro level were analyzed and characterized by means of frequency and rotor biomarkers. Next, we performed a forward translational study to evaluate these electrophysiological biomarkers at a clinical level. In 206 patients with atrial fibrillation (AF) with non-invasive body surface recordings using the Acorys system from Corify (67 electrodes, 4 second segments) (STRATIFY-AF study) were evaluated to analyze the same frequency and rotor biomarkers previously explored in vitro. Moreover, we build a complexity score that described from 0 to 1 the complexity at electrophysiological level, where 0 corresponded to simple scenarios and 1 to complex arrhythmic patterns. Patients were followed for 12 months to evaluate long term evolution. Results Complexity evaluation method identified the highest dominant frequency, median frequency and rotor time as the most important predictors for arrhythmia complexity definition. In vitro cultures results showed that samples presenting higher dominant frequency were also associated with small dominant frequency area extension and lower rotor time maintenance, i.e., with a high value of the complexity biomarker (Figure 1B). At clinical level, patients with high values of the complexity score were identified with Persistent AF patients showing complex patterns in whom AF recurred after ablation at 12 months (Figure 1D). Conclusions We developed a translational approach that enables to characterize arrhythmia complexity in different frameworks, which is crucial to evaluate potential undesirable effects of therapeutical regenerative products during the complete development and validation of the product.

中文翻译：

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一种用于电生理表征的新型平移分层系统：评估从实验室到临床的心律失常复杂性

资金致谢 资金来源类型：公共机构。主要资金来源： Instituto de Salud Carlos III CIBERCV 引言 心律失常可能是由于某些治疗性再生产品的促心律失常作用所致。体外研究已经证明了不同程度的电生理复杂性，但这些模型通常缺乏直接转化为临床实践。目的 开发一种心律失常复杂性评估方法，能够表征平移场景中的电生理复杂性。方法：为了建立一种新的评估方法，使用光学映射记录（Rhod-2AM Ca2+ 瞬态染料，30 分钟孵育，绿灯兴奋）。通过频率和转子生物标志物分析和表征在体外水平观察到的模式。接下来，我们进行了一项正向转化研究，以在临床水平上评估这些电生理生物标志物。在使用 Corify 的 Acorys 系统（67 个电极，4 秒段）（STRATIFY-AF 研究）进行无创体表记录的 206 名心房颤动 (AF) 患者中进行评估，以分析之前在体外探索过的相同频率和转子生物标志物. 此外，我们建立了一个复杂性评分，从 0 到 1 描述了电生理水平的复杂性，其中 0 对应于简单的场景，1 对应于复杂的心律失常模式。对患者进行了 12 个月的随访以评估长期演变。结果复杂性评估方法确定了最高主频、中频和转子时间作为心律失常复杂性定义的最重要预测因子。体外培养结果表明，具有较高主频的样品也与较小的主频区域扩展和较低的转子时间维持相关，即具有高复杂性生物标志物的价值（图 1B）。在临床水平上，复杂性评分值较高的患者被确定为持续性 AF 患者，这些患者表现出复杂模式，其中 12 个月消融后 AF 复发（图 1D）。结论 我们开发了一种转化方法，可以在不同的框架中描述心律失常的复杂性，