A Novel Approach to Assess Atrial Electrical Abnormalities in Patients with Brugada Syndrome: From the ECG to the Creation of a Patient-Specific Cardiac Model

Brugada syndrome (BrS) is a rare cardiovascular disease, caused by genetically-determined ion channel dysfunction, leading individuals with no overt cardiovascular abnormalities to an increased risk of cardiac arrhythmias and sudden cardiac death (SCD). Among the heterogeneous spectrum of the inherited primary arrhythmia syndromes, BrS present with the highest prevalence and a high rate of atrial arrhythmias, more specifically atrial fibrillation (AF) leading to a challenging management. Over the past two decades, our understanding of BrS has been enriched by a considerable number of studies aimed at defining the clinical characteristics, the genetic, cellular and molecular features predisposing patients to an enhanced risk of ventricular arrhythmias. In contrast, a full understanding of the pathogenic mechanisms of atrial arrhythmias in these patients is missing and very little is known about the causative role of the genetically-determined ion channel dysfunction on atrial conduction abnormality. The prognostic role of the presence of atrial arrhythmias in BrS is also controversial. Similarly, unknown is the relationship between the atrial and ventricular phenotype on standard 12-lead electrocardiogram (ECG), and whether the coexistence of a given atrial ECG phenotype with a specific ventricular ECG phenotype influences the risk of subsequent atrial and/or ventricular arrhythmias, conferring an overall higher risk profile to a patient. The best diagnostic and therapeutic management strategy for these patients is therefore unclear and needs a refinement. For the first time, I have recently demonstrated that BrS patients have a concealed abnormal atrial phenotype, despite the absence of history of AF. I hypothesize that the presence of a specific atrial phenotype in BrS is indicative of the overall arrhythmic risk, conferring to a patient higher susceptibility to either atrial or ventricular arrhythmias occurrence.Within the current research framework, I will characterize the atrial electrical abnormalities in a larger series of BrS patients with or without previous history of atrial arrhythmias and I will investigate the pathogenetic mechanisms leading to atrial arrhythmias development. Moreover, the correlation between presence of atrial electrical abnormalities and risk of life-threatening arrhythmias will be assessed and potential therapeutic strategies for AF will be explored. A multimodality multiscale approach will be used to confirm my hypothesis. I will assess patients’ clinical data, cardiac magnetic resonance (CMR), ECG advanced signals post-processing analysis, electrophysiologic study (EPS) results and high-resolution cardiac mapping. All these data will be integrated into a generic cardiac model to obtain a patient-specific model. The patient-specific cardiac model will enable the assessment of propensity to atrial arrhythmias development, the identification of the underlying pathophysiological mechanisms and the evaluation of the response to different pharmacological and invasive therapeutic strategies. This research will contribute to enlarge the therapeutic offer and improve the quality of life of patients with BrS by enhancing the mechanistic understanding of atrial electrical abnormalities and refining patient’s arrhythmic risk. Moreover, in-depth characterization of pathogenesis of atrial arrhythmias in BrS may have significant clinical implications in the diagnostic and therapeutic management of a much larger group of individuals at risk of AF and in general, in a very large group of patients affected by idiopathic AF or other cardiac causes.