Concealed Substrates in Brugada Syndrome: Isolated Channelopathy or Associated Cardiomyopathy?

Simple summary Having a new and more precise definition of BrS, based on its cardiomyopathic component, may be crucial to meliorate the current clinical management of patients, at (i) diagnostic, (ii) prognostic, and (iii) therapeutic levels: (i) diagnostic, since specific tests may be added to the current standards of BrS to identify associated arrhythmogenic substrates; (ii) prognostic, since multiple factors from an extended diagnostic workup may be associated with an increased arrhythmic risk (as already demonstrated in many cardiomyopathies), subsequently improving the patient selection for a primary prevention ICD implant; (iii) at therapeutic levels, since the identification of unexpected substrates may turn into a significant change in the current treatment practice. Brugada syndrome (BrS) is an inherited autosomal dominant genetic disorder responsible for sudden cardiac death from malignant ventricular arrhythmia. The term "channelopathy" is nowadays used to classify BrS as a purely electrical disease, mainly occurring secondarily to loss-of-function mutations in the alpha subunit of the cardiac sodium channel protein Nav1.5. In this setting, arrhythmic manifestations of the disease have been reported in the absence of any apparent structural heart disease or cardiomyopathy. Over the last few years, however, a consistent amount of evidence has grown in support of myocardial structural and functional abnormalities in patients with BrS. In detail, abnormal ventricular dimensions, either systolic or diastolic dysfunctions, regional wall motion abnormalities, myocardial fibrosis, and active inflammatory foci have been frequently described, pointing to alternative mechanisms of arrhythmogenesis which challenge the definition of channelopathy. The present review aims to depict the status of the art of concealed arrhythmogenic substrates in BrS, often resulting from an advanced and multimodal diagnostic workup, to foster future preclinical and clinical research in support of the cardiomyopathic nature of the disease.