Substrate Mapping in Brugada Syndrome: Combined Role of Conduction and Repolarization Heterogeneities in Arrhythmogenesis”

Response to Letter Regarding Article, “High-Density Substrate Mapping in Brugada Syndrome: Combined Role of Conduction and Repolarization Heterogeneities in Arrhythmogenesis” We thank Dr Santangeli et al for their kind interest in our article describing the electrophysiological features of Brugada syndrome. The authors are concerned that we have not excluded structural heart disease, which they propose requires magnetic resonance imaging and cardiac biopsy. However, the early manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) are electrocardiographic and arrhythmic, not structural, anomalies. None of these patients had electrocardiographic or arrhythmic manifestations indicative of ARVC. Moreover, there was no evidence of ARVC in first-degree relatives screened in the clinic, and a contrast echo with detailed right ventricular views was normal in all of the patients with Brugada syndrome. The emergence of abnormal right ventricular dimensions on magnetic resonance imaging in Brugada syndrome is a recent finding that still needs to be confirmed in other cohorts. Furthermore, in the magnetic resonance imaging study cited by Dr Santangeli et al, systematic biopsies were not used as part of the Brugada syndrome case definition, simply the Second Consensus Report criteria as in our study.1 In more than 105 families with confirmed ARVC seen in our specialist clinics, we have not seen the ST-elevation masquerading as the Brugada phenotype the authors describe. This is a rare manifestation of ARVC. Because our study subjects were derived from a consecutive series of patients with Brugada syndrome identified in a specialist inherited arrhythmia and familial sudden cardiac death screening clinic, a selection bias is highly unlikely. With regard to the identification of regions of slow conduction, 2 validated techniques were employed: calculation of the mean increase in delay from S1-S2 restitution curves, and activation gradient quantification.2,3 These independent measurements both identified the same sites of maximum conduction delay. Unipolar electrogram recordings, which were used in our study, provide a more precise indication of local activation as compared with bipolar signals.4 Essential information on the direction of impulse propagation can be obtained because unipolar signals are not orientation dependent as are bipolar recordings. Bipolar recordings are also affected by interelectrode distance.3 Hence, the electrogram signals obtained by bipolar means can vary depending on the configuration and wavefront direction, and they are not reproducible from 1 setting to the next. Moreover, the criteria for marking activation of complex bipolar electrograms are not well defined and thus open to interpretation. Yet we agree with Dr Santangeli et al that bipolar recordings can provide complementary information to unipolar mapping, especially with regard to endocardial voltage gradients, which would help identify fibrotic sites, the subject of future research. Our study was an initial electrophysiological investigation of a new arrhythmogenic mechanism for Brugada syndrome. As Dr Santangeli et al suggest, additional evidence lending support for this mechanism will include contact studies in which bipolar electrograms are used, as well as imaging methods to determine whether structural abnormalities are present in slow conducting regions, and perhaps also myocardial biopsies to determine whether ion channel and gap junction remodeling have occurred.