Feasibility of Improving Risk Stratification in Brugada Syndrome

It is estimated that approximately 600 apparently fit and healthy individuals aged under 35 years die suddenly in the UK every year Many of these sudden cardiac deaths (SCD) in the young are the result of inherited cardiac conditions (ICC), the majority of which are the direct consequence of single mutations in sarcolemmal ion channels (e.g. Brugada syndrome - BrS, Long QT syndrome - LQTS), intercalated disc proteins (arrhythmogenic right ventricular cardiomyopathy - ARVC) or the cardiac sarcomere (hypertrophic cardiomyopathy - HCM) Poor genotype-phenotype correlations, due in part to incomplete penetrance, variable expressivity, role of gene modifiers and external environmental factors, limits the use of an individual's genetic makeup in the core task of predicting risk of death. As a result, identifying high risk individuals who should receive an implantable cardioverter defibrillators (ICD) is still a significant challenge.

In Brugada Syndrome, follow up data from the largest registries reveal a spontaneous Type I BrS pattern (ST elevation in the anterior leads) on electrocardiogram (ECG) and/or history of syncope to be independent predictors for SCD events. These are employed in conventional risk stratification to identify those with high risk. By this approach, the low risk have an annual SCD rate below 0.5% and the high risk have an annual SCD rate ~1% 3,8,9. Therefore, not only are SCD events in the unselected BrS population relatively low, the differences in event rates between those perceived to be at high and low risk are small, highlighting the limitations of current risk stratification. Thus, calculations of sensitivity and specificity to predict SCD risk using syncope is 61%/52% and for spontaneous type I BrS ECG pattern is 86%/36% 10.

Amongst individuals presenting with SCD, a significant portion of individuals have neither spontaneous Type I BrS pattern or previous syncope, and would have been considered low-risk. Only 50% of participants in the FINGER registry with previous SCD events had spontaneous Type I BrS pattern. Similarly in a study of 50 SCD probands with a familial diagnosis of BrS, only 20% had a history of prior syncope and in those with ante-mortem ECGs, only 20% had a spontaneous type I pattern. This reflects our own experience with a cohort of 149 BrS patients; we have 10 individuals with SCD events, of whom only 1 has a spontaneous Type I BrS pattern and/or a history of syncope.

All these data seem to consistently suggest that the majority of SCD events occur in the larger 'low-risk' cohort, further underlining the limitations of current risk stratification.

The decision to implant an ICD must be weighed against the risk of complications. At present appropriate therapy occurs in around 12%, which is higher than the SCD event rate; this is consistent with normal ICD function 'over-treating' ventricular arrhythmias which would have been non-sustained. Inappropriate shock rates have been reported between 5-37% depending on follow-up time, and death has been reported from inappropriate therapy shock. Lead failure also occurred in 29% of the 378 BrS patients over as 10 year follow up. Implanting more ICDs to compensate for the limitations of risk stratification may only increase morbidity and even mortality from inappropriate therapy and complications.