Long-term outcomes in carriers of the familial idiopathic ventricular fibrillation linked to the DPP6 locus

Abstract Background Idiopathic ventricular fibrillation (IVF) is a malignant condition with no clinical sequelae except for ventricular fibrillation. The genetic basis is ill-defined but in 2009 a Dutch founder variant - the DPP6 risk haplotype - was linked to a familial form of IVF characterized by a very high incidence of sudden cardiac arrest (SCA) and sudden cardiac death (SCD). Consequently, for more than a decade asymptomatic haplotype-carriers from the ages of 18 (male) and 25 (female) have had an implantable cardioverter-defibrillator (ICD) inserted. However, the associated long-term outcomes in these individuals is unknown. Purpose To assess the long-term outcomes of DPP6 risk haplotype-carriers who presented to our tertiary referral center and qualified for ICD insertion. Methods Clinical follow-up information of DPP6 risk haplotype-carriers, including the occurrence of SCD, SCA, appropriate ICD shocks, and ICD-related complications, was collected through February 2023. ICD-carriers were classified as either asymptomatic (primary prevention), or with previous sudden cardiac arrest (secondary prevention). Survival rates are presented using a survival curve and were compared with the log-rank test. Results A total of 118 haplotype-carriers (62 males) were included. One-hundred nine (92%) carriers had an ICD inserted, for primary (n=85) or secondary prevention (n=24), and 9 patients refused a primary prevention ICD. Among primary prevention ICD-carriers and those who refused implantation (n=94), 9 (10%) patients experienced a total of 28 appropriate shocks, there was 1 SCA and no deaths, during a median follow-up of 11 years (IQR 7-13; Figure). Of these, 9 patients were ever treated with quinidine and 5 still used quinidine at last follow-up. Among secondary prevention ICD carriers, 20 (83%) patients experienced a total of 225 appropriate shocks and one patient died, during a median follow-up of 13 years (IQR 10-16). Of these patients, 11 were ever treated with quinidine, of whom one patient discontinued quinidine due to adverse effects. Overall, 14 (13%) patients experienced inappropriate shocks and 16 (15%) experienced other ICD-related complications. Conclusion Predictive genetic testing of the DPP6 haplotype provides the unique opportunity to identify asymptomatic family members at risk for SCD and insert prophylactic ICDs just on the basis of carrying the risk haplotype. Approximately 10% of DPP6 haplotype-carriers who qualified for ICD insertion for primary prevention, predominantly males, experienced appropriate ICD shocks or SCA during 11 years of follow-up, indicating that our approach to ICD implantation has presumably saved several lives. In those with an ICD for secondary prevention the incidence of appropriate ICD shocks was high, often despite quinidine therapy.Survival until appropriate shock or SCA