Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation: a focused update

Survivors of sudden cardiac arrest (SCA) are diagnosed with idiopathic ventricular fibrillation (IVF) when no cause or other phenotypic expression (such as characteristic electrocardiographic or imaging features) can be identified after comprehensive assessment of structural and functional cardiac abnormalities [1]. Although ‘true’ IVF is rare, with studies reporting that 1.2–6.8% of SCA survivors with a shockable first rhythm could be diagnosed as such,[2, 3] it is an important public health concern, predominantly affecting young and otherwise healthy individuals.

Despite a family history of sudden cardiac death (SCD) in a substantial proportion of IVF patients,[4, 5] a genetic substrate is not (yet) identifiable in most patients. However, in the Netherlands, a founder risk haplotype (i.e. a series of base pairs that are similar for all carriers instead of a similar single variant or mutation) has been associated with SCD and familial IVF [6, 7]. This risk haplotype is located on chromosome 7q36 and comprises the gene for dipeptidyl aminopeptidase-like protein 6 (DPP6). In DPP6 IVF, overexpression of DPP6 appears to be critical to the phenotype [6]. As DPP6 is involved in the rapidly recovering cardiac transient outward potassium current (I_to), it is thought that overexpression of this protein specifically increases the activity of Purkinje fiber I_to, leading to a propensity for IVF [8].

DPP6 risk haplotype-positive family members (hereafter referred to as ‘DPP6 cases’), unlike their risk haplotype-negative relatives (‘DPP6 controls’), have been extensively characterised. They are a group of patients who suffer SCD at young age from malignant short-coupled premature ventricular complexes originating predominantly from the lower part of the right ventricular free wall, without other clinical manifestations [9, 10]. DPP6 IVF thus forms a subset of so-called short-coupled IVF [11]. Specifically, for risk stratification in patients who did not previously experience IVF, no clinically useful abnormalities are detected with electrocardiography or cardiac magnetic resonance imaging in affected patients [9]. Therefore, first-degree family members of diagnosed patients are offered presymptomatic genetic testing after genetic counselling.

Based on previous observations,[6, 9] recommendations for the treatment of DPP6 cases have been formulated, of which the most pivotal aspect is the approach regarding implantable cardioverter-defibrillator (ICD) implantation. However, because of the lack of clinical features, risk stratification and management of DPP6 cases remain challenging, particularly in asymptomatic patients. The aim of this study was to assess the long-term outcomes of the current cohort of DPP6 cases and DPP6 controls, thereby focusing on mortality, IVF recurrence and appropriate ICD therapy, including ICD complications.

Patients with SCA in the absence of an identifiable cause present a challenging scenario for the clinician, as IVF is mostly defined by what is not known. As the first manifestation of IVF, including DPP6 IVF, is typically SCA, and there are often no clinical symptoms or signs before such a devastating event, risk stratification is both crucial and difficult [12]. Moreover, IVF may present as a familial problem, further stressing the importance of adequate risk stratification in family members who did not (yet) experience IVF. This update of the long-term follow-up of the Dutch IVF DPP6 risk haplotype cohort provides important new insights into the natural history of the condition and the value of ICD implantation using current risk stratification. Of additional significance is the size of this cohort, being among the largest founder cohorts worldwide [13, 14].

Nannenberg et al. reported that estimates of survival duration in inherited arrhythmia syndromes appear to increase over time, as cascade screening allows for identification of family members with the genetic variant who may not have overt clinical symptoms [15]. For DPP6 cases, it was demonstrated that after 2011, a ‘plateau’ was reached, where identification of more affected relatives no longer significantly affected survival estimates. Surprisingly, in the current study, we found that survival time increased substantially compared with these earlier estimates, suggesting that the initial overestimation of mortality in certain inherited arrhythmia syndromes may be even more marked. In addition, it seems reasonable to suggest that with initiation of cascade screening, family members at risk are now often diagnosed early and offered the option of ICD treatment, thereby reducing mortality.

Genetic analysis in survivors of SCA without a clearly identifiable cause enables identification of concealed arrhythmia syndromes and screening of relatives. Furthermore, the evaluation of specific genetic variants is an important aspect of risk stratification and management of patients with inherited arrhythmia syndromes [16]. In the absence of a clear phenotype, as is the case in IVF, determining which genes should be tested is complicated. The yield of genetic testing in these patients is relatively low, and variant classification is difficult [17, 18]. Based on a review of studies assessing the yield of genetic testing in IVF and recognising that a substantial proportion of patients with Brugada syndrome or long QT syndrome (LQTS) have a concealed phenotype, Visser et al. proposed a screening panel of SCN5A, RYR2, CALM1 and the most common LQTS genes (KCNQ1 and KCNH2) [19]. If a (likely) pathogenic variant is identified, family screening may be indicated. In addition, there appear to be structural IVF subtypes, e.g. IVF with concomitant mitral annulus disjunction or mitral valve prolapse [20, 21].

At present, risk stratification in DPP6 cases is based on the patient’s age and sex. For current clinical practice, we recommend clinical evaluation, genetic testing, and ultimately prophylactic ICD implantation in DPP6 cases at the age of 16–17 years for males and 25–27 years for females. The recommended upper age limit of prophylactic ICD implantation is also a matter of continuous evaluation but is currently around 60 years for males and 65 years for females. After extensive discussions with our patients, we decided in some cases not to perform prophylactic implantation during a period of several years before these upper age limits.

We also recommend ICD explantation in asymptomatic DPP6 cases at a sufficiently advanced age—i.e. around or above these upper limits, when the risk of VF episodes appears to be very low and equal to that of controls [9]. Although this study showed that SCD can occur at higher age, it is conceivable that common morbidities such as coronary artery disease are much more likely to contribute than previously asymptomatic DPP6, which is of course also a matter of continuous evaluation and risk-benefit assessments.

The efficacy of drug therapy in IVF, including quinidine, is another subject of investigation. For example, we documented a lethal VF storm in a DPP6 patient who received amiodarone—possibly because amiodarone blocks the fast inward sodium current that would normally prevent unopposed I_to in phase 1 of the action potential. A similar observation in DPP6 is that administration of ajmaline (e.g. to rule out Brugada syndrome in IVF patients who were not yet identified as DPP6 carrier) may aggravate the phenotype and can result in short-coupled IVF (without signs of Brugada syndrome). This reaction to ajmaline has later also been documented in non-DPP6 IVF [22].

The management and risk stratification of familial IVF and DPP6 cases remain challenging. Estimates of survival duration have increased since the first descriptions possibly due to active cascade screening and early therapy. Nonetheless, DPP6 cases, particularly males, remained at an increased risk of mortality, and a substantial proportion of family members with a primary prevention ICD experienced appropriate ICD shocks, illustrating the benefit of prophylactic ICD implantation using a risk stratification approach based on risk haplotype, sex and age.