Familial Idiopathic Ventricular Fibrillation Research Articles

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

Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation: afocused update.

The genetic risk haplotype DPP6 has been linked to familial idiopathic ventricular fibrillation (IVF), but the associated long-term outcomes are unknown. DPP6 risk haplotype-positive family members (DPP6cases) and their risk haplotype-negative relatives (DPP6 controls) were included. Clinical follow-up data were collected through March 2023. Implantable cardioverter-defibrillator (ICD) indication was divided in primary or secondary prevention. Cumulative survival and event rates were calculated. We included 327 DPP6cases and 315 DPP6 controls. Median follow-up time was 9years (interquartile range: 4-12). Of the DPP6cases, 129 (39%) reached the composite endpoint of appropriate ICD shock, sudden cardiac arrest or death, at amedian age of 45years (range: 15-97). Median overall survival was 83years and 87years for DPP6cases and DPP6 controls, respectively (p < 0.001). In DPP6cases, median overall survival was shorter for males (74years) than females (85years) (p < 0.001). Of the DPP6cases, 97 (30%) died, at amedian age of 50years. With aprophylactic ICD implantation advise based on risk haplotype, sex and age, 137 (42%) of DPP6cases received an ICD, for primary prevention (n = 109) or secondary prevention (n = 28). In the primary prevention subgroup, 10patients experienced atotal of 34 appropriate ICD shocks, and there were no deaths during follow-up. DPP6cases with asecondary prevention ICD experienced atotal of 231 appropriate ICD shocks. Patients with the DPP6 risk haplotype, particularly males, are at an increased risk of IVF and sudden cardiac death. Using arisk stratification approach based on risk haplotype, sex and age, asubstantial proportion of patients with aprimary prevention ICD experienced appropriate ICD shocks, showing the benefit of prophylactic ICD implantation with this strategy.

An emerging role for DPP6: reciprocal regulation of INa-Ito and implications for arrhythmogenesis

Abstract Background Since the association of a chromosomal risk haplotype harboring dipeptidyl peptidase-like protein-6 (DPP6) to familial idiopathic ventricular fibrillation (iVF), a growing number of DPP6 missense variants has been reported in patients with ventricular tachyarrhythmias. The mechanisms underlying DPP6 mediated-arrhythmogenesis are not yet fully elucidated. DPP6 is a subunit of the transient outward potassium (Ito) channel complex in Purkinje cells (PC) and ventricular myocytes (VM). Purpose Since other Ito-channel subunits (Navβ1, KChIP2, KCNE4 and DPP10) are also known to antagonize INa, we examined whether DPP6 could play a broader role in the inter-regulation of Kv4.3 and Nav1.5 channels. We identified two novel DPP6 variants (p.Arg274His and p.His213Tyr), each segregating in families with QT/QU prolongation. DPP6 p.Arg274His carriers suffered from iVF, ectopic beats from the conduction system, and mitral valve prolapse. Other DPP6 variants (p.Ala751Val identified in this study; p.Gln526His and DPP6-T p.His332Arg published) are associated with Brugada syndrome (BrS). We hypothesized that DPP6 has opposing effects on INa and Ito displaying a reciprocal regulation of these currents. Methods and results First, we determined the effect of the DPP6 variants on INa and Ito in transfected CHO cells. Ito density was significantly reduced only when PC subunits were co-expressed with the DPP6 p.Arg274His or p.His213Tyr variants. Indeed, DPP6 modulates Nav1.5 channels in CHO cells by reducing INa Peak and INa Late, whereas DPP6 mutants p.Arg274His or p.His213Tyr resulted in an increase of both components compared to WT. Co-immunoprecipitation experiments in human endocardium confirmed an interaction between DPP6 and Nav1.5 channels. Computing of mutant DPP6-driven Ito-INa changes in a published human PC model led to significant prolongation of the action potential duration, mainly caused by increased INa Late. On the other hand, the DPP6 p.Gln526His and p.Ala751Val variants, linked to BrS, led to a decreased INa Peak compared to the WT, while there was a tendency towards increased Ito density in both PC and VM molecular setups. DPP6 (p.Arg274His and p.Ala751Val) transfection experiments in hiPSC cardiomyocytes, expressing endogenous INa and Ito, confirmed the reciprocal results obtained in CHO cells. Conclusions DPP6 regulates INa and Ito in a reciprocal manner. The cardiac phenotype of DPP6 variants could encompass a spectrum between two opposite poles: 1) QT/QU prolongation by DPP6 variants causing loss of Ito and gain of INa, like p.Arg274His and p.His213Tyr versus 2) BrS by DPP6 variants leading to gain of Ito and loss of INa, like p.Gln526His and p.Ala751Val. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): ESC Personal research grant, obtained in 2019

PO-631-03 DEEP LEARNING FOR THE IDENTIFICATION OF PATIENTS WITH A HIGH RISK FOR IDIOPATHIC VENTRICULAR FIBRILLATION

A DPP6 gene risk haplotype, putatively enhancing Purkinje fiber transient outward current Ito, associates with familial idiopathic ventricular fibrillation (IVF). Outside this genetic disposition, no clinical risk factors nor ECG features for IVF have so far been identified to recognize those at risk for IVF.

Patients with a DPP6 risk- haplotype for familial idiopathic ventricular fibrillation have normal left systolic function but abnormal deformation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction An aberrant DPP6 mutation haplotype on chromosome 7 is associated with familial idiopathic ventricular fibrillation in severely affected Dutch families with numerous cases of sudden cardiac death (SCD) So far, no clinical parameters could be linked to predict SCD risk other than this genetic predisposition. In various other cardiac disease, global longitudinal strain (GLS) and mechanical dispersion (MD), both markers of left ventricular (LV) dysfunction, are predictive tools for patients at risk for ventricular arrhythmias (VA) and SCD. The goal of the current study was to investigate whether LV dysfunction, detected by GLS and MD, is present in patients with DPP6 haplotype. Method DPP6 risk-haplotype carriers with sufficient echocardiographic images were included as cases (n = 31, 15 males mean age 41 ± 11 years) and individuals evaluated during cascade screening who were tested but appeared not to be affected as controls (n = 14, 7 males, mean age 39 ± 12 years). Echocardiographic bi-plane ejection fraction (LVEF), GLS and MD of the left ventricular were determined. Results LVEF was similar between DPP6 cases (57.3%) and controls (60.5%, p = 0.07). In contrast, the GLS of the LV (-18.0%) of DPP6 cases was significant lower compared to controls (-21.1%, p &amp;lt; 0.0001). MD in DPP6 cases (43.4ms) was significantly higher than in controls (26.7ms, p &amp;lt; 0.0001). Conclusion DPP6 risk- haplotype carriers have similar LVEF, but significant lower LV-GLS and higher mechanical dispersion than controls. These findings can be used for clinical discrimination. Whether these markers can be used for prediction of clinical events has to be determined after a longer follow up. echocardiographic characteristics controls DPP6 p-value LVEF (%) 60.5 57.3 0.07 GLS LV (%) -21.2 -18.0 0.0001 MD ( ms) 26.7 43.4 0.0001

Abstract 17319: Distinct Effects of Human Calmodulinopathy on the Function of Small Conductance Ca 2+ -Activated K + (SK) Channels

Background: Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca 2+ -dependent ion channels. Mutations in CALM1, CALM2, and CALM3 have recently been linked to cardiac arrhythmias, such as Long QT Syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and familial idiopathic ventricular fibrillation (IVF). Small-conductance Ca 2+ - activated K + channels (SK) are voltage-independent channels that are regulated solely from beat-to-beat changes in intracellular calcium. CaM regulates the function of multiple ion channels, including SK channels, although the effect of CaM mutations on these channels is not yet understood. We hypothesize that human CaM mutations linked to sudden cardiac death disrupt SK channel function by distinct mechanisms. Methods and Results: We tested the effects of LQTS (CaM D96V , CaM D130G ), CPVT (CaM N54I , CaM N98S ), and IVF (CaM F90L ) CaM mutants compared to CaM WT on SK channel function. Using whole-cell voltage-clamp recordings, we found that CaM D96V and CaM D130G mutants significantly inhibited apamin-sensitive currents. Similarly, action potential studies in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) also revealed significant knockdown of apamin-sensitive currents. Immunofluorescent confocal microscopy confirmed that this effect was not due to changes in SK channel trafficking. Rather, co-immunoprecipitation studies showed a significant decrease in the association of these CaM mutants with the SK channel. Rosetta molecular modeling was used to identify a conformational change in CaM F90L structure compared to that of CaM WT . Conclusions: We found that CaM D96V and CaM D130G mutants significantly reduced apamin-sensitive currents, through a dominant negative effect on SK channel function. Consistent with our hypothesis, CaM F90L resulted in the least inhibitory effects. The data suggests that specific mutations with phenylalanine to leucine (CaM F90L ) may disrupt the interaction between apo-CaM with CaMBD on the SK2 channel.

Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome.

QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS. All patients who are carrier of a KCNQ1 or KCNH2 mutations without QT prolongation were enrolled. A control group was constituted of patients with negative exercise and epinephrine tests. Electrocardiogram were recorded at rest and at the maximum heart rate during MST and reviewed by two physicians. Among the 70 patients enrolled (median age 41±2.1 years, 46% male), 36 were mutation carrier for LQTS (20 KCNQ1 and 16 KCNH2), and 34 were controls. KCNQ1 and KCNH2 mutation carriers presented a longer QT interval at baseline [405(389; 416) and 421 (394; 434) ms, respectively] compared with the controls [361(338; 375)ms; P < 0.0001]. QT duration during MST varied by 9 (4; 18) ms in KCNQ1, 3 (-6; 16) ms in KCNH2, and by -22 (-29; -17) ms in controls (P < 0.0001). These QT variations were independent of heart rate (P < 0.3751). Receiver operating characteristic curve analysis identified a cut-off value of QT variation superior to -11 ms as best predictor of LQTS. It provided 97% sensitivity and 97% specificity of QT prolongation in the diagnosis of LQTS. We identified a paradoxical response of the QT interval during MST in LQTS. Easy to assess, MST may be efficient to unmask concealed LQTS in patients at risk of this pathology.

Detailed characterization of familial idiopathic ventricular fibrillation linked to the DPP6 locus

Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6). The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics. We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated. There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger ventricular volumes in haplotype-positives compared to controls (P <.05), but these were not clinically useful. Mortality and/or cardiac arrest occurred in 85 haplotype-positives (30%) and 18 haplotype-negatives (6%). Twenty-four haplotype-positives (8% male) were resuscitated from ventricular fibrillation (VF). Documented VF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Median survival in risk-haplotype haplotype-positives was 70 vs. 93 years for haplotype-negatives (P < .01), with a worse phenotype in males (median survival 63 vs. 83 years in females, P < .01). Implantable cardioverter-defibrillators were implanted in 99 patients (76 [77%] for primary prevention). Two arrhythmic events occurred in the primary prevention group during follow-up (5 ± 3 years). Despite our extensive analysis, the complexity in identifying asymptomatic IVF family members at risk for future arrhythmias based on clinical parameters is once more demonstrated.

Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition

Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I to had similar density, but PF I to differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.

Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6

In this part of a series on founder mutations in the Netherlands, we review familial idiopathic ventricular fibrillation linked to the DPP6 gene. Familial idiopathic ventricular fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial idiopathic ventricular fibrillation. Notably, ventricular fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate ventricular fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.

Familial Idiopathic Ventricular Fibrillation Linked to Chromosome 7q36 Harboring DPP6

Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial idiopathic ventricular fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p<0.001), the youngest 16 years old, males earlier than females (56 vs. 72 years, p<0.001). IVF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall and an origin in the Purkinje network was suspected. Expression-studies showed overexpression of DPP6 mRNA in carriers (p<0.01). Expression-studies in non-diseased explanted human hearts showed higher DPP6 mRNA expression in Purkinje fiber than in any other region (p<0.01). Conclusions: A new arrhythmia gene on chromosome 7q36, DPP6, is linked to familial IVF and shows a very malignant phenotype. Short-coupled extrasystoles from the right-ventricular apex/free wall, presumably originating from the Purkinje network, trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.

Familial idiopathic ventricular fibrillation characterized by increased dispersion of ventricular repolarization and steep restitution of the action potential duration

Background: Ventricular fibrillation (VF) is the result of break-up of reentrant wavefronts into multiple wavelets in the ventricle. Recent theoretical studies have suggested that, in addition to the spatial variation of ventricular refractoriness (pre-existing heterogeneity of refractoriness), its temporal variation (dynamic instability of refractoriness) plays crucial roles in the genesis of wavebreak. However, little information is available as to the arrhythmogenic substrates in patients with idiopathic VF (IVF).

Familial idiopathic ventricular fibrillation characterized by increased dispersion of ventricular repolarization and steep restitution of the action potential duration

Familial idiopathic ventricular fibrillation characterized by increased dispersion of ventricular repolarization and steep restitution of the action potential duration

Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts

OBJECTIVESThe purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder.BACKGROUNDAn inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families.METHODSTwo unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus.RESULTSOf the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 ± 18 vs. 409 ± 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42–q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood.CONCLUSIONSA distinct cardiac disorder linked to chromosome 1q42–q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.