Successful Catheter Ablation of the “R on T” Ventricular Fibrillation

In patients with idiopathic ventricular fibrillation (VF), recurrent implantable cardioverter-defibrillator (ICD) shocks might increase mortality risk and reduce patients’ quality of life. Catheter ablation of triggering ectopic beats is considered to be an effective method. We present a patient with recurrent VF, caused by the “R on T” premature ventricular complexes. In the presented case radiofrequency catheter ablation efficiently eliminated arrhythmia trigger, which was possible to detect thanks to the intracardiac electrocardiograms (ECG’s) stored in the ICD.

Prevalence of mitral annulus disjunction and mitral valve prolapse in a multicenter cohort of idiopathic ventricular fibrillation patients

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Background Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with sudden onset of ventricular fibrillation of which the origin is not identified after extensive evaluations. Recent studies suggest an association between mitral annulus disjunction (MAD), mitral valve prolapse (MVP) and ventricular arrhythmias[1,2]. The prevalence of MAD and MVP in IVF patients in this regard, is not well established. Purpose To explore prevalence of MAD and MVP in IVF patients. Methods In this retrospective multicenter cohort study, Cardiac Magnetic Resonance images from IVF patients (i.e., negative for ischemia, cardiomyopathy and channelopathies) and matched control subjects were analyzed for MAD (≥2mm) and MVP (>2mm). Results In total, 71 IVF patients (mean age 39, 59% male) and 71 controls (mean age 41, 58% male) were included. MAD in the inferolateral wall was more prevalent in IVF patients versus healthy controls (6 [10%] vs. 1 [1%], p = 0.035). MVP was only seen in IVF patients and not in controls (4 [7%] vs. 0 [0%], p = 0.037). MVP was observed both in IVF patients with (n = 3) and without (n = 1) MAD. Patients with MAD did not show papillary muscle fibrosis. Four (67%) patients with MAD showed frequent ventricular ectopy from the basal myocardial region. Conclusion Inferolateral MAD and MVP were significantly more prevalent in IVF patients compared to healthy controls (figure). This is in line with previous studies suggesting a correlation between mitral valve disease and IVF. Our findings support further exploration of the pathophysiological mechanisms underlying a subset of IVF that associates with MAD and MVP.

Concealed cardiomyopathy as a frequent cause of idiopathic ventricular fibrillation in a representative Czech cohort of survivors of sudden cardiac arrest (SCA)

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic Introduction The complex diagnostic work up in SCA survivors often does not yield a concrete cardiological diagnosis. Moreover, there is conflicting evidence whether genetic testing could support or guide clinical diagnostics. Purpose To assess the molecular architecture of idiopathic ventricular fibrillation in cases without apparent evidence of specific structural or arrhythmic cardiac disease at initial diagnostic work up in a representative Czech cohort. Patients and Methods Between 2013 - 2020 we have ascertained 100 SCA survivors (54 M / 46 F; age range at cardiac arrest 5-69 years). Genetic counselling was followed by massively parallel DNA sequencing using custom-made panels comprising 100 cardiac conditions-related genes. Subsequently, thorough cardiological screening examinations in first degree relatives were carried out. Presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results Highly likely or certain molecular aetiology (i.e. based on the presence of Class 4 or 5 variants) was disclosed in 20/100 (20%) in PKP2 (3x), SCN5A (4x), RYR2 (3x), TTN (2x), PLN, FLNC, PRKAG2, KCNH2, KCNQ1, SLC4A, TNNT2, and DSP. Interestingly, the KCNE1 p.Asp85Asn (LQT 5 lite) variant, was detected in further 3/100 cases, representing a recognized risk factor for ventricular arrhythmias. Conclusions Genetic testing facilitates stratification of the cause of arrhythmia in a substantial portion of SCA survivors. The utility of positive outcomes of genetic testing was substantiated in 10/20 gene positive patients, where the genetic stratification led to diagnosis of concealed arrhythmogenic cardiomyopathy, whose extent of morphological changes was under the diagnostic sensibility of imaging modalities or ECG. Our results enable individualized care in SCA survivors and assure targeted preventive approaches in their relatives.

Identification of Loss-of-function RyR2 Mutations Associated with Idiopathic Ventricular Fibrillation and Sudden Death

Mutations in cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most CPVT RyR2 mutations characterized are gain-of-function (GOF), indicating enhanced RyR2 function as a major cause of CPVT. Loss-of-function (LOF) RyR2 mutations have also been identified and are linked to a distinct entity of cardiac arrhythmia termed RyR2 Ca2+ release deficiency syndrome (CRDS). Exercise stress testing (EST) is routinely used to diagnose CPVT, but it is ineffective for CRDS. There is currently no effective diagnostic tool for CRDS in humans. An alternative strategy to assess the risk for CRDS is to directly determine the functional impact of the associated RyR2 mutations. To this end, we have functionally screened 18 RyR2 mutations that are associated with idiopathic ventricular fibrillation (IVF) or sudden death. We found two additional RyR2 LOF mutations E4146K and G4935R. The E4146K mutation markedly suppressed caffeine activation of RyR2 and abolished store overload induced Ca2+ release in HEK293 cells. E4146K also severely reduced cytosolic Ca2+ activation and abolished luminal Ca2+ activation of single RyR2 channels. The G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype channel. Interestingly, the RyR2-G4935R mutant carrier had a negative EST, and the E4146K carrier had a family history of sudden death during sleep, which are different from phenotypes of typical CPVT. Thus, our data further support the link between RyR2 LOF and a new entity of cardiac arrhythmias distinct from CPVT.

Why Ablation of Sites With Purkinje Activation Is Antiarrhythmic: The Interplay Between Fast Activation and Arrhythmogenesis

Ablation of sites showing Purkinje activity is antiarrhythmic in some patients with idiopathic ventricular fibrillation (iVF). The mechanism for the therapeutic success of ablation is not fully understood. We propose that deeper penetrance of the Purkinje network allows faster activation of the ventricles and is proarrhythmic in the presence of steep repolarization gradients. Reduction of Purkinje penetrance, or its indirect reducing effect on apparent propagation velocity may be a therapeutic target in patients with iVF.