Mitral Annular Disjunction in Idiopathic Ventricular Fibrillation Patients: Just a Bystander or a Potential Cause?

AIMS: Previously, we demonstrated that inferolateral mitral annular disjunction (MAD) is more prevalent in patients with idiopathic ventricular fibrillation (IVF) than in healthy controls. In the present study, we advanced the insights into the prevalence and ventricular arrhythmogenicity by inferolateral MAD in an even larger IVF cohort. METHODS AND RESULTS: This retrospective multicentre study included 185 IVF patients (median age 39 [27, 52] years, 40% female). Cardiac magnetic resonance images were analysed for mitral valve and annular abnormalities and late gadolinium enhancement. Clinical characteristics were compared between patients with and without MAD. MAD in any of the 4 locations was present in 112 (61%) IVF patients and inferolateral MAD was identified in 24 (13%) IVF patients. Mitral valve prolapse (MVP) was found in 13 (7%) IVF patients. MVP was more prevalent in patients with inferolateral MAD compared with patients without inferolateral MAD(42% vs. 2%, p < 0.001). Proarrhythmic characteristics in terms of a high burden of premature ventricular complexes (PVC) and non-sustained ventricular tachycardia (VT) were more prevalent in patients with inferolateral MAD compared to patients without inferolateral MAD (67% vs. 23%, p < 0.001 and 63% vs 41%, p = 0.046, respectively). Appropriate implantable cardioverter defibrillator therapy during follow-up was comparable for IVF patients with or without inferolateral MAD (13% vs. 18%, p = 0.579). CONCLUSION: A high prevalence of inferolateral MAD and MVP is a consistent finding in this large IVF cohort. The presence of inferolateral MAD is associated with a higher PVC burden and non-sustained VTs. Further research is needed to explain this potential interplay

The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update

Background Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. Aim To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. Methods This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. Discussion The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website (www.acmregistry.nl) and patient conferences

Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management

Predicting changes to INa from missense mutations in human SCN5A

Mutations in SCN5A can alter the cardiac sodium current INa and increase the risk of potentially lethal conditions such as Brugada and long-QT syndromes. The relation between mutations and their clinical phenotypes is complex, and systems to predict clinical severity of unclassified SCN5A variants perform poorly. We investigated if instead we could predict changes to INa, leaving the link from INa to clinical phenotype for mechanistic simulation studies. An exhaustive list of nonsynonymous missense mutations and resulting changes to INa was compiled. We then applied machine-learning methods to this dataset, and found that changes to INa could be predicted with higher sensitivity and specificity than most existing predictors of clinical significance. The substituted residues’ location on the protein correlated with channel function and strongly contributed to predictions, while conservedness and physico-chemical properties did not. However, predictions were not sufficiently accurate to form a basis for mechanistic studies. These results show that changes to INa, the mechanism through which SCN5A mutations create cardiac risk, are already difficult to predict using purely in-silico methods. This partly explains the limited success of systems to predict clinical significance of SCN5A variants, and underscores the need for functional studies of INa in risk assessment

Noninvasive unipolar electrogram T-wave upslope is an accurate marker of local refractoriness in explanted hearts with drug-induced repolarization dispersion

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French National Research Agency Matthijs Cluitmans is supported by a Veni grant from the Netherlands Organization for Scientific Research Background The relationship between T-wave morphology in local unipolar electrograms (UEGs) as mapped with noninvasive electrocardiographic imaging (ECGI) and local repolarization time (RT) has not been validated in pronounced RT dispersion. Purpose To study the time of upslope of the T-wave (Tup) in epicardial UEGs mapped with ECGI as a marker of time of local refractoriness (trefr, a surrogate for RT) in intact hearts with RT dispersion. Methods Six pig hearts were Langendorff-perfused with selective perfusion of the LAD artery and submersed in a torso-shaped tank containing 256 electrodes on the torso surface (panel A). RT was prolonged in the non-LAD regions by infusing dofetilide (‘Dof’) and shortened in the LAD region using pinacidil (‘Pin’). Tup was determined in both invasive UEGs (recorded with epicardial electrodes) and in noninvasive UEGs (reconstructed with ECGI). Programmed stimulation was used to determine trefr, defined as the shortest coupling interval with capture. Both metrics were determined relative to the common pacing spike. Results In all six hearts, selective dofetilide and pinacidil infusion resulted in delayed trefr and Tup in the non-LAD region, and shortened invasive trefr and noninvasive Tup in the LAD region, respectively (panel B and C). Over all 59 observations, Tup showed high agreement with trefr (values close to line of identity, panel D) with strong correlation (r = 0.91). This finding was independent of T-wave polarity (positive, negative or biphasic). Conclusion The moment of steepest upslope of the T-wave in a noninvasively reconstructed UEG accurately reflects end of local refractoriness in intact hearts, in case of pronounced RT dispersion. Under these circumstances, when local RT is defined by moment of re-excitability (allowing to link it to conduction block and re-entry), ECGI T-wave upslope can be taken as a truthful marker for local RT. Abstract Figure. Results </jats:sec

Noninvasive unipolar electrogram T-wave upslope is an accurate marker of local refractoriness in explanted hearts with drug-induced repolarization dispersion

Background: The relationship between T-wave morphology in local unipolar electrograms (UEGs) as mapped with noninvasive electrocar-diographic imaging (ECGI) and local repolarization time (RT) has not been validated in pronounced RT dispersion

Physiology-based regularization of the electrocardiographic inverse problem

The inverse problem of electrocardiography aims at noninvasively reconstructing electrical activity of the heart from recorded body-surface electrocardiograms. A crucial step is regularization, which deals with ill-posedness of the problem by imposing constraints on the possible solutions. We developed a regularization method that includes electrophysiological input. Body-surface potentials are recorded and a computed tomography scan is performed to obtain the torso–heart geometry. Propagating waveforms originating from several positions at the heart are simulated and used to generate a set of basis vectors representing spatial distributions of potentials on the heart surface. The real heart-surface potentials are then reconstructed from the recorded body-surface potentials by finding a sparse representation in terms of this basis. This method, which we named ‘physiology-based regularization’ (PBR), was compared to traditional Tikhonov regularization and validated using in vivo recordings in dogs. PBR recovered details of heart-surface electrograms that were lost with traditional regularization, attained higher correlation coefficients and led to improved estimation of recovery times. The best results were obtained by including approximate knowledge about the beat origin in the PBR basis

Repolarizing K+ currents I-TO1 and I-Ks are larger in right than left canine ventricular midmyocardium

Background —The ventricular action potential exhibits regional heterogeneity in configuration and duration (APD). Across the left ventricular (LV) free wall, this is explained by differences in repolarizing K + currents. However, the ionic basis of electrical nonuniformity in the right ventricle (RV) versus the LV is poorly investigated. We examined transient outward ( I TO1 ), delayed ( I Ks and I Kr ), and inward rectifier K + currents ( I K1 ) in relation to action potential characteristics of RV and LV midmyocardial (M) cells of the same adult canine hearts. Methods and Results —Single RV and LV M cells were used for microelectrode recordings and whole-cell voltage clamping. Action potentials showed deeper notches, shorter APDs at 50% and 95% of repolarization, and less prolongation on slowing of the pacing rate in RV than LV. I TO1 density was significantly larger in RV than LV, whereas steady-state inactivation and rate of recovery were similar. I Ks tail currents, measured at −25 mV and insensitive to almokalant (2 μmol/L), were considerably larger in RV than LV. I Kr , measured as almokalant-sensitive tail currents at −50 mV, and I K1 were not different in the 2 ventricles. Conclusions —Differences in K + currents may well explain the interventricular heterogeneity of action potentials in M layers of the canine heart. These results contribute to a further phenotyping of the ventricular action potential under physiological conditions. </jats:p