PROGNOSTIC IMPLICATION OF THE MITRAL VALVE TENTING GEOMETRY IN PATIENTS WITH DILATED CARDIOMYOPATHY: TRANSTHORACIC REAL-TIME 3D ECHOCARDIOGRAPHIC STUDY

BACKGROUND: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. METHODS AND RESULTS: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. CONCLUSIONS: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards

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

Cadherin 2-Related Arrhythmogenic Cardiomyopathy Prevalence and Clinical Features

Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.Methods:A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed.Results:Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).Conclusions:In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.</p

Spatial and Temporal Variability of Macroinvertebrates in Spawning and Non-Spawning Habitats during a Salmon Run in Southeast Alaska

Spawning salmon create patches of disturbance through redd digging which can reduce macroinvertebrate abundance and biomass in spawning habitat. We asked whether displaced invertebrates use non-spawning habitats as refugia in streams. Our study explored how the spatial and temporal distribution of macroinvertebrates changed during a pink salmon (Oncorhynchus gorbuscha) spawning run and compared macroinvertebrates in spawning (riffle) and non-spawning (refugia) habitats in an Alaskan stream. Potential refugia included: pools, stream margins and the hyporheic zone, and we also sampled invertebrate drift. We predicted that macroinvertebrates would decline in riffles and increase in drift and refugia habitats during salmon spawning. We observed a reduction in the density, biomass and taxonomic richness of macroinvertebrates in riffles during spawning. There was no change in pool and margin invertebrate communities, except insect biomass declined in pools during the spawning period. Macroinvertebrate density was greater in the hyporheic zone and macroinvertebrate density and richness increased in the drift during spawning. We observed significant invertebrate declines within spawning habitat; however in non-spawning habitat, there were less pronounced changes in invertebrate density and richness. The results observed may be due to spawning-related disturbances, insect phenology, or other variables. We propose that certain in-stream habitats could be important for the persistence of macroinvertebrates during salmon spawning in a Southeast Alaskan stream

A 50% Reduction of Excitability but Not of Intercellular Coupling Affects Conduction Velocity Restitution and Activation Delay in the Mouse Heart

Computer simulations suggest that intercellular coupling is more robust than membrane excitability with regard to changes in and safety of conduction. Clinical studies indicate that SCN5A (excitability) and/or Connexin43 (Cx43, intercellular coupling) expression in heart disease is reduced by approximately 50%. In this retrospective study we assessed the effect of reduced membrane excitability or intercellular coupling on conduction in mouse models of reduced excitability or intercellular coupling. Epicardial activation mapping of LV and RV was performed on Langendorff-perfused mouse hearts having the following: 1) Reduced excitability: Scn5a haploinsufficient mice; and 2) reduced intercellular coupling: Cx43(CreER(T)/fl) mice, uninduced (50% Cx43) or induced (10% Cx43) with Tamoxifen. Wild type (WT) littermates were used as control. Conduction velocity (CV) restitution and activation delay were determined longitudinal and transversal to fiber direction during S(1)S(1) pacing and S(1)S(2) premature stimulation until the effective refractory period. In both animal models, CV restitution and activation delay in LV were not changed compared to WT. In contrast, CV restitution decreased and activation delay increased in RV during conduction longitudinal but not transverse to fiber direction in Scn5a heterozygous animals compared to WT. In contrast, a 50% reduction of intercellular coupling did not affect either CV restitution or activation delay. A decrease of 90% Cx43, however, resulted in decreased CV restitution and increased activation delay in RV, but not LV. Reducing excitability but not intercellular coupling by 50% affects CV restitution and activation delay in RV, indicating a higher safety factor for intercellular coupling than excitability in R

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy

Aims Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.Methods and results Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 +/- 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P &lt;0.001).Conclusion Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).</p

Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden death. Currently 60% of patients meeting Task Force Criteria (TFC) have an identifiable mutation in one of the desmosomal genes. As much overlap is described between other cardiomyopathies and ARVC, we examined the prevalence of rare, possibly pathogenic sarcomere variants in the ARVC population. Methods: One hundred and thirty-seven (137) individuals meeting 2010 TFC for a diagnosis of ARVC, negative for pathogenic desmosomal variants, TMEM43, SCN5A, and PLN were screened for variants in the sarcomere genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1) through either clinical or research genetic testing. Results: Six probands (6/137, 4%) were found to carry rare variants in the sarcomere genes. These variants have low prevalence in controls, are predicted damaging by Polyphen-2, and some of the variants are known pathogenic hypertrophic cardiomyopathy mutations. Sarcomere variant carriers had a phenotype that did not differ significantly from desmosomal mutation carriers. As most of these probands were the only affected individuals in their families, however, segregation data are noninformative. Conclusion: These data show variants in the sarcomere can be identified in individuals with an ARVC phenotype. Although rare and predicted damaging, proven functional and segregational evidence that these variants can cause ARVC is lacking. Therefore, caution is warranted in interpreting these variants when identified on large next-generation sequencing panels for cardiomyopathies

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy

Aims Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. Methods We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. Results Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. Conclusions Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development