Anneli Svensson

Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy–Associated Genes

The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TTN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with >99% of targeted nucleotides covered by >20×. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error-causing motif located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.9% to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to loss of coverage.

Management of patients with Arrhythmogenic Right Ventricular Cardiomyopathy in the Nordic countries.

Abstract> Objectives. Diagnostics of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) are complex, and based on the 2010 Task Force document including different diagnostic modalities. However, recommendations for clinical management and follow-up of patients with ARVC and their relatives are sparse. This paper aims to give a practical overview of management strategies, risk stratification, and selection of appropriate therapies for patients with ARVC and their family members. Design. This paper summarizes follow-up and treatment strategies in ARVC patients in the Nordic countries. The author group represents cardiologists who are actively involved in the Nordic ARVC Registry which was established in 2009, and contains prospectively collected clinical data from more than 590 ARVC patients from Denmark, Norway, Sweden, and Finland. Results. Different approaches of management and follow-up are required in patients with definite ARVC and in genetic-mutation-positive family members. Furthermore, ARVC patients with and without implantable cardioverter defibrillators (ICDs) require different follow-up strategies. Conclusion. Careful follow-up is required in patients with ARVC diagnosis to evaluate the need of anti-arrhythmic therapy and ICD implantation. Mutation-positive family members should be followed regularly for detection of early disease and risk stratification of ventricular arrhythmias.

Heart transplantation in arrhythmogenic right ventricular cardiomyopathy — Experience from the Nordic ARVC Registry

OBJECTIVE There is a paucity of data on heart transplantation (HTx) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and specific recommendations on indications for listing ARVC patients for HTx are lacking. In order to delineate features pertinent to HTx assessment, we explored the pre-HTx characteristics and clinical history in a cohort of ARVC patients who received heart transplants. METHODS Data from 31 ARVC/HTx patients enrolled in the Nordic ARVC Registry, transplanted between 1988 and 2014 at a median age of 46years (14-65), were compared with data from 152 non-transplanted probands with Definite ARVC according to 2010 Task Force Criteria from the same registry. RESULTS The HTx patients were younger at presentation, median 31 vs. 38years (p=0.001). There was no difference in arrhythmia-related events. The indication for HTx was heart failure in 28 patients (90%) and ventricular arrhythmias in 3 patients (10%). During median follow-up of 4.9years (0.04-28), there was one early death and two late deaths. Survival was 91% at 5years after HTx. Age at first symptoms under 35years independently predicted HTx in our cohort (OR=7.59, 95% CI 2.69-21.39, p<0.001). CONCLUSION HTx in patients with ARVC is performed predominantly due to heart failure. This suggests that current 2016 International Society for Heart and Lung Transplantation heart transplant listing recommendations for other cardiomyopathies could be applicable in many cases when taking into account the haemodynamic consequences of right ventricular failure in conjunction with ventricular arrhythmia.

The S-wave angle identifies arrhythmogenic right ventricular cardiomyopathy in patients with electrocardiographically concealed disease phenotype

BACKGROUND Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) carries risk of sudden death. We hypothesize that the S-wave angle differentiates ARVD/C with otherwise normal electrocardiograms from controls. MATERIALS AND METHODS All patients met Task Force 2010 definite ARVD/C criteria. ARVD/C patients without Task Force depolarization/repolarization criteria (-ECG) were compared to controls. Electrocardiogram measures of QRS duration, corrected QT interval, and measured angle between the upslope and downslope of the S-wave in V2, were assessed. RESULTS Definite ARVD/C was present in 155 patients (42.7 ± 17.3 years, 68.4%male). -ECG ARVD/C patients (66 patients) were compared to 66 control patients (41.8 ± 17.6 years, 65.2%male). Only the S-wave angle differentiated -ECG ARVD/C patients from controls (<0.001) with AU the ROC curve of 0.77 (95%CI 0.53 to 0.71) and odds ratio of 28.3 (95%CI 6.4 to 125.5). CONCLUSION ARVD/C may lead to development of subtle ECG abnormalities distinguishable using the S-wave angle prior to development of 2010 Taskforce ECG criteria.

Right ventricular systolic function and mechanical dispersion identify patients with arrhythmogenic right ventricular cardiomyopathy

To assess right ventricular (RV) regional and global systolic function using feature tracking (FT) in patients with a definite diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) and to investigate if changes in strain amplitude and mechanical dispersion indicate a propensity for arrhythmia.

Predictors of appropriate therapy from implantable cardioverter-defibrillators in Scandinavian arrhythmogenic right ventricular cardiomyopathy patients

Background: Galectin 3 and ST2 are mediators and biomarkers of myocardial fibrosis and remodeling that have recently entered the clinical practice guidelines as prognostic factors in heart failure patients. Elevated galectin 3 and ST2 levels in acute myocardial infarction patients have also been associated with increased incidence of adverse events during follow-up. Purpose: We aimed to assess the comparative ability of Galectin 3 and ST2 to offer additional prognostic information for risk stratification in acute coronary syndrome (ACS) patients, on top of traditional cardiovascular risk factors and other established prognostic biomarkers. Methods: We measured the levels of galectin 3, ST2, N-terminal pro-B type natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), highsensitivity troponin T (TnT), cystatin C, and lipids in plasma collected from 524 ACS patients (STEMI, non-STEMI and unstable angina) on day 1 following the acute event. Biomarker levels were correlated with the risk to develop recurrent coronary events, in linear regression models adjusted for age, sex and traditional risk factors (smoking, diabetes mellitus, hypertension, LDL, HDL and triglycerides). Results: During a mean follow-up period of 2.13 years, 63 (12%) of the patients suffered a new coronary event. Baseline galectin 3, ST2, hsCRP, NTproBNP and cystatin C were significantly higher in these patients compared to the event-free controls. In a Cox proportional hazards model with forward step selection that included all biomarkers alongside traditional risk factors, age (HR per year of age 1.06, 95% CI 1.03-1.09), galectin 3 (HR per SD log increase 1.88, 95% CI 1.41- 2.51) and cystatin C (HR per SD log increase 1.39, 95% CI 1.12-1.74) were selected as the only independent predictors of recurrent events in the population. In receiver operating curve (ROC) analyses, addition of galectin 3 significantly improved the c-statistic of the model based on traditional risk factors alone (0.81 vs. 0.76, P (Less)