A5017000227- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Cardiac electrophysiology and arrhythmias
- Viral Infections and Immunology Research
- Genomics and Rare Diseases
- Sports injuries and prevention
- Cardiovascular Function and Risk Factors
- RNA Research and Splicing
- Genomics and Phylogenetic Studies
- RNA modifications and cancer
- Cardiac pacing and defibrillation studies
- Cardiac Structural Anomalies and Repair
- Congenital heart defects research
- Cell Adhesion Molecules Research
- Autoimmune Neurological Disorders and Treatments
- Radiopharmaceutical Chemistry and Applications
- Cancer Genomics and Diagnostics
- Eosinophilic Disorders and Syndromes
- Cardiac tumors and thrombi
- Peptidase Inhibition and Analysis
- Endoplasmic Reticulum Stress and Disease
- Genetics and Neurodevelopmental Disorders
- Genetic Associations and Epidemiology
- Protein Degradation and Inhibitors
- Ion channel regulation and function
ERN GUARD-Heart
2024
Erasmus MC
2023-2024
University Medical Center Groningen
2013-2023
University of Groningen
2013-2023
Netherlands Heart Institute
2016-2023
Erasmus University Rotterdam
2023
Dialyse Centrum Groningen
2022
OLVG
2016
Abstract The diagnostic yield of exome and genome sequencing remains low (8–70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples predict which specific disease phenotypes, develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show this unbiased method, does not rely upon individual genes, is effective in both identifying previously unknown gene associations, flagging have been incorrectly implicated GADO can be...
Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant the PLN gene results high risk developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard failure therapy transplantation. In this study, we generated novel mouse model PLN-R14del variant, performed detailed phenotyping, and tested efficacy therapies...
Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss arginine at position 14 PLN (R14del) associated with dilated cardiomyopathy high prevalence ventricular arrhythmias. How R14 deletion causes poorly understood, there are no disease-specific therapies. Methods: We used single-cell RNA sequencing to uncover R14del disease mechanisms human induced pluripotent stem cells (hiPSC-CMs). both 2-dimensional 3-dimensional functional...
The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine value serial evaluation; and (iii) establish yield first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, laboratory tests) as per ESC position statement.
Aims The non‐desmosomal phospholamban PLN p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy ( DCM ) and/or arrhythmogenic ACM ). We aimed to investigate whether this leads aggregation, aggresome formation and autophagy of mutant protein. Methods results studied 20 complete heart specimens carriers [mean age 48 ± 15 years; 55% males], either from autopsies or explants. Gross microscopic examination showed biventricular histopathological features both , i.e....
The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia (VA) and heart failure. It has been shown to lead calcium overload, cardiomyocyte damage, eventually myocardial fibrosis. This study sought investigate function, extent localization fibrosis associations ECG features VA PLN carriers.Cardiovascular magnetic resonance (CMR) data 150 carriers were analysed retrospectively. Left (LV) right (RV)...
Myocardial fibrosis can lead to heart failure and act as a substrate for cardiac arrhythmias. In dilated cardiomyopathy diffuse interstitial reactive be observed, whereas arrhythmogenic is characterized by fibrofatty replacement in predominantly the right ventricle. The p.Arg14del mutation phospholamban (PLN) gene has been associated with recently also cardiomyopathy. Aim of present study determine exact pattern fatty PLN positive patients, novel method high resolution systematic digital...
Abstract The presence of multiple pathogenic variants in desmosomal genes ( DSC2 , DSG2 DSP JUP and PKP2 ) patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity is reclassified frequently, which may result changed clinical risk prediction. Here, we present collection, reclassification, outcome correlation for largest series ARVC carrying date n = 331). After only 29% remained carriers two (likely) variants. They...
Phospholamban (PLN) p.Arg14del cardiomyopathy is associated with an increased risk of malignant ventricular arrhythmias and severe heart failure a poor prognosis from late adolescence. It can be diagnosed in whole specimens, but rarely right biopsy by PLN immunohistochemistry showing PLN-containing aggregates concentrated cardiomyocytes dense perinuclear aggresomes. The purpose this study was to determine whether used diagnose using apical left myocardial specimens harvested during assist...
Abstract Background The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic (ACM). Carriers are at increased risk of malignant ventricular arrhythmias heart failure, which has been ascribed to cardiac fibrosis. Importantly, fibrosis appears be an early feature the disease, occurring in many presymptomatic carriers before onset overt disease. As with most monogenic cardiomyopathies, no...
Abstract Clinical interpretation of exome and genome sequencing data remains challenging time consuming, with many variants unknown effects found in genes functions. Automated prioritization these can improve the speed current diagnostics identify previously disease genes. Here, we used 31,499 RNA-seq samples to predict phenotypic consequences We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses predictions combination patient’s phenotype, denoted using HPO...
The sinoatrial node exhibits high amounts of desmin and desmoplakin in structures we call “lateral intercalated disks,” connecting side-by-side adjacent cardiomyocytes. These are diminished desmin-deficient mouse models. Misregulation T-type Ca 2+ current hyperpolarization-activated cyclic nucleotide-gated K + channel 1 was proved along with prolonged interatrial conduction cardiac autonomic nervous system dysfunction.
Phospholamban (PLN) p.Arg14del mutation carriers are at risk of developing malignant ventricular arrhythmias (VAs) and/or heart failure. Currently, left ejection fraction (LVEF) plays an important role in assessment for VA these individuals. We aimed to study the incremental prognostic value mechanical dispersion (LVMD) by echocardiographic deformation imaging prediction sustained PLN carriers.We included 243 carriers, which were classified into three groups according '45/45' rule: (i)...
Abstract Genetic cardiomyopathy is caused by mutations in various genes. The accumulation of potentially proteotoxic mutant protein aggregates due to insufficient autophagy a possible mechanism disease development. objective this study was investigate the distribution myocardium such relation specific pathogenic genetic hearts. Hearts from 32 patients, 4 non‐genetic patients and 5 controls were studied. Microscopic slices an entire midventricular heart slice stained for p62 (sequestosome‐1,...