Hartritmestoornissen

Home
Onderzoekers
Hartritmestoornissen

Background

Inherited primary cardiac arrhythmia disorders are an important cause of sudden cardiac death, especially when this is occurring in young individuals. Research already enabled identification of more than 60 genes associated with these disorders, but in more than half of the patients no mutations are detected in any of the known genes and the genetic cause remains elusive. Through study of these disease genes new insight has already been gained in the pathophysiological mechanisms causing primary arrhythmias, but the picture remains far from complete. For the moment there are no therapies available that can cure the arrhythmias, only implantation of a cardioverter defibrillator can completely abolish the risk for sudden cardiac death.

Goal

We aim to further investigate the genetic causes and disease mechanisms underlying cardiac arrhythmias. This will lead to a significantly improved understanding of the disorders and provide the possibility to develop novel therapies. With our research team we aim to improve genetic diagnosis, risk prediction, optimize counseling and deliver true personalized management of patients to increase their quality of life.

Strategy

Using modern DNA sequencing techniques (including whole-exome and whole-genome sequencing) in patients without a genetic diagnosis, we will identify novel genes involved in arrhythmias. We are also focusing on the identification of genetic modifiers that play a role in the development of these disorders and can explain the phenotypic variability observed within families. The functional effect of mutations in these genes and modifiers are studied in patient samples, induced pluripotent stem cell (iPSC)-derived cardiac cells and transgenic zebrafish or mice. Hereto we are using state-of-the-art techniques such as CRISPR/Cas genome editing, transcriptomics, interactomics, proteomics, high-tech microscopy and micro-electrode arrays. Based on these novel insights, new therapeutic targets can be identified for which novel drugs can be tested in the pre-clinical disease models that we generated.

Disorders under investigation:

Brugada syndrome, Short and Long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, RYR2 related calcium release deficiency syndrome

Team members:

Bart Loeys, Maaike Alaerts, Dorien Schepers, Ewa Sieliwonczyk, Eline Simons, Bert Vandendriessche, Dogan Akdeniz, Laura Rabaut, Maaike Bastiaansen, Jarl Bastianen, Jolien Schippers, Sofie Daemen, Charlotte Claes

Cardiac arrhythmia (Doctoraat Dogan Akdeniz - lopende)
Brugada syndrome research (Doctoraat Bert Vandendriessche - lopende)
Cardiac research (Doctoraat Martina Cherubin - lopende)

Development of an innovative dual reporter hiPSC-derived cardiac microtissue-based functional assay.
Inherited Cardiac Arrhythmia (ICA) refers to a group of genetic disorders in which patients present with abnormal heart rhythm. In the field of ICA research there is a need to further unravel genetic etiology, study the effect of genetic variants of uncertain significance, uncover disease mechanisms and identify novel drugs. A high-throughput, predictive and physiologically relevant human cardiac assay based on hiPSC-CM would greatly assist in this. It would also greatly benefit cardiotoxicity screening in early drug development. I will create a model of human induced pluripotent stem cells (hiPSC) with built-in special fluorescent proteins that report on calcium and voltage signals. Starting from these hiPSCs I will make cardiomyocytes, cardiac fibroblasts and endothelial cells that I grow into cardiac microtissues (cMT). The electrical activity and calcium handling of these cMTs is monitored with a specialized fluorescence microscope. I will introduce known disease-causing alterations into the genome of these cells and study the effect on the electrical activity of the derived cMTs as well as the effect of known drug compounds on these disease models.

PhD student: Dogan Akdeniz
Promotors: Maaike Alaerts, Bart Loeys & Dorien Schepers
Elucidating the pathogenicity of genetic variants of uncertain significance in Brugada syndrome patients by functional modelling in hiPSC-derived cardiomyocytes and zebrafish.
Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels results in detection of numerous genetic “Variants of Uncertain Significance” (so called VUS), but currently functional models to prove their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiomyocyte cell model, created from human stem cells, and a novel transgenic zebrafish (Zf) model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging and electrophysiological techniques, I will assess the mutation’s effect on a cellular level and in the whole heart, proving its contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.

PhD student: Bert Vandendriessche
Promotors: Dorien Schepers, Bart Loeys & Maaike Alaerts
Development and validation of cardiomyocyte model as a predictive assay to assess functional and structural cardiac liabilities.
.....
PhD student: Martina Cherubin
Promotors: Maaike Alaerts, Pieter-Jan Guns & Vitalina Gryshkova