Cardiomyopathies

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Cardiomyopathies

Background

Cardiomyopathies are disorders of the heart muscle, resulting in improper contraction and/or relaxation of the heart. This can lead to cardiac arrhythmias, heart failure and even sudden cardiac death, sometimes in young individuals. Often these cardiomyopathies are inherited and 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 cardiomyopathies, but the picture remains far from complete. At present, there are some therapeutic options to reduce disease symptoms, but therapies that are capable of completely stopping or even reversing the disease are not yet available.

Goal

We aim to further investigate the genetic causes and disease mechanisms underlying cardiomyopathies. 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 cardiomyopathies. 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:

Hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, non-compaction cardiomyopathy.

Team members:

Bart Loeys, Maaike Alaerts, Ewa Sieliwonczyk, Emeline Van Creanenbroeck, Laura Rabaut, Maaike Bastiaansen, Jarl Bastianen, Jolien Schippers, Sofie Daemen, Charlotte Claes

Cardiomyopathies (Hanne Seghers - ongoing)
Cardiomyopathies (Reihaneh Asadi - Ongoing)

Hypertrophic cardiomyopathy - Integration of genotype and deep phenotype to tailor therapy
Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. In 30–40% of cases, a mutation in sarcomere protein genes is identified, while 10% have a non-sarcomere mutation; the remaining cases remain genetically undiagnosed.
Most patients with obstructive HCM (oHCM) present with some degree of exercise-induced symptoms and a reduced VO₂peak, a strong prognostic marker for adverse outcomes.
Recently, two novel therapeutic options have emerged in the treatment landscape of oHCM:
1. Cardiac myosin inhibitors (mavacamten): This new class of disease-specific drugs reduces cardiac hypercontractility and increases VO₂peak. It may provide greater benefits in patients with sarcomere gene mutations, but in vitro cell models and larger patient cohorts are needed to determine whether sarcomere variant status influences treatment response.
2. Exercise training: There is growing evidence that structured exercise is a safe and effective strategy to improve VO₂peak. However, whether exercise training provides additional benefits in oHCM patients treated with mavacamten and which mechanisms underlie these training-induced improvements remain to be elucidated.
We aim to gain a fundamental understanding of how phenotype and genotype influence treatment response in HCM, using both clinical studies and iPSC-derived cardiomyocytes and engineered heart tissue models carrying sarcomere and non-sarcomere mutations. Our ultimate goal is to advance precision therapy for HCM.
Promotors: Maaike Alaerts & Emeline Van Craenenbroeck
High-Throughput CRISPR Screening in Marfan iPSC Models: A Roadmap to Aneurysm Mechanisms and treatment.

Team members - Cardiomyopathies

Alumni

Hanne Boen

Discovering the role of titin (TTN) in anthracycline-induced cardiac
dysfunction in breast cancer.
Promotors: Emeline Van Craenenbroeck, Hein Heidbuchel, Bart Loeys & Maaike Alaerts

Joe Davis Velchev

In search for genetic modifiers of thoracic aortic aneurysm and dissection.
Promotors: Maaike Alaerts, Bart Loeys & Aline Verstraeten

Cardiomyopathies

Background

Team members - Cardiomyopathies

Bart Loeys

Bart Loeys

Ewa Sieliwonczyk

Ewa Sieliwonczyk

Lut Van Laer

Lut Van Laer

Maaike Alaerts