Research Program: Heart Failure & Arrhythmias
Diastolic heart failure; inherited and congenital (non-ischemic) cardiomyopathies (HCM, DCM etc); ventricular arrhythmias associated with sudden cardiac death and atrial fibrillation, which are organized within four research themes
Unique research expertise:
- Sarcomere and cardiomyocyte physiology
- Drosophila atrial fibrillation model
- Clinical and experimental electrophysiology
- IPSC-CM (inducible pluripotent stem cells-derived cardiomyocytes)
- Developmental biology
Diastolic heart failure
During the last two decades it has become evident that more than 50 percent of all heart failure patients suffer of impaired diastolic function with preserved left ventricular ejection fraction (HFpEF). Despite modern heart failure therapy, prognosis of HFpEF did not improve over the last decades. To unravel pathomechanisms underlying diastolic dysfunction, In vivo clinical studies are combined with cellular studies in human cardiac preparations. In addition, several large and small animal models are used to unravel the pathomechanisms underlying impaired diastolic function.
To unravel the complex pathophysiology of inherited and congenital cardiomyopathies, a tight collaboration is present between the different actors involved in cardiomyopathy, including (clinical) geneticists, cardiologists, pathologists, cell biologists and physiologists. Expertise is bundled within the different research fields and thereby links clinical imaging and genetic studies with mechanistic insights obtained from molecular, histological and functional studies in human cardiac muscle samples, cell systems and animal models. Established models include single cardiomyocytes systems and mouse and Drosophila, which enable mechanistic studies and drug screening. The Parelsnoer institute, CONCOR, provides access to patient data, DNA and cardiac samples on congenital heart disease (including pulmonary hypertension and Marfan syndrome).
Research within this theme aims to identify genetic risk factors and cellular pathomechanisms underlying cardiac disorders associated with increased risk of sudden cardiac death. The focus is placed on genotype-phenotype studies and arrhythmia mechanisms in different cardiac pathologies, among which hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy, primary arrhythmogenic syndromes (Long QT syndrome, cardiac conduction disease and Brugada syndrome) and myocardial infarction/ischemia. The research includes discovery of genetic factors which cause or modify cardiac disease, investigation of underlying (pro)arrhythmic mechanisms, and identification of novel targets for diagnosis, risk stratification and therapy, including the interaction between structure and function. Functional studies are performed in experimental model systems (transgenic mice, human iPSC-CM) on newly-identified genes and pathways, providing insight into the pathophysiological mechanism underlying the disease. The theme links up with other CoE’s through metabolic control of electrophysiology, calcium handling, structure-function relation and pharmacology.
Atrial Fibrillation (AF) is the most common age-related cardiac arrhythmia causing increased morbidity and mortality. AF treatment is difficult due to its persistent nature caused by progressive structural and functional changes. Studies focus on normalization of protein homeostasis to reverse structural remodeling and restore cardiomyocyte function in AF. Genetic and pharmacological manipulations are used in tachypaced atrial cardiomyocytes and Drosophila and results are validated in atrial tissue of AF patients. In addition to basic research, clinical programs including studies into the role of the autonomic nervous system, thoracoscopic ablation, hearth rhythm devices such as the subcutaneous ICD (Implantable Cardioverter Defibrillator), wireless pacemakers and drug therapies, and evaluation of neurological consequences are performed in AF patients giving rise to an entire translational research line.