Dr. Monique Jongbloed: Cardiovascular development and congenital heart disease

Head of the group: Dr. Monique Jongbloed
Research scientists:  Dr. Margot M. Bartelings

Technicians: ing. Bert Wisse, ing. Conny van Munsteren
PhDs:  Yang GeClaire Glashan,  Claire Koppel,  Tjitske Zandstra,  Wilke Koenraadt
Students: Carola Jongbloed, Sira Blom                                      

The central focus of the research group is embryology and pathomorphology of the heart, with emphasis on cardiac conduction and innervation in structural heart disease. Basic research is combined with clinical research.  The group aims to explore morphology, mechanisms and outcome of structural/congenital heart diseases, including pathological innervation patterns. The focus of the latter research is on studying determinants  of neural growth, the role of cellular contributions and signalling pathways involved. Functional techniques like fetal electrocardiography are used (Figure 1). The group uses in vivo and vivo models, as well as human tissues. The Leiden Collection of congenital heart disease contains over 2500 human specimens that has been used over past years for education and research purposes (management collection by our  cardiac pathomorphologist Dr. M.M. Bartelings). The group works closely together with the research group of Prof. Dr. M.C. de Ruiter

Figure 1: Cardiac morphology and electrophysiology in a chick RhoA-ROCK inhibition model. Modified after Vicente-Steijn et al. Cardiovasc Res 2017

Aim and focus:

Structural heart disease is the main cause of death in the developed world. Causes of structural heart disease can be congenital or acquired, such as coronary artery disease. Congenital heart disease (CHD) is the most common congenital disease with an incidence of  1:1000 life born children. In the past years, therapeutics options for the treatment of CHD have significantly improved, thus allowing progressively more patients to reach the adult age. Although early survival rates have thus improved, a major concern remains the occurrence of late complications, including fatal arrhythmias leading to sudden cardiac death (SCD) in subgroups of patients with CHD. Especially the subgroup of patients with right ventricular dysfunction are at risk. Knowledge on cardiac morphology and variations in phenotype is mandatory to understand and predict some forms of complications. In addition, understanding the molecular mechanisms leading to structural changes in cardiac tissues, is essential to eventually being able to interact with disease cascades induced by hemodynamic overload or ischemia in these patients.

Of the aquired structural heart diseases, myocardial infarction (MI) is a major cause of death in the developed world. In patients with myocardial infarction, SCD has been related to pathological innervation patterns of the left ventricle, leading to autonomic hyperinnervation with electrophysiological disarray potentially causing to electrical instability and SCD. Accumulating evidence suggests a relationship between ventricular arrhythmias, sudden cardiac death and activity of the sympathetic autonomic nerve system. Scarse data is available on the mechanisms of these disturbed innervation patterns and the relevance of pathological innervation in patients with congenital heart disease and primarily right ventrricular dysfunction.  

The aim of our clinical research is to explore cardiac morphology as related to determinants of clinical outcome in different forms of congenital heart disease. Morphological variations in phenotype have in the past years been explored in different forms of congenital heart disease, including AVSD, tetralogy of Fallot, AVSD, bicuspid aortic valve, and TGA (Figure 2). The main focus is currently on studying cardiac autonomic function in patients with structural/congenital heart diseases, and coronary anatomy in the setting of anomalous coronary arteries and in congenital heart disease.

Figure 2: Coronary anatomy variations (absence of left main stem) in bicuspid aortic valve disease. Modified from Koenraadt et al. Heart 2016 and 2017

The central focus of the basic research has been the exploration of mechanisms of congenital heart disease in mouse models, with emphasis on the cardiac conduction system and developmental contributions of the second heart field. Currently, the morphology and mechanisms of pathological cardiac innervation states in structural (acquired and congenital) heart disease is studied. We aim to determine the role of different cell types in cAND development and characterise factors influencing neuronal outgrowth (Figure 3). A g eneral aim is to bridge the gap between clinical and basic science.

Figure 3: Culture of cervical ganglion, showing axonal outgrowth

Collaboration within the LUMC

Projects are performed largely in the setting of collaborations between the depts. of Anatomy&Embryology, Molecular Cell Biology and Cardiology of the LUMC. In addition, there are collaborations with dept. of Paediatric Cardiology, Thoracic Surgery and Obstetrics. These collaborations are effectuated by sharing PhD students and by collaborations in multidisciplinary projects. The majority of PhD students aim to combine basic and clinical research in their thesis.

External Collaboration

Over the past years the group has collaborated with different European institutions, including the University of Warsaw and the University of Prague.

Grants and other funding

The group leader participates in several research consortia,  largely in collaboration with the depts. of Paediatric Cardiology and Thoracic Surgery ( e.g. The Cobra 3 study (funded by CVON), 4D flow CMR in TGA study (funded by NHS),  and Fontanergy study (funded by Stichting Hartekind))

Key Publications

RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node.
Vicente-Steijn R, Kelder TP, Tertoolen LG, Wisse LJ, Pijnappels DA, Poelmann RE, Schalij MJ, deRuiter MC, Gittenberger-de Groot AC, Jongbloed MRM.
Cardiovasc Res. 2017 Aug 1;113(10):1186-1197

The epicardium as modulator of the cardiac autonomic response during early development.
Kelder TP, Duim SN, Vicente-Steijn R, Végh AM, Kruithof BP, Smits AM, van Bavel TC, Bax NA, Schalij MJ, Gittenberger-de Groot AC, DeRuiter MC, Goumans MJ, Jongbloed MR.
J Mol Cell Cardiol. 2015 Dec;89(Pt B):251-9

Coronary anatomy in children with bicuspid aortic valves and associated congenital heart disease.
Koenraadt WMC, Bartelings MM, Bökenkamp R, Gittenberger-de Groot AC, DeRuiter MC, Schalij MJ, Jongbloed MRM.
Heart. 2017 Jul 27. pii: heartjnl-2017-311178

Part and Parcel of the Cardiac Autonomic Nerve System: Unravelling Its Cellular Building Blocks during Development
Vegh AM, Duim SN, Smits AM, Poelmann RE, ten Harkel DJ, DeRuiter MC, Goumans MJ, Jongbloed MR
J. Cardiovasc. Dev. Dis. 2016, 3(28)/ doi:10.3390/jcdd3030028. http://www.mdpi.com/2308-3425/3/3/28

Impact of surgery on presence and dimensions of anatomical isthmuses in tetralogy of Fallot.
Kapel GFL, Laranjo S, Blom NA, Hazekamp MG, Schalij MJ, Bartelings MM, Jongbloed MRM, Zeppenfeld K.
Heart. 2018 Jan 5. pii: heartjnl-2017-312452

Energetics of blood flow in cardiovascular disease: concept and clinical implications of adverse energetics in patients with a Fontan circulation
Rijnberg, F.M.a, MD; Hazekamp, M.G.a, MD, PhD; Wentzel, J.J.e, PhD; de Koning, P.J.H.b, Msc; Westenberg, J.J.M.b, PhD; Jongbloed, M.R.M., MD, PhD; Blom, N.A.c, MD, PhD; Roest, A.A.W.,c, MD, PhD- Circulation 2018- In Press

The sinus venosus myocardium contributes to the atrioventricular canal: potential role during atrioventricular node development?
Kelder TP, Vicente-Steijn R, Harryvan TJ, Kosmidis G, Gittenberger-de Groot AC, Poelmann RE, Schalij MJ, DeRuiter MC, Jongbloed MR.
J Cell Mol Med. 2015 Jun;19(6):1375-89