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The handle http://hdl.handle.net/1887/58994 holds various files of this Leiden University dissertation.
Author: Kelder, T.P.
Title: The developing heartbeat: tracing and characterization of the developing cardiac conduction system
Issue Date: 2018-01-18
1 AIM & OUTLINE OF THE THESIS
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AIM & OUTLINE OF THE THESIS
The cardiac conduction system (CCS) ensures initiation and coordination of the electrical activation of the heart, resulting in controlled contraction of the myocardium. This process is crucial to maintain constant perfusion to the organs in the body. Failure of the CCS, clinically manifested as cardiac arrhythmias, causes serious morbidity and mortality and poses an important disease burden on the pediatric and adult population.
Understanding the developmental processes ultimately giving rise to the mature CCS can help to understand the pathophysiology of cardiac arrhythmias. This in turn can lead to new therapeutic strategies to prevent or treat this group of debilitating diseases. The main aim of the current thesis is to study the embryological origin and characteristics of key components of the developing CCS.
In chapter 2 of this thesis, a general introduction on cardiac and CCS development is given. The development of the CCS is linked to clinical arrhythmias and arrhythmias occurring in the setting of congenital heart disease. Based on the results from the literature, a working model for the developmental background of clinical arrhythmias is provided.
The avian embryo has long been a popular and vital model system in developmental biology. A large number of the experiments described in the current thesis were performed using chick embryos. In chapter 3 an overview of advantages and limitations of this model system is given. Furthermore, the techniques used in the avian embryo to study the developing CCS are described.
The results obtained from these experiments are discussed briefly to underscribe the importance of the avian model system in understanding the development of the CCS.
The atrioventricular node (AVN) is an essential component of the CCS, responsible for delaying the electrical activation wave from the atria. This allows time for the right and left ventricular lumen to fill with blood during diastole, necessary for efficient output of the heart. The AVN itself is a complex structure that consists of multiple cell types.1 The developmental origin of the different components of the AVN remains controversial.1 A contribution from the myocardium of the sinus venosus to the developing AVN was suggested2 and is investigated in chapter 4.
In a recent study by Sun et al. it was suggested that the dorsal mesenchymal protrusion (DMP) acts as a temporary pacemaker during early development.3
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In chapter 5 the anatomical description of the DMP that is provided by Sun et al., and therefore the conclusion that this structure acts a temporary pacemaker during development, is probed.
Disturbance of the RHOA-ROCK signaling pathway results in bradycardia, atrial fibrillation and AV block in adult mice.4,5 The developmental processes leading to these arrhythmias remain to be elucidated. In chapter 6, the development of the sinus venosus myocardium and sinoatrial node after inhibition of the RHOA- ROCK pathway is studied in chicken embryos. The effect of inhibition of this pathway on AV canal and AVN development is studied in chapter 7.
The cardiac autonomic nervous system (cANS) modulates heart rate, contraction force and conduction velocity.6 In the adult heart, both the SAN and AVN have a rich autonomic innervation. Prior to establishment of the cANS, the early embryonic chicken heart already responds to epinephrine.7 In chapter 8 this early autonomic innervation is examined and a potential role for the epicardium in early modulation of the autonomic response is investigated.
In chapter 9 the different fate mapping and cell tracing techniques aimed at elucidating the developmental origin of the CCS are discussed. Special focus will be on the specific limitations and advantages of these techniques. The data obtained from these experiments will be evaluated critically and a possible working model for the development of the CCS is generated.
Chapter 10 provides a summary of the work described in this thesis.
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REFERENCE LIST
1. Jongbloed, M. R. et al. Normal and abnormal development of the cardiac conduction system;
implications for conduction and rhythm disorders in the child and adult. Differentiation 84, 131–148 (2012).
2. Vicente-Steijn, R. et al. Electrical activation of sinus venosus myocardium and expression patterns of RHOA and Isl-1 in the chick embryo. J. Cardiovasc.
Electrophysiol. 21, 1284–92 (2010).
3. Sun, C. et al. The short stature homeobox 2 (Shox2)- bone morphogenetic protein (BMP) pathway regulates dorsal mesenchymal protrusion development and its temporary function as a pacemaker during cardiogenesis. J. Biol. Chem. 290, 2007–23 (2015).
4. Wei, L. et al. Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved. FASEB J. 18, 857–9 (2004).
5. Sah, V. P. et al. Cardiac-specific overexpression of RHOA results in sinus and atrioventricular nodal dysfunction and contractile failure. J. Clin. Invest. 103, 1627–34 (1999).
6. Shen, M. J. & Zipes, D. P. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ. Res.
114, 1004–1021 (2014).
7. Kroese, J. M., Broekhuizen, M. L. A., Poelmann, R. E., Mulder, P. G. H. & Wladimiroff, J. W. Epinephrine affects hemodynamics of noninnervated normal and all-trans retinoic acid-treated embryonic chick hearts. Fetal Diagn. Ther. 19, 431–9 (2004).
