Developmental aspects of the electrophysiology of the heart: Function follows form

The cardiovascular system is the first organ system to form and function in the developing embryo. In a typical lifetime the heart performs roughly 2,000 million contraction-relaxation cycles (2.3 × 10 ⁹), to supply the whole body and all of its organs with oxygen and nutrients. To this end, an intricate and complex organ developed, encompassing multiple chambers containing electrical and force producing components, with nodes to activate the chambers and valves to prevent regurgitation. The cardiomyocytes of a primitive heart can be considered as a nodal cell because they display automaticity and are poorly coupled, which, together with slow propagation, gives rise to peristaltic contraction. The introduction of dominant pacemaker activity at the intake of the heart perfected such a heart into a one-way pump. Subsequently, highly localized, fast-conducting cardiac chambers were added to this nodal tube, resulting in the fourchambered hearts. Concomitant with the formation of such chambers, an adult type of electrocardiogram (ECG) can already be monitored in the embryo. Thus, cardiac design, i.e. the positioning of the atrial and ventricular chambers within the nodal tube, principally explains the coordinated activation of the heart reflected in the ECG. A crucial question is why some areas of the embryonic heart tube do not participate in the formation of atrial or ventricular working myocardium and mature in a nodal direction. As a generalized hypothesis we propose that the chamber-specific program of gene expression is specifically repressed by T-box factors and by other transcriptional repressors. Consequently, aberrant expression of these factors might be at the basis of ectopic automaticity, malformations of the conduction system and congenital heart disease in general.