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. The function of the system is to continuously pump blood throughout the body for an entire lifetime. The adult heart, as the main pump in this system, performs roughly two thousand million cycles (2.3 × 10) in a typical lifetime. This continuous cycle is necessary to supply the whole body and all of its organs with oxygen and nutrients. Realization of this requires that the heart relaxes so that its chambers, the atria and ventricles, can fill with blood and then contract to propel the blood throughout the body. To achieve this, an intricate and complex organ developed, containing multiple chambers, nodes, valves, and electrical and force-producing components. In contrast, in primitive chordates and early vertebrate embryos the heart merely constitutes a myocardial mantle enfolding a ventral aorta, in which the blood is propelled by peristaltic contractions. The cardiomyocytes of such a primitive heart can be considered as nodal cells as they display automaticity and are poorly coupled, resulting in slow propagation of the depolarizing impulse and a matching peristaltic contraction. Eventually, the development of polarity, specifically, dominant pacemaker activity at the intake of the heart, led to the evolution of a one-way pump. Although dominant pacemaker activity implies development of sinus node function, only in mammals does a morphologically distinct node actually develop.1 The addition of highly localized, fast conducting cardiac chambers to the straight heart tube is an evolutionary novel event, and resulted in the four-chambered hearts of birds and mammals with synchronous contraction for a dual circulation. Interestingly, concomitant with the formation of chambers, an adult type of electrocardiogram (ECG) can already be monitored in the embryo (Figure 2-1).2 Thus, cardiac design, e.g., the positioning of the atrial and ventricular chambers within the straight heart tube, rather than the invention of nodes, principally explains the coordinated activation of the heart reflected in the ECG. To address the question 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, we suggest 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 and congenital malformations of the cardiac conduction system in the formed human heart. © 2008 Springer-Verlag London Limited.