How Cardiac Embryology Translates into Clinical Arrhythmias

Abstract

The electrophysiological signatures of the myocardium in cardiac structures, such as the atrioventricular node, pulmonary veins or the right ventricular outflow tract, are established during development by the spatial and temporal expression of transcription factors that guide expression of specific ion channels. Genome-wide association studies have shown that small variations in genetic regions are key to the expression of these transcription factors and thereby modulate the electrical function of the heart. Moreover, mutations in these factors are found in arrhythmogenic pathologies such as congenital atrioventricular block, as well as in specific forms of atrial fibrillation and ventricular tachycardia. In this review, we discuss the developmental origin of distinct electrophysiological structures in the heart and their involvement in cardiac arrhythmias.

Keywords: arrhythmias; cardiac development; re-entry; transcription factors.

Figure 1

The electrocardiogram of the developing heart. The photographs are scanning electron microscope images of the developing chicken heart of the following stages: from left to right, Hamburger/Hamilton state 11, 14 and 18 correspond to 3, 4 and 5 weeks of human development, respectively. The electrocardiograms are recorded from different chickens of similar developmental stages to the corresponding photographs. These figures are courtesy of S. Virágh and G. Steding. Ap, arterial pole; vp, venous pole; V, ventricle; oft, outflow tract; avc, atrioventricular canal; A, atrium.

Figure 2

Phenotypes of the embryonic and adult heart (A). The embryonic myocytes in the early heart tube possess a phenotype typical for the conduction system with a high automaticity and a low conduction velocity, contractility, and sarcoplasmic reticulum activity. (B). The chambers balloon out from the initial heart tube and immediately initiate a fast conducting working myocardial phenotype. The myocardium at the venous pole, and the region interposed between the developing chambers, the atrioventricular canal, initially retains the conduction system phenotype and will form the cardiac conduction system. ra, right atria; la, left atria; oft, outflow tract; rv, right ventricle; lv, left ventricle.

Figure 3

Distribution of drivers (focal breakthroughs, asterisk; reentry events, curved arrows) in three regions is reported as the percentage of patients (Redrawn from [40]). The pink area indicates the continuum of the left atrial dorsal wall and pulmonary veins after incorporation (for explanation see text). Note that ectopic foci are nearly absent in the roof of the left atrium.

Figure 4

Atrioventricular junction and impulse propagation (A). Schematic representation of the different components of the atrioventricular junction (Inspired by [53,70]). Note that lower nodal cells share a common origin with the His bundle cells. (AV: atrioventricular) (B). In normal hearts, the electric impulses initiated by pacemaker cells in the sinoatrial node propagate through the atrial myocardium and trigger its contraction. At the atrioventricular node, the impulses are delayed for a period to facilitate alternating contraction of the atrial and ventricular myocardium. After the atrioventricular delay, the electrical impulses rapidly travel to the ventricular myocardium via the His-Purkinje system and stimulate the ventricular myocardium. In Notch1-activated and Tbx2-deficient hearts, accessory pathways are formed as a result of malformation of the atrioventricular canal myocardium, commonly right-sided in Notch1-activated mice and left-sided in Tbx2-deficient mice. Because of faster conduction through the accessory pathways than through the atrioventricular node, the ventricular myocardium is prematurely stimulated (preexcitation). The ECG shows a short PR interval, a slurred upstroke (“delta wave”) of the QRS complex and a widened QRS complex.

Figure 5

Developmental basis for RVOT arrhythmias. The adult RVOT has formed from the embryonic outflow tract (left), which is composed primary of myocardium exhibiting slow conduction and spontaneous activity. During development, the embryonic outflow tract acquires a working myocardial phenotype, e.g., fast conduction, and transforms into the RVOT. A small ring of primary myocardium, however, still remains just below the pulmonary valve, which may give rise to automaticity as seen in patients with idiopathic RVOT tachycardia. The myocardium of the free wall and septum of the adult RVOT has a working myocardial phenotype, although expression of Cx43 is lower than in the right ventricle. This may set the stage for re-entrant-based arrhythmias as seen in patients with the Brugada syndrome. Modified from [100] LV, left ventricle; RV, right ventricle; OFT, outflow tract; RVOT, right ventricular outflow tract; AO, aorta; PT, pulmonary trunk; LVOT, left ventricular outflow tract; Ca, calcium; EAD, early after depolarization; DAD, delayed after depolarization.