Accessory atrioventricular myocardial pathways in mouse heart development: substrate for supraventricular tachycardias.

Atrioventricular reentry tachycardia (AVRT) requiring an accessory atrioventricular pathway (AP) is the most common type of arrhythmia in the perinatal period. The etiology of these arrhythmias is not fully understood as well as their capability to dissipate spontaneously in the first year of life. Temporary presence of APs during annulus fibrosus development might cause this specific type of arrhythmias. To study the presence of APs, electrophysiological recordings of ventricular activation patterns and immunohistochemical analyses with antibodies specifically against atrial myosin light chain 2 (MLC-2a), Periostin, Nkx2.5, and Connexin-43 were performed in embryonic mouse hearts ranging from 11.5 to 18.5 days post-conception (dpc). The electrophysiological recordings revealed the presence of functional APs in early (13.5-15.5 dpc) and late (16.5-18.5 dpc) postseptated stages of mouse heart development. These APs stained positive for MLC-2a and Nkx2.5 and negative for Periostin and Connexin-43. Longitudinal analyses showed that APs gradually decreased in number (p = 0.003) and size (p = 0.035) at subsequent developmental stages (13.5-18.5 dpc). Expression of periostin was observed in the developing annulus fibrosus, adjacent to APs and other locations where formation of fibrous tissue is essential. We conclude that functional APs are present during normal mouse heart development. These APs can serve as transient substrate for AVRTs in the perinatal period of development.

Fetal Atrial Flutter: Electrophysiology and Associations With Rhythms Involving an Accessory Pathway.

BACKGROUND: Atrial flutter (AFl) accounts for up to one third of all fetal tachyarrhythmias and can result in premature delivery, hydrops, and fetal death in 10% of cases; however, the electrophysiology of AFl in utero is virtually unstudied. METHODS AND RESULTS: In this observational study, we reviewed 19 fetal magnetocardiography studies from 16 fetuses: 15 fetuses (21-38 weeks' gestation) referred with an echocardiographic diagnosis of AFl and 1 fetus (20 weeks' gestation) referred with a diagnosis of tachycardia that was shown by fetal magnetocardiography to have transient AFl in addition to atrioventricular reciprocating tachycardia. Thirteen fetuses showed AFl during the fetal magnetocardiography session, including 4 that presented prior to the third trimester. Five fetuses had incessant AFl; all but 1 of the others with AFl showed additional significant rhythms. Specifically, AFl showed a strong association with rhythms involving an accessory pathway: atrioventricular reciprocating tachycardia, blocked reentrant premature atrial contractions, and ventricular preexcitation. The observed initiations and terminations of AFl most often involved reentrant premature atrial contractions. Spontaneous termination of AFl showed AFl cycle length oscillations. Nine fetuses with 2:1 AFl also showed periods of 4:1 conduction or variable conduction that oscillated between 2:1 and 4:1; however, 3:1 AFl was relatively rare. CONCLUSIONS: Fetal AFl can occur as early as midgestation and is often accompanied by atrioventricular reciprocating tachycardia and other rhythms associated with an accessory pathway. The findings depict critical differences in the electrophysiology of AFl in the fetus versus the neonate.

Navigational error in the heart leads to premature ventricular excitation.

In the normal heart, an insulating barrier separates the atria and ventricles. The only way in which electrical impulses can cross this barrier is via the atrioventricular (AV) node, which delays impulse conduction to ensure the forward flow of the blood. However, in some individuals, additional muscular bundles (accessory pathways) allow rapid conduction of electrical impulses from the atria to the ventricles, resulting in premature ventricular excitation and contraction. In this issue of the JCI, two independent research groups demonstrate that erroneous development of the embryonic AV canal, which performs a similar function to that of the adult AV node, is a novel mechanism by which accessory pathways can form.

Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice.

Ventricular preexcitation, a feature of Wolff-Parkinson-White syndrome, is caused by accessory myocardial pathways that bypass the annulus fibrosus. This condition increases the risk of atrioventricular tachycardia and, in the presence of atrial fibrillation, sudden death. The developmental mechanisms underlying accessory pathway formation are poorly understood but are thought to primarily involve malformation of the annulus fibrosus. Before birth, slowly conducting atrioventricular myocardium causes a functional atrioventricular activation delay in the absence of the annulus fibrosus. This myocardium remains present after birth, suggesting that the disturbed development of the atrioventricular canal myocardium may mediate the formation of rapidly conducting accessory pathways. Here we show that myocardium-specific inactivation of T-box 2 (Tbx2), a transcription factor essential for atrioventricular canal patterning, leads to the formation of fast-conducting accessory pathways, malformation of the annulus fibrosus, and ventricular preexcitation in mice. The accessory pathways ectopically express proteins required for fast conduction (connexin-40 [Cx40], Cx43, and sodium channel, voltage-gated, type V, α [Scn5a]). Additional inactivation of Cx30.2, a subunit for gap junctions with low conductance expressed in the atrioventricular canal and unaffected by the loss of Tbx2, did not affect the functionality of the accessory pathways. Our results suggest that malformation of the annulus fibrosus and preexcitation arise from the disturbed development of the atrioventricular myocardium.

Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways.

Ventricular preexcitation, which characterizes Wolff-Parkinson-White syndrome, is caused by the presence of accessory pathways that can rapidly conduct electrical impulses from atria to ventricles, without the intrinsic delay characteristic of the atrioventricular (AV) node. Preexcitation is associated with an increased risk of tachyarrhythmia, palpitations, syncope, and sudden death. Although the pathology and electrophysiology of preexcitation syndromes are well characterized, the developmental mechanisms are poorly understood, and few animal models that faithfully recapitulate the human disorder have been described. Here we show that activation of Notch signaling in the developing myocardium of mice can produce fully penetrant accessory pathways and ventricular preexcitation. Conversely, inhibition of Notch signaling in the developing myocardium resulted in a hypoplastic AV node, with specific loss of slow-conducting cells expressing connexin-30.2 (Cx30.2) and a resulting loss of physiologic AV conduction delay. Taken together, our results suggest that Notch regulates the functional maturation of AV canal embryonic myocardium during the development of the specialized conduction system. Our results also show that ventricular preexcitation can arise from inappropriate patterning of the AV canal-derived myocardium.