Congenital heart disease and the specification of left-right asymmetry

Abstract

Complex congenital heart disease (CHD) is often seen in conjunction with heterotaxy, the randomization of left-right visceral organ situs. However, the link between cardiovascular morphogenesis and left-right patterning is not well understood. To elucidate the role of left-right patterning in cardiovascular development, we examined situs anomalies and CHD in mice with a loss of function allele of Dnaic1, a dynein protein required for motile cilia function and left-right patterning. Dnaic1 mutants were found to have nodal cilia required for left-right patterning, but they were immotile. Half the mutants had concordant organ situs comprising situs solitus or mirror symmetric situs inversus. The remaining half had randomized organ situs or heterotaxy. Looping of the heart tube, the first anatomical lateralization, showed abnormal L-loop bias rather than the expected D-loop orientation in heterotaxy and nonheterotaxy mutants. Situs solitus/inversus mutants were viable with mild or no defects consisting of azygos continuation and/or ventricular septal defects, whereas all heterotaxy mutants had complex CHD. In heterotaxy mutants, but not situs solitus/inversus mutants, the morphological left ventricle was thin and often associated with a hypoplastic transverse aortic arch. Thus, in conclusion, Dnaic1 mutants can achieve situs solitus or inversus even with immotile nodal cilia. However, the finding of abnormal L-loop bias in heterotaxy and nonheterotaxy mutants would suggest motile cilia are required for normal heart looping. Based on these findings, we propose motile nodal cilia patterns heart looping but heart and visceral organ lateralization is driven by signaling not requiring nodal cilia motility.

Primary Ciliary Dyskinesia. Recent Advances in Diagnostics, Genetics, and Characterization of Clinical Disease

“…There are increased postoperative respiratory complications in patients with heterotaxy and congenital heart disease, which suggests that some of these patients may have PCD (46). Indeed, studies in mice with mutations (Dnai1) in motile cilia suggest that cilia are required for normal heart development (looping) (47). Moreover, patients with heterotaxy and congenital heart disease have a high prevalence of respiratory ciliary dysfunction, which highlights the critical role of cilia function in normal cardiac development (48,49).…”

Ruptured Sinus of Valsalva Aneurysm Associated with Situs Ambiguus, Isolated Levocardia, and Polysplenia

“…A cluster of motile ciliary cells at the Hensen node generates a gradient that establishes a left-right axis. 6,17,18 Defects in these cilia result in abnormal left-right patterning that can present as situs ambiguus or situs inversus. 6,17,18,19 Left-right patterning is crucial in the siting of the great cardiac vessels and in atrial morphology.…”

“…6,17,18 Defects in these cilia result in abnormal left-right patterning that can present as situs ambiguus or situs inversus. 6,17,18,19 Left-right patterning is crucial in the siting of the great cardiac vessels and in atrial morphology. 6,19 Accordingly, the atrial appendages are used to denote isomerism, as in our patient with left isomerism (2 morphologic left atrial appendages).…”

Cils et morphogenèse cardiaque

“…Ainsi, les oreillettes droite et gauche diffèrent par leur morphologie, mais aussi par le drainage veineux et la nature des valves conduisant au ventricule adjacent. La signalisation droite/gauche est aussi requise pour des mouvements de courbure du coeur embryonnaire (Figure 3, E8,5), qui conduisent au positionnement relatif des ventricules et des troncs artériels, ainsi qu'au positionnement du coeur , qui n'affecte pas la ciliogenèse mais la motilité des cils, conduit à des défauts de la courbure du coeur, se traduisant par un mauvais positionnement du coeur si la courbure est inversée, ou à une hétérotaxie si la courbure est incomplète [21]. Quand la kinase ciliaire Nek8 (NIMA-related kinase 8) est mutée, les cils se forment normalement.…”