Opportunities and short-comings of the axolotl salamander heart as a model system of human single ventricle and excessive trabeculation

Figure 1. Anatomy of the axolotl heart. (A) Ventral view of the in situ axolotl heart showing the principle chambers, namely sinus venosus, atrium (internally divided by an almost complete atrial septum), ventricle and conus arteriosus. The ventricle is positioned on the right and the blunt apex is positioned caudally. The arterial outflow tract is a solitary trunk (truncus arteriosus) with left–right paired channels, giving rise to the third (3rd), fourth (4th), fifth (5th) and sixth (6th) gill arch arteries. There is no diaphragm between the heart and liver. (B) Dorsal view, showing the presence of a left sinus horn. Notice that a solitary pulmonary vein connects to the atrium in a position that equals the human embryonic position, i.e. immediately cranial to the sinus venosus and to the left of the sinuatrial junction. (C) View of the ventricular base and the atrial septum. The pulmonary vein connects to the left atrium in a primitive position, i.e. close to the ventricular base and next to the atrial septum. (D) Left-sided view of the atrial septum, showing a small gap between its leading edge and the atrioventricular canal, i.e. the primary foramen of the atrial septum. (E) Image from…

Figure 2. Anatomy of double inlet left ventricle patient 2. (A) Anterior view, complete. (B) Posterior view, complete. (C) Anterior view, right ventricle removed. (D) Both ventricles removed, appreciate anterior/posterior relationship of atria. (E) 4-chamber view. (F) Pathway of oxygen-poor blood stream. (G) Superior-inferior relationship of the atria. (H) Pathway of oxygen-rich blood stream. VSD, ventricular septal defect.

Figure 3. Anatomy and 4D streaming analysis of double inlet left ventricle patient 3. (A) 3-chamber view. (B) Sagittal view. (C) Coronal view. (D) Early ventricular filling phase depicting oxygen-poor (blue) blood and oxygen-rich (red) blood streams entering the left ventricle through the right and left atrioventricular valves respectively. (E) Late ventricular filling phase depicting oxygen-poor (blue) blood and oxygen-rich (red) blood streams entering the left ventricle through the right and left atrioventricular valves respectively. (F) Ventricular ejection phase depicting oxygen-poor (blue) blood and oxygen-rich (red) blood streams entering the pulmonary artery and aorta respectively. Oxygen-poor blood is not ejected in the aorta, blood ejected into the pulmonary artery seems partially oxygen-rich and oxygen-poor. (G) Ejection of blood in aorta (left) and pulmonary artery (right).

Figure 4. Cardiac flow separation in the axolotl demonstrated with ultrasonography. Top left: Anatomical model of the gill arches in the axolotl (3rd arch red, 4th arch purple, 5th arch green, 6th arch blue). Top right: Ultrasonographic transversal cross sections in the outflow tract at four time points in the injection series of negative contrast agent (amphibian Ringer’s solution). Notice the signal decrease (arrows) as diluted blood perfuse the three ventral gill arches after 30 and 3 cardiac cycles of contrast agent infusion at 0.5 and 5 ml min−1 respectively. Main part: Signal traces in right and left arches over time. Traces on the right are magnifications of the last 63 cardiac cycles with a high rate of infusion of contrast agent. Notice the final signal decrease in the 3rd, 4th, and 5th gill arches supplying the gills but not in the 6th gill arch supplying the lungs indicating a lack of complete mixing of blood in the heart as hypointense contrast agent is injected into the sinus venosus at a high flow rate (5ml min-1).

Figure 5. Ventricular wall composition in amphibians and human with normal and excessively trabeculated left ventricle. (A,B) Transverse section of the ventricular base of an axolotl (A) and a Xenopus frog (B), showing that the ventricle is highly trabecular and the compact wall is extremely thin. It can also be seen that the solitary atrioventricular canal (AVC) is left-sided and the solitary outflow tract (OFT) is right-sided. (C) Transverse section of the human ventricles at gestational week 20. This heart is not much bigger than the Xenopus heart (B), but the compact wall is much thicker and the trabeculations are much fewer and greater in size. (D) Transverse section of a case of fetal human excessive trabeculation at gestational week 20. Compared to the heart shown in (C), the compact wall is thinner and the trabeculations are more numerous, but this heart is still much different from the amphibian hearts (A–B). (E) Transmural histology of a normal left ventricle of an adult human, showing a thick compact wall and a few trabeculations. (F) Transmural histology of a case of left ventricular excessive trabeculation of an adult human. Compared to the heart shown in (E), the compact wall…