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PLoS One
2012 Jan 01;79:e44231. doi: 10.1371/journal.pone.0044231.
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Identifying the evolutionary building blocks of the cardiac conduction system.
Jensen B, Boukens BJ, Postma AV, Gunst QD, van den Hoff MJ, Moorman AF, Wang T, Christoffels VM.
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The endothermic state of mammals and birds requires high heart rates to accommodate the high rates of oxygen consumption. These high heart rates are driven by very similar conduction systems consisting of an atrioventricular node that slows the electrical impulse and a His-Purkinje system that efficiently activates the ventricular chambers. While ectothermic vertebrates have similar contraction patterns, they do not possess anatomical evidence for a conduction system. This lack amongst extant ectotherms is surprising because mammals and birds evolved independently from reptile-like ancestors. Using conserved genetic markers, we found that the conduction system design of lizard (Anolis carolinensis and A. sagrei), frog (Xenopus laevis) and zebrafish (Danio rerio) adults is strikingly similar to that of embryos of mammals (mouse Mus musculus, and man) and chicken (Gallus gallus). Thus, in ectothermic adults, the slow conducting atrioventricular canal muscle is present, no fibrous insulating plane is formed, and the spongy ventricle serves the dual purpose of conduction and contraction. Optical mapping showed base-to-apex activation of the ventricles of the ectothermic animals, similar to the activation pattern of mammalian and avian embryonic ventricles and to the His-Purkinje systems of the formed hearts. Mammalian and avian ventricles uniquely develop thick compact walls and septum and, hence, form a discrete ventricular conduction system from the embryonic spongy ventricle. Our study uncovers the evolutionary building plan of heart and indicates that the building blocks of the conduction system of adult ectothermic vertebrates and embryos of endotherms are similar.
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Figure 2. The atrioventricular junction in ectotherms is not interrupted by an insulating plane.Picro-sirius red stain for collagen (red) on 10 µm sections of hearts of adult ectotherms showing the atrioventricular canal to be in full communication (+) with the ventricle. l(r)a, left(right) atrium.
Figure 3. The phenotype of the slow propagating atrioventricular canal is evolutionary conserved.Numbers in the phylogenetic tree indicate time in millions of years since major splits in tetrapod evolution. (A–E) The hearts of mature ectotherms (blue) and embryonic endotherms (red) maintain complete muscular connection in the atrioventricular canal (avc). (F–J) Markers of fast propagating chamber myocardium (Nppa and Gja5) are absent from the atrioventricular canal (arrowheads). Note that the specimen in H is contracted, obscuring the spongy design otherwise visible. Scale bars in (A–E), 300 µm; (F–J), 100 µm.
Figure 4. The developmental gene programme of amniotes is maintained in the mature heart of Anolis.(A–D) Stage 17/19 Anolis hearts show complementary expressions of Bmp2 and Tbx3 to Gja5 in the developing myocardial atrioventricular canal (arrowheads). (E–H) The developmental expression of Bmp2, Tbx3 and Gja5 is maintained in the mature myocardial atrioventricular canal (left side shown). la, left atrium; ra, right atrium; ven, ventricle. Scale bars are 100 µm.
Figure 5. Three-dimensional reconstructions of Tbx3 (yellow) expression in amniotes reveal a shared design.Reconstructions are based on in-situ hybridizations of serial sections, except in human (based on immunohistochemistry, modified from [57], [58]). The Tbx3 domains are strikingly similar in the early phases of chamber formation (upper panel). The Tbx3 expression of the Anolis ventricle is very similar to that associated with ventricular septation (black arrows) in the other amniotes (lower panel).
Figure 6. Tbx2 expression in the atrioventricular canal of the formed heart of the zebrafish (in-situ hybridization).Nppa is expressed in a complementary pattern. a, atrium; ven, ventricle.
Figure 7. Tbx2 expression (in-situ hybridization) in developing Xenopus (st 48).Tbx2 is expressed in the atrioventricular canal and base of the myocardial outflow tract and complementary to Nppa, marker of chamber myocardium. In ectotherms primitive myocardium (p), remnants of the embryonic heart tube, can be recognized by its smooth surface as opposed to the trabeculated myocardium (t) formed during chamber formation. The primitive myocardium of the ventricular base of st 48 Xenopus hearts already has the adult configuration. The trabecular component is far from fully developed. a, atrium; avc, atrioventricular canal; c, conus arteriosus (myocardial outflow tract); p, primitive (atrabecular) myocardium; t, ventricular trabeculated myocardium; ven, ventricle.
Figure 8. Development of compact walls.The development of the compact walls (Nppa and Gja5 negative) of mammals and birds leaves the trabeculated myocardium (Nppa and Gja5 positive) as a thin inner lining of the ventricular lumina in the fully formed hearts. Nppa is not expressed birds[36]. Scalebars, 100 µm. ivs, interventricular septum; lv, left ventricle.
Figure 9. Trabeculated ventricles are activated from base to apex.(A, D, G, J) Markers of fast propagating myocardium (Nppa and Gja5) are homogenously expressed in the ventricular trabeculated myocardium from base to apex (ap). (B, E, H) Ventricular activation occurs from base to apex. Early activation is red, late activation is blue. Note that the time-colour coding in panel E is different from that in panels B and H. (K) In species with thick compact myocardium, surface breakthrough of the activation front is earlier in the apical region than in the base. (C, F, I, L) Graphs show the average activation time of the apex and base and the total ventricular activation time. Note that in zebrafish, Xenopus and Anolis, the ventricular base is activated earlier than the apex whereas in mice the ventricular base is activated later than the apex (* Significantly different (one-way ANOVA P<0.05)). n is 3, 6, 9 and 2, respectively. Scale bars in (B, E, H, K) indicate respectively 0.2, 1, 0.5 and 0.1 millimetre. avc, atrioventricular canal; ven, ventricle.
Figure 10. The trabecular myocardium is activated from base to apex in all vertebrates.(A–C) The trabecular myocardium gives rise to the His-Purkinje system in mammals and birds and remains activated from base to apex. (C) On the epicardial surface of septated and thick-walled ventricles, as in the formed hearts of mammals and birds, activation is seen to occur from apex to base and the luminal base-to-apex activation is obscured.
Figure 1. Background and hypothesis.(A) Anatomical works concluded that the specialized cardiac conduction system evolved independently in mammals and birds because similar structures could not be found in ectothermic vertebrates. (B) We are testing the hypothesis that a primordial version of the specialized cardiac conduction system can be found in ectothermic vertebrates.
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