Loading

Abnormal Rotation of the Primary Heart Tube. Linking Embryogenesys to Malformed Cardiac Phenotypes: Future Perspectives

Original Research | Open Access Volume 3 | Issue 1 |

  • 1. Private Organization Carrara, Italy
+ Show More - Show Less
Corresponding Authors
Athos Capuani, Private Organization Carrara, via Maggiani 59, 54033 Carrara, Italy, Tel: 3403456535.
Abstract

We observed the Trabecula Septomarginalis anatomy in malformed cardiac phenotypes reviewing the related literature and the current concepts on cardiac embryogenesis.

The embryological and anatomical insights in formed cardiac phenotypes support the hypothesis that the ventriculo arterial cardiac connections in any pathological settings recapitulate an abnormal counterclockwise rotation on the ventricular base-apex axis of the primary cardiac tube in the first month of life at the Carnegie stages XIV-XVII.

The Trabecula rotates and follows the development of the Right ventricle in every specific pathological formed phenotype: a teratological continuum encompassing single phenotypes.

The Trabecula’s rotation at bulbar level (embryologic conus) on the septal aspect of the right ventricle links embryology to anatomy and finally to new investigations during pregnancy possibly leading up to less severe or even normal cardiac phenotypes what we refer to as Molecular Cardiac Surgery.

It is beyond the scope of this paper to enter into embryological dissertations or to appraise the hitherto postulated morphogenesis of specific phenotypes.

The purpose of this paper is to provide further evidence of the sequential Trabecula Septomarginalis rotation in formed phenotypes with embryological traits related to the development during the first month of life.

We are currently investigating the contribution of external forces on the interventricular septum rotational process during looping in the chick heart and we are organizing a biologists network to realize a research protocol based on exosomes for early detection of Congenital Heart Disease.

Citation

Capuani A (2020) Abnormal Rotation of the Primary Heart Tube. Linking Embryogenesys to Malformed Cardiac Phenotypes: Future Perspectives. Arch Paediatr Dev Pathol 3(1): 1022.

Keywords
  • Cardiac Embryogenesis
  • Trabecula Septomarginalis
  • Outlet Septum
  • Looping
  • Exosomes
ABBREVIATIONS

CHD: Congenital Heart Disease; TSM: Trabecula Septomarginalis; VS: Ventricular Septum; AL: Anterior Limb; PL: Posterior Limb; VIF: Ventriculo Infundibular Fold; RV: Right Ventricle; CSV: Crista Supraventricularis; OS: Outlet Septum; VSD: Ventricular Septal Defect; TF: Tetralogy of Fallot; TGA: Transposition of Great Arteries; DORV: Double Outlet Right Ventricle; DOLV: Double Outlet Left Ventricle; UH: Univentricular Heart; CS: Carnegie Stages* ; Horizon**: Cushion/Swelling/Ridge

* Carnegie stages are named after the Institute which first classifyied embryos in the early 1900’s. Stages are based on the external and/or internal development and are not directly dependent on age or size. The embryonic period is divided into 23 Carnegie stages covering the first 8 weeks post-ovulation. Criteria beyond morphological features include age in days, number of somites, and crown rump length.

**The developmental term “Horizon”defines 23 stages in human embryos from fertilization to the first two months from Streeter G.L. [1,2] and O’Railly R.[3].

INTRODUCTION

For the terminology and classification of CHD refer to Van Praagh R. 1972 [4] ; Shinebourne E.A., Macarteney F.J., Anderson R.H. 1976 [5]; Anderson R.H., Becker A.E., Van Mierop L.H.S. 1977 [6]; Anderson R.H.,Tynan M. 1984 [7]; International Paediatric and Congenital Cardiac Code (IPCCC) and European Paediatric Cardiac Code (EPCC) : http://www.IPCCC.net [8].

We refer to the Trabecula Septomarginalis (TSM) definition introduced by Tandler in 1913 [9] and described by Brandt 1953 [10], Grant 1961 [11-12], Wenink 1977 [13], Anderson 1977 [7].

In formed phenotypes the TSM is an extensive compaction of the septal trabeculations on the right septal surface of the ventricular septum. It is composed of two limbs, the Anterior Limb and the Posterior Limb. The AL is committed to the Outlet Septum and the PL to the Ventriculoinfundibular Fold. Capuani et al [14-17]. The moderator band, first observed by Leonardo da Vinci [18], is the continuation of the TSM towards the apicolateral side of the right ventricle.

In our vision the ideal plane passing through the two limbs rotates clockwise on the apex-base axis of the septum during the development of the Right Ventricle determining the formed cardiac phenotypes.

Any pathological deviation from this pre-established architectural design in cardiac embryogenesis carries abnormal phenotypes. The cardiac morphogenesis is a continuous very complex process which involves rotation, looping and partitioning of the primary straight cardiac tube at different levels and stages aligning finally the aorta and the pulmonary artery with the left and right ventricle respectively.

MATERIALS AND METHODS

We refer to the Visible Embryo Project [21,22], the Virtual Human Embryo Project [23]; the embryos and phenotypes data from the collection of Carnegie Institution Washington Baltimore and from the following centers and researchers in alphabetical order: Anderson RH et al. [24-31]; Asami I. [32]; Bersch W. [33]; Bostrom MPG, Hutchins GM. [34] Capuani A et al. [14]; Chuaqui B, Bersh W. [35,36]; Castellanos LM, Vasquez MA, Kuri MJ. [37- 39]; Conte G, Grieco M, Arrigoni P.[19,20]; Davis CL. [40]; De La Cruz MV et al. [41,42-51]; De Vries PA, Saunders JB de CM. [52]; Doerr W. [53-56]; Goor DA et al. [57,58-62]; Grant RP et al. [11,12,63,64]; Kramer TC. [65]; Lomonico MP et al. [66,67]; Manasek FJ, Monroe RG. [68]; Manner J, Monroe RG, Seidl W, Steding G. [69-73]; Markwald RR, Trusk T, Moreno-Rodriguez R. [74]; Meredith MA, Hutchins GM, Moore GW. [75]; McBride RE, Moore GW, Hutchins GM. [76]; 0’Rahilly R. [3]; Orts-Llorca F, Puerta-Fonolla J, Sobrado J. [77]; Pexieder T. [78-80]; Spitzer A. [81,82]; Streeter GL. [1,2]; Thiene G et al. [83]; Van Mierop LHS et al. [84-89]; Van Praagh R et al. [90-96]; Wenink ACG. [13,97]; Zavaleta D et al. [98]. Other Authors are cited under specific topics.

We drew Schemes 1-2 illustrating the heart rotational process and we have reproduced the morphology of specific phenotypes to underline the ideal TSM rotation during the first month of life (Figures 6-16).

We discuss the presented concepts on embryogenesis and morphology while linking the embryogenetic process to formed phenotypes. On the base of our vision we comment on new potential treatments of CHD.

RESULTS

From Dextroposition of Aorta to Tetralogy of Fallot (TF), Single Outlets, Double Outlets Right Ventricles (DORV), Transposition of Great Arteries (TGA), and towards Double Outlets Left Ventricles (DOLV), the CSV, the OS and the VS progressively divorces with partial or complete loss of the outflow spiraling flow and development of pulmonary mitral continuity (Scheme 1,2).

Morphology of formed phenotypes

DISCUSSION

The Doerr’s Vectorial Bulbus Rotation Hypothesis [53-56]from Chuaqui B. and Bersch W. 1973, 1979 [35,36] according to the photograms by Asami I. 1969 [32].

Schwalbe in 1906 introduced in biology the concept of Teratological Series as developmental anomalies with a similar pathogenetic disturbance [120]. These entities represent distinct manifestations of a similar process occurring at different sequential times and are morphogenetically linked. On the one extreme the least deviation from normal and on the other the most severe malformation.

Spitzer in 1923, 1928 [81,82] in a new phylogenetic hypothesis for the Transposition of Great Arteries (the general organs develop in series from fishes to birds and mammals in response to forces of varying conditions) applied the Schwalbe concept arguing that an incomplete torsion of the primitive cardiac tube is the causation of cardiac defects.

He postulated that in transpositions of great vessels there is a torsion of the bulboventricular septum recapitulating phylogenetically an earlier form: the reptilian left Aorta which becomes obliterated while the right Aorta regains patency.

Doerr in 1938 [53-56] introduced the Spitzer concept to the “Vectorial Bulbus Rotation Hypothesis” in the morphogenesis of cardiac malformations from the Eisenmenger Complex to Tetralogy of Fallot, Taussig Bing and Transposition of Great Arteries.

The morphogenetic disturbance involved is an arrest, to a varying extent, of the Vectorial Bulbus Rotation.

Basically the rotation process of the primary cardiac tube consists in (Figures 1-3 ):

Figure 1 In german literature the ascending limb of the primary heart tube at the level of the developing right ventricle is named Metampulla. Distally, at the Ostium  Bulbi level, it continues with the Bulbus* (embryologic conus). The term Proampulla is applied to the trabeculated areas. The outflow tract of the right ventricle contains  both metaampulla and bulbus [57]

Figure 1 In german literature the ascending limb of the primary heart tube at the level of the developing right ventricle is named Metampulla. Distally, at the Ostium Bulbi level, it continues with the Bulbus* (embryologic conus). The term Proampulla is applied to the trabeculated areas. The outflow tract of the right ventricle contains both metaampulla and bulbus [57].

*Bulbus, Conus, Infundibulum: Davis 1927 in 1927 [40] introduced the term Bulbus (embryologic conus: the region between the growing RV and the truncus arteriosus in the primary straight heart tube) to designate a region of the primary straight tube that gives origin to the right ventricle. Kramer in 1942 [65] recommended to substitute the Bulbus term with Conus.

The conus or infundibulum has two parts: one proximal, septal band and moderator band always part of the morphological right ventricle and one distal, parietal band (CSV) which is not inseparable part of the right ventricle because it may be located predominantly above the left ventricle [90]. The actual right-left translocation of the primordia is unknown. The precise origin of the free-standing infundibulum is still unexplained. In the present paper we distinguish: 1- the bulbar ridge A which starts proximally on the anterior wall of the conoventricular junction and spirals through the left wall of the conus to the right wall of the truncus; 2- the bulbar ridge B which starts on the back wall of the conoventricular junction and spirals to the left wall of the truncus Goor DA 1975 [57].

The Part A corresponds to the proximal sinistroventral (inferior) conal cushion of Van Mierop and the Part B to the proximal right dextrodorsal (posterior) conal cushion [84-89].

Normally the anterior endocardial crest of the Interventricular Septum (septal band, Tandler’s TSM) is committed to the sinistroventral conal swelling A and spirals rightleft. The enlargement of the AV canal brings the dextrodorsal conal swelling B (where the Crista Supraventricularis originates Wenink 1981) [97] close to the superior AV endocardial cushion with which blends.

This right ventricular remodeling and the formation of the spiral conotruncal septum align the pulmonary artery (6th aortic arch) with the right ventricle and the aorta (4th aortic arch) with the left ventricle.

At this stage we can figure out the malrotation of the TSM (inter ventricular primary foramen endocardial crest) resulting in twisted cephalic interventricular septum in formed phenotypes (in discussion).

During the normal ventricular remodeling the anterior endocardial crista free edge (developing TSM) of the embryonic primary interventricular foramen stems from the sinistroventral conal swelling (part A), spirals in the developing right ventricle right-left. The posterior free edge connects to the dextrodorsal conal swelling (part B) via a ridge that crosses the fusion of the endocardial AV cushions and continues to the aortic arch placing the CSV in the normal position.

Figure 2 From Streeter G.L. [1,2] as reported by De la Cruz M.V, Miller B.L. [41]. The flow path wax models were made from embryo 836 of the Carnegie collection by  Mr. Heard and drawn from De Vries P.A. and Saunders J.B. de C.M. illustrations [52] as reported by Grant R.P. [10]. The embryo 836 is the prototype of the Visible Embryo  Project NIH founded to comunicate life (http://embryo.asu.edu/about/network.php) [21-23].

Figure 2 From Streeter G.L. [1,2] as reported by De la Cruz M.V, Miller B.L. [41]. The flow path wax models were made from embryo 836 of the Carnegie collection by Mr. Heard and drawn from De Vries P.A. and Saunders J.B. de C.M. illustrations [52] as reported by Grant R.P. [10]. The embryo 836 is the prototype of the Visible Embryo Project NIH founded to comunicate life (http://embryo.asu.edu/about/network.php) [21-23].

Figure 3 The primary interventricular foramen closes at stage XIX-XX. Grant 1962 [12] Wenink 1977 [13] Note

Figure 3 The primary interventricular foramen closes at stage XIX-XX. Grant 1962 [12] Wenink 1977 [13] Note,

1. the widening of the atrioventricular canal and the development of the trabecular zones that gives origin to the ventricles, 2- the knee where the bulbus and the truncus meet (bulbo truncal orifice),

2. the counterclockwise torsion of the ascending Limb at the bulbo truncal orifice up to 150° and the displacement of the Bulbus to the left with clockwise torsion of 45° on the long axis at bulbo metaampullar orifice (Ostium Bulbi).

3. The meeting points of the TSM spiral rotation with the truncal cushions and the bulboventricular flange [32] will pose the pulmonary artery above the RV. The term metampulla is applied by german authors to the ascending limb at the level of the developing right ventricle; the term proampulla applies to the proximal trabeculated area of the primary heart tube.

A. displacement of the bulbus to the left and clockwise rotation of 45°on the long axis at the level of the metaampullar orifice so called Ostium Bulbi* (anticlockwise rotation seen from the heart base) from XV through XVI Streeter stages;

B. counterclockwise torsion of 150°on the orizontal plane at the level of the Bulbotruncal Orifice in the direction of blood flow. The bulbus septation does not start until stage XVII.

As stated by Chuaqui and Bersch 1973, 1979 [35-36] the results abtained by De Vries and Saunders 1962 [52] and Asami 1969 [32] on development of the ventricles may be considered as a verification of the Vectorial Bulbus Rotation Hypothesis.

In our vision any spatial relationships between Truncus, Conus (Infundibulum) and Ventricles have to be linked to the embryological TSM’s rotation (anterior and posterior crest of the primary interventricular foramen) during the ventricular septation process (Figure 4).

Figure 4 5b: reconstruction: oblique coronal dissection showing the proximal parts of the cushion A (left anterior) and B (right posterior) and the continuity of the part  A with the endocardial crest (cr) of the interventricular muscular septum (S) (TSM primordia). The part B (right posterior cushion) in continuity with atrioventricular  cuschions cranio ventral and right lateral runs towards the proximal anterior truncal ridge spiraling distally. The aorta (Ao) overrides the interventricular muscular  septum (S). The endocardial crest cr spirals right left and develops towards the anterior atrioventricular cushion. 6: oblique coronal section x 70 corresponding to the  reconstruction.

Figure 4 5b: reconstruction: oblique coronal dissection showing the proximal parts of the cushion A (left anterior) and B (right posterior) and the continuity of the part A with the endocardial crest (cr) of the interventricular muscular septum (S) (TSM primordia). The part B (right posterior cushion) in continuity with atrioventricular cuschions cranio ventral and right lateral runs towards the proximal anterior truncal ridge spiraling distally. The aorta (Ao) overrides the interventricular muscular septum (S). The endocardial crest cr spirals right left and develops towards the anterior atrioventricular cushion. 6: oblique coronal section x 70 corresponding to the reconstruction.

Figure 5 The roof of the right ventricle has been removed. The greatest part of the CSV is the inner curvature of the parietal wall of the RV: the VIF. In the normal heart  a very small part of the CSV separates the aortic and pulmonary outflow tracts as free standing subpulmonary Infundibulum or Conus (Outlet Septum): there is no a “real  Outlet Septum”. Removal of CSV insertion into the interventricular septum creates a hole beneath the anterior coronary cusp. The TSM is the limit between the Outlet and  the anatomical RV: the junction between the conus and the trabeculated portion of the RV corresponds to the inferior edge of the CSV and the TSM

Figure 5 The roof of the right ventricle has been removed. The greatest part of the CSV is the inner curvature of the parietal wall of the RV: the VIF. In the normal heart a very small part of the CSV separates the aortic and pulmonary outflow tracts as free standing subpulmonary Infundibulum or Conus (Outlet Septum): there is no a “real Outlet Septum”. Removal of CSV insertion into the interventricular septum creates a hole beneath the anterior coronary cusp. The TSM is the limit between the Outlet and the anatomical RV: the junction between the conus and the trabeculated portion of the RV corresponds to the inferior edge of the CSV and the TSM.

Scheme 1 On the long septal axis base apex, from normal 1A, to TF 1B, DORV with subaortic VSD 1C, Taussig-Bing 1D, TGA 1E. There is simultaneous counter clockwise  rotation of the OS with increasing ? angle (ventricular septum-deviated crista) from 30°(normal) to about 180°(TGA) and dextroanterior rotation of the aorta around the  pulmonary artery. The VSD is cradled between the TSM limbs. From 1B to 1C the PL is committed to the VIF and the VSD is subaortic, from 1D to 1E the PL is committed  to the OS and the VSD is subpulmonary outlining the TSM rotation. In Truncus 1F and Doubly Committed Juxtaarterial VSD there is malrotation of the TSM and absence  of the OS. TSM brown, OS green, Aorta red, Pulmonary yellow

Scheme 1 On the long septal axis base apex, from normal 1A, to TF 1B, DORV with subaortic VSD 1C, Taussig-Bing 1D, TGA 1E. There is simultaneous counter clockwise rotation of the OS with increasing β angle (ventricular septum-deviated crista) from 30°(normal) to about 180°(TGA) and dextroanterior rotation of the aorta around the pulmonary artery. The VSD is cradled between the TSM limbs. From 1B to 1C the PL is committed to the VIF and the VSD is subaortic, from 1D to 1E the PL is committed to the OS and the VSD is subpulmonary outlining the TSM rotation. In Truncus 1F and Doubly Committed Juxtaarterial VSD there is malrotation of the TSM and absence of the OS. TSM brown, OS green, Aorta red, Pulmonary yellow

Scheme 2 Simultaneous dextro-anterior counterclockwise rotation of the aorta around the Pulmonary with malrotation of the TSM’s limbs and the resulting  phenotypes from normal to TF-DORV with subaortic VSD, Taussig-Bing, Transposition. From normal to TF and DORV with subaortic VSD the PL is committed to the Inner  Curvature. In Taussig-Bing and Transposition the AL is committed to the Inner Curvature. From the first pathological phenotype to the last anomaly there is about 180°  degree rotation. Aorta red, Pulmonary Artery blue, PL green, AL yellow

Scheme 2 Simultaneous dextro-anterior counterclockwise rotation of the aorta around the Pulmonary with malrotation of the TSM’s limbs and the resulting phenotypes from normal to TF-DORV with subaortic VSD, Taussig-Bing, Transposition. From normal to TF and DORV with subaortic VSD the PL is committed to the Inner Curvature. In Taussig-Bing and Transposition the AL is committed to the Inner Curvature. From the first pathological phenotype to the last anomaly there is about 180° degree rotation. Aorta red, Pulmonary Artery blue, PL green, AL yellow.

Figure 6 The conal rotation results in dextroposition of the aorta and conal malseptation with anterior deviation of the outlet septum which inserts anterior to the TSM  ( highlighted red). The OS is deviated anteriorly and is attached to the TSM’s AL as a free standing structure producing pulmonary stenosis. The PL is committed to the VIF which stops short of the PL with tricuspid-mitral continuity. Adapted.

Figure 6 The conal rotation results in dextroposition of the aorta and conal malseptation with anterior deviation of the outlet septum which inserts anterior to the TSM ( highlighted red).

The OS is deviated anteriorly and is attached to the TSM’s AL as a free standing structure producing pulmonary stenosis. The PL is committed to the VIF which stops short of the PL with tricuspid-mitral continuity. Adapted.

Figure 7 The PL is committed to the VIF. The AL blends with the OS. The VIF is well represented creating a complete muscular antero-posterior subaortic infundibulum.  The TSM is highlighted red. Adapted

Figure 7 The PL is committed to the VIF. The AL blends with the OS. The VIF is well represented creating a complete muscular antero-posterior subaortic infundibulum. The TSM is highlighted red. Adapted.

Figure 8 The OS fuses with the PL rather than the AL creating a subaortic infundibulum. The AL is displaced anteriorly in a cephalic position. The great vessels are side  by side.

Figure 8 The OS fuses with the PL rather than the AL creating a subaortic infundibulum. The AL is displaced anteriorly in a cephalic position. The great vessels are side by side.

Figure 9 The aorta is to the right of pulmonary artery side by side. There is a large sub-pulmonary VSD, coarctation of the aorta and “banding” of the pulmonary artery.  The TSM rotation above 90° is close to the rotation observed in Transposition of Great Arteries. Adapted.

Figure 9 The aorta is to the right of pulmonary artery side by side. There is a large sub-pulmonary VSD, coarctation of the aorta and “banding” of the pulmonary artery. The TSM rotation above 90° is close to the rotation observed in Transposition of Great Arteries. Adapted.

Figure 10 The PL blends with the VIF forming a muscular posteroinferior rim of the doubly committed subarterial VSD separated from the membranous septum by the  TSM. There is absence of the OS. The TSM limbs rotation form the anterior cephalic part of the ventricular septum. Adapted.

Figure 10 The PL blends with the VIF forming a muscular posteroinferior rim of the doubly committed subarterial VSD separated from the membranous septum by the TSM. There is absence of the OS. The TSM limbs rotation form the anterior cephalic part of the ventricular septum. Adapted.

The anatomical spectrum of the embryological cardiac rotation extend from TF [99,100], to Double Outlet Ventricles [100-103], classic TGA [90,107-110,111-115], TGA with left aorta [121], Truncus Arteriosus [105,106], Corrected TGA [116-118,91], anatomically corrected TGA [92-93] and DOLV [94,122]. In concordant and discordant atrioventricular connections, univentricular [119,95,96] and biventricular hearts.

According to Chuaqui B, Bersch W. 1973,1979 [35,36], the Vectorial Bulbus Rotation hypothesis explain the position of great arteries while other hypothesis are inadequately supported by known facts (straight bulbotruncal septum De La Cruz 1951 [53] [42], abnormal heart skeleton Grant 1962 [108], conal inversion Van Praagh 1966 [90].

From Embryology to Formed Phenothypes. The Looping Process

Excellent morphogenetic studies describe the development of the cardiac chambers and the embryogenesis of the outflow tract. Many of these works are coupled with molecular aspects 0,84,85,86,87,88,89,97,1,2,41,52,3,33,19,20,14,3,33,19,20,14,24- 31,32,35,36,37-39,42-51,53-56,58-62,63,64,66,67,68,69- 73,74,75,76,77,78-80,81,82,123-150].

Despite this, the cardiac embryogenetic process is still controversial. As stated by Kramer in 1942 [65]“ the region of the heart in which the partitioning process is most difficult to interpret is where the atrioventricular cushions, the bulbar ridges and the crest of the interventricular septum meet ”.

In this study we link the malformed cardiac phenotypes to the rotation of the primitive cardiac tube underlining the importance of the primary interventricular foramen crest, future TSM, during the first month of life. This concept open to new diagnostic and therapeutic perspectives.

The primary heart tube remains a straight symmetrical structure during stage IX (Embryo:1,5-2,5 mm, around 20 days) when right and left interventricular sulcus appear. At stage X-XI the primary tube bends (loops) medially and dorsally: the segments (atrial, ventricular, outflow) are defined by the right atrioventricular sulcus and the left interventricular sulcus. The disappearance of the right sulcus produces the initial lateral asymmetry of the primary tube [57,33,75].

The symmetry breaking process is followed by the Looping and transformation of the straight embryonic heart tube in Helical Wound Loop. Rotation, septation and spiralling of the outflow tract ridges are independent closely related consequences of the looping process [68-74,150,151-156].

By stage XIV (Embryo 5-7 mm, around 32 days) the left interventricular forms a spiral whose ventral limb passes caudally to the crest of the anterior interventricular groove (Septal Band TSM) and cranially towards the dorsal atrioventricular forming the Crista Supraventricularis.

At stages XIV-XV Grant in 1962 [12]and Wenink in 1977 [13,97] described a non trabeculated ridge on the interventricular septal surface emerging over the interventricular foramen and evolving into the Tandler’s Trabecula Septomarginalis which separates the right bulbar musculature from the ventricular trabecular in origin. This has to be underlined in this work.

The 180° elicoidal rotation of the aortic and pulmonary truncoconal septum at the Streeter Horizons XIV-XVIII (the primary interventricular foramen closes at Horizon XIX) ends up to the normal twisted relationships.

If the spiral process is not complete the aorta remains overriding the Primary Interventricular Foramen and there will be DORV morphology in a fully developed heart.

Since the 6th pulmonary arch develops posteriorly to the 4th aortic arch, we assume that the pulmonary conus is dorsal (posterior) to the aortic conus. Following D-Looping [4,90,60- 62] the presumptive aortic conus is right sided and the presumptive pulmonary conus is left sided. The converse applies in L-Looping. To understand the process of bulboventricular rotation it is important to focus that the embryological extra cardiac segments (the atria and the aortic sac) are anatomically fixed and the elongation of the tube, mainly due to the growth of the bulbus cordis, is forced to bend. The anterior protrusion of the pulmonary conus twists the developing great arteries because they are fixed distally.

In our vision the TSM sequential malrotation (Septal Band) from stage XIV to XVI is the “anatomical teratological continuum” (Schwalbe 1906) [157] of the Doerr’s Vectorial Bulbus Rotation Hypothesis [53-56]. We definitely agree with Pexieder 1992 [78-80], who stated that in Transposition of Great Arteries the primary impact is situated in the Looping process and not in the conotruncal development.

Conus and Truncus

The basic concept emerging from the presented embryological and anatomical observations is that the Conus (Infundibulum) and the Truncus ( Great Arteries) are independent structures.

The conotruncus may be twisted in one direction and the ventricular loop in the opposite direction. Why this occurrence, as documented originally by Van Praagh 1964,1965,1966,1975,1977,1998 [91-93,119,96] is nowdays still inexplicable.

The Conus is not an inseparable part of the morphological right ventricle because it may be located predominantly above the left ventricle and may bear any relationships with the ventricle.

In the normal heart the proximal end of the spiral conotruncal septum is coincident with that of the muscular portion of the interventricular septum stemming from the TSM (Figure 1-2).

Any spatial relationships between Truncus, Conus (Infundibulum) and Ventricles is related to the embryological TSM (anterior and posterior crest of the interventricular foramen) rotation during the septation process and the transition from DORV to Transpositions Phenothypes.

If the spiral process is not complete the aorta remains overriding. If the interventricular Foramen remains open with overriding aorta there is a DORV morphology in a fully developed heart.

The stage XV is a transitory normal stage present in all embryos before the closure of the ventral part of the Interventricular Foramen (the interventricular septum develops towards the bulbar septum and not vice versa). Conte et al 1967,1984 [19,20] (Figure 3).

DORV may result not only from an abnormal development of the embryonic Conotruncus but also from an abnormal connection between the muscular Ventricular Septum and the Conus septum.

Normally the torsion of the bulbotruncal orifice at the truncus level produces the spiral course of the already formed truncal septum and at the bulbus level a straight course of the ridges A and B.

If the endocardial bulbar cushions A does not spiral right-left towards the distal B and from the ventricle to the aortic arch, the distal A becomes anterior and the distal B posterior: the flow from the RV will go into the 4th aortic arch and the flow from the left ventricle into the 6th aortic arch forming the TGA phenotype.

According to De la Cruz, in situs solitus the development of a straight conotruncal septum is responsible for the transposition of great vessels [42-51]. The truncoconal ridges may develop with an anticlockwise rotation of 180° (normal heart) or in a straight fashion (0° rotation, transposition of great arteries with anterior Aorta or 90°rotation with side by side great arteries) or may not develop at all (truncus arteriosus).

The straight truncal septum in transposition as proposed by De La Cruz according to Chuaqui 1973,1979 [35,36] should be regarded as the result and not the cause of the pathogenetic bulbotruncal process.

We argue that the abnormal septation at ventricular level (Malrotation of the posterior endocardial crest of the interventricular foramen) coupled with an arrested bulbar rotation will end to 180° TSM’s malrotation observed in formed Transposition of Great Arteries phenotypes.

Embryological Evidence of The Bulboventricular Rotational Process. Laterality And Ptx2 Gene

The heart rotates between Carnegie stages XIV-XIX [34,66,67]. During Looping and septation, in an ideal transverse plane, has been documented a rotation of the axis of the semilunar valves of 121° frontal counterclockwise, 196° sagittal counterclockwise and 240° transverse clockwise with a simultaneous lengthening of the great arteries. This will line the muscular Outflow Tract with the ventricular septum.

The ventricle moves ventrally and to the right while the atrium moves dorsally and to the left. That rotation will locate the aorta posteriorly and wedged between the atrioventricular valves and the Outlet and Ventricular Septum (TSM plane in our observations) become aligned.

The valve position in normal hearts were reported similar to the stage XIX whereas in Tetralogy of Fallot was similar to XVIII stage and in transposition of great arteries to XV stage. The majority of hearts with DORV resembled stage XVI. These data confirm an arrest of the normal rotation at the junction of the Outflow Tract and great arteries leaving the aortic valve over the right ventricle as in Carnegie stage XVI.

During the VI to IX Carnegie stages the arterial orifice is not in one plane: it has a curved and twisted configuration and reaches up the origin of the 4th and 6th branch of arch arteries. As a consequence the pulmonary trunk is short and the ascending aorta is long, the pulmonary outlet is long and the aortic outlet is short. The truncal septation incorporate the anterolateral Outlet into the right ventricle and the posteromedial into the left ventricle.

We now know that the Outflow tract is recruited from the secondary heart field [158-161,162], however the actual rightleft primordia translocation is unknown. We do not know yet the molecular changes involved. Markwald RR, Trusk T, Moreno Rodriguez R. in 1998 proposed the myocardialisation process [74]; Pexieder T. in 1975 and Poelmann RE, Gittenberger-deGroot AC. in 2005 suggested the Apoptosis [78,146].

An asymmetric expression of the primitive mesenchyme on the pulmonary side of the outflow tract pushing in frontal position the outflow tract has been recently advocated by others [148] and that would eliminate the need of introducing a tissue teratogenic process [78,145] in conotruncal inversion hypothesis [90].

Molecular expression analyses have confirmed that the Outflow Tract myocardial wall rotates before and during the formation of great vessels [163]. In fact, in hearts with persisting Truncus Arteriosus , DORV and Transposition the rotation is arrested or fails to initiate and 70% of PITX2c gene mutants have TGA morphology. Because the PITX2c is involved in left- right signaling this suggest that the embryonic laterality affects rotation of the myocardial wall during the outflow tract maturation.

Bending is an intrinsic process while dextral torsion is caused by external forces [154] as compressive loads [155]. Internal and external forces can induce anatomical defects [164]. Mechanical forces and the directional flow mediated by beating cilia [164- 167] or chiral spreading of the cells translate into asymmetric cell migration [167] resulting in heterotaxis [168].

According to Ramsdell 2005, 2017 [156,157] errors in left-right axis determination are associated with complex CHD. More than 80 genes are associated with laterality in animal models [168] and he majority of genes implicated in the leftright pathway are expressed prior the organogenesis which demonstrate that they are relevant to the formation of Looping [156].

The TBx5 gene specifies the left-right ventricles and the ventricular septum position [172-164]; PITX2 gene function is associated with abnormal Looping which is linked to VSD, DORV and TGA in formed phenotypes. The PITX2 gene is a source of positional informations for the cells inducing left-right translation into anatomical asymmetry. The symmetry breaking process is followed by the Looping and the remodeling of the left-right PITX2 expression [157,169-171]which is essential in modulating the mutations. The modular activation of the gene with distinct roles at different developmental stages is important for understanding the sequential phenotypic expressions at the molecular level.

We believe that the modular activation of PITX2 with distinct roles at different developmental stages [156-157,162,172,169- 171]explains the phenotypes heterogeneity.

In our vision the Doerr “similar pathogenetic process” [53- 56] during the embryonic period is the remodeling at ventricular level and we speculate that the TSM sequential observations in malformed phenotypes under a pathological PTX2 expression recapitulates the embryogenetic process between Streeter’s stages XIV-XVI [1,2].

Figure 11 The Outlet Septum is absent and the doubly committed VSD is cradled between the rotated TSM limbs. Note the similarity with Truncus Arteriosus Fig.10.  Adapted. In a and b The VSD is perimembraneous. Extreme anterior deviation of the Outlet Septum (SI). Atretic pulmonary infundibulum. The TSM is rotated and  displaced in cephalic position. Adapted

Figure 11 The Outlet Septum is absent and the doubly committed VSD is cradled between the rotated TSM limbs. Note the similarity with Truncus Arteriosus Fig.10. Adapted. In a and b The VSD is perimembraneous. Extreme anterior deviation of the Outlet Septum (SI). Atretic pulmonary infundibulum. The TSM is rotated and displaced in cephalic position. Adapted

Figure 12 The aorta is posterior and to the right. There is anterior deviation of the OS obstructing the aortic inlet. The VSD is subpulmonary. The pulmonary artery is  situated above the VSD which is mainly committed to the right ventricle. Adapted.

Figure 12 The aorta is posterior and to the right. There is anterior deviation of the OS obstructing the aortic inlet. The VSD is subpulmonary. The pulmonary artery is situated above the VSD which is mainly committed to the right ventricle. Adapted.

Figure 13 The right atrium connects with the morphological right ventricle through the mitral Valve. The right ventricle is to the left (ML: Lancisi muscle). The  pulmonary artery is atretic. The Aorta arises from the left sided right ventricle with distorted TSM and Lancisi muscle (ML). There is a muscular infundibulum between  aorta and tricuspid valves. Adapted.

Figure 13 The right atrium connects with the morphological right ventricle through the mitral Valve. The right ventricle is to the left (ML: Lancisi muscle). The pulmonary artery is atretic. The Aorta arises from the left sided right ventricle with distorted TSM and Lancisi muscle (ML). There is a muscular infundibulum between aorta and tricuspid valves. Adapted.

Figure 14 The right atrium connects with the morphological right ventricle through the mitral Valve. The right ventricle is to the left (ML: Lancisi muscle). The  pulmonary artery is atretic. The Aorta arises from the left sided right ventricle with distorted TSM and Lancisi muscle (ML). There is a muscular infundibulum between  aorta and tricuspid valves. Adapted

Figure 14 The right atrium connects with the morphological right ventricle through the mitral Valve. The right ventricle is to the left (ML: Lancisi muscle). The pulmonary artery is atretic. The Aorta arises from the left sided right ventricle with distorted TSM and Lancisi muscle (ML). There is a muscular infundibulum between aorta and tricuspid valves. Adapted.

Figure 15 Absent right atrioventricular connection with hypoplastic left venytricle. The left atrium connects to the subaortic morphological right ventricle. Note the  distorted TSM with tricuspid chordae insertion. Adapted.

Figure 15 Absent right atrioventricular connection with hypoplastic left venytricle. The left atrium connects to the subaortic morphological right ventricle. Note the distorted TSM with tricuspid chordae insertion. Adapted.

Figure 16 The right atrium connects to the right ventricle with an evident TSM. Note the tricuspid chordae insertion to the interventricular septum and the subaortic  infundibulum separating the aorta from the tricuspid valve.

Figure 16 The right atrium connects to the right ventricle with an evident TSM. Note the tricuspid chordae insertion to the interventricular septum and the subaortic infundibulum separating the aorta from the tricuspid valve.

From Classic Diagnostic and Corrective Strategies to New Potential Approaches

Congenital Heart Diseases (CHD) represent about 1-2 % of all live births with a very high human and socioeconomic fallout [173,174]. Moreover, the patients with CHD that are seen clinically represent a small percent of all cases: the others died in the first month of life. When this is taken in consideration, CHD proves to be a vastly greater cause of human mortality [12].

The etiology is multifactorial and is in relation to anomalous expression of genes and epigenetic factors. Genetic abnormalities appear to be the primary cause of CHD but identifying precise defect has proven challenging [175].

  1. We have to consider that: [176-196]Numerous signaling pathways regulating anterior-posterior, dorso-ventral and left-right axes are prime targets for genetic and toxic insults in the first two weeks of development.
  2. single gene defects can cause both syndromic and isolated CHD,
  3. several pathways act during development independently or in combination,
  4. a specific signaling pathway vary as development proceed,
  5. the same gene or genetic locus or identical mutation may cause different types of CHD even in the same family (phenotypic heterogeneity),
  6. the same malformation may result from mutation in different genes (locus heterogeneity).

 For these reasons changes in gene function have to be integrated and correlated with morphological changes particularly when viewed over time in living embryos using dynamic imaging approaches [197].

Diagnosis and Treatment

Most congenital malformations originate during primary morphogenesis and can be basically clustered by a pathogenetic process (Clark 1996) [136].

Ultrasound in prenatal screening improves the outcome in CHD providing planned delivery, genetic counseling and perinatal management, however, often represent a diagnostic challenge [180,198-202].

Recent advances on molecular technologies applied to liquid biopsies (maternal blood) and circulating cell free /DNA-RNA molecules [203-205] can effectively provide a not invasive access to genetic informations. Non-invasive, liquid biopsy-based diagnostics is currently incorporated into standard healthcare practice and precision medicine.

Two complementary technical advanced technologies [206- 212], DNA microarrays and massively parallel DNA sequencing, can provide unprecedented insights into the genome opening to new possibilities for prenatal and postnatal treatments.

Diagnostic Genes panel based approaches (Next-Sequencing platforms) in clinical practice by Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) can provide novel gene discovery [206-212].

The WES (High-troughput sequencing of target-enriched genomic DNA) allows for the detection of small variants missed by WGS [213] and has been utilized to identify causative mutation in familial CHD using candidate gene list [214]. WES has proven an effective alternative in genetic screening panel based expanding the candidate gene list.

Future Therapeutic Potentialities of Congenital Heart Diseases

Despite terrific advances in diagnosis and treatment, conventional heart surgery still carryes significant mortality and morbidity in severe forms [215-217]. For exemple, the estimated mortality in Truncus Arteriosus plus Interrupted Aortic Arch has been reported 29.8%.

Can we do better?

The genetic diagnosis of CHD has to provide targeted curative strategies and, in our vision, the knowledge of the molecular mechanisms determining the heart rotation during embryogenesis will let to interfere with the ongoing process wat we call Molecular Cardiac Surgery [218-222].

Nowadays, somatic cells can be programmed into induced pluripotent stem-cells and differentiated cells can be dedifferentiated or transdifferentiated into other types of differentiated cells [223-224].

Prenatal cardiac interventions [180,225-226,201]entail risks to the mather and baby and few medical centers have the resources and the skill to perform such procedures. However, fetal cardiac surgery may be considered in fetuses with evolving hypoplastic left heart syndrome or with pulmonary atresia and intact ventricular septum.

Identifying in the first month after conception the TSM malrotation sequence, may be possible to reactivate the neonatal myocardial plasticity [231,232] and /or interfere with the ongoing process by stem-cells [229-233,223,234]or CRISPRCas9 based techniques [235-241].

Besides, forced expression of the cardiogenic transcription factors holds a potential therapeutic use inducing the cardiac progenitors that control cardiac development early during gastrulation with induction of cardiomyogenesis [79].

Knowing the sequential genomic identity we believe that it will be possible to reactivate the embryogenetic myocardial process since the heart retains significant growth plasticity during fetal life [227-229] linking embryology to clinical practice [221,222,242,243,173,174,215]

The recent CRISPR/Cas9 technique may dramatically interfere with the ongoing cardiogenesis. Although embryo’s gene editing raises ethical and technical problems [235-241] facing extremely challenging queries for the human being, genome editing (molecular scissors) CRISPR/Cas9 can without doubt cut out and even replace strands of DNA molecules. Moreover CRISPR-Cas9 based techniques have the potential for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis.

There is a lack of models to investigate the pathogenesis of malformed hearts since it is very difficult to reproduce in a significant percentage a specific malformation and it is impossible and arguable to replicate the genetic architecture in a model. In this context, the TSM morphogenetic process has to be considered a “biological model” for investigating and treating the developing heart linking embryology, anatomy and clinical practice [218-222].

CONCLUSION
  1. The Trabecula Septomatrginalis during the early bulboventricular morphogenetic process miss the appointment with the Outlet Septum. As the two structures divorce, the Trabecula and the Outlet Septum become evident with specific features for each pathological phenotype. The Trabecula progressive malrotation is traceable in all different formed segmental configurations and there is a tight morphological relation with the development of the right ventricle.
  2. The conus is not an inseparable part of the morphological right ventricle and may bear any relationships with the ventricle. The conotruncus may be twisted in one direction and the ventricular loop in the opposite direction as well as the bulbus and the ventricle.
  3. The abnormal ventriculoarterial connections originate by a pathological torsion of the primary cardiac tube at the level of the Conus (Infundibulum) and by an abnormal remodelling of the primitive ventricle at the atrioventricular region in relation to an abnormal spiralling of the primary interventricular foramen endocardial crest. Disturbances of the rotation process produce the malformed outlet phenotypes.
  4. The key point is the torsion (Looping) of the cardiac tube. Many genes are involved eventually regulated by epigenetic factors.
  5. The knowledge and the control of the factors determining the rotation of the TSM will allow to interfere onto the cardiogenesis modifying the ventricular development and finally reducing the incidence and the severity of the resulting pathological phenotypes.

 

ACKNOWLEDGEMENT

In memory of G. CONTE and M. GRIECO Professors of Human Anatomy and Embryology at Pisa University Medical School during the Author’s medical formation.

We wish to express our gratitude to:

  1. All Authors of the basic embryological-anatomical studies and the reproduced figures especially from CODIFICAZIONE DIAGNOSTICA E ATLANTE DELLE CARDIOPATIE CONGENITE, Progetto Patologia Neonatale, Consiglio Nazionale delle Ricerche, Italia. Casa Editrice LINT Trieste 1984;
  2. Mrs. Marianna AS Capuani for the unvaluable assistance reviewing the scientific literature and the manuscript;
  3. Mr Nazzareno Bedini from the Library of Pisa University Medical School for collecting the mentioned publications;
  4. Mirko&Marika Idealfoto Carrara www.idealfotoevideo.it for the images reproduction service.

 The reproduced figures are adapted as Author’s proof for the Trabecula Septomarginalis rotational concept.

CONFLICTS OF INTEREST

The Author has no financial or no financial competing interests. This study received no specific grant from any funding agency, commercial or not-for-profit sectors.

These data were presented in part at the following meetings:

  -  23d World Society of the Cardio-Thoracic Surgeons, Split Croazia 2013;

  -  24th meeting on Advances in Perinatal Cardiology, St. Petersburg Florida 2014;

  -  27th Congress of European Society of Pathology, Belgrade Serbia 2015;

  -  27th Meeting of the Arab Division of International Academy of Pathology, Dubai 2015;

  -  28th Congress of the European Society of Pathology and XXXI Congress of the International Academy of Pathology, Cologne Germany 2016;

  -  Congress of the Italian Society of Anatomia Patologica SIAPEC and International Academy of Pathology, Genova Italia 2016;

  -  7th World Congress of Pediatric Cardiology & Cardiac Surgery, Barcelona Spain 2017;

  -  24th Annual Cardiologists Conference, Conferenceseries. com, Barcelona Spain 2018;

  -  2019 Joint Conference: Advances in Pediatric Cardiovascular Disease Management, Columbia University, New York City 2019.

REFERENCES

1. Streeter GL. Developmental horizons in human embryos. Description of age group XI, 13-20 somites and age group XII, 21-29 somites. Carnegie Inst Publ. 541. 1942; Cont Embyol. 30: 211.

2. Streeter GL. Developmental horizons in human embryos, description of age group XV, XVI, XVII, and XVIII. Carnegie Inst Publ 575. Cont Embryol. 1948; 32:133.

3. O’Rahilly R. The timing and sequence of events in human cardiogenesis. Acta Anat. 1971; 79:70-75.

4. Van Praagh R. The segmental approach to diagnosis in congenital heart disease. Birth Defects: Original Article Series. 1972; 8: 4-23.

5. Shinebourne EA, Macartney FJ, Anderson RH. Sequential chamber localization-logical approach to diagnosis in congenital heart disease. Br Heart J. 1976; 38: 327-340.

6. Anderson RH, Becker AE, Van Mierop LHS. What should we call the “crista”? Br Heart J. 1977; 39: 856-859.

7. Anderson RH, Tynan M. Complete transposition. The significance of describing separately connexions arterial relationships and infundibular morphology. Int J Cardiol. 1984; 5: 19-20.

8. International Paediatric and Congenital Cardiac Code (IPCCC) and European Paediatric Cardiac Code (EPCC).

9. Tandler J. Anatomie des Herzens. In Karl von Bardeleben’s Handbuch der Anatomie des Menschen. 1913; G. Fisher-Verlag, Jena Germany.

10. Brandt W. Structure and Function of the Infundibulo-Ventricular Crest (Crista Supraventricularis) of the Human Heart. Acta Anat. 1953; 18: 202-207.

11. Grant RP, Downey FM, MacMahon H. The Architecture of the Right Ventricular Outflow Tract in the Normal Human Heart and in the Presence of Ventricular Septal Defects. Circulation. 1961; 24: 223-235.

12. Grant RP. The Embryology of the Ventricular Flow in Man. Circulation. 1962; XXV: 756-759.

13. Wenink ACG. The medial papillary complex. Br Heart J. 1977; 39: 1012-1018.

14. Capuani A, Uemura H, Yen Ho S, Anderson RH. Anatomic Spectrum of Abnormal Ventriculoarterial Connections: Surgical Implications. Ann Thorac Surg. 1995; 59: 352-360.

15. Capuani A, Soulé N, Meot M, Aupy B, Vaillant MC, Poinsot J, et al. Landmarks for diagnosis and surgery in abnormal ventriculo-arterial corrections with usual arrangement. Proceedings of the 23d congress of World Society of the Cardio-Thoracic Surgeons. September 2013: Split, Croazia. J Cardiothorac Surg. 8 (Suppl.1): 0251.

16. Capuani A. The trabecula septomarginalis (Leonardo’s cord) in abnormal ventriculo-arterial connections: anatomic and morphogenetic implications. J Cardiothorac Surg. 2014; 9: 71-81.

17. Capuani A. The trabecula septomarginalis (Leonardo’scord) in abnormal ventriculo-arterial connections: anatomic and morphogenetic implications. Annual James Henry Keynote Speaker. Advances in Perinatal Cardiology. St. Petersburg Florida. 2014; 23-26.

18. Leonardo da Vinci. Anatomical Drawings RL.19118-19v. 1485- 1515. The Royal Library Collection Windsor Castle UK - Biblioteca Ambrosiana Milano.

19. Conte G, Arrigoni P. Precisazioni embriologiche su due alterazioni congenite di prima formazione del cuore: Aorta a cavaliere e trasposizione completa dei grossi vasi. Atti Soc It Cardiol. 1967; 2: 13- 14.

20. Conte G, Grieco M. Closure of the Interventricular Foramen and Morphogenesis of the Membranous Septum and Ventricular Septal Defects in the Human Heart. Anat Anz. 1984; 155: 39-55.

21. Doyle MD, Ang CS, Martin DC, Noe A. The Visible Embryo Project: Embedded Program objects for knowledge access, creation and management through the World Wide Web. Compiut Med Imaging Graph. 1996; 20: 423-431.

22. Doyle MD, Pescitelli MJjr, Williams BS, Michaels GS. Multidimensional Microdissections and Morphological Reconstructions of Genomic or Proteomic Expression Activity. United States Patent No. US10, 011, 864B2 (Date of Patent Jul.3,2018).

23. Gasser RF, Cork RJ. The Virtual Human Embryo (VHE) Project. Digitally Reproduced Embryonic Morphology Hosted by the Endowment for Human Development (EHD.org)

24. Anderson RH, Wilkinson JL, Arnold R, Lubkiewicz KL. Morphogenesis of bulboventricular malformations. I: Considerations of embryogenesis in the normal heart. Br Heart J. 1974; 36: 242-255.

25. Anderson RH, Wilkinson JL, Arnold R, Becker AE, Lubkiewicz KL. Morphogenesis of bulboventricular malformations II. Observations on malformed hearts. Br Heart J. 1974; 36: 948-970.

26. Anderson RH, Galbraith R, Gibson R, Miller G. Double outlet left ventricle. Br Heart J. 1974; 36: 554-558.

27. Anderson RH, Shinebourne EA, Gerlis LM. Criss-Cross Atrioventricular Relationships Producing Paradoxical Atrioventricular Concordance or Discordance. Their Significance to Nomenclature of Congenital heart Disease. Circulation. 1974; 50: 176-180.

28. Anderson RH, Becker AE, Losekoot TG, Gerlis LM. Anatomically corrected malposition of great arteries. Br Heart J. 1975; 37: 993- 1013.

29. Anderson RH, Becker AE, Wilkinson JL, Gerlis LM. Morphogenesis of univentricular hearts. Br Heart J. 1976; 38: 558-572.

30. Anderson RH, Webb S, Brown NA, Lamers W, Moorman A. Development of the heart: (2) Septation of the atriums and ventricles. Heart. 2003; 89: 949-958.

31. Anderson RH, Webb S, Brown NA, Lamers W, Moorman A. Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart. 2003; 89: 1110- 1118.

32. Asami I. Beitrag zur Entwicklung des Kammerseptums im menschlichen herzen mit besonderer Berücksichtigung der sogenannten Bulbusdrehung. Zeitschrift fur Anatomie und Entwicklungsgeschichte.1969; 128: 1-17.

33. Bersch W. On the Importance of the Bulboauricular Flange for the Formal Genesis of Congenital Heart Defects with Special regard to the Ventricular Septum Defects. Virchows Arch Abt A Path Anat. 1971; 354: 252-267.

34. Bostrom MPG, Hutchins GM. Arrested rotation of the outflow tract may explain double-outlet right ventricle. Circulation. 1988; 77: 1258- 1265.

35. Chuaqui B, Bersch W. The formal genesis of the transposition of the great arteries. Virchows Arch. 1973; 358: 11-34.

36. Chuaqui B. Doerr’s theory of morphogenesis of arterial transposition in light of recent research. Br Heart J. 1979; 41: 481-485.

37. Muñoz-Castellanos L, Vásquez MA. La “Crista Supraventricularis” En Las Cardiopatias Congenitas Infundibulares. Arch Inst Cardiol Méx. 1980; 50: 639-647.

38. Muñoz-Castellanos L, Kuri Nivon M, Vásquez Antona C.A, Sanchez Salinas HC. Investigation Basica: Ausencia de Conexion Atrioventricular Derecha e Izquierda. Arch Inst Cardiol Méx. 2000; 70: 536-551.

39. Muñoz-Castellanos L, Kuri M. Doble salida de ventriculo derecho. Enfoque embryològico. Arch Cardiol Méx. 2012; 82: 273-281.

40. Davis CL. Development of the human heart from its first appearance to the stage found in embryos of twenty paired somites. Carnegie Inst. Wash. Cont. Embryol. 1927; 107: 245-284 plates 1-8. 

41. De la Cruz MV, Lynn Miller B. Double-Inlet Left Ventricle. Two Pathological Specimens with Comments on the Embryology and on its relation to Single Ventricle. Circulation. 1968; 37: 249-260.

42. De La Cruz MV, Da Rocha JP. An Ontogenic Theory for The Explanation Of Congenital Malformations Involving The Truncus And Conus. Am. Heart J. 1951; 5; 782-805.

43. De la Cruz MV, Anselmi G, Cisneros F, Reinhold M, Portillo B, EspinoVela J. An Embryologic Explanation for the Corrected Transposition of the Great Vessels: Additional Description of the Main Anatomic Features of this Malformation and Its Variations. Am Heart J. 1959; 57: 104-117.

44. De la Cruz MV, Espino-Vela J, Attie S, Mu?z L. An embryologic theory for ventricular inversions and their classifications. Am Heart J. 1967; 73: 777-793.

45. De la Cruz MV, Sánchez Gómez C, Arteaga MM, Argüello C. Experimental study of the development of the truncus and the conus in the chick embryo. J Anat. 1977; 123: 661-686.

46. De la Cruz MV, Arteaga M, Espino-Vela J, Quero-Jiménez M, Anderson RH, Diaz GF. Complete transposition of the great arteries: types and morphogenesis of ventriculoarterial discordance. Am Heart J. 1981; 102: 271-281.

47. De la Cruz MV, Sánchez Gómez C, Cayre R. The developmental components of the ventricles: their significance in congenital cardiac malformations. Cardiol Young. 1991; 1: 123-128.

48. De la Cruz MV, Cayré R, Arista-Salado M, Sadowinsky S, Serrano A. The infundibular interrelationships and the ventriculoarterial connection in double outlet right ventricle. Clinical and surgical implications. Int J Cardiol. 1992; 35: 153-164.

49. De la Cruz MV. Embryological Development of the Outlet of Each Ventricle. In De la Cruz MV, Markwald RR. Eds. Living Morphogenesis of the Heart. 1998; Springer Science-Business Media New York. Chapter 7: 158-168.

50. De la Cruz MV, Moreno-Rodriguez R. Embryological Development of the Apical Trabeculated Region of Both Ventricles. The Contribution of the Primitive Interventricular Septum in the Ventricular Septation. In De la Cruz MV, Markwald RR. Eds. 1998. Living Morphogenesis of the Heart. Springer Science-Business Media New York. Chapter 5: 121-130.

51. De la Cruz MV, Markwald RR, Krug EL, Rumenoff L, Gómez CS, Sadowinsky S, et al. Living morphogenesis of the ventricles and congenital pathology of their component parts. Cardiol Young. 2001; 11: 588-600.

52. De Vries PA, Saunders JB de CM. Development of the ventricles and spiral outflow tract in the human heart from age group IX to age group XV. Contr. Embriol. 1962; 256: 87-114.

53. Doerr W. Zur Transposition der Herzschlagadern. Ein kritischer Beitrag zur Lehre der Transpositionen. Virchows Arch B. 1938; 303: 168-205.

54. Doerr W. Ueber Missbildungen des menschlichen Herzens mit besonderer Berücksichtigung von Bulbus und Truncus. Virchows Archiv B. 1943; 310: 304-368.

55. Doerr W. Pathologische Anatomie Typischer Grundformen Angeborener Herzfehler. Monatsschrift für Kinderheilkunde. 1951; 100: 107-117.

56. Doerr W. ?eber ein formales Prinzip der Koppelung von Entwicklungsstörungen der venösen und arteriellen Kammerostien. Zeitschrift für Kreislaufforschung. 1952; 41: 269-284.

57. Goor DA, Lillehei CW. The Embriology of the Heart. Chapter 2. In: Congenital Malformations of the Heart. Goor DA, Walton Lillehei C. Editors. 1975; Grune&Stratton Inc New York, San Francisco, London.

58. Goor DA, Edwards JE, Lillehei CW. The Development of the Interventricular Septum of the Human Heart; Correlative Morphogenetic Study. Chest. 1970; 58: 453-467.

59. Goor DA, Lillehei W, Edwards JE. Ventricular Septal Defects and Pulmonic Stenosis with and without Dextroposition. Anatomic Features and Embryologic Implications. Chest. 1971; 60: 117-128.

60. Goor DA, Edwards JE. The transition from double outlet right ventricle to complete transposition. A pathological study. Am J Cardiol. 1972; 29: 267.

61. Goor DA, Dische R, Lillehei CW. The conotruncus. I. Its normal inversion and conus absorption. Circulation. 1972; 46: 375-384.

62. Goor DA, Edwards JE. The Spectrum of Transposition of Great Arteries with specific reference to Developmental Anatomy of the Conus. Circulation. 1973; 48: 406-415.

63. Grant RP. Morphogenesis of transposition of the great vessels. Circulation. 1962; 26: 819-840.

64. Grant RP. The Morphogenesis of Corrected Transposition and Other Anomalies of Cardiac Polarity. Circulation.1964; 29: 71-83.

65. Kramer TC. The Partitioning of the Truncus and Conus and the Formation of the Membranous Portion of the Interventricular Septum in the Human Heart. Am J Anat. 1942; 71: 343-370.

66. Lomonico MP, Moore GW, Hutchins GM. Rotation of the junction of the outflow tract and great arteries in the embryonic human heart. Anat Rec. 1986; 216: 544-549.

67. Lomonico MP, Bostrom MPG, Moore GW, Hutchins GM. Arrested rotation of the outflow tract may explain tetralogy of Fallot and transposition of the great arteries. Pediatr Pathol. 1988; 8: 267-281.

68. Manasek FJ, Monroe RG. Early Cardiac Morphogenesis is Independent of Function. Dev Biol. 1972; 27: 584-588.

69. Männer J, Seidl W, Steding G. Correlation between the embryonic head flexures and cardiac development. Anat Embryol. 1993; 188: 269-285.

70. Männer J, Seidl W, Steding G. Embryological Observations on the Morphogenesis of Double-Outlet Right Ventricle with Subaortic Ventricular Septal Defect and Normal Arrangement of the Great Arteries. Thorac and Cardiovasc Surgeon. 1995; 43: 307-312.

71. Manner J. On Rotation, Torsion, Lateralization, and Handedness of the Embryonic Heart Loop: New Insights from a Simulation Model for the Heart Loop of Chick Embryos. Anat Rec Part A. 2004; 278A: 481-492.

72. Manner J. The anatomy of cardiac Looping: a step towards the understanding of the morphogenesis of several forms of congenital cardiac malformations. Clin Anat. 2009; 22: 21-35.

73. Manner J. On the form problem of embryonic heart loops, its geometrical solutions and a new biophysical concept of cardiac looping. Ann Anat. 2013; 195: 312-323.

74. Markwald RR, Trusk T, Moreno-Rodriguez R. Formation and Septation of the Tubular heart: Integrating the Dynamics of Morphology With Emerging Molecular Concepts. In: Living Morphogenesis of the Heart. De la Cruz MV, Markwald RR. Editors. Chapter 5: pp. 43-84. Springer Science-Business Media New York. 1998.

75. Meredith MA, Hutchins GM, Moore GW. Role of the Left Interventricular Sulcus in Formation of the Interventricular Septum and Crista Supraventricularis in Normal Human Cardiogenesis. Anat Rec. 1979; 194: 417-428.

76. McBride RE, Moore GW, Hutchins GM. Development of the Outflow Tract and Closure of the Interventricular Septum in the Normal Human heart. Am J Anat. 1981; 160: 309-331.

77. Orts-Llorca F, Puerta-Fonolla J, Sobrado J. The formation, septation and fate of the truncus arteriosus in man. J Anat. 1982; 134: 41-56.

78. Pexieder T. Cell death in morphogenesis and teratogenesis of the heart. Adv Anat Embryol Cell Biol. 1975; 51: 1-100.

79. Pexieder T. Development of the Outflow Tract of the Embryonic heart. Birth Defects-Original Article Series. 1978; 14: 29-68.

80. Pexieder T. Prenatal pathogenesis of the transposition of great arteries. In Transposition of great arteries 25 years after Rashkind Balloon Septostomy. 1992; Vogel M, Bühlmeyer K. Editors. SpringerVerlag Berlin.11-27.

81. Spitzer A. ?ber den Bauplan des normalen und miβbildeten Herzens. Virchows Arch. Path.Anat.Berlin Verlag von J. Springer. 1923; 243: 81- 272.

82. Spitzer A. ?ber Dextroversion, Transposition und Inversion des Herzens und die gegenseitige Larvierung der beiden letzteren Anomalien. Nebst Bemerkungen über das Wesen des Situs inversus. Virchows Arch. 1928; 226-303.

83. Thiene G, Frescura C. Codificazione Diagnostica e Atlante delle Cardiopatie Congenite. Progetto Medicina Preventiva e Riabilitativa : Patologia Perinatale. CNR Italia. 1984. Casa Editrice LINT Trieste.

84. Van Mierop LHS, Alley RD, Kausel HW, Stranahan A. The Anatomy and Embryology of Endocardial Cushions Defects. J Cardiovasc Surg. 1962; 43: 71-83.

85. Van Mierop LHS, Alley RD, Kausel HW, Stranahan A. Pathogenesis of Transpositions Complexes: I. Embryology of the ventricles and great arteries. Am J Cardiol. 1963; 12: 216-225.

86. Van Mierop LHS, Wiglesworth FW. Pathogenesis of Transposition Complexes: II. Anomalies due to faulty transfer of the posterior great artery. Am J Cardiol. 1963; 12: 226-232.

87. Van Mierop LHS, Wiglesworth FW. Pathogenesis of Transposition Complexes: III. True Transposition of the GreatArteries. Am J Cardiol. 1963; 12: 233-239.

88. Van Mierop LHS. Embryology of the Atrioventricular Canal Region and Pathogenesis of Endocardial Cushion Defects. In ATRIOVENTRICULAR CANAL DEFECTS Chapter 1, pp 1-12, Feldt R.H. Edit. by W.B. Saunders Company Philadelphia. 1976.

89. Van Mierop LHS, Kutsche LM. Development of the ventricular septum of the heart. Heart Vessels. 1985; 1:114-119.

90. Van Praagh R, Van Praagh S. Isolated Ventricular Inversion. A Consideration of the Morphogenesis, Definition and Diagnosis of Non Transposed and Transposed Great Arteries. Am J Cardiol. 1966; 17: 395-406.

91. Van Praagh R, Papagiannis J, Grünenfelder J, Bartram U. Martanovic P. Pathologic anatomy of corrected transposition of the great arteries: Medical and Surgical implications. Am Heart J. 1998; 135: 772-785.

92. Van Praagh R, Van Praagh S. Anatomically Corrected Transposition of the Great Arteries. Br Heart J. 1967; 29: 112-119.

93. Van Praagh R, Durnin RE, Jockin H, Wagner HR, Korns M, Garabedian H, et al. Anatomically Corrected Malposition of the Great Arteries (S, D, L). Circulation. 1975; 51: 20-31.

94. Van Praagh R, Weinberg PM. Double Outlet Left Ventricle. In: Heart Disease in Infantes, Children and Adolescents. Moss AJ, Adams FH, Emmanouilides GC. Editors. 1977; 2nd Edition. William&Wilkins Company Baltimore.

95. Van Praagh R, Ongley PA, Swan HJC. Anatomic types of single ventricle in man: morphologic and geometric aspects of 60 necropsied cases. Am J Cardiol. 1964; 13: 367-386.

96. Van Praagh R, Van Praagh S, Vlad P, Keith JD. Diagnosis of the Anatomic Types of Single or Common Ventricle. Am J Cardiol. 1965; 15: 345-366.

97. Wenink ACG. Embryology of the Ventricular Septum: Separate Origin of Its Components. Virchows Arch A Pathol Anat Histol. 1981; 390: 71-79.

98. Zavaleta D, Attié F, Meza J, Muñoz-Castellanos L, Buendia A, Ovseyevitz J, et al. Doble Camara de Salida del ventriculo derecho con Conexion Atrioventricular Discordante. Arch Inst Cardiol Méx.1987; 57: 199- 206.

99. Lev M, Eckner FAO. The pathologic anatomy of Tetralogy of Fallot and its variations.Chest.1964; 45: 251-261.

100. Becker AE, Connor M, Anderson RH. Tetralogy of Fallot: a morphometric and geometric study. Am J Cardiol. 1975; 35: 402- 412.

101. Lev M, Bharati S, Meng CC, Liberthson RR, Paul MH, Idriss F. A concept of double-outlet right ventricle with Situs Solitus and Atrioventricular Concordance. J Thorac Cardiovasc Surg. 1972; 64: 271-281.

102. Van Praagh R. What is the Taussig-Bing Malformation? Circulation. 1968; 38: 445-449.

103. Van Praagh S. Davidoff A, Chin A, Shiel FS, Reynolds J, Van Praagh R. Double Outlet Right Ventricle. Anatomic Types and Developmental Implications Based on a Study of 101 Autopsied Cases. Coeur.1982; vol.XIII(4) Numéro Spécial. Journées de Cardiologie CAHORS 1981 (MALOINE S.A. Edit.)

104. Uemura H, Yagihara T, Kawashima Y, Nishigaki K, Kamiya T, Yen HO S, et al. Coronary arterial anatomy in double-outlet right ventricle with subpulmonary VSD. Ann Thorac Surg. 1995; 59: 591-597.

105. Van Praagh R, Van Praagh S. The Anatomy of Common Aorticopulmonary Trunk (Truncus Arteriosus Communis) and Its Embryologic Implications. Am J Cardiol. 1965; 16: 406-425.

106. Thiene G, Bortolotti U, Gallucci G, Terribile V, Pellegrino PA. Anatomical study of truncus arteriosus communis with embryological and surgical considerations. Br Heart J. 1976; 38: 1109-1123.

107. Walmsley T. Transposition of the ventricles and the arterial stems. J Anat. 1931; 65: 528-540.

108. Harris JS, Farber S. Transposition of the great cardiac vessels with special reference to the phylogenetic theory of Spitzer. Arch Pathol. 1939; 28: 427-502.

109. Lev M. The pathologic anatomy of cardiac complexes associated with transposition of arterial trunks. Lab Invest. 1953; 2: 296-311.

110. Grant RP. Morphogenesis of transposition of the great vessels. Circulation. 1962; 26: 819-840.

111. Quero-Jiménez MC, Gussoni C, Granados M. Transposition des gros vaisseaux. Anatomie pathologique. COEUR: Revue de cardiologie medico-chirurgicale,

112. Quero-Jiménez M, Raposo Sonnenfeld I. Isolated ventricular inversion with situs solitus. Br Heart. 1975; 37: 293-304.

113. Milanesi O, SY Ho, Thiene G, Frescura C, Anderson RH. The ventricular septal defect in complete transposition of the great arteries: pathologic anatomy in 57 cases with emphasis on subaortic, subpulmonary, and aortic arch obstruction. Hum Pathol. 1987; 18: 392-396.

114. Anderson RH, Henry GW, Becker AE. Morphologic aspects of complete transposition. Cardiol Young. 1991; 1: 41-53.

115. Unolt M, Putotto C, Silvestri LM, Marino D, Scarabotti A, Massaccesi V, et al. Transposition of Great Arteries: New Insights into the pathogenesis. Front Pediatr. 2013; 1: 1-7.

116. Cardell BS. Corrected Transposition of the Great Vessels. Br Heart J. 1956; 18: 186-192.

117. Raghib G, Anderson RC, Edwards JE. Isolated Bulbar Inversion in Corrected Transposition. Am J Cardiol. 1966; 17: 407-410.

118. Arribard N, Mostefa-Kara M, Bonnet D, Hascoet S, Houyel L. Congenital corrected transposition of the great arteries: is it really a transposition? European Society of Cardiology Working Group on Development, Anatomy and Pathology. 2018; Marseille Cardiovascular Development meeting 22-24 October 2018.

119. Frescura C, Thiene G. Front Ped. The new concept of univentricular heart. Front Pediatr. 2014; 2: 62.

120. Schwalbe E. Die Morphologie der Missbildungen des Menschen und der Tiere. Part I: Allgemeine Missbildungslehre (Teratologie). G. FischerVerlag. JenaGermany.1906.

121. Houyel L, Van Praagh R, Lacour-Gayet F, Serraf A, Petit J, Bruniaux J, et al. Transposition of the Great Arteries ( S,D,L ). Pathologic anatomy, diagnosis, and surgical management of a newly recognized complex. J Thorac Cardiovasc Surg. 1995; 110: 613-624.

122. Bharati S, Lev M, Stewart R, McAllister HAjr, Kirklin JW. The morphologic spectrum of double outlet left ventricle and its surgical significance. Circulation. 1978; 58: 558-565.

123. Moorman A, Brown NA, Lamers SW, Anderson RH. Development of the heart: (1) formation of the cardiac chambers and arterial trunks. Heart. 2003; 89: 806-814.

124. Van den Berg G, Moorman AFM. Concepts of Cardiac Development in Retrospect. Pediatr Cardiol. 2009; 30: 580-587.

125. Wenink ACG, Gittenberger De Groot AC. Left and right ventricular trabecular patterns. Consequence of ventricular septation and valve development. Br Heart J. 1982; 48: 462-468.

126. Lamers WH, Wessels A, Verbeeck FT, Moorman AF, Virág S, Weninck AC, et al. New Findings Concerning Ventricular Septation in the Human Heart. Implications for Maldevelopment. Circulation.1992; 86: 1194-1205.

127. Wenink ACG, Wisse BJ, Groenendijk PM. Development of the inlet septum of the right ventricle in the embryonic rat heart: the basis for tricuspid valve development. Anat Rec. 1994; 239: 216-223.

128. Lamers WH, Moorman AFM. Cardiac Septation: A Late Contribution of the Embryonic Primary Myocardium to Heart Morphogenesis. Circ Res. 2002; 91: 93-103.

129. Gittenberger-de-Groot AC, Bartelings MM, Deruiter MC, Poelmann RE. Basics of Cardiac Development for the Understanding of Congenital Heart Malformations. Pediatr Res. 2005; 57: 169-175.

130. Bartelings MM, Gittenberger de Groot AC. The outflow tract of the heart: embryologic and morphologic correlations. Int J Cardiol. 1989; 22: 289-300.

131. Bartelings MM, Gittenberger-de-Groot AC. Morphogenetic considerations on congenital malformations of the outflow tract. Part I: common arterial trunk and tetralogy of Fallot. Int J Cardiol. 1991; 32: 213-230.

132. Bartelings MM, Gittenberger-de-Groot AC. Morphogenetic considerations on congenital malformations of the outflow tract. Part 2: Complete transposition of the great arteries and double outlet right ventricle. Int J Cardiol. 1991; 33:5-26.

133. Webb S, Qayyum SR, Anderson RH, Lamers WH, Richardson MK. Sepatation and separation within the outflow tract of the developing heart. J Anat. 2003; 202: 327-342.

134. Boukens BJ, Coronel R, Christoffels VM. Embryonic development of the right ventricular outflow tract and arrhythmias. Heart Rhythm. 2016; 13: 616-622.

135. Clark EB. Pathogenetic Mechanisms of Congenital Cardiovascular Malformations Revisited. Sem Pathol. 1996; 20: 465-472.

136. Wenink ACG, Gittenberger-de Groot A. Pathogenesis of congenital cardiac malformations and mechanisms of cardiac remodelling. Cardiol Young. 2005; 15: 3-6.

137. Sedmera D, McQuinn T. Embryogenesis of heart muscle. Heart Fail Clin. 2008; 4: 235-245.

138. Paige SL, Plonowska K, Xu A. Molecular regulation of Cardiomyocite Differentiation. Circ Res. 2015; 116: 341-353.

139. Huang JB, Liu YL, Lv XD. Pathogenic mechanisms of congenital heart disease. J Fetal Ped Pathol. 2010; 29: 359-372.

140. Sizarov A, Ya J, De Boer BA, Lamers WH, Christoffels VM, Moorman AFM. Formation of the Building Plan of the Human Heart. Morphogenesis, Growth, and Differentiation. Circulation. 2011; 123: 1125-1135.

141. Sizarov A, Baldwin HS, Srivastava D, Moorman AFM. Development of the heart: Morphogenesis, Growth, and Molecular Regulation of Differentiation. In Section I: From the Gene to Neonate. Moss and Adams, Allen H, Shaddy R, et al. Edts. 2016.

142. Gittenberger-de Groot AC, Calkoen EE, Poelmann RE, Bartelings MM, Jongbloed MRM. Morphogenesis and molecular considerations on congenital cardiac septal defects.2014; 46: 640-652.

143. Moorman AFM, Christoffels VM. Cardiac chamber formation: Development, Genes, and Evolution. 2003; Physiol Rev. 83:1223- 1267.

144. Rana MS, Christoffels VM, Moorman FM. A molecular and genetic outline of cardiac morphogenesis. Acta Physiol. 2013; 207: 588-615.

145. Poelmann RE, Gittenberger-de-Groot AC. Apoptosis as an instrument in cardiovascular development. Birth Defects Res C Embryo Today. 2005; 75: 305-313.

146. Gittenberger-de-Groot AL, Poelmann RE, Vicente-Steijn R, Bartelings MM, Bogaard HJ, Jongbloed RM. Normal Development and Morphology of the Right Ventricle: Clinical Relevance. In The Right Ventricle in Health and Disease. Voelkel NF, Schranz D (Eds) Springer Science Business Media ,New York, 2015.

147. Scherptong RW, Jongbloed MR, Wisse LJ. Morphogenesis of the outflow tract rotation during cardiac development: the pulmonary push concept. Dev Dyn. 2012; 241: 1413-1422.

148. Tabibiazar R, Wagner RA, Liao A, Quertermous T. Transcriptional Profiling of the Heart Reveals Chamber-Specific Gene Expression Patterns. Circ Res. 2003; 93: 1193-1201.

149. Delgado-Olguin P. Embryological Origins: How does the Right Ventricle Form. In: Right Ventricular Physiology, Adaptation and Failure in Congenital and Acquired heart Disease. Friedberg MK, Redington AN Eds. 2018. Springer International Publishing AG.

150. Harvey RP. Cardiac Looping-an uneasy deal with laterality. Stem Cell Develop Biol. 1998; 9: 101-108.

151. Taber LA. Biophysical mechanisms of cardiac looping. Int J Dev Biol. 2006; 50: 323-332.

152. Ramasubramanian A, Nerurkar NL, Achtien KH, Filas BA, Voronov DA, Taber LA. On Modeling Morphogenesis of the Looping Heart Following Mechanical Perturbations. J Biomech Eng. 2008; 130: 061-018.

153. Bayraktar M, M?nner J. Cardiac looping may be driven by compressive loads resulting from unequal growth of the heart and pericardial cavity. Observation on a physical simulation model. Front Physiol. 2014; 5: 112.

154. Ramsdell AF, Jost HJ. Cardiac Looping and the Left-Right Axis: Integrating Morphologic, Molecular, and Genetic Analyses of Vertebrate Left-Right Asymmetry. In: Formation of the Heart and its Regulation; Eds Tomanek RJ, Runyan RB, Chapter 3. 2017 Springer Nature Switzerland AG, Part of Springer Nature. Publisher: Birkhäuser, Boston MA. Print ISBN 978-1-4612-6662-4

155. Ramsdell AF. Left-right asymmetry and congenital cardiac defects: Getting to the heart of the matter in vertebrate left-right axis determination. Dev Biol. 2005; 288: 1-20.

156. Schwalbe E. Die Morphologie der Missbildungen des Menschen und der Tiere. Part I: Allgemeine Missbildungslehre (Teratologie). G. FischerVerlag. JenaGermany.1906

157. Waldo KL, Kumiski DH, Wallis KT, Stadt HA, Hutson MR, Platt DH, et al. Conotruncal myocardium arises from a secondary heart field. Development. 2001; 128: 3179-3188.

158. Kelly RG, Brown NA, Buckingham ME. The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell. 2001; 1: 435-440.

159. Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R. The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol. 2001; 238: 97-109.

160. Zaffran S, Frasch M. Early Signals in Cardiac Development. Circ Res. 2002; 91: 457-469.

161. Brand T. Heart development: molecular insights into cardiac specification and early morphogenesis. Develop Biol. 2003; 258: 1-19.

162. Bajolle F, Zaffran S, Kelly RG, Hadchouel J, Bonnet D, Brown NA, et al. Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries. Circ Res. 2006; 98: 421-428.

163. Granaados-Riveron JT, Brook JD. The Impact of Mechanical Forces in Heart Morphogenesis. Circ Cardiovasc Genet. 2012; 5: 132-142.

164. Norris DP. Cilia, calcium and the basis of left-right asymmetry. BMC Biol. 2012; 10: 102-109.

165. Babu D, Roy S. Left-Right asymmetry: cilia stir up new surprises in the node. Open Biol. 2013; 3: 130052.

166. Ferreira RR, Vermot J. The balancing roles of mechanical forces during left-right patterning and asymmetric morphogenesis. Mech Develop. ELSEVIER. 2017; 144: 71-80.

167. Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxis. Eur J Hum Gen. 2006; 14: 17-25.

168. Dykes IM. Left Right Patterning, Evolution and Cardiac Development. J Cardiovasc Dev Dis. 2014; 1: 52-72.

169. Campione M, Franco D. Current perspectives in Cardiac Laterality. J Cardiovasc Dev Dis. 2016; 3: 34.

170. Franco D, Sedmera D, Lozano-Velasco E. Multiple Roles of Pitx2 in Cardiac Development and Disease. J Cardiovasc Develop Dis. 2017; 4: 16.

171. Wang J, Xin YF, Xu WJ, Liu ZM, Qiu XB, Qu XK, et al. Prevalence and Spectrum of PITX2C Mutations Associated with Congenital Heart Disease. DNA Cell Biol. 2013; 32: 708-716.

172. Li P, Kaslan M, Lee SH. Progress in Exome Isolation Techniques. Theranostics. 2017; 7: 789-804.

173. Boyd PA, Haeusler M, Barisic I, Loane M, Garne E, Dolk H. Paper 1: The EUROCAT network-organization and processes. Birth Defects Res A Clin Mol Teratol. 2011; 91(Suppl 1):S2-15.

174. Triedman JK, Newburger JW. Trends in Congenital Heart Disease. The Next Decade.Circulation. 2016; 133: 2716-2733.

175. Sadler TW. Establishing the Embryonic Axes: Prime Time for Teratogenic Insults. J Cardiovasc Dev Dis. 2017; 15: 1-7.

176. Richards AA, Garg V. Genetics of Congenital Heart Disease. Curr Cardiol Rev. 2010; 6: 91-97.

177. Kazuki K, Yamagishi H. A Decade of Advances in the Molecular Embryology and Genetics Underlyng Congenital Heart Defects. Circ J. 2011; 75: 2296-2304.

178. Ghosh TK, Granados-Riveron JT, Buxton S, Setchfield K, Loughna S, Brook JD. Studies of genes Involved in Congenital Heart Disease. J Cardiovasc Dev Dis. 2014; 1: 134-145.

179. Pierpont ME, Basson CT, Benson jr DW, Gelb BD, Giglia TM, Goldmuntz E, et al. Genetic Basis for Congenital Heart Defects: Current Knowledge. A Scientific Statement from the American Heart Association Congenital Cardiac Defects Committee, Council of Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007; 115: 3015-3038.

180. Strachan T, Read AP. Identifying human disease genes. In: Human Molecular Genetics 3. New York, NY: Garland Science. 2004: 415- 433.

181. Chowdhury S, Erickson SW, Mac-Leod SL, Cleves MA, Hu P, Karim MA, et al. Maternal Genome-Wide DNA Methylation Patterns and Congenital Heart Defects. PLoS ONE. 2011; 6: e 16506.

182. McCulley DJ, Black BL. Transcription Factor Pathways and Congenital Heart Disease. Curr Top Dev Biol. 2012; 100: 253-277.

183. Waardenberg AJ, Ramialison M, Bouveret R, Harvey RP. Genetic Networks Governing Heart Development. Cold Spring Harb Perspect Med. 2014; 4: a013839.

184. Kathiriya IS, Nora EP, Bruneau BG. Investigating the Transcriptional Control of Cardiovascular Development. Circ Res. 2015; 116: 700- 714.

185. Paige SL, Plonowska K, Xu A, Wu SM. Molecular Regulation of Cardiomyocite Differentiation. Circ Res. 2015; 116: 341-353.

186. Fox CS, Hall JL, Arnett DK, Ashley EA, Delles C, Engler MB, et al. Future Translational Applications From the Contemporary Genomics Era: A Scientific Statement From the American Heart Association. Circulation. 2015; 131: 1715-1736.

187. Solomon T, Smith EN, Matsui H, Braekkan SK, INVENT consortium, et al. Associations Between Common and Rare Exonic Genetic Variants and Serum levels of 20 Cardiovascular-Related Proteins. The Troms? Study. Circogenetics. 2016; 9: 375-383.

188. Azhar M, Ware SM. Genetic and Developmental Basis of Cardiovascular Malformations. Clin Perinatol. 2016; 43: 39-53.

189. Chaix MA, Andelfinger G, Khairy P. Genetic testing in congenital heart disease: A clinical approach. World J Cardiol. 2016; 8: 180-191.

190. Edwards JJ, Gelb BD. Genetics of congenital heart disease. Curr Opin cardiol. 2016; 31: 235-241.

191. Akhirome E, Walton NA, Nogee JM, Jay P. The Complex Genetic Basis of Congenital Heart Defects. Circ J. 2017; 81: 629-634. 

192. Blue GM, Kirk EP, Giannoulatou E. Advances in the Genetics of Congenital Heart Disease. JACC. 2017; 69: 859-870.

193. Zaidi S, Brueckner M. Genetics and Genomics of Congenital Heart Disease. Circ Res. 2017; 120: 923-940.

194. Sun C, Kontaridis MI. Physiology of cardiac development: from genetics to signaling to therapeutic strategies. Curr Opinion Physiol. 2018; 01: 123-139.

195. Maslen CL. Recent advances in Placenta-Heart interactions. Front Physiol. 2018; 9: 735.

196. Barnett P, Van den Boogaard M, Christoffels V. Localized and Temporal Gene Regulation in Heart Development, Vol.100, 1st Edition, Acadenic Press 2012. Chapter 6:171-201.

197. Norton ME, Baer RJ, Wapner RJ, Kuppermann M, Jelliffeet-Pawlowski LL, Currier RJ. Cell-free DNA vs sequential screening for the detection of fetal chromosomal abnormalities. Am J Obstet Gynecol. 2016; 214: 727. e1-6.

198. Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017; 50: 302- 314.

199. Lapierre C, Rypens F, Grignon A, Dubois J, Déry J, Garel L. Prenatal Ultrasound Screening of Congenital of Congenital Heart Disease in the General Population: General Concepts, Guidelines, Differential Diagnoses. Ultrasound Quarterly Wolters Kluwer 2013; 29:111-124.

200. Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Mark S, Sklansky MS, et al. Diagnosis and Treatment of Fetal Cardiac Disease. A Scientific Statement From the American Heart Association. Circulation 2014; 129: 2183-2242.

201. Hunter LE, Simpson JM. Prenatal screening for structural congenital heart diaease. Nat Rev Cardiol. 2014; 11: 323-334.

202. Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet. 2016; 17: 333-351.

203. Li X, Xiong X, Yi C. Epitranscriptome sequencing technologies: decoding RNA modifications. Nature Methods. 2017; 14: 23-31.

204. Cai X, Janku F, Zhan Q, Janku F, Zan Q, Fan JB. Accessing Genetic Information with Liquid Biopsies. Trends Genet. 2015; 31: 564-575.

205. McElhinney DB, Tworetzky W, Lock JE. Current Status of Fetal cardiac Intervention. Circulation. 2010; 121: 1256-1263.

206. Moon-Grady AJ, Morris SA, Belfort M, Chmait R, Dangel J, Devlieger R, et al. International Fetal Cardiac Intervention Registry. A Worldwide Collaborative Description and Preliminary Outcomes. JACC. 2015; 66: 388-399.

207. Shendure J. The beginning of the end of microarrays? Nature Methods. 2008; 5: 585-586.

208. Mardis ER. Next-Generation Sequencing Platforms. Annu Rev Anal Chem. 2013; 6: 287-303.

209. Blue GM, Winlaw DS. Next Generation Sequencing in Congenital Heart Disease: Gene Discovery and Clinical Application. Next Generat Sequenc & Applic. 2015; 2: 113.

210. Costain G, Silversides CK, Bassett AS. The importans of copy number variation in congenital heart disease. Npj Genomic Medicine. 2016; 1: 16031.

211. Tae Park S, Kim J. Trends in Next-generation Sequencing and a New Era for Whole Genome Sequencing. Int Neurourol J. 2016; 20:76-83.

212. Properzi F, Logozzi M, Fais S. Exosomes: the future of biomarkers in medicine. Biomarkers Med. 2013; 7: 769-778.

213. Clark MJ, Chen R, Lam HYK, Karczewski KJ, Chen R, Euskirchen G, et al. Performance comparison of EXOME DNA sequencing technologies. Nat Biotechnol. 2014; 29: 908-914.

214. European Surveillance of Congenital Anomalies Central Data Base. EUROCAT ANNUAL SURVEILLANCE REPORT 2014.

215. Erikssen G, Liestøl K, Seem E, Birkeland S, Saatvedt KJ, Hoel TN, et al. Achievements in Congenital Heart Defect Surgery. A Prospective, 40-Year Study of 7038 Patients. Circulation. 2015; 131: 337-346.

216. Jacobs JP, He X, Mayer JE jr, Austin III EH, Quintessenza JA, Karl TL, et al. Mortality Trands in Pediatric and Congenital Heart Surgery: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database. Ann Thorac Surg. 2016: 102:1345-1352.

217. Exome Aggregation Consortium, Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennel T, et al. Analysis of protein coding genetic variations in 60.706 humans. Nature. 2016; 18: 536: 285- 291.

218. Capuani A. Potential treatment of complex congenital heart malformations during cardiac morphogenesis. Virchows Arch. 2015; 467(Suppl1): S1-S279.PS-05-005. s97.

219. Capuani A. Anatomical insights in cardiac embryogenesis: the potential for fetal treatments. 2nd Emirates Surgical Pathology Conference and 27th Annual Meeting of the Arab Division of the International Academy of Pathology, Dubai, UAE. 2015.

220. Capuani A. Targeting exome sequences in congenital heart diseases: are we there yet? Proceedings of the XXXI Congress of the International Academy of Pathology and 28th Congress of the European Society of Pathology. September 2016; Cologne, Germany. Virchows Archiv. 2016; 469(Suppl1):S1-S346.E-PS-02-003. s242.

221. Capuani A. Exome and Whole Genome Sequencing for CHD Diagnosis and Treatment during Pregnancy. Proceedings of the “Congresso Triennale di Anatomia Patologica” SIAPEC ( Società Italiana di Anatomia Patologica e Citopatologia)-IAP ( International Academy of Pathology) Genova 2016. PATHOLOGICA 2016; 108: 278-279.

222. McClain LE, Flake AW. In utero stem cell transplantation and gene therapy: Recent progress and the potential for clinical application. Best Pract Res Cl Ob. 2016; 31: 88-98.

223. Duelen R, Sampaolesi M. Stem Cell Technology in Cardiac Regeneration: A Pluripotent Stem Cell Promise. EBioMedicine. 2017; 16: 30-40.

224. Rosengart TK, Patel V, Selike FW. Cardiac Stem Cell Trials and New World of Cellular Reprogramming: Time to Move On. J Thorac Cardiovasc Surg. 2018; 155: 1642-1646.

225. Lemcke H, Veronina M, Steinhoff G, David R. Recent Progress in Stem Cell Modification for Cardiac Regeneration. Stem Cells Int. 2018; 1-20.

226. Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. Correction of a pathogenetic gene mutation in human embryos. Nature. 2017; 548: 413-419.

227. Egli D, Zuccpiro MV, Kosicki M, Church GM, Bradley A, Jasin M. Interhomologue repair in fertilized human eggs? Nature. 2018; 560: E5- E7.

228. Drenckhahn JD. Growtz plasticity of the embryonic and fetal heart. BioEssays. 2009; 31:1288-1298.

229. Bloomekatz J, Galvez-Santisbeban M, Chi NC. Myocardial Plasticity: Examples in Development Regeneration and Diesease. Curr Opin Genet Dev. 2016; 40:120-130.

230. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126: 663-676.

231. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012; 485: 593-598.

232. Srivastava D, DeWitt N. In vivo Cellular Reprogramming: The Next generation. Cell. 2016; 166: 1386-1396.

233. Keeler AM, EIMallah MK, Flotte TR. Gene therapy: Progress and Future Directions. Clin Transl Sci. 2017; 10: 242-248.

234. DOI:10.1161/CIRCULATIONAHA.116.023544

235. Gelb BD, Chung WK. Complex Genetics and the Etiology of Human Congenital Heart Disease. Cold Spring Harb Perspect Med. 2014; 4: a013953.

236. Charpentier E, Doudna JA. Biotechnology: rewriting a genome. Nature. 2013; 495: 50-51.

237. Ran FA, Hsu PD, Wright J, Agarwala V, Scott A, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013; 8: 2281-2308.

238. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013; 339: 819-823.

239. Chin A. CRISPR/Cas9 Therapeutics: A Technology Overview. Oxford Biotech. 2015. scienceunion.org/.../2015/.../crispr-cas9- therapeutics-a-technol.

240. Reardon S. First CRISPR clinical trial gets green light from US panel. Nature News. 2016.

241. Capuani A. New Perspectives in Cardiac Surgery: the Virtual Ventricle and the Molecular Cardiac Surgery. Proceedings of the 7th World Congress of Pediatric Cardiology & Cardiac Surgery. July 2017; Barcelona, Spain. P2271: 726-727.

242. Li AH, Hanchard N, Furthner D, Fernbach SD, Azamian M, Nicosia A, et al. Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. Gen Med. 2017; 9: 95.

Capuani A (2020) Abnormal Rotation of the Primary Heart Tube. Linking Embryogenesys to Malformed Cardiac Phenotypes: Future Perspectives. Arch Paediatr Dev Pathol 3(1): 1022.

Received : 27 Aug 2020
Accepted : 05 Dec 2020
Published : 28 Dec 2020
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X