Development of the coronary arteries

The formation of a coronary arterial circulation originating from the aortic root is a relatively late event during embryonic development. When assessing development of the murine heart, note should be taken of the differences in arrangement of the coronary arteries, not least that – in the mouse – the epicardial vessels are encased within the superficial layers of the ventricular myocardium, rather than being directly epicardial as in humans. Development sequences, however, parallel the events seen in humans,Reference Hutchins, Kessler-Hanna and Moore⁷ with antegrade perfusion of the epicardial and mural vessels not established until after closure of the embryonic interventricular communication – a process that occurs, for the mouse, during the 14th embryonic day. Before this stage, primordial vessels can be recognised within a so-called “peritruncal plexus”, which develops within the adventitial coverings of the intrapericardial arterial trunks.Reference Chen, Poduri and Numi⁵ The arterial trunks themselves are developed within the distal part of the embryonic outflow tract by proliferation within the pericardial cavity of tissues initially derived from the second cardiac lineage.Reference Anderson, Chaudhry and Mohun⁸ The smooth muscle components of the coronary circulation are formed predominantly from cells that migrate from the epicardial organ, located in the transverse septum, onto the surface of the heart, although evidence exists that the endothelial cells originate from the embryonic systemic venous sinus and to some extent from the endocardium.Reference Red-Horse, Ueno, Weissman and Krasnow⁹ In the stages immediately before closure of the embryonic interventricular communication, however, the ventricular walls are composed predominantly of a trabecular meshwork, with the compact component of the developing walls barely formed (Fig 1a). At this stage, therefore, nourishment of the cardiomyocytes can be accomplished by perfusion from the ventricular cavities. It is only with growth of the compact component of the walls, occurring during the 15th embryonic day in the mouse (Fig 1b), and subsequent to Carnegie stage 23 in man, that it becomes necessary to establish an antegrade circulation from the aortic root.

Figure 1 The images, taken in the four-chamber plane through episcopic data sets produced from developing mouse hearts, show the growth of the compact layer of the ventricular walls during embryonic days E13.5 and E14.5. At E13.5 (a), the embryonic interventricular communication (IVC) remains patent. The ventricular walls are composed primarily of a meshwork of ventricular trabeculations (double-headed red arrow). By the end of E14.5, the IVC has closed (b), and there has been marked growth of the compact layer of the ventricular wall (double-headed green arrow), which is now beginning to match the thickness of the trabecular layer (double-headed red arrow). The growth of the compact layer necessitates the formation of a coronary arterial circulation fed from the aortic root.

The mechanisms of formation of the circulation originating from the aortic root have generated some controversy. It was initially thought that buds grew from both the aortic and pulmonary roots.Reference Hackensellner¹⁰ No evidence was forthcoming to substantiate this notion, and it then became accepted that the epicardially derived vessels grew into the developing adjacent sinuses of the aortic root.Reference Bogers, Gittenberger-de Groot, Dubbledam and Huysmans¹¹ More recently, it was shown that endocardial strands grew out of the aortic root, specifically from the wall adjacent to the pulmonary trunk.Reference Chen, Poduri and Numi⁵ The evidence from examination of episcopic data sets prepared from developing mouse hearts supports this account of development. When the first few stems are seen extending from the aortic root, during the 14th embryonic day, they are not in contact with the developing epicardial coronary vessels (Fig 2a). At this stage, furthermore, there has been no formation of the arterial valvar sinuses, with the coronary arterial stems taking their origin distal to the margins of the outflow cushions that are cavitating to form the aortic valvar leaflets (Fig 2a). During normal development, the coronary arteries take their origin from the two sinuses that are adjacent to the pulmonary trunk (Fig 2b). It is not until the 16th day of development in the mouse that the arterial stems achieve a position proximal to the sinutubular junction (Fig 2c), having by this time been incorporated within the newly developed aortic valvar sinuses, although there is marked individual variability in the mouse, particularly regarding the origin of the right coronary artery.

Figure 2 The images, taken from episcopic data sets prepared from developing mouse hearts, show the steps involved in the formation of a coronary arterial circulation originating from the aortic root. Panel (a), from a mouse at embryonic (E) day 13.5, and sectioned in the frontal plane, shows an outgrowth from the aortic root distal to the margins of the developing valvar leaflets, which is yet to make contact with the prominent epicardial vessels. Only by day E15.5 has there been ongoing formation of the aortic valvar sinuses, with the coronary arterial orifices by then having joined the epicardial network, and becoming incorporated into the sinuses adjacent to the pulmonary trunk (b), a short-axis section viewed from above. Sectioning the same data set in the frontal plane (c) reveals that the coronary arterial orifices are now proximal to the sinutubular junction.

At the stage when the proximal origins of the coronary arteries are first seen emerging from the newly separated aortic component of the distal outflow tract, the outflow cushions themselves have fused to separate the intermediate component of the outflow tract into the putative aortic and pulmonary roots. The peripheral margins of the cushions, however, remain unfused. It is these peripheral parts of the major outflow cushions along with the intercalated cushions that will cavitate with ongoing development to give rise to the arterial valvar leaflets (Fig 3a). Separation of the intrapericardial arterial trunks themselves depends on fusion of a protrusion from the dorsal wall of the aortic sac, the aortopulmonary septum, with the distal margin of the fused central parts of the major outflow cushions, thus closing the embryonic aortopulmonary foramen.Reference Anderson, Chaudhry and Mohun⁸ It is subsequent to this stage that the origins of the coronary arteries are seen emerging from the base of the newly formed aortic trunk, but distal to the margins of the excavating outflow cushions. It is then during embryonic days 14 and 15 in the mouse that ongoing growth of the aortic root produces the aortic valvar sinuses, with this growth also serving to incorporate the orifices of the coronary arteries within the newly formed sinuses (Fig 3b). Normal separation of the arterial roots, therefore, along with normal formation of the valvar sinuses, is required to produce the situation in which the coronary arteries achieve their anticipated origin either within or adjacent to the two aortic sinuses that face the pulmonary trunk (Fig 2b).

Figure 3 The images are from episcopic data sets prepared from developing mice at embryonic (E) days 13.5 (a) and 14.5 (b). As shown in panel (a), taken to replicate the oblique subcostal echocardiographic cut, the peripheral margins of the fused distal major outflow cushions are beginning to cavitate to form the arterial valvar leaflets. The outgrowth from the aortic root that will form the stem of the right coronary artery (white arrow with red borders) is distal to the distal margins of the cushions. By the end of the next day of development (b), ongoing growth of the walls of the arterial valvar sinuses have incorporated the orifice of the coronary artery proximal to the developing sinutubular junction (white arrow with red borders (b)), although in some mice the arterial origin remains distal to the sinutubular junction. The cut producing panel (b) is reciprocal to the one shown in panel (a), revealing the left ventricular aspect of the developing aortic root.

The need for attitudinally appropriate descriptions

The first rule of anatomy taught during the education of medical students is that all structures should be described with the patients standing upright and facing the observer – the so-called anatomical position.Reference Anderson and Loukas⁴ It is unfortunate that, for centuries, anatomists and pathologists have ignored this rule when describing the heart. Thus, the accepted nomenclature for cardiac components, including the coronary arteries, is based on the concept of the heart sitting on its apex, with the right atrium and ventricle presumed truly to be right-sided compared with their left partners. This “Valentine” arrangement is not the usual position of the heart within the chest.Reference Anderson and Loukas⁴ In life, the heart is usually positioned with its inferior surface lying on the diaphragm, with the apex of the ventricular cone pointing to the left. Cross-sections across the ventricular cone in this position show that the artery located within the interventricular groove, usually said to be posterior and descending, is located inferiorly. It is no coincidence that blockage of this artery produces inferior myocardial ischaemia and infarction. With the increasing use of three-dimensional techniques to reveal coronary arterial disease during life, such as three-dimensional echocardiography and CT, it is preferable to describe the heart as it is seen during life, rather than using the incorrect terms derived from its visualisation in the Valentine position. Description in this manner shows that the aortic valvar sinuses giving rise to the coronary arteries are not positioned directly to the right and to the left. They are appropriately described, however, as being the left coronary and right coronary aortic sinuses. It is only in extremely rare circumstances that the third aortic sinus gives rise to one or other of the coronary arteries. In such rare events, the sinus can no longer be described as being “non-coronary”. It is also preferable, therefore, to describe the sinus as being non-adjacent rather than non-coronary. It is then the case that if the observer – figuratively speaking – places himself or herself within this non-adjacent sinus and looks towards the pulmonary trunk then one of the adjacent sinuses will always be to his or her right-hand side, whereas the other sinus will be to the left-hand side. This permits the sinuses always to be described as being sinus #1, to the right-hand side of the observer, or sinus #2, to the left-hand side of the observer. In the usual situation, it is then sinus #1 that gives rise to the right coronary artery, with the left coronary artery originating from sinus #2 (Fig 4). Description in this manner permits the aortic sinuses giving rise to the coronary arteries to be distinguished from one another, and coronary arterial origins to be compared, irrespective of the relationships of the aorta to the pulmonary trunk.

Figure 4 The image shows the dissected aortic root from above, having reflected anteriorly the pulmonary trunk and its supporting infundibulum. The coronary arteries arise from the two aortic valvar sinuses adjacent to the pulmonary root. The third sinus, therefore, is the non-adjacent sinus. If the observer, figuratively speaking, considers himself or herself to be standing in the non-adjacent sinus, and looking towards the pulmonary trunk, then the other sinuses will be to his or her left-hand side or right-hand side. It has now become accepted that the right-handed sinus can be described as #1, whereas the left-handed sinus can be described as #2. In the normal heart, the right-handed sinus gives rise to the right coronary artery and the left-handed sinus to the left coronary artery.

The arrangement of the normal coronary arteries in humans

The major coronary arteries in humans, as in the mouse, normally arise from the two aortic valvar sinuses that are adjacent to the pulmonary trunk (Fig 4). Although it is exceedingly rare for a coronary artery to arise from the third aortic valvar sinus, this does happen (Fig 5). As we have explained, for this reason, it is more accurate to describe the sinus in question as being non-adjacent rather than non-coronary. Although in most instances there are only two coronary arterial stems arising from the aorta, there are three major coronary arteries. These are the right coronary artery, the anterior interventricular artery, and the circumflex artery. The arrangements of the epicardial coronary arteries, however, show significant differences between man and mouse. In man, the left coronary artery usually has a short main stem, which runs into the space between the left atrial appendage and the pulmonary trunk before dividing into the anterior interventricular and circumflex arteries. On occasion, this main stem can trifurcate rather than bifurcate (Fig 6a). On other occasions, the anterior interventricular and circumflex arteries can arise from separate orifices within the aortic valvar sinus. Such arrangements are best considered as anatomical variants rather than congenital malformations.

Figure 5 The image shows a view from the opened left ventricular outflow tract of the aortic root in a heart removed from a patient with a doubly committed ventricular septal defect. The probe is in the orifice of the left coronary artery. Rather than arising from its expected sinus (sinus #2), it originates from the non-adjacent aortic valvar sinus. It would be a mistake in this heart, therefore, to describe either sinus #2 as the “left coronary aortic sinus” or the non-adjacent sinus as the “non-coronary sinus”. Note that the coronary artery crosses the valvar commissure as it extends to enter the pericardial cavity. This is the so-called intramural arrangement.

Figure 6 The images show the arrangement of the coronary arteries in the setting of so-called left coronary arterial dominance. In this heart, the main stem of the left coronary artery gives rise to a small intermediate branch along with the anterior interventricular and circumflex arteries (a). As is shown in panel (b), the circumflex artery then extends around the mural leaflet of the mitral valve, giving rise to the inferior interventricular artery (not seen). Note, however, that the right coronary artery ramifies into a sheath of relatively small vessels and does not extend around the right atrioventricular junction.

When describing the normal arrangements, note should be taken of the epicardial course of the major arteries, as well as their sinusal origin. The right coronary artery, in most individuals, runs an extensive course through the right atrioventricular groove, reaching to the crux of the heart and giving rise to the inferior interventricular artery. This is the so-called right ventricular dominance, and is found in nine-tenths of the normal population. In the other 10% of the population, it is the circumflex artery that gives rise to the inferior interventricular artery, producing the so-called left coronary arterial dominance (Fig 6a). In the setting of left coronary arterial dominance, the circumflex artery is usually closely related to the full extent of the mural leaflet of the mitral valve before giving rise to the inferior interventricular artery. With this arrangement, the right coronary artery does not then reach to the cardiac crux (Fig 6b). In some individuals, nonetheless, there can be a so-called balanced arrangement, with both the right and the circumflex coronary arteries supplying the diaphragmatic surface of the ventricular mass at the cardiac crux.

Anomalous pulmonary origin of a coronary artery

Anomalous origin of a coronary artery from the pulmonary circulation is the essence of the so-called Bland–White–Garland syndrome. In most instances, it is the left coronary artery that arises anomalously. Almost always, it takes its origin from the right-handed sinus of the pulmonary trunk (Fig 7a). The consequence of the anomalous pulmonary origin is to produce left ventricular ischaemia, giving a picture that can closely resemble the impact of dilated cardiomyopathy. Abnormal coronary origin from the pulmonary trunk, therefore, should be distinguished from the cardiomyopathic variant, as the anomalously arising coronary artery can readily be re-implanted into the aortic root.Reference Backer, Stout and Zales¹² On occasion, the abnormal coronary artery can take its origin from the left pulmonary artery or even from the right pulmonary artery. It can then take a bizarre course before reaching the base of the heart and dividing into the anterior interventricular and circumflex arteries (Fig 7b).

Figure 7 The images show anomalous origin of the left coronary artery from the pulmonary circulation. Panel (a) shows the usual variant, in which the artery arises anomalously from the right-handed side of the two adjacent pulmonary valvar arterial sinuses. This is the usual substrate for the Bland–White–Garland syndrome. On occasion, the artery can arise more distally (Fig 8a) or from a pulmonary artery. In panel (b), an example is shown of the left coronary artery arising from the right pulmonary artery (RPA), and then extending between the left atrial appendage and the left pulmonary veins to reach the base of the heart. LPA=left pulmonary artery.

It is also possible for the anterior interventricular artery to arise in isolation from the pulmonary trunk. This will produce less-severe symptoms, as will anomalous origin of the right coronary artery from the pulmonary trunk, usually from the left-handed side of the two adjacent pulmonary arterial valvar sinuses, but sometimes from the trunk itself (Fig 8b). The much rarer variant of anomalous origin of both coronary arteries from the pulmonary trunk, as might be anticipated, produces much more severe symptoms. If suspected and diagnosed, nonetheless, this lesion is now amenable to timely surgical repair.Reference Heusch, Quagebeur, Paulus, Krogmann and Bourgeois¹³ Anomalous origin of one or the other coronary artery from the pulmonary trunk can also be found when the heart itself is congenitally malformed. It cannot be coincidence that the association is frequent in the setting of an aortopulmonary window (Fig 8). The latter lesion, of course, represents failure to close the embryonic aortopulmonary foramen. This feature, in turn, points to a potential role for normal separation of the arterial pathways in determining the appropriate origin of the coronary arteries from the aortic root. This potential relationship between normal septation and normal sinusal origin of the coronary arteries is then further supported by the fact that the abnormal pulmonary origin of the coronary artery in the setting of an aortopulmonary window is frequently found distally relative to the pulmonary sinutubular junction, in other words with high take-off (Fig 8).

Figure 8 The images show (a) anomalous origin of the left coronary artery from the pulmonary trunk and (b) anomalous origin of the right coronary artery, again from the pulmonary trunk. In both instances, there is an associated aortopulmonary window, and in both examples the anomalous coronary artery arises distal relative to the sinutubular junction.

Anomalous aortic origin of a coronary artery

When the arrangement of the coronary arteries is normal, the main stems arise from the sinuses of the aortic root that are adjacent to the pulmonary trunk (Fig 4). As already discussed, arrangements such as separate origin of the anterior interventricular and circumflex arteries from sinus #2 are best considered as anatomic variants rather than congenital variations. Such high origin of a coronary artery from the aortic root is seen with sufficient frequency in both humans and mice to be considered in likewise manner as an anatomic variant, the more so because it is rarely the case that in humans both the coronary arteries originate from the midpoint of their respective arterial sinuses. Problems arise, furthermore, in determining how far above the sinutubular junction a coronary artery must originate before being considered as high origin. The higher above the sinutubular junction an artery arises, the more likely it is to take an oblique course through the aortic wall. It is this arrangement that is believed to potentiate towards narrowing as a cause of sudden cardiac death. High origin, therefore, is a frequent finding (Fig 9) and better considered a variant rather than a malformation. The frequent finding of high origin of one or the other coronary artery, and often both, does lend further support to the notion that, when first formed, the stems of the arteries bud out from the aorta distal to the level of the developing sinutubular junction. It is only as part of normal development that, in most instances, they become incorporated within the adjacent valvar sinuses.

Figure 9 The image shows high origin of the right coronary artery above the sinutubular junction. The left coronary artery arises at the level of the sinutubular junction. The arteries, however, other than taking high origin, are appropriately positioned relative to the valvar sinuses. This finding is best considered an anatomical variant rather than a congenital malformation.

Congenitally abnormal origin of the coronary arteries from the aorta can take the form of origin from an inappropriate sinus, origin of a solitary coronary artery, or atresia of the main stem of the coronary artery. It is likely significant that all these lesions have been observed in developing murine hearts (unpublished observations). In humans, the significance is that all these abnormalities have been implicated as a cause of sudden cardiac death. It is the origin from an inappropriate sinus along with intramural coursing relative to the valvar commissure that is the commonest finding. Either the left coronary artery can take its origin from sinus #1 (Fig 10a) or the right coronary artery can arise from sinus #2 (Fig 10b). We have already illustrated anomalous origin of a coronary artery from the non-adjacent sinus of the aortic valve. This latter lesion is particularly rare. It has not thus far, to the best of our knowledge, been identified as a cause of sudden cardiac death. As our illustrated example (Fig 5) shows an intramural course across the valvar commissure, nonetheless, this finding should be anticipated to present the potential for causing sudden cardiac death.

Figure 10 The images show (a) anomalous origin of the left coronary artery from sinus #1 and (b) anomalous origin of the right coronary artery from sinus #2. Both arteries take an intramural course across the commissure between the valvar leaflets. Note that, in the heart shown in panel (b), there is a bicuspid valve with fusion of the two coronary aortic leaflets. The intramural course is across the site of the raphe marking the line of fusion. The left coronary artery also takes its origin adjacent to the commissure.

Solitary coronary arteries can take two forms. In the first variant, a solitary coronary artery can arise from either of the adjacent coronary aortic sinuses and then branch to supply the right, anterior interventricular, and circumflex arteries. With this pattern, one or more of the arteries will be required to take an antero-pulmonary or retroaortic course so as to reach its expected epicardial location. Alternatively, the artery can take a course between the aortic and pulmonary trunks. This can occur at the level of the sinutubular junction, through the tissue plane between the aortic root and the subpulmonary infundibulum, or within the musculature of the ventricular septum. Any of these courses can provide the potential for obstruction and sudden cardiac death. In the second variant, the solitary artery can again originate from either aortic coronary sinus, but without branching into right and left stems. If originating from sinus #1, the solitary artery will extend through both the right and the left atrioventricular grooves, terminating as the anterior interventricular artery. If the artery arises from sinus #2, it will give rise to the anterior interventricular and circumflex arteries, but the circumflex artery will continue beyond the crux to enter the right atrioventricular groove, and will supply the normal territory of the right coronary artery. It is unlikely that these variants will produce the risk of sudden cardiac death. Atresia of the main stem of the left coronary artery, in contrast, although another very rare lesion (Fig 11), is known to be associated with sudden cardiac death.Reference Debich, Williams and Anderson¹⁴ Other variations are to be found with regard to the epicardial course of the coronary arteries, such as duplication of the anterior interventricular artery or origin of the anterior interventricular artery from the right coronary artery. The latter lesion is of particular importance in the setting of congenital cardiac malformations such as tetralogy of Fallot, as it can preclude the option of an infundibular incision.

Figure 11 The image shows atresia of the main stem of the left coronary artery, with well-formed anterior interventricular and circumflex arteries. This lesion is recognised as a cause of sudden cardiac death.Reference Debich, Williams and Anderson¹⁴ The marked difference in calibre of the main stem and the patent interventricular and circumflex arteries is well explained by the separate embryological origins of these components of the left coronary artery.

Abnormal communications with the coronary arteries

When the heart is otherwise normal, fistulous communications, if present, arise from the right coronary artery in half of reported cases – from the anterior interventricular artery in one-third and from the circumflex artery in the remaining one-fifth of cases. Irrespective of the artery giving rise to the fistulous connection, it terminates in a right-sided chamber in four-fifths of cases. The artery feeding the fistula is usually grossly dilated, but tends to resume its normal diameter distal to the origin of the communicating channel (Fig 12).

Figure 12 The image, taken in the operating room by the late Benson R. Wilcox, shows the divided ends of a large fistula extending from the origin of the right coronary artery and opening into the right atrium. Note the normal calibre of the right coronary artery distal to the take-off of the fistula.

Fistulous communications between the coronary arteries and the ventricular cavities are found with some frequency in the setting of hypoplasia of either the right or the left ventricles when the ventricular septum is intact. Fistulous communications in the setting of pulmonary atresia with an intact ventricular septum carry a bad prognostic significance, being found in those cases with the smallest right ventricular cavities (Fig 13a). They produce the so-called right ventricular-dependent coronary arterial circulation, in which multiple obstructive lesions in the coronary arteries themselves obstruct antegrade flow from the aortic root. Fistulous communications in the setting of hypoplastic left heart syndrome are also frequent, but typically much smaller than those found with right heart hypoplasia, and are found only subsequent to microscopic examination. Large fistulas can be found and they also carry a grave prognostic significance (Fig 13b).

Figure 13 The images show fistulous communications from the ventricular cavity to an ectatic coronary artery in the setting of (a) pulmonary atresia with an intact ventricular septum and (b) hypoplastic left heart syndrome.

Comment

There are many classifications and descriptions provided to account for the manifold variations and abnormalities of coronary arterial origin and epicardial course. The old notion of “major” and “minor” anomalies, as promoted by Ogden,Reference Ogden¹⁵ was optimal in terms of simplicity, but has been shown to be fallible when it was realised that seemingly minor lesions such as inappropriate origin from an aortic valvar sinus could frequently be identified as the cause of sudden cardiac death. The multiplicity of variants requiring attention is demonstrated by the extensive list of lesions collated by AngeliniReference Angelini² in his excellent review of the topic. In our brief review, we have concentrated on the major lesions, which can be summarised in terms of anomalous pulmonary origin, anomalous aortic origin, and fistulous communications. Even within these simple categories, nonetheless, there can be marked anatomical variation, with difficulties encountered on occasion in distinguishing the lesions to be diagnosed as malformations or as mere anatomical variations. Only ongoing accurate descriptions, with correlations of any observed consequence, will eventually permit full appreciation of the clinical significance of these variations.

The findings we have described do lend support to recent suggestions regarding the likely development of the arteries, most notably the fact that the main stems grow out of the aorta,Reference Chen, Poduri and Numi⁵ rather than growing into the aorta, as was previously believed.Reference Bogers, Gittenberger-de Groot, Dubbledam and Huysmans¹¹ The notion of initial outgrowth of the proximal parts of the arteries from the aortic root distal to the developing sinutubular junction, before formation of the aortic valvar sinuses, is supported by the frequent finding of high origin of the arteries above the sinutubular junction and also by the observation that the main stem of the left coronary artery can be atretic when both of its branches are of relatively normal calibre. The frequent association of pulmonary origin of a coronary artery with an aortopulmonary window, nonetheless, combined with origin of the anomalous artery distal to the sinutubular junction, suggests that normal separation of the intrapericardial arterial trunks is additionally involved in connection of the arteries to their appropriate aortic sinuses.