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Although bicuspid aortic valve (BAV) is the most common congenital heart disease (CHD), data are limited regarding associated coronary artery variants and how they may impact clinical outcomes, and importantly how this association may inform our understanding of the genetics of aortic root and coronary embryogenesis. An increased incidence in separate left coronary ostia, left dominant systems and high take-off coronary arteries among patients with BAV has been identified particularly among type IB BAVs (without raphe).1 However, among patients with BAV and associated CHD, pathological characteristics of coronary ostia including high take-off variants arising above the sinotubular junction have not previously been described. In this edition of Heart, Koenraddt et al report novel findings of 84 postmortem heart specimens with BAV and associated CHD and observed that high take-off coronaries were common, noted in 45% of hypoplastic left ventricle specimens and 62% of specimens with aortic hypoplasia, high take-off left coronary artery (LCA) occurred more often than high take-off right coronary artery (RCA), and high take-off RCAs were more commonly associated with type IA BAV (with raphe)2. Why these coronary patterns are seen more frequently in patients with BAV, particularly those with associated CHD, remains unclear. Refining our understanding of structural associations may provide important insights into embryological and genetic underpinnings of CHD development.
BAV disease and embryogenesis
BAV disease is common with male predominance, may be isolated or may be associated with other CHD such as coarctation of the aorta, patent ductus arteriosus, hypoplastic left heart syndrome or genetic syndromes such as Turner syndrome. Among isolated cases, valve dysfunction and aortic dilation generally predict outcomes. The semilunar valve leaflets arise from the conotruncal and intercalated cushions of the outflow tract. A BAV results from abnormal aortic cusp development during valvulogenesis, where adjacent cusps fuse or fail to divide, resulting in a single large cusp with two rather than three commissures, and anatomic variability includes presence or absence of a raphe. Approximately 10% of patients with BAV have first-degree family members with BAV or associated non-valvular abnormalities such as aortic coarctation, thoracic aortic aneurysms, ventricular septal defects or mitral valve disease. Autosomal-dominant transmission of BAV has been observed in small percentage of families notably involving the NOTCH1 gene;3 however, most BAV cases are sporadic. There is no single-gene model clearly explaining BAV inheritance, suggesting a complex genetic model involving multiple interacting genes.4 Interestingly, familial clustering of hypoplastic left heart syndrome and BAV has been observed and the high heritability of hypoplastic left heart syndrome suggests that it is determined largely by genetic factors.5
Coronary artery development and variants
Coronary artery buds begin as angiogenic sprouts from the sinus venosus which create sinusoids within the developing myocardium, specifically within the epicardial atrioventricular and interventricular grooves near the apex. As these vascular endothelial networks coalesce, their proximal segments grow towards and ultimately connect into the aortic sinuses.
Coronary artery anatomy can be divided into three categories: normal, normal variants and anomalous origins. Normal coronary origins are defined as arising within the mid third of the appropriate sinus (LCA from the left sinus of Valsalva and RCA from the right sinus of Valsalva) and perpendicular to the sinus wall. Normal coronary origin variants are common in the general population and include those where the origin may be more leftward or rightward within the appropriate cusp, or just above the sinotubular junction (termed high take-off and defined as ostial position within 5 mm above the sinotubular junction). It is known that the high take-off variant involving the RCA is more commonly seen among patients with BAV.
Coronary artery anomalies are rare and found in <1% of the general population. The most common variants include separate ostia of the left anterior descending and left circumflex and followed by anomalous origin of the left circumflex from the right sinus of Valsalva with retroaortic course, both typically benign lesions. Anomalous coronaries from the opposite sinus of Valsalva which course between the great arteries (interarterial), such as RCA from the left sinus of Valsalva and LCA from the right sinus of Valsalva, are quite rare; however, they are clinically most important as they represent the second most common cause of sudden cardiac death among young athletes. Interarterial coronaries with an intramural or hypoplastic proximal segment within the aortic wall are highest risk (LCA>RCA), and the length of the intramural course correlates with adverse events.6 Coronary arteries that arise well above the sinotubular junction are also rare, have been associated with a narrowed intramural proximal course traversing vertically within the tunica media and may demonstrate impaired coronary perfusion due to acute angulation. Narrowing may be further strained with dilation or with torsion of the aorta during exercise. Additionally, distance from the sinus of Valsalva is important as the sinuses facilitate maximal coronary diastolic perfusion.
Clinical assessment and implications of BAV with associated coronary variants
Appropriate imaging is critical to identification of coronary position, dominance and ostial characteristics among patients with BAV prior to surgical intervention. Non-invasive imaging has quickly supplanting invasive coronary angiography to identify coronary variants among patients with CHD. Although cardiac MRI or echocardiogram may be used in children, coronary CT angiography (CTA) is currently regarded as the diagnostic standard for the evaluation of coronary origins as it offers the best performance in spatial resolution, acquisition time and image contrast, however at the cost of radiation exposure. Coronary CTA may be performed with negligible radiation exposure (1.5–3 mS)7 providing detailed assessment of coronary origins and ostial characteristics, determination of proximal course to identify interarterial variants with intramural segments, dominance pattern as well as presence of absence of atherosclerosis.
Although high take-off coronary variants are most often benign, they may complicate invasive coronary angiography and identification is important before surgical aortotomy as cross-clamping of the aorta below a high-origin coronary artery may result in unsuccessful induction of cardioplegia. Importantly there are reports of sudden death associated with high take-off well above the sinotubular junction and distinguishing these variants from benign normal variants is critical. In the current study, it is unclear if any of the coronaries examined had a narrowed proximal intramural course which would predispose to adverse outcome. Additionally it is not known if the coronary variants identified contributed to the demise of the children in this cohort.
Koenraadt et al previously demonstrated that type IB BAVs show more left dominant coronary systems and more significant coronary artery disease.1 It is unclear if this is due to increased atherosclerosis burden within the coronary tree or congenital vessel abnormalities such as coronary hypoplasia that may drive events. Nonetheless, atherosclerosis prevention remains of paramount importance in adults with CHD particularly with known left dominant systems.
Understanding associations between coronary variants and CHD with BAV may lend to future genetic insights
The genetic underpinning of abnormal coronary development is not well understood and identifying association with congenital left heart disease and aortic root abnormalities may shed some light on a potential common developmental landscape. Embryological formation of the human heart requires a complex integration of a myriad of genes, many of which are not cardiac specific, and is only partially understood.8 It is presumed that ectopic coronary origins occur as a consequence of disordered molecular signalling with potential genetic underpinnings.
It is clear that a relationship exists between BAVs and coronary variants and it is plausible that variations in coronary anatomy may be part of the developmental comorbid abnormalities with BAV. The process of ingrowth of the coronary stems to the appropriate cusp is guided by molecular signalling events from epicardial-derived cells dictated by the borders of the valves in a regionalized fashion; however, mechanisms are incompletely elucidated. It is possible that when these borders are ill-defined such as in BAV, variations in coronary anatomy may occur. However, some argue that BAV is unable to influence the development of coronary arteries as the arteries join the aorta at a later stage.9 This is consistent with the concept that genetic variation affecting both valvular formation and coronary guidance alters basic regional cellular functionality such as motility, migration or cell–cell communication required across both processes. In this study, increased prevalence of high take-off LCA compared with RCA was identified, notably higher among patients with BAV and associated CHD compared with isolated BAV. The authors comment that this may be due to the fact that left and right coronary ostia are patterned by different mechanisms as animal models have identified that transcription factor Tbx1 expressed in the outflow tract promotes development of the left but not right proximal coronary ostium.
Given the complexity of genetic modeling, collaboration across CHD centres and enthusiastic support of consortium work is critical to promote progress in this field. As we refine our understanding of associated CHD patterns, we may improve insights into defining the underlying molecular basis of BAV, the developmental and genetic underpinnings of coronary development as well as common cellular origins that underlie associated CHD.
Contributors DDY is solely responsible for the idea generation and writing this editorial.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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