Patients after Norwood procedure for HLHS have native pulmonary valve in the systemic position. The presence of pulmonary autograft in the systemic position (under systemic pressure), as occurs in patients after the Ross procedure and arterial switch operation, is considered to be an independent risk factor for aortic dilatation [16–18]. A remodeling process of pulmonary autograft in systemic position has been studied in patients after Ross procedure by Rabkin-Aikawa et al. [19]. They found granulation tissue as an early sign of damaged arterial wall of the autograft, which progresses to accumulation of collagen and focal loss of normal muscle cells and elastin, which suggests scarring formation. These histological findings may explain progressive dilation of pulmonary autograft over time. Histopathological examinations of dilated aortic wall are also conducted in patients with HLHS, which showed cystic medial degenerative changes both in native and graft tissues, which is similar to aortopathy associated with bicuspid aortic valves and connective tissue disorders [7, 9]. Moreover, lack of supportive structure of semilunar valves may be related to neo-aortic root dilation. The normal aortic root annulus is wedged between the left and right atrioventricular valve annuli and thick left ventricular myocardium, whereas the pulmonary valve complex has only slight support from the thin right ventricular myocardium [5, 20].

While the genetic basis of HLHS remains largely unknown, several studies suggest that HLHS is heritable and is genetically related to bicuspid aortic valve which is known to be associated with aortopathy [21, 22]. HLHS has been shown to be predisposed to certain well-defined genetic disorders, such as Turner and Jacobsen syndromes [23, 24]. The widely accepted concept is that HLHS is a severe form of left-sided valve malformation secondary to embryonic alterations in blood flow, such as mitral or aortic stenosis [22]. In fact, in the embryonic chick, ligation of the left atrium resulted in left ventricular hypoplasia due to diminished flow through the left ventricle [25]. Observations of familial clustering of HLHS and bicuspid aortic valve prompted an investigation to determine the size of the genetic effect of HLHS by Hinton et al. [22, 26, 27]. They performed echocardiograms on family members of HLHS probands with aortic valve hypoplasia and dysplasia to assess the presence of cardiovascular malformations. Overall, 21 out of 38 (55 %) families had more than one affected individual, and 36 % of participants had cardiovascular malformations, including 11 % with bicuspid aortic valve. Maximum likelihood-based variance decomposition showed that the heritability of HLHS alone and with associated cardiovascular malformations were as high as 99 % and 74 % (p > 0.00001), respectively, suggesting that HLHS is determined largely by genetic effects. Similar analysis assuming an autosomal recessive trait reduced estimated heritability of HLHS, which questioned the assumption that HLHS is inherited as a simple Mendelian autosomal recessive condition and implicated HLHS as a complex trait. The sibling recurrence risk for HLHS was 8 % and 22 % for cardiovascular malformations. The genetic basis of HLHS and its relationship to bicuspid aortic valve was further investigated by the same group [21]. They performed family-based nonparametric genome-wide linkage analysis to identify disease loci for HLHS and bicuspid aortic valve. The recurrence risk ratio of BAV in HLHS families (8.05) was nearly identical to that in bicuspid aortic valve families (8.77). Linkage to multiple chromosomal regions, such as 10q22 and 6q23, was identified in HLHS kindreds, suggesting genetic heterogeneity of HLHS. Moreover, a shared chromosomal locus on 14q23 was identified for HLHS and bicuspid aortic valve, which provides the first direct evidence of a genetic relationship between HLHS and bicuspid aortic valve.

Recent studies have revealed that the transforming growth factor (TGF)-β signaling plays an important role in vascular remodeling. It has been theorized that fibrillin interacts with latent TGF-β binding protein to control TGF-β activity [28]. Thus, fibrilin-1 deficiency as in Marfan syndrome causes dysregulated TGF-β activation, which can result in matrix degradation and aortic dilation [29]. Correspondingly, suppression of TGF-β signaling by angiotensin II receptor antagonists has been shown to prevent vascular damage in Marfan syndrome [30, 31]. In fact, increased TGF-β signaling is shown to be universally present in aneurysms of various etiologies, which are not limited to the fibrillin-1 deficiency [29, 32]. While dysregulation of TGF-β activation has not been well substantiated in CHD-associated aortic dilation, TGF-β signaling have been shown to contribute to cardiac embryogenesis such as in cardiac neural crest cell migration and the formation of the cardiac outflow tracts [33]. Moreover, fibrillin-1 gene variants in individuals with tetralogy of Fallot are reported to be at an eight times greater risk of aortic dilatation [34]. A novel mutation of SMAD3, which encodes an intracellular member of the TGF-β signaling pathway, is reported in a patient with HLHS with significant aortic aneurysm, but the causal relationship remains to be elucidated.

In patients with tetralogy of Fallot, factors associated with excessive flow through the aorta, such as higher age at operation, pulmonary atresia, and longer presence of surgically created aortopulmonary shunts, are associated with an aortic dilatation [16, 35–38]. Therefore, chronic aortic overflow has been attributed to aortic dilation. In patients with HLHS, a valuable study comparing long-term outcome between those with modified BT shunt and those with the right ventricular to pulmonary artery shunt as initial shunt for Norwood procedure has suggested a contribution of aortic overflow [39, 40]. Neo-aortic annular dimension Z-scores were significantly greater in the modified BT shunt group before stage II operation. However, the differences were no longer significant in the longer term at 14 months.