Bicuspid Aortic Valve in 2 Model Species and Review of the Literature

Abstract

Bicuspid aortic valve (BAV) is the most common human congenital cardiac malformation. Although the etiology is unknown for most patients, formation of the 2 main BAV anatomic types (A and B) has been shown to rely on distinct morphogenetic mechanisms. Animal models of BAV include 2 spontaneous hamster strains and 27 genetically modified mouse strains. To assess the value of these models for extrapolation to humans, we examined the aortic valve anatomy of 4340 hamsters and 1823 mice from 8 and 7 unmodified strains, respectively. In addition, we reviewed the literature describing BAV in nonhuman mammals. The incidences of BAV types A and B were 2.3% and 0.03% in control hamsters and 0% and 0.3% in control mice, respectively. Hamsters from the spontaneous model had BAV type A only, whereas mice from 2 of 27 genetically modified strains had BAV type A, 23 of 27 had BAV type B, and 2 of 27 had both BAV types. In both species, BAV incidence was dependent on genetic background. Unlike mice, hamsters had a wide spectrum of aortic valve morphologies. We showed interspecific differences in the occurrence of BAV between humans, hamsters, and mice that should be considered when studying aortic valve disease using animal models. Our results suggest that genetic modifiers play a significant role in both the morphology and incidence of BAV. We propose that mutations causing anomalies in specific cardiac morphogenetic processes or cell lineages may lead to BAV types A, B, or both, depending on additional genetic, environmental, and epigenetic factors.

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes

“…17). Virtually the same spectrum has been described in animal models, in which the anatomical variation depends on the severity of the embryonic defect [66,67,69,76].…”

“…In complex-presentation forms like BAV associated with genetic syndromes, right non-cusp fusion is more common in patients with Down syndrome, and right-left cusp fusion is more common in patients with Turner syndrome and Shone complex, suggesting different abnormalities in developmental pathways [8]. Based on the results from animal experiments, it can be assumed that the embryological background of the fused types is that of abnormal remodelling/maturation (excavation) of the valve cushions (the 3 fused types may be explained by defective excavation) or a mild defect during outflow tract septation for fused right-left phenotypes and during endocardial cushion formation/positioning for the fused right non-and left nonphenotypes [65][66][67][68][69].…”

Excess Provisional Extracellular Matrix: A Common Factor in Bicuspid Aortic Valve Formation

“…At early time points, this may involve a series of chemically stained histological sections shown alongside a 3D reconstruction derived from each section through the developing AoV [54]. Episcopic imaging [73] and scanning electron microscopy [74] are high-quality methods that will also reveal BAV morphology. At post-natal time points, microdissection and simple light microscopy can be sufficient [54].…”

“…At post-natal time points, microdissection and simple light microscopy can be sufficient [54]. Wild-type evaluation for BAV is imperative since there are different frequencies of BAVs among strains with significant genetic modifiers that promote BAV in the C57Bl/6 genotype [58,60,74]. There are reports that the type of BAV cusp 'fusion' may be indicative of its genetic origins during development [74][75][76].…”

“…Wild-type evaluation for BAV is imperative since there are different frequencies of BAVs among strains with significant genetic modifiers that promote BAV in the C57Bl/6 genotype [58,60,74]. There are reports that the type of BAV cusp 'fusion' may be indicative of its genetic origins during development [74][75][76]. The term 'fusion' is common in describing BAV, however, investigations reveal the bicuspid morphology is primarily due to the failure to fully form each cusp rather than a 'fusion' event between two distinct cusps.…”