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CLINICAL RESEARCH: VALVULAR HEART DISEASE

Bicuspid Aortic Valves With Different Spatial Orientations of the Leaflets Are Distinct Etiological Entities

Borja Fernández, PhD^_*,_*, Ana C. Durán, PhD^_*, Teresa Fernández-Gallego, BSc^_*, M. Carmen Fernández, BSc^_*, Miguel Such, MD, Josep M. Arqué, MD and Valentín Sans-Coma, PhD^_*

^_* Department of Animal Biology, Faculty of Science, University of Málaga, Málaga, Spain
Department of Cardiovascular Surgery, University Hospital Virgen de la Victoria, Málaga, Spain
Department of Cardiovascular Surgery, University Hospital Carlos Haya, Málaga, Spain

Manuscript received February 16, 2009; revised manuscript received June 24, 2009, accepted July 6, 2009.

^_* Reprint requests and correspondence: Dr. Borja Fernández, Department of Animal Biology, Faculty of Science, University of Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain (Email: borjafe{at}uma.es).

Objectives: The aim of this study was to decide whether bicuspid aortic valves (BAVs) with fused right and noncoronary leaflets (R-N) and BAVs with fused right and left leaflets (R-L) have different etiologies or are the product of a single diathesis.

Background: The BAV is the most common congenital cardiac malformation. The R-N and R-L BAVs are the most frequent BAV subtypes.

Methods: The study was carried out in adult and embryonic hearts of endothelium nitric oxide synthase knock-out mice and inbred Syrian hamsters with a high incidence of R-N and R-L BAVs, respectively. The techniques used were histochemistry, immunohistochemistry, and scanning electron microscopy.

Results: The R-N BAVs result from a defective development of the cardiac outflow tract (OT) endocardial cushions that generates a morphologically anomalous right leaflet. The left leaflet develops normally. The R-L BAVs are the outcome of an extrafusion of the septal and parietal OT ridges that thereby engenders a sole anterior leaflet. The noncoronary leaflet forms normally.

Conclusions: The R-N and R-L BAVs are different etiological entities. The R-N BAVs are the product of a morphogenetic defect that happens before the OT septation and that probably relies on an exacerbated nitric oxide–dependent epithelial-to-mesenchymal transformation. The R-L BAVs result from the anomalous septation of the proximal portion of the OT, likely caused by a distorted behavior of neural crest cells. Care should be taken in further work on BAV genetics because R-N and R-L BAVs might rely on different genotypes. Detailed screening for R-N and R-L BAVs should be performed for a better understanding of the relationships between these BAV morphologic phenotypes and other heart disease.

Key Words: bicuspid aortic valve • etiology • embryology • endothelial nitric oxide synthase • cardiac neural crest • animal models

Abbreviations and Acronyms   BAV = bicuspid aortic valve   CoA = coarctation of the aorta   E/M = epithelial-to-mesenchymal   eNOS–/– = endothelium nitric oxide synthase knock-out   NC = neural crest   OT = outflow tract   R-L = right and left coronary leaflet   R-N = right and noncoronary leaflet   SM = smooth muscle

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