Commentary: You cannot always go with the flow

Central MessageEndothelial nitric oxide synthase expression is not regionally dependent in the aortas of patients with unicuspid aortic valves.See Article page 157. Endothelial nitric oxide synthase expression is not regionally dependent in the aortas of patients with unicuspid aortic valves. See Article page 157. Non-tricuspid aortic valve (TAV) configurations are associated with ascending aortic aneurysms, but the mechanisms remain unclear. Competing genetic (ie, inherent aortic wall defects) and valve-mediated hemodynamic causes are the subject of considerable study.1Guzzardi D.G. Barker A.J. van Ooij P. Malaisrie S.C. Puthumana J.J. Belke D.D. et al.Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.J Am Coll Cardiol. 2015; 66: 892-900Crossref PubMed Scopus (250) Google Scholar In this edition of the Journal, Ballint and colleagues2Balint B. Kollmann C. Gauer S. Federspiel J.M. Schäfers H.-J. Endothelial nitric oxide synthase alterations are independent of turbulence in the aorta of patients with a unicuspid aortic valve.J Thorac Cardiovasc Surg Open. 2021; 8: 157-169Scopus (4) Google Scholar define the expression of endothelial nitric oxide synthase (eNOS), a mediator of vascular remodeling in response to altered arterial flow, in the ascending aorta of patients with unicuspid aortic valves (UAVs). The authors build on the methodologic techniques first established in patients with bicuspid aortic valves by Drs Della Corte and Cotrufo from Italy, whereby intraoperative tissue collection from the convexity and concavity correspond to differences in valve-mediated wall shear stresses.3Cotrufo M. Della Corte A. De Santo L.S. Quarto C. De Feo M. Romano G. et al.Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results.J Thorac Cardiovasc Surg. 2005; 130: 504-511Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar In the present study, similar tissue collection was undertaken from patients with UAV and TAV, with both aneurysmal and nonaneurysmal arms within each group. Comparing the 2 valve configurations directly, the authors report decreased eNOS protein expression in the nondilated aortic wall of patients with UAV compared with those with TAV, although no differences were observed between dilated aortic tissue from patients with UAV and TAV. As one of the few studies interrogating the role of eNOS in non-TAV aorta, this work by Ballint and colleagues2Balint B. Kollmann C. Gauer S. Federspiel J.M. Schäfers H.-J. Endothelial nitric oxide synthase alterations are independent of turbulence in the aorta of patients with a unicuspid aortic valve.J Thorac Cardiovasc Surg Open. 2021; 8: 157-169Scopus (4) Google Scholar provides a unique contribution toward understanding the molecular profile within the aortic wall of patients with UAV. The authors document increased eNOS protein expression in dilated compared with nondilated UAV aortic tissue, suggesting aneurysm development influences and/or is influenced by eNOS. The precise role of eNOS in this process requires further clarification but is congruent with previous work in BAV aortic wall, where elevated eNOS expression was observed in the region known to preferentially dilate and subject to elevated valve-mediated wall shear stress.4Kotlarcyzk M.P. Billaud M. Green B.R. Hill J.C. Shiva S. Kelley E.E. et al.Regional disruptions in endothelial nitric oxide pathway associated with bicuspid aortic valve.Ann Thorac Surg. 2016; 102: 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar In contrast, the present study did not find regional differences (ie, convexity vs concavity) within the UAV aorta, suggesting that inherent aortic wall defects may play a larger role in proximal aortic disease as compared with UAV-mediated hemodynamic derangements. However, in the absence of directly quantified valve-mediated hemodynamics beyond measures of stenosis or regurgitation,5Barker A.J. Markl M. Burk J. Lorenz R. Lorenz R. Bock J. et al.Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.Circ Cardiovasc Imaging. 2012; 5: 457-466Crossref PubMed Scopus (308) Google Scholar of which patients in this study had mixed valve lesions, these data do not fully preclude a role for UAV-mediated hemodynamics. Moreover, eNOS expression may vary at different stages of the aneurysm formation process, the nuances of which may not be fully captured in this study. In contrast to these UAV data, the authors found no difference in eNOS protein expression between dilated and nondilated TAV aortic wall, suggesting that eNOS may not play as prominent a role in TAV-mediated aortopathy. Also, opposite to the UAV data, regional differences in eNOS expression were appreciated within the TAV aortic wall, albeit at the mRNA level rather than protein expression. Overall, Ballint and colleagues2Balint B. Kollmann C. Gauer S. Federspiel J.M. Schäfers H.-J. Endothelial nitric oxide synthase alterations are independent of turbulence in the aorta of patients with a unicuspid aortic valve.J Thorac Cardiovasc Surg Open. 2021; 8: 157-169Scopus (4) Google Scholar provide a novel contribution to our understanding of the molecular mechanisms of aortic wall remodeling in UAV patients. Their results suggest UAV-mediated hemodynamics may not play a substantial role as an inherent aortic wall defect, but further studies to clarify this and the precise role of eNOS in UAV-associated aortopathy are warranted. Endothelial nitric oxide synthase alterations are independent of turbulence in the aorta of patients with a unicuspid aortic valveJTCVS OpenVol. 8PreviewCertain aortic valve malformations predispose to ascending aortic aneurysm, although the mechanisms are incompletely understood. The aim of this study was to determine whether turbulence across the unicuspid aortic valve (UAV) contributes to regional differences in endothelial nitric oxide (eNOS) signaling in the ascending aortic wall. Full-Text PDF Open Access

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