The Etiological Heterogeneity of Bicuspid Aortopathy between Ascending and Root Morphotype
Heterogeneity of Bicuspid Aortopathy
DOI:
https://doi.org/10.1532/hsf.3333Keywords:
Aortic Aneurysm, Wall Shear Stress, Matrix Metalloproteinases, 4D Flow CMRAbstract
Background: Valve-related hemodynamics and intrinsically regulated matrix proteases are 2 determined pathogenetic factors associated with medial elastin degeneration in bicuspid aortopathy. This study analyzed the association between elastic fiber deterioration and the 2 pathogenetic factors in ascending and root morphotypes, aiming to elucidate the etiological heterogeneity between the 2 morphotypes.
Methods: Four-dimensional flow cardiac magnetic resonance was used to measure the regional wall shear stress (WSS) on the ascending aorta, and matrix metalloproteinase (MMP) expression was assessed by immunoblotting. After histopathology analysis of aortic tissue, we assessed whether elevated regional WSS and increased MMP expression corresponded with medial elastin thinning.
Results: Increased regional WSS corresponded with medial elastin thinning in both morphotypes. Increased expression of different MMP isoforms corresponded with medial elastin degeneration in bicuspid aortopathy. The significantly increased expression of MMP-2 corresponded with a decrease of elastic fiber thickness in the ascending morphotype (P = .046), whereas elastic fiber thinning was associated with high levels of MMP-3 expression (P = .012) in the root morphotype. No association was observed between regional WSS and MMP expression.
Conclusion: There is no difference in the effect of valve-related hemodynamics between ascending and root morphotype, and MMPs are not involved in the process of elastic fiber degeneration induced by increased WSS. The increased expression of different MMP isoforms was observed in the context of elastic fiber degeneration between the 2 morphotypes, implying that heterogeneity between them is revealed in the different intrinsic pathway of medial elastin degradation.
References
Basso C, Boschello M, Perrone C, et al. An echocardiographic survey of primary school children for bicuspid aortic valve. Am J Cardiol 2004;93:661-663.
Bollache E, Guzzardi DG, Sattari S, et al. Aortic valve-mediated wall shear stress is heterogeneous and predicts regional aortic elastic fiber thinning in bicuspid aortic valve-associated aortopathy. J Thorac Cardiovasc Surg 2018;156:2112-2120.e2.
Cotrufo M, Della Corte A, De Santo LS, 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;130:504-511.
Eleid MF, Forde I, Edwards WD, et al. Type A aortic dissection in patients with bicuspid aortic valves: Clinical and pathological comparison with tricuspid aortic valves. Heart 2013;99:1668-1674.
Fazel SS, Mallidi HR, Lee RS, et al. The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch. J Thorac Cardiovasc Surg 2008;135:901-907.e1-2.
Fedak PW, Verma S, David TE, et al. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106:900-904.
Girdauskas E, Borger MA, Secknus MA, Girdauskas G, Kuntze T. Is aortopathy in bicuspid aortic valve disease a congenital defect or a result of abnormal hemodynamics? A critical reappraisal of a one-sided argument. Eur J Cardiothorac Surg 2011;39:809-814.
Guzzardi DG, Barker AJ, van Ooij P, et al. Valve-related hemodynamics mediate human bicuspid aortopathy: Insights from wall shear stress mapping. J Am Coll Cardiol 2015;66:892-900.
Hiratzka LF, Creager MA, Isselbacher EM, et al. Surgery for aortic dilatation in patients with bicuspid aortic valves: A statement of clarification from the american college of cardiology/american heart association task force on clinical practice guidelines. J Am Coll Cardiol 2016;67:724-731.
Huang TS, Yang GJ, Tang GY. A fast two-dimensional median filtering algorithm. IEEE Trans Acoust Speech Signal Process 1979;27:13-18.
Jackson V, Petrini J, Caidahl K, et al. Bicuspid aortic valve leaflet morphology in relation to aortic root morphology: A study of 300 patients undergoing open-heart surgery. Eur J Cardiothorac Surg 2011;40:e118-e124.
Kang JW, Song HG, Yang DH, et al. Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction and bicuspid aortopathy: Comprehensive evaluation using MDCT and echocardiography. JACC Cardiovasc Imaging 2013;6:150-161.
Kari FA, Fazel SS, Mitchell RS, Fischbein MP, Miller DC. Bicuspid aortic valve configuration and aortopathy pattern might represent different pathophysiologic substrates. J Thorac Cardiovasc Surg 2012;144:516-517.
Kazhdan M, Hoppe H. Screened poisson surface reconstruction. ACM Trans Graph 2013;32:29.
Kendall A, Koochesfahani M. A method for estimating wall friction in turbulent wall-bounded flows. Exp Fluids 2008;44:773-780.
Li F, Gao Q, Qiao E, et al. Contributing factor of proximal arch dilation in patients with bicuspid aortic valve—Wall shear stress or upward extension of ascending aorta dilation? Heart Surg Forum 2020;23:E435-E440.
Longobardo L, Jain R, Carerj S, Zito C, Khandheria BK. Bicuspid aortic valve: Unlocking the morphogenetic puzzle. Am J Med 2016;129:796-805.
Michelena HI, Prakash SK, Della Corte A, et al. Bicuspid aortic valve: Identifying knowledge gaps and rising to the challenge from the international bicuspid aortic valve consortium (BAVCon). Circulation 2014;129:2691-2704.
Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem 1999;274:21491-21494.
Otsu N. A threshold selection method from gray level histograms. IEEE Trans Syst Man Cybern 1979;9:62-66.
Rabkin SW. The role matrix metalloproteinases in the production of aortic aneurysm. Prog Mol Biol Transl Sci 2017;147:239-265.
Sbardella D, Fasciglione GF, Gioia M, et al. Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes. Mol Aspects Med 2012;33:119-208.
Schaefer BM, Lewin MB, Stout KK, et al. The bicuspid aortic valve: An integrated phenotypic classification of leaflet morphology and aortic root shape. Heart 2008;94:1634-1638.
Sievers HH, Stierle U, Hachmann RM, Charitos EI. New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics. Eur J Cardiothorac Surg 2016;49:439-446.
Troeberg L, Tanaka M, Wait R, et al. E. coli expression of timp-4 and comparative kinetic studies with timp-1 and timp-2: Insights into the interactions of timps and matrix metalloproteinase 2 (gelatinase A). Biochemistry 2002;41:15025-15035.
Wang CY, Qi G, Wang HP, et al. Divergence-free smoothing for volumetric piv data. Exp Fluids 2016;57:1-23.
Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000;83:81-85.
Wojnarski CM, Svensson LG, Roselli EE, et al. Aortic dissection in patients with bicuspid aortic valve-associated aneurysms. Ann Thorac Surg 2015;100:1666-1673.
Yamashita T, Hayashi T, Tabata T, Hirata KI. Bicuspid aortic valve-associated aortic dilatation—What is the mechanism of bicuspid aortopathy? Circulation 2018;82:2470-2471.
Zhang J, Fan G, Zhao H, et al. Targeted inhibition of focal adhesion kinase attenuates cardiac fibrosis and preserves heart function in adverse cardiac remodeling. Sci Rep 2017;7:43146.
