Comparison of ascending aortic cohesion between patients with bicuspid aortic valve stenosis and regurgitation

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1 European Journal of Cardio-Thoracic Surgery Advance Access published September 18, 2014 European Journal of Cardio-Thoracic Surgery (2014) 1 5 doi: /ejcts/ezu358 ORIGINAL ARTICLE Comparison of ascending aortic cohesion between patients with bicuspid aortic valve stenosis and regurgitation Jaroslav Benedik a, *, Daniel S. Dohle a, Daniel Wendt a, Kevin Pilarczyk a, Vivien Price a, Fanar Mourad a, Elizaveta Zykina a, Ferdinand Stebner b, Konstantinos Tsagakis a and Heinz Jakob a a Department of Thoracic and Cardiovascular Surgery, West-German Heart Center, University Hospital Essen, University of Duisburg Essen, Essen, Germany b Department of Research on Learning and Instruction, Institute of Educational Science, Ruhr-University Bochum, Bochum, Germany * Corresponding author. Department of Thoracic and Cardiovascular Surgery, West German Heart Center, University Hospital Essen, Hufelandstrasse 55, Essen, Germany. Tel: ; fax: ; jaroslav.benedik@uk-essen.de ( J. Benedik). Received 13 April 2014; received in revised form 4 August 2014; accepted 7 August 2014 Abstract OBJECTIVES: A bicuspid aortic valve (BAV) is commonly associated with aortic wall abnormalities, including dilatation of the ascending aorta and increased potential for aortic dissection. We compared the mechanical properties of the aortic wall of BAV patients with aortic valve stenosis (AS) and regurgitation (AR) using a dissectometer, a device mimicking transverse aortic wall shear stress. METHODS: Between March 2010 and February 2013, 85 consecutive patients with bicuspid aortic valve undergoing open aortic valve replacement at our institution were prospectively enrolled, presenting either with stenosis (Group 1, n = 58) or regurgitation (, n = 27). Aortic wall cohesion measured by the dissectometer (Parameters P7, P8 and P9), aortic diameters measured by transoesophageal echocardiography (TOE) and thickness of the wall were compared. One patient presenting with the Marfan syndrome was excluded from the study. RESULTS: Patients with aortic regurgitation were significantly younger (48.2 ± 15.8 vs 64.7 ± 10.7, P < 0.001), and had a significantly thicker aortic wall (2.30 ± 0.49 mm vs 2.06 ± 0.35 mm, P = 0.029). Transoesophageal echocardiography diameters (annulus, aortic sinuses and sinotubular junction) were significantly larger in the AR group (27.3 ± 3.6 vs 25.5 ± 2.4, P = 0.008; 41.1 ± 7.7 vs 36.7 ± 8.0, P = 0.011; 37.6 ± 9.7 vs 33.8 ± 9.1, P = 0.049). The ascending aortic diameter did not differ (43.2 ± 10.6 vs 40.3 ± 9.1, P = 0.292). Patients with AR had significantly worse aortic cohesion, as measured by shear stress testing (P7: 97.2 ± 45.0 vs ± 84.9, P = 0.015; P8: 2.00 ± 0.65 vs 3.82 ± 1.56, P < 0.001; P9: 2.96 ± 0.82 vs 4.98 ± 1.80, P < 0.001) compared with those with AS. CONCLUSIONS: We observed significantly worse aortic wall cohesion, a thicker aortic wall and a larger aortic root in patients presenting with bicuspid AR compared with patients with AS. These results suggest that bicuspid AR represents a different disease process with possible involvement of the ascending aorta, as demonstrated by dissectometer examination. Keywords: Aortic wall Bicuspid aortic valve Dissection Aortic wall cohesion testing INTRODUCTION A bicuspid aortic valve (BAV) is an aortic valve malformation that is often associated with aortic wall pathology [1]. It is not currently possible to predict future dilatation of the aorta or the risk of aortic dissection (AD) in patients with BAV. However, recent studies have identified aortic stenosis in patients with BAV acting as a trigger for post-stenotic dilatation, a potential risk factor for further aortic complications [2]. This type of aortic dilatation is probably combined with complete other aortic wall quality as these by patient with aortic bulbus dilatation and aortic valve regurgitation (AR) [3]. Histological examination of the ascending aorta of BAV patients regularly shows abnormalities of the media including fragmentation of elastin or accumulation of various deposits, leading to an alteration of the mechanical properties of the aortic wall [4]. Patients with AR become symptomatic at a younger age compared with those with bicuspid stenosis, which can even be an incidental finding at aortic valve replacement in advanced age. The presence of a BAV is an independent risk factor for progressive aortic dilatation, aneurysm formation and dissection. It is for this reason that the recommendation for concomitant ascending aortic replacement during valve replacement surgery is stricter in BAV patients than in those with tricuspid valves [5]. Moreover, as there might be a link between aortic regurgitation and aortic pathology, one explanation of this missing disparity between tricuspid and bicuspid valves might be the high proportion of stenotic valves. This hypothesis is encouraged by another study of our group revealing impaired quality of the ascending aorta in patients with AR compared with those with AS [6]. Based on these results, we focused in the current study on comparing patients with a stenotic BAV with those presenting with an incompetent BAV by our recently introduced Dissectometer device. The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 2 J. Benedik et al. / European Journal of Cardio-Thoracic Surgery MATERIALS AND METHODS Study design The study was approved by the Institutional Review Board and patients written informed consent was obtained. This single-centre, non-randomized study included 85 consecutive patients with BAV who underwent aortic valve replacement with or without other concomitant cardiac surgery at the West-German Heart Center Essen between March 2010 and February The study population of 85 patients was divided into two groups: 58 patients (Group 1) presented with bicuspid stenosis and 27 patients with bicuspid regurgitation (). One patient with Marfan syndrome was excluded from the study. Aortic diameters (aortic annulus, bulbus, sinotubular junction and ascending aortic dimensions) were assessed by intraoperative transoesophageal echocardiography (TOE). Patients with dilatation of the aortic root or ascending aorta scheduled for aortic replacement also underwent a computer tomography scan to aid with procedural planning. Sample collection The operations were carried out through a median sternotomy with ascending aortic cannulation. After transverse aortotomy, a sample of the aortic wall was harvested from the edge of the aortic incision site ( 5 20 mm), as previously described, and was immediately placed in cold saline until the cohesion test was performed (within 2 h after surgery) [6, 7]. The aortic incision was closed in the usual manner without any resulting complications. Aortic wall thickness was measured immediately before cohesion testing, using a micrometer (Kometex B.V./Hogetex, Varsseveld, Netherlands). Intraoperative echocardiography TOE was performed with a multiplane MHz (6T-RS) phased-array probe (Vivid i, GE Healthcare, Milwaukee, WI, USA) prior to cardiopulmonary bypass in all patients. All aortic dimensions (diameter of the aortic annulus, aortic sinuses, sinotubular junction and ascending aorta) were measured. Aortic wall cohesion testing Aortic wall cohesion testing was performed using the Dissectometer as previously described [7], and the results of the dissecting process were visualized as tensile strain curves (TSCs), which were subsequently converted into numerical parameters. P1, P2, P5 and P6 correspond to points on the curve. P1 (mm) is the beginning of the positive deviation the point when the dissectometer registers the tension in the sample. P2 (mm) is the point of the dissection, and the power has a value of zero. P5 (N) is the first power maximum (at this point the power has decreased temporarily). After this point, the aortic wall sample is damaged irreversibly. P6 (N) represents the dissection limit after which the power necessary to disrupt the aorta decreases. P3 (N mm 1 )is the angle of the line between P1 and P5. This characteristic describes the elasticity of the aortic wall the sharper the angle, the higher is the elasticity of the aorta. P4 (N mm 1 ) is the angle of the power decrease, which characterizes the cohesion of the Figure 1: Tensile strain curve the localization of the parameters P4, P6 and P7; mathematical formula for P8 and P9. aortic wall. P7 (N mm) represents the area under the TSC that describes the total cohesion of the aorta. These seven parameters were used to mathematically derive the next two parameters, P8 and P9. P8 is described as the dissection tendency (calculated as the maximal force divided by the downward angle) and P9 as the dissection potential (calculated as the sum of P8 and the square root of P7 divided by 10). The parameters with the highest sensitivity and specificity for discriminating between histologically stable und unstable aortic wall identified in a previous study (P7, P8 and P9) were analysed in the present study (Fig. 1)[6, 7]. All cohesion tests were performed and analysed by one observer blinded to all patient data including aortic valve pathology. Statistics Descriptive statistics are summarized for categorical variables as frequencies (%). Continuous variables are reported as mean ± standard deviation. The continual variables were compared using the Student t-test or Mann-Whitney U test. For categorical variables, Pearson s χ 2 or Fisher s exact tests were used. A P-value of <0.05 was considered to indicate statistical significance. All statistical analyses were performed using the SPSS System, version 19.0 (IBM Corp., Armonk, NY, USA). RESULTS Demographics and preoperative characteristics of both groups are listed in Table 1. Of 86 patients, 58 presented with bicuspid stenosis while 28 had bicuspid regurgitation. Patients with AR were significantly younger than patients with AS, and male gender predominated in both groups. Distribution of comorbidities was similar in both groups except for chronic obstructive pulmonary disease, which had a significantly higher prevalence in the AR group. Underlying pathology is summarized in Table 2; the echocardiographic and the dissectometer-derived results are summarized in Table 3. A total of 37 patients underwent replacement of the ascending aorta or aortic root (23 in Group 1 and 14 in Group 2; P = 0.291). Acute AD was observed in only 1 case, in. This patient underwent complex aortic repair with replacement of the aortic arch and descending frozen elephant trunk. Patients in Group 1 had significantly thinner aortic walls (2.06 ± 0.35 mm vs 2.30 ± 0.49 mm, P = 0.029). Aortic diameter as assessed by TOE (i.e. the annulus, aortic sinuses, sinotubular junction and

3 J. Benedik et al. / European Journal of Cardio-Thoracic Surgery 3 Table 1: Table 2: Demographics Underlying pathology Ascending aneurysm 18 (31.0) 10 (37.3) Aortic root dilatation 10 (17.2) 9 (33.3) CAD 23 (39.7) 6 (22.2) Dissection 0 (0) 1 (3.6) Data are presented as number (%). CAD: coronary artery disease; *: Group 1 vs. Table 3: Transoesophageal dimensions and tensile strain curves results Age (years) 64.7 ± ± 15.8 <0.001 Female 16 (27.6) 6 (22.2) 0.6 Hypertension 47 (81.0) 18 (66.7) Diabetes mellitus 5 (8.6) 2 (7.4) 0.85 Renal insufficiency 5 (8.6) 2 (7.4) Hypercholesterolaemia 30 (51.7) 10 (37.0) COPD 10 (17.2) 0 (0) Data are presented as mean ± SD or number (%). COPD: chronic obstructive pulmonary disease; *: Group 1 vs. Aortic wall thickness (mm) 2.06 ± ± Aortic annulus (mm) 25.5 ± ± Aortic sinuses (mm) 36.7 ± ± Sinotubular junction (mm) 33.8 ± ± Ascending aorta (mm) 40.3 ± ± LV 49.0 ± ± P ± ± P ± ± 0.65 <0.001 P ± ± 0.82 <0.001 Data are presented as mean ± SD. LV: left ventricle function (%); P7, P8 and P9: dissectometer parameters; *: Group 1 vs. ascending aorta) was larger in (the difference in the diameter of the ascending aorta was too small to be statistically significant). We observed statistically significant differences in aortic wall cohesion between the two groups as shown by the dissectometer parameters (P7: ± 84.9 vs 97.2 ± 45.0, P = 0.015; P8: 3.82 ± 1.56 vs 2.00 ± 0.65, P < 0.001; P9: 4.98 ± 1.80 vs 2.96 ± 0.82, P < 0.001). The main results are also presented in a detailed box-plot diagram (Fig. 2). DISCUSSION A BAV is a common, predominantly congenital, form of aortic valve malformation. Aortic stenosis is the most frequent complication of BAV, in many cases requiring aortic valve replacement. Bicuspid valves are present in the majority of patients aged years with significant aortic stenosis, reflecting the propensity for premature fibrosis, stiffening and calcium deposition in these abnormally functioning valves. In contrast, aortic regurgitation in the presence of a BAV usually occurs due to cusp prolapse, fibrotic retraction or dilatation of the annulus or sinotubular junction. As there is a growing body of evidence in the literature that the type of valve pathology stenosis or regurgitation greatly influences aortic wall properties, we compared the aortic wall cohesion in BAV patients with stenosis against those with regurgitation. Many investigators have attempted to establish a link between aortic valve morphology and abnormalities of the ascending aorta. For many years aneurysm formation in patients with BAV was believed to be a result of haemodynamic changes due to stenosis or regurgitation, and this was corroborated by La Canna group s finding that there was no difference in aneurysm formation between patients with normally functioning bicuspid and tricuspid valves [8]. However, the haemodynamic changes caused by BAV without stenosis or insufficiency seem to be an insufficient explanation for the development of aortic complications. Yasuda et al. [9] demonstrated that early elective aortic valve replacement in patients with BAV without ascending aortic replacement did not prevent future aortic dilatation, which differs from what has been observed in patients with tricuspid aortic valve. The authors also suggest that in patients with aortic insufficiency, the aortic dilatation progresses more acutely than in valvular stenosis. Patients with connective tissue disorders and a bicuspid AV regularly have increased fibrillin degradation, as reflected by increased matrix metalloproteinase activity [10]. Each morphological group of BAV (right-left coronary, left-noncoronary and right-non-coronary) possesses unique signatures of matrix metalloproteinases and endogenous tissue inhibitors of metalloproteinases [11 13], but it is unclear whether the type of fusion could influence aneurysm formation. Russo et al. [14] showed, that patients with right-left fusion tend more severe aortic degeneration; however, some degree of degeneration was found in all patients. Interestingly, Kang et al. [15] have previously described that the fusion of the right or left coronary cusp with the non-coronary cusp was associated with a significantly higher aortopathy rate than that seen with fusion of the right and left coronary cusp. Schaefer et al. [16] repeated these results, but in contrast to Kang et al. they observed more patients with fusion of the right and left coronary cusp. Regarding morphometric analysis, patients with BAVs have a thinner media with a greater distance between the elastic lamellae [4]. This observation could be one explanation for inferior cohesion of the aortic wall. In a previous study, we could not demonstrate any difference in the aortic wall quality between patients with bicuspid and tricuspid aortic valves assessed with the dissectometer, in contrast to many others [17]. Viscardi et al. [18] model the ascending aortic flow to demonstrate the asymmetrical distribution of velocity field in the convexity of the ascending aorta by the bicuspid compared with tricuspid valves. The changes were most pronounced in Type 2 bicuspid fusions (fusion of one coronary and non-coronary cusps) than in Type 1 bicuspid fusions (fusion of both coronary cusps).

4 4 J. Benedik et al. / European Journal of Cardio-Thoracic Surgery Figure 2: The box-plot diagram of dissectometer variables. Green: Group 1; Red:. Girdauskas et al. [19] was one of the first to describe the loss of elastic fibres in the aortic media as the cause of the thinner, more vulnerable aortic wall in patients with bicuspid AR. In contrast, our results showed a thicker wall in this group of patients. In contrast to our patient population, all of their patients had an aortic dilatation of >5 cm. Our patients presenting with bicuspid AS had a thinner aortic wall than those with AR, and greater thickness of the aortic wall was associated with poorer cohesion. Della Corte et al. found that root phenotype and aortic regurgitation in patients with BAV were predictors of faster progression of dilatation of the ascending aorta [20]. Although the incidence of ascending aortic aneurysm was comparable between the two groups, dilatation of the aortic annulus, aortic root and sinotubular junction segment was observed more frequently in the AR group, which corresponds with root phenotype. We observed significantly worse cohesion of the aortic wall in these patients. With regard to aortic dimensions, we decided to use the absolute aortic diameter within the present study, which although widely used, does not represent an indexed aortic diameter that is proportional to the patients body surface area [21, 22]. We have recently shown the value of dissectometer parameters (P7, P8 and P9) in determining aortic wall instability [6, 17]. In this study, bicuspid AR patients developed symptoms at a younger age, and had larger aortic annuli, root and sinotubular junction parameters than those patients presenting with bicuspid AS, which is in agreement with the current literature. In our previous study comparing aortic wall cohesion between patients presenting either with bicuspid or tricuspid valve, we failed to find any differences in aortic wall quality [17]. The article was discussed by Girdauskas and Rouman [23], and so we decided to focus on the patients with bicuspid valve only with a larger patient group. The current study showed that patients with bicuspid regurgitation were more prone to aortic wall instability than those with bicuspid aortic stenosis. CONCLUSION Our current study showed that bicuspid aortic regurgitation is closely associated with impaired aortic wall quality in the cohesion test. These results may allow us to infer that patients with aortic regurgitation of a bicuspid valve represent a subset of patients more prone to aortic complications than patients with aortic stenosis. However, this remains to be confirmed in a larger group of patients with a longer follow-up period. Limitations The present study was performed at a single tertiary care medical centre. The long-term follow-up of patients for the development of aortic complications, including dissections and aneurysms, was not included. As a major limitation, we did not perform a power calculation prior to commencement of the present study and the timeframe of enrolment was arbitrarily set. There is currently a lack of a physical mechanical theory to explain these results. Future or more sophisticated analyses might help to gain a better understanding. Conflict of interest: The authors disclose no conflict of interests in regard to the present manuscript. REFERENCES [1] Siu SC, Silversides CK. Bicuspid aortic valve. J Am Coll Cardiol 2010;55: [2] Davies RR, Kaple RK, Mandapati D, Gallo A, Botta D, Elefteriades JA et al. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann Thorac Surg 2007;83: [3] Girdauskas E, Borger MA, Kuntze T. Novel Phenotypes in Bicuspid Aortic Valve Disease, Aortic Valve Prof. Chen Ying-Fu (Ed.). ISBN: In Tech, [4] Bauer M, Pasic M, Meyer R, Goetze N, Bauer U, Siniawski H et al. Morphometric analysis of aortic media in patients with bicuspid aortic valve. Ann Thorac Surg 2002;74: [5] Borger MA, Preston M, Ivanov J, Fedak PWM, Davierwala P, Armstrong S et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve? J Thorac Cardiovasc Surg 2004;128: [6] Benedik J, Pilarczyk K, Wendt D, Price V, Tsagakis K, Perrey M et al. Is there any difference in aortic wall quality between patients with aortic stenosis and those with regurgitation? Eur J Cardiothorac Surg 2013;44: [7] Benedik J, Azhari P, Tsagakis K, Pilarczyk K, Indruch J, Baba HA et al. Dissectometer a new device for tensile strength testing of the vascular wall. Minim Invasive Ther Allied Technol 2012;21:

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