JOURNAL OF MAGNETIC RESONANCE IMAGING 40:294–300 (2014)
Original Research
Association Between Leaflet Fusion Pattern and Thoracic Aorta Morphology in Patients With Bicuspid Aortic Valve Bryce A. Merritt, BA,1* Alexander Turin, BS,1 Michael Markl, PhD,1,2 S. Chris Malaisrie, MD,3,4 Patrick M. McCarthy, MD,3,4 and James C. Carr, MD1,4,5 Key Words: BAV; CMR; thoracic aorta
Purpose: To determine if patients with certain bicuspid aortic valve (BAV) phenotypes are predisposed to particular morphological abnormalities of the thoracic aorta.
J. Magn. Reson. Imaging 2014;40:294–300. C 2013 Wiley Periodicals, Inc. V
Materials and Methods: One hundred ninety-two patients with BAV who underwent magnetic resonance angiography between January 2007 and July 2010 were retrospectively identified. Aortic morphology was examined through measurements of aortic size index at nine levels along the thoracic aorta, three-dimensional volume of the ascending aorta, vessel asymmetry, and assessment of aortic root morphology. Results: We found 140 patients (73%) with right and left coronary cusps (R-L) fusion, 46 patients (24%) with R-N fusion, and 6 patients (3%) with left and noncoronary cusps (L-N) fusion. Mean aortic volume in the proximal ascending aorta was significantly greater in R-L patients (0.93 versus 0.60 cm3/m2; P < 0.01). R-N patients possessed greater aortic size index at the distal ascending aorta and proximal aortic arch, and were also significantly more likely to have Type 2 patterns of aortic dilatation. Conclusion: Our results suggest that BAV with R-L fusion is associated with increased dimensions of the aortic root, while BAV with R-N fusion is associated with increased dimensions of the distal ascending aorta and proximal arch. Our findings illustrate the morphological heterogeneity that exists among BAV phenotypes.
1 Northwestern University, Feinberg School of Medicine, Department of Radiology, Chicago, Illinois, USA. 2 Department of Biomedical Engineering, Northwestern University, Chicago, Illinois, USA. 3 Northwestern University, Feinberg School of Medicine, Division of Cardiac Surgery, Chicago, Illinois, USA. 4 Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, Chicago, Illinois, USA. 5 Northwestern University, Feinberg School of Medicine, Department of Medicine, Chicago, Illinois, USA. *Address reprint requests to: B.A.M., 420 E. Ohio Street, #23D, Chicago, IL 60611. E–mail: [email protected] Received March 7, 2013; Accepted August 5, 2013. DOI 10.1002/jmri.24376 View this article online at wileyonlinelibrary.com. C 2013 Wiley Periodicals, Inc. V
BICUSPID AORTIC VALVE (BAV) is the most common congenital heart defect, affecting 0.5–2.0% of the general population (1). This condition may be responsible for more deaths and morbidity than the combined effects of all other congenital heart defects, and is the most common underlying cause for aortic valve replacement in the United States (2,3). While the influence of BAV on valvular disorders such as aortic regurgitation and aortic stenosis has been extensively documented (2,4,5), this condition is increasingly recognized as a disease of the entire aortic root, ascending aorta, and the aortic arch (6). BAV is associated with a high risk of aortic dilation (7–11), and patients with BAV have larger diameters and a higher prevalence of aortic root and ascending thoracic aortic dilation than those with tricuspid aortic valve (12). It is widely known that with increasing size of an ascending aortic aneurysm, the risk of aortic dissection and aneurysm rupture increases (1). Furthermore, autopsy reports of patients with aortic dissection demonstrate BAV in 7–9% of cases and BAV has been shown to occur in as many as 28% of aortic dissection cases in patients 4 cm was found. Statistical Analysis For continuous variables, Student’s t-test /analysis of variance were used for single/multiple variables with normal distribution. x2 tests were performed to compare frequencies between groups. Categorical data are given as total number (relative frequency). Continuous
BAV Phenotype and Thoracic Aorta Morphology
297
Figure 2. Cardiac MRI annotated to illustrate the measurements used to estimate the volume of the ascending aorta, from the sinotubular junction to the proximal innominate trunk. Cross-sectional images show the two diameter measurements used for each aortic level.
data are given as mean 6 standard deviation. Statistical significance was defined as a value of P < 0.05.
RESULTS Patient Characteristics There were 139 males and 53 females and the mean age was 45.8 6 13.1 years (range: 20–79 years). Mean body surface area was 1.98 6 0.23m2 (range: 1.42– 2.70 m2). The patterns of cusp fusion were as follows: 140 patients (73%) were classified as R-L, 46 patients (24%) were classified as R-N, and 6 patients (3%) were classified as L-N. As L-N BAV was rare, no conclusions could be drawn from this data and thus these patients were excluded from analysis. A total of 20 (10.4%) of
patients possessed a bovine arch. Of those patients with bovine arches, 15 (75%) had R-L valves and 5 (25%) had R-N valves. There were no significant differences in gender (P ¼ 0.93), age (P ¼ 0.064), or BSA (P ¼ 0.28) among the three BAV phenotypes. No significant differences existed between groups in three additional risk factors for aortic dilation: smoking history, diabetes mellitus history, and hypertension (Table 2). Aortic Dimensions When all BAV phenotypes were compared, R-N patients were shown to have significantly greater aortic size indices (cm/m2) at the distal ascending aorta (P ¼ 0.014) and proximal aortic arch (P ¼ 0.011). Additionally, R-L patients were shown to have significantly
Figure 3. Cardiac MRIs illustrating each of the four aortic morphologies classified in the study.
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Table 2 Patient Characteristics
n Age (years) Males (%) Body SA (m2) Smokers (%) Diabetes (%) Hypertension (%)
R-L
R-N
L-N
Total
140 (73%) 47.1 101 (72%) 1.97 28 (32%) n ¼ 87 2 (1%) n ¼ 134 16 (13%) n ¼ 126
46 (24%) 42.7 34 (74%) 2.03 11 (34%) n ¼ 32 2 (4%) n ¼ 45 5 (12%) n ¼ 42
6 (3%) 39.4 4 (67%) 2.04 1 (25%) n¼4 0 (0%) n¼6 1 (17%) n¼6
192 45.8 6 13.11 139 (72%) 1.98 6 .23 40 (33%) n ¼ 123 4 (2%) n ¼ 185 22 (13%) n ¼ 174
Clinical and demographic characteristics of the study population. Table 3 BAV Phenotype vs. Aortic Size Index (cm/m2) 1
2
3
4
5
6
7
8
9
R-L 1.60* 1.97z 1.82* 2.03 2.01 1.78 1.65 1.27 1.15* R-N 1.49 1.77 1.71 1.97 2.03 1.91y 1.77y 1.22 1.07 *P < 0.05 P < 0.01 z P < 0.001 1. Aortic annulus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proxmial Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm Variations in aortic diameter with bicuspid aortic valve fusion pattern type.
(22%) had Type 2 morphology, and 52 patients (28%) had Type 3 morphology. Comparing R-L and R-N fusion phenotypes showed a significantly greater percentage of R-L patients with Type 1 morphology (P ¼ 0.009). R-N patients were more likely to have Type 2 aortic morphology (P ¼ 0.035) (Table 6).
y
greater aortic size indices at the aortic annulus (P ¼ 0.032), sinus of Valsalva (P ¼ 0.00002), sinotubular junction (P ¼ 0.013), and distal descending aorta (P ¼ 0.025) (Table 3). R-N patients were more likely to possess an asymmetric sinus of Valsalva compared with R-L patients (P ¼ 0.00002) (Table 4). There was no significant difference in total ascending aortic volume between fusion phenotypes. However, when regions were analyzed individually, region 1 volume (cm3/m2), from STJ to proximal ascending aorta, was significantly greater in R-L patients compared with R-N (P ¼ 0.0097) (Table 5). Aortic Morphology Overall, 52 patients (28%) had Type 0 morphology, 42 patients (23%) had Type 1 morphology, 40 patients
DISCUSSION Overall, our results suggest that BAV with fusion of the right and left coronary cusps (R-L) is associated with increased dimensions of the aortic root, while BAV with fusion of the right and noncoronary cusps (R-N) is associated with increased dimensions of the distal ascending aorta and proximal arch. Furthermore, the present study finds greater morphological differences between BAV phenotypes than has been reported in previous research. In our measurements of aortic size indices, R-L patients showed significantly increased dimensions at each level of the aortic root when compared with R-N patients. These results are in accordance with the findings of prior studies showing significantly larger mean aortic root diameters in those with R-L fusion (3,26). The results of our ascending aortic volume measurements agree with this data, with R-L patients shown to have increased aortic volume from the sinotubular junction to the proximal ascending aorta. Our findings provide further evidence that disproportionate dilation of the root is more common among patients with R-L fusion pattern. There was a reversing trend in aortic dimensions more distally along the thoracic aorta, with R-N
Table 4 BAV Phenotype vs. Rate of Vessel Asymmetry
R-L (%) (n ¼ 140) R-N (%) (n ¼ 46)
1
2
3
4
5
6
7
8
9
75.7 (n ¼ 106) 80.4 (n ¼ 37)
22.9 (n ¼ 32) 56.5z (n ¼ 26)
12.1 (n ¼ 17) 17.4 (n ¼ 8)
7.9 (n ¼ 11) 4.3 (n ¼ 2)
6.4 (n ¼ 9) 6.5 (n ¼ 3)
5.7 (n ¼ 8) 0 (n ¼ 0)
7.1 (n ¼ 10) 8.7 (n ¼ 4)
17.1 (n ¼ 24) 13.0 (n ¼ 6)
10.0 (n ¼ 14) 17.4 (n ¼ 8)
*P < 0.05 y P < 0.01 z P < 0.001 Variations in aortic vessel asymmetry with bicuspid aortic valve fusion pattern type. 1. Aortic annulus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proximal Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm.
BAV Phenotype and Thoracic Aorta Morphology
299
Table 5 BAV Phenotype vs. Ascending Aortic Volume (cm3/m2) Region 1 R-L R-N
Region 2
Region 3
Region 4
Total Volume
0.86 0.88
0.66 0.70
0.64 0.68
3.08 2.86
y
0.93 0.60
*P < 0.05 P < 0.01 Variations in ascending aortic volume with bicuspid aortic valve fusion pattern type. Region 1: Sinotubular Junction to Proximal Ascending Aorta; Region 2: Proximal Ascending Aorta to MidAscending Aorta; Region 3: Mid-Ascending Aorta to Distal Ascending Aorta; Region 4: Distal Ascending Aorta to Proximal Aortic Arch. y
patients displaying significantly larger aortic diameters at the distal ascending aorta and the proximal aortic arch. These findings substantiate the trend reported in earlier literature that R-N shows greater arch dimensions than R-L (3,11,27). While certain publications have failed to show an association between fusion phenotypes and differing patterns of dilation, such studies have either only used echocardiography (16,18) or failed to comprehensively assess the ascending aorta and arch (6). We suggest that fusion pattern should be taken into consideration when approaching aortic resection in patients with BAV, as R-N patients are more likely to involve repair of the distal ascending aorta and proximal arch. Providing further illustration of the differing patterns of aortic dilation between fusion phenotypes, our aortic morphology classification showed patients with R-L fusion are more likely to have isolated dilation of aortic roots (Type 1 morphology). Conversely, R-N fusion is associated with enlargement of the tubular portion of the ascending aorta (Type 2 morphology), and this phenotype was also found more likely to possess vessel asymmetry at the sinus of Valsalva. Differences in aortic dimensions amongst BAV phenotypes may reflect differences in aortic hemodynamics associated with BAV geometry. Irrespective of the genetic origins of BAV, altered flow through a morphologically abnormal valve is likely to alter aortic flow patterns and thus viscous forces at the artery wall (28). These forces, known as wall shear stress (WSS), are a known pathophysiological stimulus cited to alter gene expression and promote endothelial remodeling (29). A recent study by Girdauskas et al (30) provides a comprehensive review of the clinical literature regarding BAV patient studies, including the recent work by Hope et al. using 4D flow MR imaging to show that different BAV fusion patterns result in different orientation of eccentric systolic flow jets (31). Table 6 BAV Phenotype vs. Aortic Morphology Type 0 (%) R-L R-N
38 (27.1) 14 (30.4)
Type 1 (%) y
38 (27.1) 4 (8.7)
Type 2 (%)
Type 3 (%)
25 (17.9) 15 (32.6)*
39 (27.9) 13 (28.2)
*P < 0.05 P < 0.01 Variations in aortic morphology with bicuspid aortic valve fusion pattern type. y
These recent flow studies have reported high velocity flow jets in patients with R-L fusion that direct the maximal force at the right anterior of the aortic root and flow jets in patients with R-N fusion that create greater WSS more distally on the posterior aortic wall (31,32). These flow jet patterns, with R-L and R-N valves experiencing increased force at the aortic root and tubular ascending aorta, respectively, corresponds to the patterns of dilation demonstrated in the present study. Our findings, i.e., the differences in aortic shape and dimension for different BAV geometries support the role of hemodynamics in the aortic dilation seen in patients with BAV. However, further study is needed to explore the degree to which altered flow patterns are implicated in ascending aortic dilation. Our results suggest the need for considering differences in cusp fusion pattern when evaluating the influence of BAV on aortic disease. To date, most studies have used only echocardiography to detect aortic dilatation in patients with BAV (1). While echocardiography allows accurate measurement of the proximal aorta, it has limitations in the assessment of ascending aorta and arch dimensions. The present study has shown that BAV phenotypes are associated with differences in aortic dilation that extend into the proximal aortic arch. For this reason, and due to the fact that the ascending aorta is usually the site of maximum dilation in patients with BAV (8,33,34), it has been argued that MR is a more appropriate tool for the assessment of aortic dilation in this population (6,10). Our study was not without limitations. First, as this was a retrospective study, no follow up or longitudinal data could be obtained to evaluate the relationship between BAV fusion pattern and outcome/prognosis. Second, as our volume estimation equation relied on just five measurement levels for ascending aortic diameter, the values we obtained do not fully account for small fluctuations in vessel shape. In addition, the approximation as a sum over a small number of cone frustums represents an approximation of the true aortic volumes. ACKNOWLEDGMENTS We thank Ms. Jennifer McDonald, Dr. Ann Ragin, and Dr. Mauricio Galizia for their contributions to the data acquisition and statistical analysis. REFERENCES 1. Braverman AC. Aortic involvement in patients with a bicuspid aortic valve. Heart 2011;97:506–513. 2. Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000;83:81–85. 3. 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. 4. Fedak PWM, Verma S, Tirone DE, Leask RL, Weisel RD, Butany J. Clinical and Pathophysiological Implications of a Bicuspid Aortic Valve. Circulation 2002;106:900–904. 5. Fernandes SM, Khairy P, Sanders SP, Colan SD. Bicuspid aortic valve morphology and interventions in the young. J Am Coll Cardiol 2007;49:2211–2214. 6. Buchner S, Hulsmann M, Poschenrieder F, et al. Variable phenotypes of bicuspid aortic valve disease: classification by cardiovascular magnetic resonance. Heart 2010;96:1233–1240.
300 7. Gurvitz M, Chang RK, Drant S, Allada V. Frequency of aortic root dilation in children with a bicuspid aortic valve. Am J Cardiol 2004;94:1337–1340. 8. Ferencik M, Pape L. Changes in size of ascending aorta and aortic valve function with time in patients with congenitally bicuspid aortic valves. Am J Cardiol 2003;92:43–46. 9. Della Corte A, Romano G, Tizzano F, et al. Echocardiographic anatomy of ascending aorta dilatation: correlations with aortic valve morphology and function. Int J Cardiol 2006;113:320–326. 10. Debl K, Djavidani B, Buchner S, et al. Dilatation of the ascending aorta in bicuspid aortic valve disease: a magnetic resonance imaging study. Clin Res Cardiol 2009;98:114–120. 11. Fazel SS, Mallidi MD, Lee R, 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. 12. Nistri S, Sorbo MD, Marin M, Palisi M, Scognamiglio R, Thiene G. Aortic root dilatation in young men with normally functioning bicuspid aortic valves. Heart 1999;82:19–22. 13. Thanassoulis G, Yip JWL, Filion K, et al. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med 2008;5:821–828. 14. Sabet HY, Edwards WD, Tazelaar HD, Daly RC. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases. Mayo Clin Proc 1999;74:14–26. 15. Fernandes SM, Sanders SP, Khairy P, et al. Morphology of bicuspid aortic valve in children and adolescents. J Am Coll Cardiol 2004;44:1648–1651. 16. Cecconi M, Manfrin M, Moraca A, et al. Aortic dimensions in patients with bicuspid aortic valve without significant valve dysfunction Am J Cardiol 2005;95:292–294. 17. Alegret J, Duran I, Palazon O, et al. Prevalence of and predictors of bicuspid aortic valves in patients with dilated aortic roots. Am J Cardiol 2003;91:619–622. 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;4:e118–e124. 19. Burman ED, Keegan J, Kilner PJ. Aortic root measurement by cardiovascular magnetic resonance: specification of planes and lines of measurement and corresponding normal values Circ Cardiovasc Imaging 2008;1:104–113. 20. Malaisrie SC, Carr JC, Mikati I, et al. Cardiac magnetic resonance imaging is more diagnostic than two-dimensional echocardiography in determining the presence of bicuspid aortic valve. J Thorac Cardiovasc Surg 2011;144:370–376.
Merritt et al. 21. Tanaka R, Yoshioka K, Niinuma H, et al. Diagnostic value of cardic CT in the evaluation of bicuspid aortic stenosis: comparison with echocardiography and operative findings. AJR Am J Roentgenol 2010;195:895–899. 22. Jassal DS, Bhagirath KM, Tam JW, et al. Association of bicuspid aortic valve morphology and aortic root dimensions: a substudy of the aortic stensosis progression observation measuring effects of Rosuvastatin (ASTRONOMER) study. Echocardiography 2010; 27:174–179. 23. Bireley WR, Diniz LO, Groves EM, Dill K, Carroll TJ, Carr JC. Orthogonal measurement of thoracic aorta luminal diameter using ECG-gated high-resolution contrast-enhanced MR angiography. J Magn Reson Imaging 2007;26:1480–1485. 24. Davies RR, Gallo A, Coady MA, et al. Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg 2006;81:169–177. 25. Kang J, Song H, Yang D, 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. 26. Russo C, Cannata A, Lanfranconi M, et al. Is aortic wall degeneration related to bicuspid aortic valve anatomy in patients with valvular disease. J Thorac Cardiovasc Surg 2008;136:937–942. 27. Novaro GM, Tiong IY, Pearce GL, et al. Features and predictors of ascending aortic dilatation in association with congenital bicuspid aortic valve. Am J Cardiol 2003;93:99–101. 28. Barker AJ, Lanning C, Shandas R. Quantification of hemodynamic wall shear stress in patients with bicuspid aortic valve using phase-contrast MRI. Ann Biomed Eng 2010;38:788–800. 29. Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999;282:2035–2042. 30. Girdauskas E, Borger MA, Secknus MA, 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 2010;39:809–814. 31. Hope MD, Hope TA, Meadows AK, et al. Bicuspid aortic valve: four-dimensional mr evaluation of ascending aortic systolic flow patterns. Radiology 2010;255:53–61. 32. Barker AJ, Markl M, Burk J, et al. Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta. Circ Cardiovasc Imaging 2012;5; 457–466. 33. Nistri S, Sorbo MD, Basso C, Thiene G. Bicuspid aortic valve: abnormal aortic elastic properties. J Heart Valve Dis 2002;11: 369–373. 34. Della Corte A, Bancone C, Quarto C, et al. Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression. Eur J Cardiothorac Surg 2007;31:397– 404.
Original Research
Association Between Leaflet Fusion Pattern and Thoracic Aorta Morphology in Patients With Bicuspid Aortic Valve Bryce A. Merritt, BA,1* Alexander Turin, BS,1 Michael Markl, PhD,1,2 S. Chris Malaisrie, MD,3,4 Patrick M. McCarthy, MD,3,4 and James C. Carr, MD1,4,5 Key Words: BAV; CMR; thoracic aorta
Purpose: To determine if patients with certain bicuspid aortic valve (BAV) phenotypes are predisposed to particular morphological abnormalities of the thoracic aorta.
J. Magn. Reson. Imaging 2014;40:294–300. C 2013 Wiley Periodicals, Inc. V
Materials and Methods: One hundred ninety-two patients with BAV who underwent magnetic resonance angiography between January 2007 and July 2010 were retrospectively identified. Aortic morphology was examined through measurements of aortic size index at nine levels along the thoracic aorta, three-dimensional volume of the ascending aorta, vessel asymmetry, and assessment of aortic root morphology. Results: We found 140 patients (73%) with right and left coronary cusps (R-L) fusion, 46 patients (24%) with R-N fusion, and 6 patients (3%) with left and noncoronary cusps (L-N) fusion. Mean aortic volume in the proximal ascending aorta was significantly greater in R-L patients (0.93 versus 0.60 cm3/m2; P < 0.01). R-N patients possessed greater aortic size index at the distal ascending aorta and proximal aortic arch, and were also significantly more likely to have Type 2 patterns of aortic dilatation. Conclusion: Our results suggest that BAV with R-L fusion is associated with increased dimensions of the aortic root, while BAV with R-N fusion is associated with increased dimensions of the distal ascending aorta and proximal arch. Our findings illustrate the morphological heterogeneity that exists among BAV phenotypes.
1 Northwestern University, Feinberg School of Medicine, Department of Radiology, Chicago, Illinois, USA. 2 Department of Biomedical Engineering, Northwestern University, Chicago, Illinois, USA. 3 Northwestern University, Feinberg School of Medicine, Division of Cardiac Surgery, Chicago, Illinois, USA. 4 Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, Chicago, Illinois, USA. 5 Northwestern University, Feinberg School of Medicine, Department of Medicine, Chicago, Illinois, USA. *Address reprint requests to: B.A.M., 420 E. Ohio Street, #23D, Chicago, IL 60611. E–mail: [email protected] Received March 7, 2013; Accepted August 5, 2013. DOI 10.1002/jmri.24376 View this article online at wileyonlinelibrary.com. C 2013 Wiley Periodicals, Inc. V
BICUSPID AORTIC VALVE (BAV) is the most common congenital heart defect, affecting 0.5–2.0% of the general population (1). This condition may be responsible for more deaths and morbidity than the combined effects of all other congenital heart defects, and is the most common underlying cause for aortic valve replacement in the United States (2,3). While the influence of BAV on valvular disorders such as aortic regurgitation and aortic stenosis has been extensively documented (2,4,5), this condition is increasingly recognized as a disease of the entire aortic root, ascending aorta, and the aortic arch (6). BAV is associated with a high risk of aortic dilation (7–11), and patients with BAV have larger diameters and a higher prevalence of aortic root and ascending thoracic aortic dilation than those with tricuspid aortic valve (12). It is widely known that with increasing size of an ascending aortic aneurysm, the risk of aortic dissection and aneurysm rupture increases (1). Furthermore, autopsy reports of patients with aortic dissection demonstrate BAV in 7–9% of cases and BAV has been shown to occur in as many as 28% of aortic dissection cases in patients 4 cm was found. Statistical Analysis For continuous variables, Student’s t-test /analysis of variance were used for single/multiple variables with normal distribution. x2 tests were performed to compare frequencies between groups. Categorical data are given as total number (relative frequency). Continuous
BAV Phenotype and Thoracic Aorta Morphology
297
Figure 2. Cardiac MRI annotated to illustrate the measurements used to estimate the volume of the ascending aorta, from the sinotubular junction to the proximal innominate trunk. Cross-sectional images show the two diameter measurements used for each aortic level.
data are given as mean 6 standard deviation. Statistical significance was defined as a value of P < 0.05.
RESULTS Patient Characteristics There were 139 males and 53 females and the mean age was 45.8 6 13.1 years (range: 20–79 years). Mean body surface area was 1.98 6 0.23m2 (range: 1.42– 2.70 m2). The patterns of cusp fusion were as follows: 140 patients (73%) were classified as R-L, 46 patients (24%) were classified as R-N, and 6 patients (3%) were classified as L-N. As L-N BAV was rare, no conclusions could be drawn from this data and thus these patients were excluded from analysis. A total of 20 (10.4%) of
patients possessed a bovine arch. Of those patients with bovine arches, 15 (75%) had R-L valves and 5 (25%) had R-N valves. There were no significant differences in gender (P ¼ 0.93), age (P ¼ 0.064), or BSA (P ¼ 0.28) among the three BAV phenotypes. No significant differences existed between groups in three additional risk factors for aortic dilation: smoking history, diabetes mellitus history, and hypertension (Table 2). Aortic Dimensions When all BAV phenotypes were compared, R-N patients were shown to have significantly greater aortic size indices (cm/m2) at the distal ascending aorta (P ¼ 0.014) and proximal aortic arch (P ¼ 0.011). Additionally, R-L patients were shown to have significantly
Figure 3. Cardiac MRIs illustrating each of the four aortic morphologies classified in the study.
298
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Table 2 Patient Characteristics
n Age (years) Males (%) Body SA (m2) Smokers (%) Diabetes (%) Hypertension (%)
R-L
R-N
L-N
Total
140 (73%) 47.1 101 (72%) 1.97 28 (32%) n ¼ 87 2 (1%) n ¼ 134 16 (13%) n ¼ 126
46 (24%) 42.7 34 (74%) 2.03 11 (34%) n ¼ 32 2 (4%) n ¼ 45 5 (12%) n ¼ 42
6 (3%) 39.4 4 (67%) 2.04 1 (25%) n¼4 0 (0%) n¼6 1 (17%) n¼6
192 45.8 6 13.11 139 (72%) 1.98 6 .23 40 (33%) n ¼ 123 4 (2%) n ¼ 185 22 (13%) n ¼ 174
Clinical and demographic characteristics of the study population. Table 3 BAV Phenotype vs. Aortic Size Index (cm/m2) 1
2
3
4
5
6
7
8
9
R-L 1.60* 1.97z 1.82* 2.03 2.01 1.78 1.65 1.27 1.15* R-N 1.49 1.77 1.71 1.97 2.03 1.91y 1.77y 1.22 1.07 *P < 0.05 P < 0.01 z P < 0.001 1. Aortic annulus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proxmial Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm Variations in aortic diameter with bicuspid aortic valve fusion pattern type.
(22%) had Type 2 morphology, and 52 patients (28%) had Type 3 morphology. Comparing R-L and R-N fusion phenotypes showed a significantly greater percentage of R-L patients with Type 1 morphology (P ¼ 0.009). R-N patients were more likely to have Type 2 aortic morphology (P ¼ 0.035) (Table 6).
y
greater aortic size indices at the aortic annulus (P ¼ 0.032), sinus of Valsalva (P ¼ 0.00002), sinotubular junction (P ¼ 0.013), and distal descending aorta (P ¼ 0.025) (Table 3). R-N patients were more likely to possess an asymmetric sinus of Valsalva compared with R-L patients (P ¼ 0.00002) (Table 4). There was no significant difference in total ascending aortic volume between fusion phenotypes. However, when regions were analyzed individually, region 1 volume (cm3/m2), from STJ to proximal ascending aorta, was significantly greater in R-L patients compared with R-N (P ¼ 0.0097) (Table 5). Aortic Morphology Overall, 52 patients (28%) had Type 0 morphology, 42 patients (23%) had Type 1 morphology, 40 patients
DISCUSSION Overall, our results suggest that BAV with fusion of the right and left coronary cusps (R-L) is associated with increased dimensions of the aortic root, while BAV with fusion of the right and noncoronary cusps (R-N) is associated with increased dimensions of the distal ascending aorta and proximal arch. Furthermore, the present study finds greater morphological differences between BAV phenotypes than has been reported in previous research. In our measurements of aortic size indices, R-L patients showed significantly increased dimensions at each level of the aortic root when compared with R-N patients. These results are in accordance with the findings of prior studies showing significantly larger mean aortic root diameters in those with R-L fusion (3,26). The results of our ascending aortic volume measurements agree with this data, with R-L patients shown to have increased aortic volume from the sinotubular junction to the proximal ascending aorta. Our findings provide further evidence that disproportionate dilation of the root is more common among patients with R-L fusion pattern. There was a reversing trend in aortic dimensions more distally along the thoracic aorta, with R-N
Table 4 BAV Phenotype vs. Rate of Vessel Asymmetry
R-L (%) (n ¼ 140) R-N (%) (n ¼ 46)
1
2
3
4
5
6
7
8
9
75.7 (n ¼ 106) 80.4 (n ¼ 37)
22.9 (n ¼ 32) 56.5z (n ¼ 26)
12.1 (n ¼ 17) 17.4 (n ¼ 8)
7.9 (n ¼ 11) 4.3 (n ¼ 2)
6.4 (n ¼ 9) 6.5 (n ¼ 3)
5.7 (n ¼ 8) 0 (n ¼ 0)
7.1 (n ¼ 10) 8.7 (n ¼ 4)
17.1 (n ¼ 24) 13.0 (n ¼ 6)
10.0 (n ¼ 14) 17.4 (n ¼ 8)
*P < 0.05 y P < 0.01 z P < 0.001 Variations in aortic vessel asymmetry with bicuspid aortic valve fusion pattern type. 1. Aortic annulus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proximal Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm.
BAV Phenotype and Thoracic Aorta Morphology
299
Table 5 BAV Phenotype vs. Ascending Aortic Volume (cm3/m2) Region 1 R-L R-N
Region 2
Region 3
Region 4
Total Volume
0.86 0.88
0.66 0.70
0.64 0.68
3.08 2.86
y
0.93 0.60
*P < 0.05 P < 0.01 Variations in ascending aortic volume with bicuspid aortic valve fusion pattern type. Region 1: Sinotubular Junction to Proximal Ascending Aorta; Region 2: Proximal Ascending Aorta to MidAscending Aorta; Region 3: Mid-Ascending Aorta to Distal Ascending Aorta; Region 4: Distal Ascending Aorta to Proximal Aortic Arch. y
patients displaying significantly larger aortic diameters at the distal ascending aorta and the proximal aortic arch. These findings substantiate the trend reported in earlier literature that R-N shows greater arch dimensions than R-L (3,11,27). While certain publications have failed to show an association between fusion phenotypes and differing patterns of dilation, such studies have either only used echocardiography (16,18) or failed to comprehensively assess the ascending aorta and arch (6). We suggest that fusion pattern should be taken into consideration when approaching aortic resection in patients with BAV, as R-N patients are more likely to involve repair of the distal ascending aorta and proximal arch. Providing further illustration of the differing patterns of aortic dilation between fusion phenotypes, our aortic morphology classification showed patients with R-L fusion are more likely to have isolated dilation of aortic roots (Type 1 morphology). Conversely, R-N fusion is associated with enlargement of the tubular portion of the ascending aorta (Type 2 morphology), and this phenotype was also found more likely to possess vessel asymmetry at the sinus of Valsalva. Differences in aortic dimensions amongst BAV phenotypes may reflect differences in aortic hemodynamics associated with BAV geometry. Irrespective of the genetic origins of BAV, altered flow through a morphologically abnormal valve is likely to alter aortic flow patterns and thus viscous forces at the artery wall (28). These forces, known as wall shear stress (WSS), are a known pathophysiological stimulus cited to alter gene expression and promote endothelial remodeling (29). A recent study by Girdauskas et al (30) provides a comprehensive review of the clinical literature regarding BAV patient studies, including the recent work by Hope et al. using 4D flow MR imaging to show that different BAV fusion patterns result in different orientation of eccentric systolic flow jets (31). Table 6 BAV Phenotype vs. Aortic Morphology Type 0 (%) R-L R-N
38 (27.1) 14 (30.4)
Type 1 (%) y
38 (27.1) 4 (8.7)
Type 2 (%)
Type 3 (%)
25 (17.9) 15 (32.6)*
39 (27.9) 13 (28.2)
*P < 0.05 P < 0.01 Variations in aortic morphology with bicuspid aortic valve fusion pattern type. y
These recent flow studies have reported high velocity flow jets in patients with R-L fusion that direct the maximal force at the right anterior of the aortic root and flow jets in patients with R-N fusion that create greater WSS more distally on the posterior aortic wall (31,32). These flow jet patterns, with R-L and R-N valves experiencing increased force at the aortic root and tubular ascending aorta, respectively, corresponds to the patterns of dilation demonstrated in the present study. Our findings, i.e., the differences in aortic shape and dimension for different BAV geometries support the role of hemodynamics in the aortic dilation seen in patients with BAV. However, further study is needed to explore the degree to which altered flow patterns are implicated in ascending aortic dilation. Our results suggest the need for considering differences in cusp fusion pattern when evaluating the influence of BAV on aortic disease. To date, most studies have used only echocardiography to detect aortic dilatation in patients with BAV (1). While echocardiography allows accurate measurement of the proximal aorta, it has limitations in the assessment of ascending aorta and arch dimensions. The present study has shown that BAV phenotypes are associated with differences in aortic dilation that extend into the proximal aortic arch. For this reason, and due to the fact that the ascending aorta is usually the site of maximum dilation in patients with BAV (8,33,34), it has been argued that MR is a more appropriate tool for the assessment of aortic dilation in this population (6,10). Our study was not without limitations. First, as this was a retrospective study, no follow up or longitudinal data could be obtained to evaluate the relationship between BAV fusion pattern and outcome/prognosis. Second, as our volume estimation equation relied on just five measurement levels for ascending aortic diameter, the values we obtained do not fully account for small fluctuations in vessel shape. In addition, the approximation as a sum over a small number of cone frustums represents an approximation of the true aortic volumes. ACKNOWLEDGMENTS We thank Ms. Jennifer McDonald, Dr. Ann Ragin, and Dr. Mauricio Galizia for their contributions to the data acquisition and statistical analysis. REFERENCES 1. Braverman AC. Aortic involvement in patients with a bicuspid aortic valve. Heart 2011;97:506–513. 2. Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000;83:81–85. 3. 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. 4. Fedak PWM, Verma S, Tirone DE, Leask RL, Weisel RD, Butany J. Clinical and Pathophysiological Implications of a Bicuspid Aortic Valve. Circulation 2002;106:900–904. 5. Fernandes SM, Khairy P, Sanders SP, Colan SD. Bicuspid aortic valve morphology and interventions in the young. J Am Coll Cardiol 2007;49:2211–2214. 6. Buchner S, Hulsmann M, Poschenrieder F, et al. Variable phenotypes of bicuspid aortic valve disease: classification by cardiovascular magnetic resonance. Heart 2010;96:1233–1240.
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