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Prevalence and Complications of Bicuspid Aortic Valve in Chinese According to Echocardiographic Database
Prevalence and Complications of Bicuspid Aortic Valve in Chinese According to Echocardiographic Database Yijian Li, MD, Xin Wei, MD, Zhengang Zhao, MD, Yanbiao Liao, MD, Jialing He, MD, Tianyuan Xiong, MD, Yuanning Xu, MD, Wenyu Lv, MD, Yuanweixiang Ou, MD, Hong Tang, MD*, Yuan Feng, MD*, and Mao Chen, MD, PhD* As transcatheter aortic valve replacement has become an alternative treatment for patients at high risk for surgical aortic valve replacement, bicuspid aortic valve (BAV) draws our attention again. The reported frequency of BAV was 0.5% to 2% in western population. However, there was no such epidemiologic study in Chinese population. Our study sought to investigate the prevalence and complications of BAV in China by echocardiographic database. A total of 668 cases who were confirmed with BAV, identified from 195,708 echocardiographic records of 157,039 patients in the echocardiographic database of West China Hospital (between June 2008 and June 2012), were analyzed retrospectively. The incidence of BAV was 0.43% in the cohort, and 579 (86.68%) patients were complicated by various degree of aortic valve stenosis or aortic valve regurgitation. The incidence of infective endocarditis and aortic dissection was 0.68% episodes per patient-years with mean age of 42.96 – 11.25 years and 0.18% episodes per patient-years with mean age of 43.00 – 5.14 years, respectively. In conclusion, our study demonstrated that the prevalence of BAV and complications in Chinese was similar to that in the western population. Ó 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;-:-e-)
Transcatheter aortic valve replacement (TAVR) has become a well-established treatment for patients deemed inoperable or at high risk for surgical aortic valve replacement. However, arguments remain with regard to the expansion of TAVR indications. One of the most common topics is bicuspid aortic valve (BAV), which has been considered a relative contraindication because of the procedural risk related to annular eccentricity, asymmetrical valve calcification, unequally sized leaflets, and concomitant aortopathy.1e3 The frequency of BAV cases in western TAVR registries was much lower compared with an incidence of 47.5% from the first Chinese TAVR trial.3 Although the prevalence of BAV is estimated between 0.5% and 2% in western population with a male predominance of approximately 3:1,4e6 we have no knowledge about current situation of BAV in Chinese population. And we also have no knowledge about the complication of BAV in Chinese. Thus, our study sought to investigate the prevalence and complications of BAV in Chinese based on a large echocardiographic database.
Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China. Manuscript received January 16, 2017; revised manuscript received and accepted April 4, 2017. The work was funded by a grant from the Sichuan Provincial Supporting Project for Science and Technology (grant number: 2016FZ0078, Sichuan, China) and Sichuan Provincial Innovation Team of Science and Technology (grant number: 2017TD0004, Sichuan, China). Drs. Li, Wei, and Zhao contributed equally to the article. See page 4 for disclosure information. *Corresponding author: Tel: (86) 28-85423362; fax: (86) 28-85423170. E-mail address: [email protected] (H. Tang) or [email protected] (Y. Feng) or [email protected] (M. Chen). 0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.04.025
Methods This study retrospectively analyzed the echocardiographic database at West China Hospital, Sichuan University, from June 2008 to June 2012. The database included all echocardiographic reports of outpatients and hospitalized patients who underwent such examination at our institution since June 2008. Echocardiography was most commonly performed in the following clinical scenarios: suspected cardiac etiology based on symptoms, signs, or other testing; evaluation and follow-up of subjects with cardiovascular disease (valvular heart disease, congenital heart disease [CHD], coronary artery disease, heart failure, cardiomyopathy, arrhythmia, hypertension); routine evaluation of cardiac structure and function before noncardiac surgery; or other invasive procedures under general anesthesia. All echocardiographic examinations were done by an experienced echocardiographic doctor and reports were reviewed by a senior echocardiographic doctor. A total of 790 reports of BAV were identified from 195,708 echocardiographic records of 157,039 patients. Eighty suspected cases of BAV were excluded. For patients who underwent echocardiographic examination more than once during this period, the first examination recording was analyzed (Figure 1). According to Sievers et al,7 BAV was defined as 2 functional cusps forming a valve mechanism with <3 zones of parallel apposition between cusps, including both BAV type 0 with only 2 cusps and no raphe and BAV type 1 or type 2 with 3 cusps and 1 or 2 raphe. Diagnosis of a BAV was evaluated by 2-dimensional transthoracic echocardiography using the short-axis view in systole and in diastole to observe both cusps and commissures. www.ajconline.org
2
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Figure 1. Enrollment of the records of echocardiography.
In this study, aortic stenosis (AS) was defined as the peak velocity across the aortic valve 2.0 m/s, mild AS was defined as 2.0 to 2.9 m/s, moderate AS was defined as 3.0 to 3.9 m/s, and severe AS was defined as 4.0 m/s according to the 2014 American College of Cardiology/American Heart Association guideline for the management of patients with valvular heart disease.8 Aortic regurgitation (AR) was identified according to the extent of diastolic turbulent flow in the left ventricular; mild AR was defined as aortic jet width <25% of left ventricular outflow tract (LVOT), moderate AR was defined as aortic jet width between 25% and 64% of LOVT, and severe AR was defined as 65% of LVOT, in line with American College of Cardiology/American Heart Association guideline.8 The major echocardiographic criteria for infective endocarditis (IE) were vegetation and abscess, in line with recommendations from the European Association of Echocardiography.9 According to recommendations from the European Society of Cardiology, the demonstration of an intimal flap separating 2 lumens is the basis for diagnosing aortic dissection. If the false lumen is completely thrombosed, central displacement of the intimal flap, calcification, or separation of intimal layers can be regarded as definitive signs of aortic dissection.10 BAV patients were classified into 4 age groups (group 1: 0 to 20 years; group 2: 21 to 40 years; group 3: 41 to 60 years; group 4: 61 to 83 years). Aortic valve function and the prevalence of various complications were analyzed and compared between age groups. Continuous data were shown as mean standard deviation (SD), and categorical variables were presented as number and percentage. Data analysis was performed using IBM SPSS Statistics software (version 19.0; SPSS, Inc., Chicago, IL). Results A total of 668 patients with BAV were included consisting of 438 men and 230 women (mean age 41.36 19.99 years, range 0 to 83) from 195,708 echocardiographic reports of 157,039 patients. The incidence of BAV was 0.56% (438/77,931) for men and 0.29% (230/79,108) for women. The incidence of BAV in the entire cohort was
0.48% (748/157,039) if suspected cases were included, and was 0.43% (668/157,039) if only confirmed cases were analyzed. The incidence of BAV decreased from 1.16% (138/11,867) in patients aged 0 to 20 years to 0.18% (127/69,320) in patients aged 61 to 83 years (Table 1). Eighty-nine (13.32%) patients were free from aortic valve disease, while 579 (86.68%) patients have various degree of AS or AR. Almost half of the patients who were diagnosed BAV have different degrees of aortic valve disease after 40 years. There were 42.07% patients who had AS accompanied with AR. The number of patients who have moderate or severe AS or AR increased with age. The percentage of patients with pure AS and pure AR was 27.10% and 17.51%, respectively (Table 1, Figure 2). We analyzed the constituent ratio of calcific AS in different age groups among 462 patients who have AS. With increasing age, the constituent ratio of calcific AS increased from 0% in group 1 (0 to 20 years) to 50% in group 4 (over 60 years) (Figure 3). The incidence of infective endocarditis was 0.68% episodes per patient-years in our study, 4.11% (18/438) and 2.17% (5/230) in men and women, respectively. The mean age when infective endocarditis occurred was 42.96 11.25 years. Aortic dissection occurred in 6 patients: 5 men and 1 woman with a mean age of 43.00 5.14 years. The incidence of aortic dissection was 0.18% episodes per patientyears. A total of 51 (7.6%) BAV patients had coexisting CHD which was recorded by echocardiographic screening (Table 2). Discussion Although TAVR has eventually matured as an alternative treatment for surgically high-risk patients with AS, BAV has been regarded as one of the relative contraindications. The reported frequency of BAV according to TAVR registries in the western world ranges from 1.6% to 6.7%, which was much lower compared with those observed in Chinese TAVR population.11 Although 47.5% of Chinese patients referred for TAVR had a BAV,3 our echocardiographic database showed that the incidence of BAV was 0.43%, which was comparable with previous studies in western population.4e6 So did the male-to-female ratio which was 1.9:1 (438:230).4e6 The percentage of BAV patients who underwent isolated aortic valve replacement for AS was reported as 41.7% in septuagenarians and 27.5% in octogenarians.12 Therefore, a possible explanation for the similar incidence of BAV in general against a high percentage of BAV in TAVR population is that patients referred for TAVR in China are much younger with a mean age of 74 years.3 In contrast, the mean age of patients in European and US TAVR registries are well above 80 years. In contrast, as the sensitivity and specificity for the detection of BAV with echocardiography is lower than with cardiac computed tomography,13,14 the echocardiography-based incidence of BAV might have represented an underestimation. A common complication of BAV is AS. In a surgical series, 49% of the patients had BAV among 932 patients
Valvular Heart Disease/BAV in Chinese according to Echocardiographic Database
3
Table 1 Echocardiographic results based on different age groups Group None AS with AR Moderate or severe Pure AS Mild Moderate Severe Pure AR Mild Moderate Severe Incidence (%)
1: 0-20 yrs (n¼138) 23 46 30 40 14 9 17 29 25 2 2 1.16%
(3.44%) (6.89%) (4.49%) (5.99%) (2.10%) (1.34%) (2.54%) (4.34%) (3.74%) (0.29%) (0.29%) (138/11867)
2: 21-40 yrs (n¼166) 29 67 46 35 17 7 11 35 22 5 8 0.70%
(4.34%) (10.03%) (6.89%) (5.24%) (2.54%) (1.05%) (1.65%) (5.24%) (3.29%) (0.75%) (1.20%) (166/23810)
3: 41-60 yrs (n¼237) 25 117 102 55 21 15 19 40 23 11 6 0.46%
(3.74%) (17.51%) (15.27%) (8.23%) (3.14%) (2.25%) (2.84%) (5.99%) (3.44%) (1.65%) (0.90%) (237/52042)
4: 60-83 yrs (n¼127) 12 51 43 51 17 11 23 13 7 3 3 0.18%
(1.80%) (7.63%) (6.44%) (7.63%) (2.54%) (1.65%) (3.44%) (1.95%) (1.05%) (0.45%) (0.45%) (127/69320)
Total (n¼668) 89 281 221 181 69 42 70 117 77 21 19 0.43%
(13.32%) (42.07%) (33.08%) (27.10%) (10.33%) (6.29%) (10.48%) (17.51%) (11.52%) (3.14%) (2.84%) (668/157039)
AS ¼ aortic stenosis; AR ¼ aortic regurgitation; AS with AR ¼ aortic stenosis accompanied with regurgitation.
Figure 2. Pure aortic stenosis and pure aortic regurgitation.
with AS who underwent surgical aortic valve replacement.12 In our study, 69.2% of BAV patients had AS regardless of severity, and 49.9% had moderate or severe AS. Echocardiographic study has shown that the progression of sclerosis starts in the second decade and calcification often increases prominently by 40 years of age.15 This is confirmed in our study, which showed that up to 64.0% of BAV patients who had moderate or severe AS were over 40 years old. As we have already known that increasing age leads to higher prevalence of AS in the population,16,17 the relation between age and BAV stenosis, which has the same tendency, is shown in the surgical series: it occurred in 33% of patients aged 21 to 30 years, 60% aged 31 to 40 years, 64% aged 41 to 50 years, 69% aged 51 to 60 years, 60% aged 61 to 70 years, 42% aged 71 to 80 years, and 28% aged 81 to 90 years.12 Although adults with BAV often have various degrees of AR, the prevalence of pure AR varied from study to study. Braverman et al18 suggested that 85% of patients with BAV had some degree of cusp prolapse. In the echocardiographic
study from Olmsted County, 47% patients with BAV had some degree of AR.19 We revealed that 59.58% of BAV patients had any degree of AR, and 65.8% (77/117) of patients had mild AR in the pure AR cohort, which was consistent with the western population. Meanwhile, the patients with AR are younger than those with AS from the European experience,20 which is similar to our study. The incidence of infective endocarditis was 0.68% episodes per patient-years according to our data, which were much more than 3 to 10 episodes per 100,000 patient-years in general population.21 And it was consistent with the incidence from recent estimates reported as 0.9% to 2% episodes per patient-years.19,22 In our study, only the first examination was included. But in cases with initially negative examination, repeated echocardiography within 7 to 10 days is excluded. Thus, the incidence of infective endocarditis may be underestimated. As a rare but critical complication, aortic dissection is associated with high mortality rate. The incidence of aortic dissection in BAV patients ranges from 3% to 5%.15,23
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Figure 3. Constituent ratio of calcific aortic stenosis in different age groups.
Table 2 Bicuspid aortic valve coexisting with congenital heart disease Category Ventricular septal defect Patent ductus arteriosus Ventricular septal defect þ Patent ductus arteriosus Atrial septal defect Aortic coarctation Others*
Subjects (number þ percentage) 27 6 4
4.0 0.9 0.6
5 4 7
0.7 0.6 1.0
* Others, including incomplete endocardial cushion defect in 2, dextrocardia in 2, pulmonary valve stenosis, Taussig-Bing symptom, and right ventricular outflow tract obstruction accompanied with pulmonary valve dysplasia in single case.
However, the prevalence of dissection was 0.1% per patientyear of follow-up in the Toronto study, and no cases of dissection were reported from the Olmsted County study,19,22 which is similar to the incidence from our study of 0.18% episodes per patient-years. According to the recent estimate in pediatric and young adult subjects, 39% of BAV patients had coexisting CHD.24 From Hinton et al,25 BAV is associated with hypoplastic left heart syndrome, while from Roos-Hesselink et al,26 approximately 50% to 75% patients with aortic coarctation have BAV. Although many kinds of cardiovascular malformation were reported to have a high correlation to BAV, only 7.6% of BAV patients had coexisting CHD in our study, and the most frequent coexisting CHD was ventricular septal defect, followed by patent ductus arteriosus. Fifteen percent of BAV patients from the Olmsted County study were reported to have coexisting CHD, which was similar to our study.19 Our study has several limitations. First, as a single-center study in a tertiary hospital, the selection bias is mainly increased by the asymptomatic BAV patients who do not come to our institution. Second, albeit the convincing large sample size, our study can partially reflect the incidence of BAV in China. Future screening studies among general
population are required to determine the true incidence of BAV in Chinese. Finally, as a cross-sectional study, it lacks longitudinal data, thus the natural course of the disease and patient outcomes could not be assessed. Disclosures The authors have no conflicts of interest to disclose. 1. Zegdi R, Ciobotaru V, Noghin M, Sleilaty G, Lafont A, Latremouille C, Deloche A, Fabiani JN. Is it reasonable to treat all calcified stenotic aortic valves with a valved stent? Results from a human anatomic study in adults. J Am Coll Cardiol 2008;51:579e584. 2. Wijesinghe N, Ye J, Rodes-Cabau J, Cheung A, Velianou JL, Natarajan MK, Dumont E, Nietlispach F, Gurvitch R, Wood DA, Tay E, Webb JG. Transcatheter aortic valve implantation in patients with bicuspid aortic valve stenosis. JACC Cardiovasc Interv 2010;3: 1122e1125. 3. Jilaihawi H, Wu Y, Yang Y, Xu L, Chen M, Wang J, Kong X, Zhang R, Wang M, Lv B, Wang W, Xu B, Makkar RR, Sievert H, Gao R. Morphological characteristics of severe aortic stenosis in China: imaging corelab observations from the first Chinese transcatheter aortic valve trial. Catheter Cardiovasc Interv 2015;85(Suppl 1):752e761. 4. Larson EW, Edwards WD. Risk factors for aortic dissection: a necropsy study of 161 cases. Am J Cardiol 1984;53:849e855. 5. Basso C, Boschello M, Perrone C, Mecenero A, Cera A, Bicego D, Thiene G, De Dominicis E. An echocardiographic survey of primary school children for bicuspid aortic valve. Am J Cardiol 2004;93: 661e663. 6. Tutar E, Ekici F, Atalay S, Nacar N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. Am Heart J 2005;150:513e515. 7. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226e1233. 8. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438e2488. 9. Habib G, Badano L, Tribouilloy C, Vilacosta I, Zamorano JL, Galderisi M, Voigt JU, Sicari R, Cosyns B, Fox K, Aakhus S; European Association of Echocardiography. Recommendations for the practice of echocardiography in infective endocarditis. Eur J Echocardiogr 2010;11:202e219.
Valvular Heart Disease/BAV in Chinese according to Echocardiographic Database 10. Erbel R, Alfonso F, Boileau C, Dirsch O, Eber B, Haverich A, Rakowski H, Struyven J, Radegran K, Sechtem U, Taylor J, Zollikofer C, Klein WW, Mulder B, Providencia LA; Task Force on Aortic Dissection, European Society of Cardiology. Diagnosis and management of aortic dissection. Eur Heart J 2001;22:1642e1681. 11. Zhao ZG, Jilaihawi H, Feng Y, Chen M. Transcatheter aortic valve implantation in bicuspid anatomy. Nat Rev Cardiol 2015;12: 123e128. 12. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005;111:920e925. 13. Alkadhi H, Leschka S, Trindade PT, Feuchtner G, Stolzmann P, Plass A, Baumueller S. Cardiac CT for the differentiation of bicuspid and tricuspid aortic valves: comparison with echocardiography and surgery. AJR Am J Roentgenol 2010;195:900e908. 14. Tanaka R, Yoshioka K, Niinuma H, Ohsawa S, Okabayashi H, Ehara S. Diagnostic value of cardiac CT in the evaluation of bicuspid aortic stenosis: comparison with echocardiography and operative findings. AJR Am J Roentgenol 2010;195:895e899. 15. Beppu S, Suzuki S, Matsuda H, Ohmori F, Nagata S, Miyatake K. Rapidity of progression of aortic stenosis in patients with congenital bicuspid aortic valves. Am J Cardiol 1993;71:322e327. 16. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005e1011. 17. Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. The Tromso study. Heart 2013;99:396e400. 18. Braverman AC, Guven H, Beardslee MA, Makan M, Kates AM, Moon MR. The bicuspid aortic valve. Curr Probl Cardiol 2005;30: 470e522. 19. Michelena HI, Desjardins VA, Avierinos JF, Russo A, Nkomo VT, Sundt TM, Pellikka PA, Tajik AJ, Enriquez-Sarano M. Natural history
20. 21.
22. 23. 24.
25. 26.
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of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation 2008;117:2776e2784. Iung B, Baron G, Tornos P, Gohlke-Barwolf C, Butchart EG, Vahanian A. Valvular heart disease in the community: a European experience. Curr Probl Cardiol 2007;32:609e661. Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, Moreillon P, de Jesus Antunes M, Thilen U, Lekakis J, Lengyel M, Muller L, Naber CK, Nihoyannopoulos P, Moritz A, Zamorano JL. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 2009;30:2369e2413. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, Webb GD, Siu SC. Outcomes in adults with bicuspid aortic valves. JAMA 2008;300:1317e1325. David TE, Armstrong S, Ivanov J, Webb GD. Aortic valve sparing operations: an update. Ann Thorac Surg 1999;67:1840e1842; discussion 1853e1856. Niaz T, Poterucha JT, Johnson JN, Craviari C, Nienaber T, Palfreeman J, Cetta F, Hagler DJ. Incidence, morphology, and progression of bicuspid aortic valve in pediatric and young adult subjects with coexisting congenital heart defects. Congenit Heart Dis 2016, http://dx.doi.org/10.1111/chd.12429. Hinton RB Jr, Martin LJ, Tabangin ME, Mazwi ML, Cripe LH, Benson DW. Hypoplastic left heart syndrome is heritable. J Am Coll Cardiol 2007;50:1590e1595. Roos-Hesselink JW, Scholzel BE, Heijdra RJ, Spitaels SE, Meijboom FJ, Boersma E, Bogers AJ, Simoons ML. Aortic valve and aortic arch pathology after coarctation repair. Heart 2003;89: 1074e1077.
Transcatheter aortic valve replacement (TAVR) has become a well-established treatment for patients deemed inoperable or at high risk for surgical aortic valve replacement. However, arguments remain with regard to the expansion of TAVR indications. One of the most common topics is bicuspid aortic valve (BAV), which has been considered a relative contraindication because of the procedural risk related to annular eccentricity, asymmetrical valve calcification, unequally sized leaflets, and concomitant aortopathy.1e3 The frequency of BAV cases in western TAVR registries was much lower compared with an incidence of 47.5% from the first Chinese TAVR trial.3 Although the prevalence of BAV is estimated between 0.5% and 2% in western population with a male predominance of approximately 3:1,4e6 we have no knowledge about current situation of BAV in Chinese population. And we also have no knowledge about the complication of BAV in Chinese. Thus, our study sought to investigate the prevalence and complications of BAV in Chinese based on a large echocardiographic database.
Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China. Manuscript received January 16, 2017; revised manuscript received and accepted April 4, 2017. The work was funded by a grant from the Sichuan Provincial Supporting Project for Science and Technology (grant number: 2016FZ0078, Sichuan, China) and Sichuan Provincial Innovation Team of Science and Technology (grant number: 2017TD0004, Sichuan, China). Drs. Li, Wei, and Zhao contributed equally to the article. See page 4 for disclosure information. *Corresponding author: Tel: (86) 28-85423362; fax: (86) 28-85423170. E-mail address: [email protected] (H. Tang) or [email protected] (Y. Feng) or [email protected] (M. Chen). 0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.04.025
Methods This study retrospectively analyzed the echocardiographic database at West China Hospital, Sichuan University, from June 2008 to June 2012. The database included all echocardiographic reports of outpatients and hospitalized patients who underwent such examination at our institution since June 2008. Echocardiography was most commonly performed in the following clinical scenarios: suspected cardiac etiology based on symptoms, signs, or other testing; evaluation and follow-up of subjects with cardiovascular disease (valvular heart disease, congenital heart disease [CHD], coronary artery disease, heart failure, cardiomyopathy, arrhythmia, hypertension); routine evaluation of cardiac structure and function before noncardiac surgery; or other invasive procedures under general anesthesia. All echocardiographic examinations were done by an experienced echocardiographic doctor and reports were reviewed by a senior echocardiographic doctor. A total of 790 reports of BAV were identified from 195,708 echocardiographic records of 157,039 patients. Eighty suspected cases of BAV were excluded. For patients who underwent echocardiographic examination more than once during this period, the first examination recording was analyzed (Figure 1). According to Sievers et al,7 BAV was defined as 2 functional cusps forming a valve mechanism with <3 zones of parallel apposition between cusps, including both BAV type 0 with only 2 cusps and no raphe and BAV type 1 or type 2 with 3 cusps and 1 or 2 raphe. Diagnosis of a BAV was evaluated by 2-dimensional transthoracic echocardiography using the short-axis view in systole and in diastole to observe both cusps and commissures. www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
Figure 1. Enrollment of the records of echocardiography.
In this study, aortic stenosis (AS) was defined as the peak velocity across the aortic valve 2.0 m/s, mild AS was defined as 2.0 to 2.9 m/s, moderate AS was defined as 3.0 to 3.9 m/s, and severe AS was defined as 4.0 m/s according to the 2014 American College of Cardiology/American Heart Association guideline for the management of patients with valvular heart disease.8 Aortic regurgitation (AR) was identified according to the extent of diastolic turbulent flow in the left ventricular; mild AR was defined as aortic jet width <25% of left ventricular outflow tract (LVOT), moderate AR was defined as aortic jet width between 25% and 64% of LOVT, and severe AR was defined as 65% of LVOT, in line with American College of Cardiology/American Heart Association guideline.8 The major echocardiographic criteria for infective endocarditis (IE) were vegetation and abscess, in line with recommendations from the European Association of Echocardiography.9 According to recommendations from the European Society of Cardiology, the demonstration of an intimal flap separating 2 lumens is the basis for diagnosing aortic dissection. If the false lumen is completely thrombosed, central displacement of the intimal flap, calcification, or separation of intimal layers can be regarded as definitive signs of aortic dissection.10 BAV patients were classified into 4 age groups (group 1: 0 to 20 years; group 2: 21 to 40 years; group 3: 41 to 60 years; group 4: 61 to 83 years). Aortic valve function and the prevalence of various complications were analyzed and compared between age groups. Continuous data were shown as mean standard deviation (SD), and categorical variables were presented as number and percentage. Data analysis was performed using IBM SPSS Statistics software (version 19.0; SPSS, Inc., Chicago, IL). Results A total of 668 patients with BAV were included consisting of 438 men and 230 women (mean age 41.36 19.99 years, range 0 to 83) from 195,708 echocardiographic reports of 157,039 patients. The incidence of BAV was 0.56% (438/77,931) for men and 0.29% (230/79,108) for women. The incidence of BAV in the entire cohort was
0.48% (748/157,039) if suspected cases were included, and was 0.43% (668/157,039) if only confirmed cases were analyzed. The incidence of BAV decreased from 1.16% (138/11,867) in patients aged 0 to 20 years to 0.18% (127/69,320) in patients aged 61 to 83 years (Table 1). Eighty-nine (13.32%) patients were free from aortic valve disease, while 579 (86.68%) patients have various degree of AS or AR. Almost half of the patients who were diagnosed BAV have different degrees of aortic valve disease after 40 years. There were 42.07% patients who had AS accompanied with AR. The number of patients who have moderate or severe AS or AR increased with age. The percentage of patients with pure AS and pure AR was 27.10% and 17.51%, respectively (Table 1, Figure 2). We analyzed the constituent ratio of calcific AS in different age groups among 462 patients who have AS. With increasing age, the constituent ratio of calcific AS increased from 0% in group 1 (0 to 20 years) to 50% in group 4 (over 60 years) (Figure 3). The incidence of infective endocarditis was 0.68% episodes per patient-years in our study, 4.11% (18/438) and 2.17% (5/230) in men and women, respectively. The mean age when infective endocarditis occurred was 42.96 11.25 years. Aortic dissection occurred in 6 patients: 5 men and 1 woman with a mean age of 43.00 5.14 years. The incidence of aortic dissection was 0.18% episodes per patientyears. A total of 51 (7.6%) BAV patients had coexisting CHD which was recorded by echocardiographic screening (Table 2). Discussion Although TAVR has eventually matured as an alternative treatment for surgically high-risk patients with AS, BAV has been regarded as one of the relative contraindications. The reported frequency of BAV according to TAVR registries in the western world ranges from 1.6% to 6.7%, which was much lower compared with those observed in Chinese TAVR population.11 Although 47.5% of Chinese patients referred for TAVR had a BAV,3 our echocardiographic database showed that the incidence of BAV was 0.43%, which was comparable with previous studies in western population.4e6 So did the male-to-female ratio which was 1.9:1 (438:230).4e6 The percentage of BAV patients who underwent isolated aortic valve replacement for AS was reported as 41.7% in septuagenarians and 27.5% in octogenarians.12 Therefore, a possible explanation for the similar incidence of BAV in general against a high percentage of BAV in TAVR population is that patients referred for TAVR in China are much younger with a mean age of 74 years.3 In contrast, the mean age of patients in European and US TAVR registries are well above 80 years. In contrast, as the sensitivity and specificity for the detection of BAV with echocardiography is lower than with cardiac computed tomography,13,14 the echocardiography-based incidence of BAV might have represented an underestimation. A common complication of BAV is AS. In a surgical series, 49% of the patients had BAV among 932 patients
Valvular Heart Disease/BAV in Chinese according to Echocardiographic Database
3
Table 1 Echocardiographic results based on different age groups Group None AS with AR Moderate or severe Pure AS Mild Moderate Severe Pure AR Mild Moderate Severe Incidence (%)
1: 0-20 yrs (n¼138) 23 46 30 40 14 9 17 29 25 2 2 1.16%
(3.44%) (6.89%) (4.49%) (5.99%) (2.10%) (1.34%) (2.54%) (4.34%) (3.74%) (0.29%) (0.29%) (138/11867)
2: 21-40 yrs (n¼166) 29 67 46 35 17 7 11 35 22 5 8 0.70%
(4.34%) (10.03%) (6.89%) (5.24%) (2.54%) (1.05%) (1.65%) (5.24%) (3.29%) (0.75%) (1.20%) (166/23810)
3: 41-60 yrs (n¼237) 25 117 102 55 21 15 19 40 23 11 6 0.46%
(3.74%) (17.51%) (15.27%) (8.23%) (3.14%) (2.25%) (2.84%) (5.99%) (3.44%) (1.65%) (0.90%) (237/52042)
4: 60-83 yrs (n¼127) 12 51 43 51 17 11 23 13 7 3 3 0.18%
(1.80%) (7.63%) (6.44%) (7.63%) (2.54%) (1.65%) (3.44%) (1.95%) (1.05%) (0.45%) (0.45%) (127/69320)
Total (n¼668) 89 281 221 181 69 42 70 117 77 21 19 0.43%
(13.32%) (42.07%) (33.08%) (27.10%) (10.33%) (6.29%) (10.48%) (17.51%) (11.52%) (3.14%) (2.84%) (668/157039)
AS ¼ aortic stenosis; AR ¼ aortic regurgitation; AS with AR ¼ aortic stenosis accompanied with regurgitation.
Figure 2. Pure aortic stenosis and pure aortic regurgitation.
with AS who underwent surgical aortic valve replacement.12 In our study, 69.2% of BAV patients had AS regardless of severity, and 49.9% had moderate or severe AS. Echocardiographic study has shown that the progression of sclerosis starts in the second decade and calcification often increases prominently by 40 years of age.15 This is confirmed in our study, which showed that up to 64.0% of BAV patients who had moderate or severe AS were over 40 years old. As we have already known that increasing age leads to higher prevalence of AS in the population,16,17 the relation between age and BAV stenosis, which has the same tendency, is shown in the surgical series: it occurred in 33% of patients aged 21 to 30 years, 60% aged 31 to 40 years, 64% aged 41 to 50 years, 69% aged 51 to 60 years, 60% aged 61 to 70 years, 42% aged 71 to 80 years, and 28% aged 81 to 90 years.12 Although adults with BAV often have various degrees of AR, the prevalence of pure AR varied from study to study. Braverman et al18 suggested that 85% of patients with BAV had some degree of cusp prolapse. In the echocardiographic
study from Olmsted County, 47% patients with BAV had some degree of AR.19 We revealed that 59.58% of BAV patients had any degree of AR, and 65.8% (77/117) of patients had mild AR in the pure AR cohort, which was consistent with the western population. Meanwhile, the patients with AR are younger than those with AS from the European experience,20 which is similar to our study. The incidence of infective endocarditis was 0.68% episodes per patient-years according to our data, which were much more than 3 to 10 episodes per 100,000 patient-years in general population.21 And it was consistent with the incidence from recent estimates reported as 0.9% to 2% episodes per patient-years.19,22 In our study, only the first examination was included. But in cases with initially negative examination, repeated echocardiography within 7 to 10 days is excluded. Thus, the incidence of infective endocarditis may be underestimated. As a rare but critical complication, aortic dissection is associated with high mortality rate. The incidence of aortic dissection in BAV patients ranges from 3% to 5%.15,23
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Figure 3. Constituent ratio of calcific aortic stenosis in different age groups.
Table 2 Bicuspid aortic valve coexisting with congenital heart disease Category Ventricular septal defect Patent ductus arteriosus Ventricular septal defect þ Patent ductus arteriosus Atrial septal defect Aortic coarctation Others*
Subjects (number þ percentage) 27 6 4
4.0 0.9 0.6
5 4 7
0.7 0.6 1.0
* Others, including incomplete endocardial cushion defect in 2, dextrocardia in 2, pulmonary valve stenosis, Taussig-Bing symptom, and right ventricular outflow tract obstruction accompanied with pulmonary valve dysplasia in single case.
However, the prevalence of dissection was 0.1% per patientyear of follow-up in the Toronto study, and no cases of dissection were reported from the Olmsted County study,19,22 which is similar to the incidence from our study of 0.18% episodes per patient-years. According to the recent estimate in pediatric and young adult subjects, 39% of BAV patients had coexisting CHD.24 From Hinton et al,25 BAV is associated with hypoplastic left heart syndrome, while from Roos-Hesselink et al,26 approximately 50% to 75% patients with aortic coarctation have BAV. Although many kinds of cardiovascular malformation were reported to have a high correlation to BAV, only 7.6% of BAV patients had coexisting CHD in our study, and the most frequent coexisting CHD was ventricular septal defect, followed by patent ductus arteriosus. Fifteen percent of BAV patients from the Olmsted County study were reported to have coexisting CHD, which was similar to our study.19 Our study has several limitations. First, as a single-center study in a tertiary hospital, the selection bias is mainly increased by the asymptomatic BAV patients who do not come to our institution. Second, albeit the convincing large sample size, our study can partially reflect the incidence of BAV in China. Future screening studies among general
population are required to determine the true incidence of BAV in Chinese. Finally, as a cross-sectional study, it lacks longitudinal data, thus the natural course of the disease and patient outcomes could not be assessed. Disclosures The authors have no conflicts of interest to disclose. 1. Zegdi R, Ciobotaru V, Noghin M, Sleilaty G, Lafont A, Latremouille C, Deloche A, Fabiani JN. Is it reasonable to treat all calcified stenotic aortic valves with a valved stent? Results from a human anatomic study in adults. J Am Coll Cardiol 2008;51:579e584. 2. Wijesinghe N, Ye J, Rodes-Cabau J, Cheung A, Velianou JL, Natarajan MK, Dumont E, Nietlispach F, Gurvitch R, Wood DA, Tay E, Webb JG. Transcatheter aortic valve implantation in patients with bicuspid aortic valve stenosis. JACC Cardiovasc Interv 2010;3: 1122e1125. 3. Jilaihawi H, Wu Y, Yang Y, Xu L, Chen M, Wang J, Kong X, Zhang R, Wang M, Lv B, Wang W, Xu B, Makkar RR, Sievert H, Gao R. Morphological characteristics of severe aortic stenosis in China: imaging corelab observations from the first Chinese transcatheter aortic valve trial. Catheter Cardiovasc Interv 2015;85(Suppl 1):752e761. 4. Larson EW, Edwards WD. Risk factors for aortic dissection: a necropsy study of 161 cases. Am J Cardiol 1984;53:849e855. 5. Basso C, Boschello M, Perrone C, Mecenero A, Cera A, Bicego D, Thiene G, De Dominicis E. An echocardiographic survey of primary school children for bicuspid aortic valve. Am J Cardiol 2004;93: 661e663. 6. Tutar E, Ekici F, Atalay S, Nacar N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. Am Heart J 2005;150:513e515. 7. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226e1233. 8. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438e2488. 9. Habib G, Badano L, Tribouilloy C, Vilacosta I, Zamorano JL, Galderisi M, Voigt JU, Sicari R, Cosyns B, Fox K, Aakhus S; European Association of Echocardiography. Recommendations for the practice of echocardiography in infective endocarditis. Eur J Echocardiogr 2010;11:202e219.
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