Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction: A meta‐analysis

1 INTRODUCTION

The bicuspid aortic valve (BAV) is the most common congenital cardiac defect that observed in 1%–2% of general population,1 with a male to female ratio of about 3:1. Patients with BAV are at a high risk of developing aortic valve dysfunction, either stenosis or regurgitation, or both. Studies have suggested that 33% of patients with BAV will suffer serious and life-threatening complications in their lifetime. Therefore, early detection and prevention of the complications caused by BAV are of paramount importance.2 BAV appears to be inherited in an autosomal dominant fashion with incomplete penetrance. It has been postulated that the defective genes encoding the protein matrix structure could be responsible for developmental impairment of heart, and leading to valvular abnormalities.3-5 BAV presents several phenotypes, and an animal experiment demonstrated that different BAV phenotypes are caused by different developmental processes, suggesting that different BAV phenotypes should be considered as different etiological entities with different valvular lesions, aortic size, and elasticity.6 Thus, more credit should be given to the association between BAV phenotypes with valvular dysfunction.7

The most common BAV pattern is fusion of the right and left coronary cusps, and fusion of the right and noncoronary cusps.8, 9 Previous evidence suggests that various BAV types, distinguished by the morphology of the valve cusp fusion, may carry different relationships with valvular dysfunction; however, the published literature is incoherent in this regard. Several studies have reported an increased frequency of significant valvulopathy in pediatric patients with right and left coronary cusps fusion,10 while another longitudinal follow-up study claimed that BAV phenotype failed to demonstrate a prognostic implication.11

2 AIM OF THE STUDY

Therefore, the purpose of our study was to evaluate the impact of different BAV cusp fusion morphology on the incidence of valvular dysfunction, and provide clues and evidence for early clinical diagnosis and prevention of complications.

3 METHODS 3.1 Search strategy

A systematic search was performed in the electronic databases (PubMed, The Cochrane Library, Web of Science, and CNKI), using the following search terms in all possible combinations: bicuspid aortic valve, aortic regurgitation, aortic stenosis, valve dysfunction. Articles were rejected on initial screening if from the title or the abstract it was judged that the article does not report aortic valve dysfunction and BAV morphology. Subsequently, the full text of the remaining articles was retrieved. All the references were also scanned. The particular studies were examined to exclude duplicated and overlapped data. Finally, only studies evaluating aortic stenosis and aortic regurgitation were included. In case of missing data, the authors were contacted by e-mail to try to retrieve the original data. Each article was analyzed by two independent individuals and data extraction was done independently. In case of disagreement, a third investigator was consulted. Discrepancies were resolved by consensus. Data extraction was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) (Figure 1).12

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Flow diagram for study selection. This flow chart shows the initial search results and final review of 11studies after consideration of exclusions

3.2 Study selection and data extraction

Inclusion criteria were as follows: (1) the domestic and foreign published literature, all studies that participants were diagnosed as BAV by TTE or TEE or CT; (2) An information about the morphology of BAV (RL morphology and RN morphology) according to previously mentioned definition and information related to valve dysfunction. (3) More complete raw data is available in the literature for calculation of odds ratio (OR).

Exclusion criteria were as follows: (1) No data on the BAV morphology and valve dysfunction, or there is not enough data available for odds ratio (OR) calculations; (2) Review article, case studies, animal experiments, and conference abstracts. (3) Research that not able to access the full text through various channels is only an abstract.

The following data were also extracted from each study: first author, year of publication, used imaging modality, study population characteristics including mean age, male gender percentage, sample size (number of subjects in particular BAV subtypes), number of patients with AS, and number of patients with AR.

3.3 Statistical analyses and risk of bias assessment

The presented meta-analysis was performed using Statistica 15.1. The frequency variable is expressed as n (%). Differences among AS and AR between the two types of BAV patients were expressed as odds ratio (OR) with pertinent 95% CI for dichotomous variables. Overall effect was tested using Z scores, and significance was set at p < .05. Statistical heterogeneity among studies was assessed with the chi-square Cochran's Q test and with the I2 statistic, which measures the inconsistency across study results and describes the proportion of total variation in study estimates. To evaluate the individual impact of each study on the overall effect size, sensitivity analysis was conducted using the leave-one-out approach, by estimating the weighted mean difference in the absence of each single study.

The presence of publication bias was evaluated using Egger's weighted regression tests and Begg's rang correlation. Publication bias was evaluated visually by inspection of funnel plots of SE and mean difference asymmetry. Visual inspection of funnel plot asymmetry was performed to address for possible small-study effect, as well as the Egger test to address publication bias, over and above any subjective evaluation. p < .05 was considered statistically significant.13

4 RESULTS 4.1 Search results and study characteristics

The total of 2376 articles were searched from PubMed, The Cochrane Library, Web of Science, and CNKI. Articles that abstracts and titles were irrelevant to our objection were excluded during the initial screening. Then, full texts of 23 articles were analyzed. At last, 1314-26 articles meet the inclusion criteria. The number of patients varied from 67 to 785, mean age ranged from 17.2 to 59 years, and the prevalence of male sex is from 60% to 78%. The following imaging modalities were used in analyzed studies: transthoracic echocardiography (TEE), transesophageal echocardiography (TTE), computed tomography (CT), and complex MDCT/TEE imaging. The baseline characteristics of the all included studies are presented in Tables 1 and 2.

TABLE 1. Description of the studies included into the analysis of AS associated with BAV morphology Reference Time Imaging Country RL RN Mean age (y) Man (%) AS N AS N Sun21 2017 TTE/TEE Korea 269 361 292 320 59 ± 12 62.0 Ruzmetov17 2015 TTE US 27 96 56 114 17.2 ± 9.9 60.0 Ren XS24 2017 TTE China 37 125 49 74 50.3 ± 3.8 65.5 Miśkowiec15 2016 TTE/TEE Poland 26 46 15 21 55.3 ± 6.7 78.0 Tabriziet19 2018 TTE/TEE Iran 51 188 63 112 40 ± 16 72.0 Kang14 2013 TTE/CT Korea 43 93 49 74 54.6 ± 4.4 68.9 Hong22 2014 TTE/CT Korea 33 192 37 80 51.7 ± 4.4 72.7 Huang16 2013 TTE Singapore 27 117 25 74 48.4 ± 5.8 67.0 Tuluce20 2017 TTE/TEE Turkey 42 105 33 49 37 (17–70) 71.4 Wei Liqun23 2018 TTE China 55 89 103 141 52.6 ± 5.0 51.6 Evangelist18 2017 TTE Spain 146 590 58 195 47.4 ± 6.8 70.2 AR N AR N Sun21 2017 TTE/TEE Korea 144 361 71 320 59 ± 12 62.0 Ruzmetov17 2015 TTE US 40 96 60 114 17.2 ± 9.9 60.0 Ren XS24 2017 TTE China 74 125 13 74 50.3 ± 3.8 65.5 Miśkowiec15 2016 TTE/TEE Poland 42 46 18 21 55.3 ± 6.7 78.0 Tabriziet19 2018 TTE/TEE Iran 150 188 77 112 40 ± 16 72.0 Kang14 2013 TTE/CT Korea 31 93 5 74 54.6 ± 4.4 68.9 Hong22 2014 TTE/CT Korea 58 192 11 80 51.7 ± 4.4 72.7 Huang16 2013 TTE Singapore 49 117 26 74 48.4 ± 5.8 67.0 Tuluce20 2017 TTE/TEE Turkey 75 105 36 49 37 (17–70) 71.4 Wei Liqun23 2018 TTE China 44 89 39 141 52.6 ± 5.0 51.6 Evangelist18 2017 TTE Spain 146 590 44 195 47.4 ± 6.8 70.2 TABLE 2. Description of the studies included into the analysis of valvular dysfunction associated with BAV morphology (Raphe+ vs. Raphe−) Reference Time Imaging Country Raphe+ Raphe− Mean age (y) Man (%) AS N AS N Kong25 2017 TTE Netherlands 721 1881 51 237 47.0 ± 8.0 72.0 Sievers26 2014 NA Germany 550 1247 64 115 54.2 ± 3.4 76.7 Ren XS24 2017 TTE China 25 109 61 88 50.3 ± 3.8 65.5 Hong22 2014 TTE/CT Korea 50 120 50 89 51.7 ± 4.4 72.7 Evangelist18 2017 TTE Spain 166 644 16 144 47.4 ± 6.8 72.0 AR N AR N Kong25 2017 TTE Netherlands 144 361 71 320 47.0 ± 8.0 72.0 Sievers26 2014 NA Germany 40 96 60 114 54.2 ± 3.4 76.7 Ren XS24 2017 TTE China 74 125 13 74 50.3 ± 3.8 65.5 Hong22 2014 TTE/CT Korea 42 46 18 21 51.7 ± 4.4 72.7 Evangelist18 2017 TTE Spain 150 188 77 112 47.4 ± 6.8 72.0 Abbreviations: AR, aortic regurgitation (at least moderate); AS, aortic stenosis (at least moderate); CT, computed tomography; NA, data not available; RL, right and left cusp fusion bicuspid aortic valve morphology; RN, right and noncoronary cusp fusion bicuspid aortic valve morphology; TTE, transthoracic echocardiography. 4.2 Correlation between BAV morphology(RL and RN)and aortic stenosis

Eleven studies,14-24 including 2002 BAV-RL and 1254 BAV-RN patients, showed that AS was reported in 37.8% BAV-RL subjects and in 62.1% BAV-RN patients (OR = 0.66; 95% CI: 0.58 to 0.76; p = .000), the difference was statistically significant. Heterogeneity among studies was not significant (I2 = 28.4%; p = .124). The combined effect quantity OR was determined using a fixed effect model. Fixed effects meta-regression suggests that age (slope: 0.01; 95% CI: −0.01–0.03; Z = −0.59; p = .396), male gender (slope: −0.02; 95% CI: −0.04–0.01; Z = 0.46; p = .122) does not associated with the incidence of aortic regurgitation. Forest plot summarizing the meta-analysis of studies comparing aortic stenosis between RL and RN BAV groups is shown in Figure 2A.

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Forest plots. (A) Incidence of Aortic stenosis in patients with RL BAV and RN BAV; (B) Incidence of aortic regurgitation in patients with RL BAV and RN BAV. RL = right and left cusp fusion of bicuspid aortic valve; RL = right or left and noncoronary cusp fusion of bicuspid aortic valve; 95% CI = 95% confidence interval

4.3 Correlation between BAV morphology (RL and RN) and aortic regurgitation

In 11 studies,14-24 including 2002 BAV-RL and 1254 BAV-RN patients, AR was reported in 42.6% of BAV-RL subjects and 31.9% BAV-RN patients (OR = 1.46; 95% CI: 1.12 to 1.90; p = .005), the difference was statistically significant. Heterogeneity among studies was significant (I2 = 65.0%; p = 0.001). Random-effects meta-regression suggests that age (slope: 0.02; 95% CI:−0.01–0.05; Z = −0.59; p = .215), male gender (slope: 0.01; 95% CI: −0.05–0.06; Z = −0.59; p = .767) does not associated with the incidence of aortic regurgitation. Forest plot summarizing the meta-analysis of studies comparing aortic regurgitation between RL and RN BAV groups is shown in Figure 2B.

4.4 Correlation between BAV morphology (raphe vs. without raphe) with aortic regurgitation

Five studies,18, 22, 24-26 including 4674 patients, exhibit 4001 (85.6%) BAV patients has raphe, and 673 (14.4%) BAV patients are without raphe. Bicuspid aortic valves with raphe had a higher frequency to develop aortic regurgitation (28.9% vs. 21.4%; OR = 1.67; 95% CI: 1.04–2.67, p = .032). Heterogeneity among studies was significant (I2 = 80.3%, p = .001), the combined effect quantity OR was determined using Random effect model. Forest plot summarizing the meta-analysis of studies comparing aortic regurgitation between raphe and without raphe BAV groups is shown in Figure 3A.

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Forest plots. (A) Forest plot diagram of correlation between bicuspid aortic valve classification (Raphe vs. Nonraphe) and aortic regurgitation (AR); (B). Forest plot diagram of correlation between bicuspid aortic valve classification (Raphe vs. Nonraphe) and aortic stenosis (AS)

4.5 Correlation between BAV morphology (raphe vs. without raphe) with aortic stenosis

Five studies18, 22, 24-26 demonstrated that bicuspid aortic valves with or without raphe do not affect the incidence of developing aortic stenosis (37.8% vs. 36.0%, OR = 0.96, 95% CI: 0.53–1.76, p = .907). Heterogeneity among studies was significant (I2 = 90.3%; p = 0.000), the combined effect quantity OR was determined using Random effect model. Forest plot summarizing the meta-analysis of studies comparing aortic stenosis between raphe and without raphe BAV groups is shown in Figure 3B.

4.6 Sensitivity analysis

Presented pooled results were found to be robust in the performed leave-one-out sensitivity analysis, removing 1 study at a time. Obtained stability of the presented results confirms a significant difference in the frequency of aortic stenosis and aortic regurgitation between the BAV-RL and BAV-RN groups. For the analysis of the association between BAV phenotype and aortic stenosis, I2 ranged from 8.5% to 42.7%, showing increased heterogeneity (Table S1). For the analysis of the association between BAV phenotype and aortic regurgitation, I2 ranged from 60.0% to 69.5%, the results did not differ from the previous ones. (Table S2).

4.7 Publication bias analysis

Because it is recognized that publication bias can affect results of meta-analyses, we attempted to assess this potential bias using funnel plot visual analysis. Our results suggest that there is no potential bias for the comparison of BAV-RL and BAV-RN in aortic stenosis and aortic regurgitation. The Begg rank correlation test (Kendall tau with continuity correction: Pr > |z| = 0.53, Z = 0.62) and the Egger linear regression test (intercept: −1.71, 95% CI: −3.7 to 0.35; t = −1.88, p > |t| = .093) exhibit no evidence of publications bias when comparing the incidence of aortic stenosis between BAV-RL and BAV-RN patients. Moreover, the Begg rank correlation analysis (Kendall tau with continuity correction: Pr > |z| = 0.35, Z = 0.93), and the Egger linear regression test (intercept: 1.8, 95% CI: −1.87 to 5.62; t = 1.13, p > |t| = 0.287) suggested also no evidence of publications bias when comparing the incidence of aortic stenosis between BAV-RL and BAV-RN patients.

5 DISCUSSION

Our meta-analysis shows that BAV patients with right and left cusp fusion are incline to develop aortic regurgitation, while patients with right and noncoronary cusp fusion are more likely to develop aort

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