Bicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives.
Graphical abstract
Bicuspid aortic valve (BAV) is the most common congenital heart valve malformation with an estimated prevalence of 0.5% to 2% in the general population. , The prevalence of BAV is increased in first-degree relatives of an index case and is estimated to be 10-fold higher compared with the general population. , Familial studies have shown that BAV is heritable, with a heritability index of 0.89 (±0.06, p <0.001), suggesting a major genetic component. The inheritance pattern of BAV is complex, characterized by autosomal dominant inheritance with low penetrance, variable expressivity, and male predominance (male to female ratio of 3:1). BAV can present in different anatomical forms. According to the Sievers classification there are 3 main types, based on the number of raphes and the configuration of cusp fusion ( Figures 1 and 2 ). Previous studies have demonstrated an association between the different valvular phenotypes, the type and degree of aortic valve dysfunction and the type and incidence of aorthopathy. , This suggests that the valvular phenotype may have a role in the development and severity of aortic complications. , We conducted this study to characterize the heritability pattern of BAV morphology in a large family cohort from 2 academic medical centers followed by a systematic literature review to increase the study power.
Methods
The study was approved by the institutional review boards of both participating medical centers. We collected data from 2 medical centers from 2010 to 2020. Index patients with BAV were recruited at both institutions. We systematically contacted first-degree relatives of index cases and evaluated them by echocardiography. BAV status was determined by an experienced echo-cardiologist or by a senior pathologist based on surgical specimen. In case of a discrepancy between methods, the patient was excluded. Patients with syndromes known to be associated with BAV (e.g., Turner and Shone syndromes) and patients with an uncertain diagnosis on imaging were excluded. Data collection included: (1) demographics and medical history – age, gender, presence of hypertension; presence of aortic dilatation; history of aortic valve replacement; and presence of other cardiovascular malformations; (2) imaging data – aortic valve morphology; aortic measurements (aortic annulus diameter, sinus of Valsalva diameter, sinotubular junction diameter, and the diameter of the proximal ascending aorta); and presence and degree of aortic regurgitation (AR) and aortic stenosis (AS). This trial was conducted in compliance with good clinical practices as specified in the Israeli Ministry of Health regulations and in the International Conference on. Harmonisation good clinical practices Guidelines. All participants signed informed consent before participating in the study.
Aortic valve morphology was defined by two-dimensional echocardiography using parasternal short-axis view imaging of the aortic valve demonstrating a partial or total fusion of 2 cusps. BAV phenotypes were defined according to Sievers classification . AR and AS were assessed according to the American Society of Echocardiography (ASE) Guidelines, classified as none, mild, moderate, or severe. Aortic measurements were performed according to EAE/ASE recommendations. The aortic annulus was measured at peak systole from the inner edge to the inner edge. Other aortic measurements were performed in diastole from leading edge to inner edge, as per guidelines. Z scores were used to determine the presence of aortic dilatation in the pediatric population based on the size of the aorta measurements inner to inner edge in systole, and body surface area. Z scores of >2 were considered positive.
Heritability is a statistical parameter used to define the degree of phenotype variation that is genetically determined in the target population. To estimate BAV heritability we used the CHARRGe calculator which is an R tool designed to calculate genetic parameters from epidemiological parameters and vice versa.
To estimate the concordance of BAV morphology within families, we compared the observed concordance to the concordance expected by chance. The observed concordance rate was evaluated in a pair of relatives with BAV from each family and defined as the percentage of family pairs with the same type divided by the number of family pairs. If more than 2 family members were identified, we included the index case and the after member that was diagnosed. The expected concordance rate was calculated as the proportion of families that are predicted to have a matching type by chance, according to the prevalence within our cohort. Statistical significance was calculated using a one-tailed binomial test. This was assessed both for the cohort overall and by country of origin.
Systematic literature review: The Preferred Reporting Items for Systematic Review and Meta-Analysis guideline were used to perform the systematic literature review. The review was registered on the international prospective register of systematic reviews PROSPERO (identification: CRD42021240124). We searched two online databases, PubMed and Embase, between the years 1990 to 2020, using prespecified search terms and phrases (search algorithm is available in Supplementary Material). Studies were eligible for inclusion if they were original articles, written in English, and were published in peer-reviewed journals with available full text. We included studies reporting on BAV morphology within families, with at least 2 members with BAV in a family. Exclusion criteria included duplicated publications and publications that did not specify valve morphology diagnosis and morphology classification criteria and method. Data collection included: gender, age (years, mean ± SD), imaging type, the prevalence of BAV, the valve classification and distribution. First, we screened all publications by titles and/or abstracts. For articles deemed relevant, we assessed eligibility by full-text articles according to the inclusion and exclusion criteria by 2 investigators (I.T. and N.R.) independently, resolving conflicts by discussion and consensus. Finally, we performed qualitative synthesis and analysis of the eligible articles. The flow diagram is presented in Supplementary Material 2.
Power calculation: The genetic regulation of valve morphology may be monogenic (i.e., Mendelian) or multifactorial. We computed the power of our concordance analysis to identify Mendelian inheritance with full penetrance. We computed the expected within-family concordance under either dominant or recessive models. Based on the prevalence of the different morphologies found in the literature review, the models predict a range of expected values for the concordance: from a full agreement between family members (concordance rate of 1), down to a rate of 0.73. To detect a concordance of 0.73 and above with 80% power (at significance level 0.05), a sample size of 80 pairs is sufficient.
We performed the statistical analysis using SPSS software (IBM SPSS Statistics for Windows, Version 21.0. Armonk, New York). We reported categorical variables as number and percentage and compared using the chi-square test or Fisher’s exact test. We reported continuous variables as mean ± SD and compared using Student t test or Mann-Whitney U test. We evaluated whether variables are normally distributed using histograms and QQ plots. We considered p <0.05 as statistically significant. To account for multiple testing in the valve type comparisons we used Bonferroni correction.
Results
We identified 107 BAV index cases and screened 301 relatives. In this cohort, 70 familial BAV cases were identified in 31 families. In addition, 327 sporadic BAV cases were collected. At least 1 family member with BAV was identified in 29% (31 of 107) of the screened families. In these families, BAV was present in 14% (39 of 276) of the screened relatives. Male and female relatives were screened with equal frequency (male to female rate of 0.95:1), with BAV found in 17% (25 of 146) of males and 10% (15 of 155) of females. The heritability index of BAV was 0.92. A comparison of demographic and echocardiographic characteristics of BAV cases and their healthy relatives are presented in Table 1 .
| Variable | BAV patients | TAV relatives | P-value |
|---|---|---|---|
| Age (years) * | 48.1 (±17.8) | 40.2 (±18.9) | <0.001 |
| Male † | 287/396 (72.5%) | 130/279 (46.6%) | <0.001 |
| Hypertension † | 118/349 (33.8%) | 32/214 (15%) | <0.001 |
| Diabetes mellitus † | 16/324 (4.9%) | 11/194 (5.7%) | 0.717 |
| Hyperlipidemia † | 108/346 (31.2%) | 32/108 (15.1%) | <0.001 |
| Smoker † | 49/346 (14.2%) | 47/210 (22.4%) | 0.13 |
| Aortic dilatation † , ‡ | 213/368 (57.9%) | 13/237 (5.5%) | <0.001 |
| Aortic valve replacement † | 154/396 (38.9%) | 2/279 (0.7%) | <0.001 |
| Cardiac surgery † | 190/323 (58.8%) | 1/195 (0.5%) | <0.001 |
| Aortic stenosis † | |||
| None | 87/191 (45.5%) | 106/107 (99.1%) | <0.001 |
| Mild | 24/191 (12.6%) | 0/107 (0%) | <0.001 |
| Moderate/sever | 80/191 (41.9%) | 1/107 (0.9%) | <0.001 |
| Aortic regurgitation † | |||
| None | 33/224 (14.7%) | 69/87 (79.3%) | <0.001 |
| Mild | 92/224 (41.1%) | 15/87 (17.2%) | <0.001 |
| Moderate/sever | 99/224 (44.2%) | 3/87 (3.4%) | <0.001 |
| Arterial diameters (mm) * | |||
| Aortic annulus | 23.8 (±4.8) | 20.3 (±3.4) | <0.001 |
| Sinus of Valsalva | 35.85 (±7.28) | 29.56 (±6.03) | <0.001 |
| Sinotubular junction | 30.97 (±7.24) | 26.10 (±6.13) | <0.001 |
| Ascending aorta | 38.65 (±8.85) | 28.02 (±6.01) | <0.001 |
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