Valvular heart disease Original research article Heart: first published as 10.1136/heartjnl-2018-313802 on 15 October 2018. Downloaded from http://heart.bmj.com/ on January 31, 2022 by guest. Protected by copyright. Familial clustering of bicuspid aortic valve and its relationship with aortic dilation in first-degree relatives Laura Galian-Gay,1 Amelia Carro Hevia,1 Gisela Teixido-Turà,1 José Rodríguez Palomares,1 Laura Gutiérrez-Moreno,1 Giuliana Maldonado,1 María Teresa Gonzàlez-Alujas,1 Augusto Sao-Aviles,1 Pastora Gallego,2 Francisco Calvo-Iglesias,3 Javier Bermejo,4 Juan Robledo-Carmona,5 Violeta Sánchez,6 Daniel Saura,7 Teresa Sevilla,8 Sergio Burillo-Sanz,9 Andrea Guala,1 David Garcia-Dorado,1 Arturo Evangelista,1 On behalf of the BICUSPID investigators ►► Additional material is Abstract exists that BAV results from abnormal fusion during published online only. To view Objective Bicuspid aortic valve (BAV) is the most embryonic development8; however, the specific please visit the journal online (http://d​ x.​doi.o​ rg/​10.​1136/​ common congenital heart disease. This study aimed to initiating mechanisms are not fully understood. heartjnl-2​ 018-​313802). determine the prevalence rate of BAV in first-degree Different morphological types of BAV according to relatives (FDR) and the inheritance pattern according to the cusps fused have been described, with the most For numbered affiliations see different morphotypes and aortic dilation. frequent (70%–80%) being right and left coronary end of article. cusp fusion with an anteroposterior opening config- Methods BAV probands were consecutively studied at eight tertiary referral centres. After sequential screening, uration.9 10 A pure BAV, without raphe, appears Correspondence to Dr Arturo Evangelista, FDR were included in the study. The BAV morphotype, in 7%–15% of the population.11 Whether valve Department of Cardiology, Vall aortic dilation and aortic phenotype were assessed by morphotype plays a role in the familial inheritance d’Hebron Hospital, Barcelona transthoracic echocardiography. pattern remains unknown. Complications related 08035, Spain; a​ rtu​revan​ gel​ista​ Results Seven hundred and twenty-four FDR of 256 to aortic valve dysfunction appear in 16%–68%12 masip@​gmail.​com and aortic dilation in 20%–84% of adults with BAV probands agreed to undergo family screening. Received 3 July 2018 The prevalence of BAV was 6.4% in FDR (9.2% in BAV,13 which may appear combined or alone. Aortic Revised 30 August 2018 men, 3.5% in women, p=0.002). Aortic dilation was dilation has also been documented in first-degree Accepted 6 September 2018 diagnosed in 9.6% of FRD with tricuspid aortic valves relatives (FDR) of patients with tricuspid aortic Published Online First (TAV), with a root phenotype in 2.7% and tubular in valve (TAV). The prevalence of this phenomenon 15 October 2018 6.9% and more frequently in the presence of arterial ranges from 3%4 10 to 32%14; however, its inher- hypertension (OR 4.48; CI 95% 2.51 to 7.99; p=0.0001) itance pattern remains unknown, probably due to and valvular regurgitation (OR 5.87, CI 95% 1.37 to the different methods and heterogeneous nature 25.16; p=0.025). The heritability (h2) of BAV was highly of studies. BAV screening in FDR is considered significant (0.47; p=0.002); however, no concordance appropriate in the current clinical practice guide- was observed among valve morphotypes. Aortic dilation lines; however, the degree of recommendation is heritability was not significant. not established.15 16 Data on the possible impact Conclusions The BAV prevalence rate in FDR was low of screening on outcomes or cost-effectiveness are (6.4%) but aortic dilation was observed in 9.6% of scant.17 FDR with TAV. The heritability of BAV was high without The aims of this cross-sectional, multicentre concordance in valve morphotypes, and aortic dilation study were: (1) to establish the prevalence rate of heritability was not observed. Patients with BAV should BAV among FDR using echocardiography; (2) to be made aware of its familial pattern. determine the inheritance pattern of BAV according to the different morphological types of valve, valve dysfunction and aortic dilation; and (3) to evaluate the presence and risk factors of aortic dilation in ►► http://​dx.​doi.​org/​10.​1136/​ Introduction FDR. heartjnl-2​ 018-​314063 Although bicuspid aortic valve (BAV) is considered a relatively benign condition, significant aortic valve Methods dysfunction, aortic dilation or aortic dissection can Study population © Author(s) (or their appear at any time in life.1–3 Several clinical and Patients with BAV documented by echocardiog- employer(s)) 2019. No experimental studies confirmed the familial clus- raphy were consecutively assessed prospectively at commercial re-use. See rights tering of BAV.4–6 Some studies suggested an autoso- eight tertiary referral centres from 2012 to 2015. and permissions. Published mal-dominant inheritance pattern,4–7 while others Exclusion criteria were a non-definitive diagnosis by BMJ. showed that although BAV heritability is almost of BAV or the presence of another connective To cite: Galian-Gay L, Carro entirely genetic, the inheritance pattern may be tissue disorder. From 852 patients included in our Hevia A, Teixido-Turà G, et al. explained by a polygenic inheritance with incom- previous study,18 256 agreed to undergo family Heart 2019;105:603–608. plete penetrance and variable expression.5 Evidence screening. Anamnesis, three-generation pedigree, Galian-Gay L, et al. Heart 2019;105:603–608. doi:10.1136/heartjnl-2018-313802   603 Valvular heart disease physical examination and transthoracic echocardiography were The aortic root and ascending aorta were assessed using the performed in each index case. FDR (parents, siblings and chil- parasternal long-axis view and at least three measurements were Heart: first published as 10.1136/heartjnl-2018-313802 on 15 October 2018. Downloaded from http://heart.bmj.com/ on January 31, 2022 by guest. Protected by copyright. dren) were identified and invited to participate in the study. taken (sinuses of Valsalva, sinotubular junction and tubular Those who finally agreed to be screened were included in the diameter), at end-diastole from leading edge to leading edge.16 A study. Approval of the hospital Ethics Committees was obtained non-standard parasternal long-axis window with an upper inter- for all participating centres. All participants provided their space and medial transducer position was obtained to visualise written informed consent. distal ascending aorta diameter. We measured the maximum diameter that can be obtained in these views. Echocardiographic Clinical and family study studies were centrally analysed by two expert ecchocardiogra- Anthropometric measurements (height and weight) were taken phers (AC and GM) using dedicated software (Echo PAC, GE and body mass index and body surface both calculated in all Healthcare, Little Chalfont, UK). patients with BAV and their FDR. Clinical history, presence of cardiovascular risk factors (hypertension, diabetes, dyslipidaemia Aortic dilation definition and smoking), comorbidities and other associated cardiac malfor- Recently, different studies showed aortic diameters to be strongly mations were obtained by personal interview at the time of echo- influenced by age, body size and sex. For this reason, the aorta is cardiographic study and completed from medical records. Three considered to be dilated when its diameter is 1.96 SD above the generations per proband were included, yielding a median of 3 predicted diameter for a particular patient.19 Thus, the Z-score (IQR 2–4) family members per proband. was applied to all aortic measurements in our population.19 Dila- tion of the aorta was examined at aortic root (sinuses of Valsalva) Echocardiographic studies and ascending aorta levels. The aorta phenotype classification Transthoracic echocardiography was performed in all patients was assigned according to the segment of the vessel showing the by experienced cardiologists using commercially-available, largest diameter.20 high-resolution ultrasound systems. Standard two-dimensional views were obtained and colour, continuous and pulsed Doppler Statistical analysis were used to assess dysfunctional valve quantification according Quantitative variables are expressed as mean ±SD and qualita- to European Association of Cardiovascular Imaging Standards. tive variables in percentages. Intergroup comparison was made BAV was defined as the presence of two cusps and commis- using Student’s t-test for continuous variables and Fisher´s exact sures, with or without partial or total raphe, in either structure. test for qualitative variables. When the distribution was not Each aortic valve was analysed and characterised in systole and normal, the Mann-Whitney U test was used. The 95% CI was diastole. Diagnosis was established by the systolic fish-mouth calculated. Logistic regression was used to calculate the odds appearance of the orifice in parasternal short-axis views using ratios and confidence intervals. A p value <0.05 was considered a zoom tool. significant. Statistical test for intergroup comparisons where According to the fusion pattern of commissures, three morpho- chosen under the assumption of independence between groups. logical types were considered: type R-L, fusion of the right and These analyses were made using the statistical software left cusps; type R-N, fusion of the right and non-coronary cusps; programme SPSS V.9.0 for Windows. Additive genetic herita- and type L-N, fusion of the left and non-coronary cusps. bility was calculated with the SOLAR genetic statistics package. Patients were categorised in three groups according to the This software calculates the fraction of the total variance that degree and type of valvular dysfunction: a non-significant can be explained by additive genetic variance. The method dysfunctional group, including normally functioning valve, compares the sporadic model and the polygenic model based mild aortic stenosis (AS) or mild aortic regurgitation (AR), an on log-likelihood values. A subset of the whole cohort included AS-dominant group and an AR-dominant group, when valve in this work was used for heritability analysis. In order to have dysfunction was moderate or severe. homogeneous pedigrees, only families with proband’s siblings Figure 1 Representative scheme of study population. BAV, bicuspid aortic valve; FDR, first-degree relative. 604 Galian-Gay L, et al. Heart 2019;105:603–608. doi:10.1136/heartjnl-2018-313802 Valvular heart disease Table 1 Demographics, valve characteristics and aortic characteristics of all probands and FDRs Heart: first published as 10.1136/heartjnl-2018-313802 on 15 October 2018. Downloaded from http://heart.bmj.com/ on January 31, 2022 by guest. Protected by copyright. P value P-values Statistical All probands All FDRs probands vs FDRs with BAV FDRs without BAV BAV FDR vs power analysis (n=256) (n=724) BAV FDR (n=46) (n=678) TAV FDR (1-β err prob) Demographic data  Age, years 46.41±16.40 41.68±18.66 0.272 43.46±18.75 41.55±18.66 0.497 0.10  Males, N (%) 182 (71) 356 (49.2) 0.001 33 (71.7) 323 (47.6) 0.002 0.73  BSA, m2 1.84±0.19 1.73±0.29 0.99 1.84±0.24 1.72±0.29 0.016 0.88  Hypertension, N (%) 84/227 (37) 101/718 (14.1) 0.001 12/43 (27.9) 89 (13.2) 0.012 0.73  Diabetes, N (%) 13/226 (5.8) – – –  Dyslipidaemia, N (%) 63/226 (27.9) - – –  Smoker, N (%) 73/225 (32.4) – – – Valve characteristics  BAV R-L, N (%) 162/229 (63.3) – 34 (73.9) –  BAV R-N, N (%) 60/229 (26.2) – 11 (23.9) –  BAV L-N, N (%) 7/229 (3.1) – 1 (2.2) –  Presence of raphe, N (%) 187/229 (81.7) – 34 (73.9) – Valve dysfunction  Non-dysfunction, N (%) 139 (54.3) 709 (97.9) 0.001 40 (87) 669 (98.7) 0.001 0.93  AS-dominant, N (%) 50 (19.5) 3 (0.4) 0.01 2 (4.3) 1 (0.1) 0.001 0.99  AR-dominant, N (%) 67 (26.2) 12 (1.7) 0.01 4 (8.7) 8 (1.2) 0.001 0.81 Aortic diameters  Aortic root, mm 36.61±5.75 30.61±4.90 0.024 34.54±5.45 30.34±4.75 0.001 0.99  Aortic root, mm/m2 19.93±3.26 17.98±4.12 0.032 18.89±2.80 17.91±4.19 0.001 0.58  Aortic root, Z-score 1.39±1.4 1.05±0.22 0.443 1.23±0.43 1.04±0.2 0.0001 0.82  Ascending tubular, mm 40.83±7.72 29.55±5.45 0.001 35.24±7.41 29.15±5.07 0.001 0.99  Ascending tubular, mm/m2 22.28±4.68 17.33±4.30 0.001 19.21±3.78 17.20±4.31 0.001 0.92  Ascending tubular, Z-score 3.2±1.56 1.12±0.32 0.0001 1.47±0.5 1.09±0.29 0.0001 0.99 Aortic dilation  Dilation according to Z-score, N (%) 217 (84.8) 87 (12) 0.001 22 (47.8) 65 (9.6) 0.001 0.99  Dilation in the aortic root, N (%) 9 (3.5) 16 (2.2) 0.789 2 (4.3) 14 (2.1) 0.329 0.24  Dilation in ascending aorta, N (%) 208 (81.3) 71 (9.8) 0.001 20 (43.5) 51 (7.5) 0.001 0.99  Aortic root phenotype, N (%) 31 (12.1) 21 (2.9) 0.268 3 (6.5) 18 (2.7) 0.139 0.37  Ascending aorta phenotype, N (%) 186 (72.7) 66 (9.1) 0.001 19 (41.3) 47 (6.9) 0.001 0.99  Aortic dilation ≥45 mm, N (%) 85 (33.2) 6 (0.8) 0.0002 3 (6.5) 3 (0.4) 0.0001 0.82  Aortic dilation ≥50 mm, N (%) 31 (12.1) 3 (0.4) 0.268 3 (6.5) 0 (0) 0.0001 – In 27 cases, the valve morphology could not be definitively established. AR, aortic regurgitation; AS, aortic stenosis; BAV, bicuspid aortic valve; BSA, body surface area; FDR, first-degree relative. were included. The resulting subset was composed of 153 Valve characteristics and dysfunction probands and 236 siblings. Heritability power was calculated Characteristics and BAV morphotypes in probands are shown in with h2power command of SOLAR software with 10 replicates table 1. BAV morphotypes among relatives were as follows: BAV as the power to detect the corresponding observed heritability at R-L in 34 (73.9%), BAV R-N in 11 (23.9%) and BAV L-N in 1 a significance level of 0.05. (2.2%). No significant relationship was found among probands and relatives according to BAV morphotype. Pure BAV without Results raphe was present in 26.1% of FDR with BAV with no signifi- Two hundred and fifty-six BAV probands from a BAV data- cant differences with the probands. Regarding valve dysfunction, base agreed to undergo family screening. Through sequential 45.7% of probands had dysfunctional aortic valves (19.5% AS screening techniques, 1253 FDR were identified as candidates and 26.2% AR), while 13% of FDR with BAV had dysfunctional for inclusion in the study. Of these, 237 (18.9%) had died and valves (4.3% AS and 8.7% AR). 292 (23.3%) were not available (refused to participate, changed residence or did not attend appointments). Finally, 724 FDR were included in the screening echocardiographic study (figure 1). The Aortic dilation mean age of FDR was 41.7±18.7 years and 49.2% were males. Aortic dilation was more frequent in FDR with BAV compared Forty-six (6.4%) were identified as having a BAV, 218 probands with FDR with TAV (47.8% vs 9.6%; p=0.001) (table 1). had no relatives with BAV, 31 had one relative with BAV, 6 had Dilation of the tubular ascending aorta was more frequent in two relatives with BAV and 1 had three relatives with BAV. A FDR with BAV compared with FDR without BAV (20 (43.5%) new affected member was identified in 14.8% of the families (46 vs 51 (7.5%); p=0.001), while dilation of the aortic root was BAV in FDR distributed in 38 families). FDRs with BAV were similar between groups (2 (4.3%) vs 14 (2.1%); p=0.329). The more frequently men (71.7% vs 47.6%; p=0.002) and more ascending aortic phenotype also appeared more frequently in often hypertensive (27.9% vs 13.2%; p=0.012) (table 1). the FDR with BAV group (19 (41.3%) vs 47 (6.9%); p=0.001), Galian-Gay L, et al. Heart 2019;105:603–608. doi:10.1136/heartjnl-2018-313802 605 Valvular heart disease aortic dilatation h2 was calculated in siblings without BAV and Table 2 Characteristics of FDRs with dilation and non-dilation of the in siblings with BAV. Aortic dilation heritability did not reach Heart: first published as 10.1136/heartjnl-2018-313802 on 15 October 2018. Downloaded from http://heart.bmj.com/ on January 31, 2022 by guest. Protected by copyright. aorta statistical significance in any case. Statistical Valvular morphotype in siblings with BAV (n=43) was not power associated with proband morphotype (online supplementary Non-dilated Dilated analysis (1-β FDRs with TAV (n=613) (n=65) P values err prob) table 2), and the BAV prevalence rate was not related to proband BAV morphotype (online supplementary table 3). Age, years 40.7±18.4 49.1±19.1 0.0001 0.91 Males, N (%) 288/613 (47) 35 (53.8) 0.299 0.18 Hypertension, N (%) 67/613 (10.9) 22/62 (35.5) 0.0001 0.99 Discussion Valve dysfunction This large multicentre study found the prevalence rate for FDR Non-dysfunctional valve, 607/613 (99) 62/65 (95.4) 0.02 0.60 of BAV subjects to be 6.4%, being higher in men (9.2%) than N (%) in women (3.5%). A new affected member was identified by Presence of AS, N (%) 1/613 (0.2) 0/65 (0) 0.268 – conventional echocardiography in 14.8% of families. BAV heri- Presence of AR, N (%) 5/613 (0.8) 3/65 (4.6) 0.006 0.16 tability was moderate and not related to valve morphotype. In three cases, hypertension variable could not be definitively established. Aortic dilation prevalence in FDR with TAV was relatively high AS, aortic stenosis; AR, aortic regurgitation; FDR, first-degree relative; TAV, tricuspid (9.6%). Most dilations were mild and more frequently observed aortic valve. in patients with hypertension. In one subgroup of patients with TAV with aorta dilation, CT defined the presence of a mini- but no significant differences were observed in the aortic root raphe not previously diagnosed by TTE (41%). phenotype. A dilated aorta ≥45 mm was present in 6.5% of FDR This is the most extensive series to analyse the BAV prevalence with BAV and 0.4% of FDR with TAV and a significantly dilated rate in FDR. The characteristics of BAV probands in the current aorta (≥50 mm) was present in 6.5% of FDR with BAV and 0% series were similar to those of other studies. BAV was more of FDR with TAV. prevalent in men (71% of cases), and BAV R-L more common Sixty-five individuals (9.6%) of the FDR with TAV had aortic than BAV-R-N (63.3% vs 26.2%, p<0.0001). Over 50% of our dilation. They were older, with a higher prevalence of hyper- relatively young population (mean age: 46.4±16.4 years) had tension and AR, than those without dilation (table 2). History no significant valvular dysfunction. The prevalence rate of BAV of hypertension and significant AR were more frequent in this in FDR was 6.4%, in the range of previously published data of population (OR 4.48; CI 95% 2.51 to 7.99; p=0.0001 and OR 4.6%10 to 11%.4 5 14 21 Using a maximum-likelihood-based vari- 5.87, CI 95% 1.37 to 25.16; p=0.025, respectively). Angio CT ance composition method, we estimated the heritability of BAV to was performed in 22 FDR with aortic dilation from the coor- be 0.47, suggesting that in this population, the determination of dinator centre. Mini-raphe (small fusion between cusps), not BAV is not entirely genetic. Taken together, these results suggest defined by TTE, was diagnosed in 9 of whom (figure 2), 5 of that there may be a significant but incomplete genetic basis whom underwent 4D-MRI study which showed eccentric jet underlying BAV morphology. Some previous studies reported with an increase in rotational flow and axial wall shear stress. that heritability for BAV and other left ventricular outflow tract obstruction defects ranged from approximately 0.7 to 0.9 (5–6). Heritability These values were slightly higher than those reported in our Significant heritability was found in our cohort of siblings for series; however, we analysed isolated BAVs excluding other asso- BAV (h2=0.47; p<0.05) (table 3). Overall aorta dilation heri- ciated congenital heart defects, and the prevalence rate of the tability was not significant (p=0.06) and, since BAV and aortic disease was significantly lower in comparison with other studies. dilation traits were associated (online supplementary table 1), In contrast to the small series of Huntington et al in which the male-to-female ratio was 1:1,4 a similar ratio in probands and FDR with BAV was found in our larger study, which agrees with the ratio of community cohort studies.2 In our series, no significant relationship was found between probands and relatives according to BAV morphotype (56% concordance). This finding concurs with the results of other series10 and supports the hypothesis that although BAV is deter- mined by genetic factors, BAV morphology is defined in the embryological phase, and must be related to epigenetic and/or environmental factors.22 Dilation of the ascending aorta is common in patients with BAV and can occur in the absence of significant aortic valve dysfunction, providing support to the genetic/aortopathy theory.23 Some researchers suggest two different theories for the cause of aneurysms in patients with BAV (the haemodynamic theory vs the aortopathy theory). However, interaction between Figure 2 FDR of a patient with BAV showing a tricuspid leaflet valve genetic substrate and haemodynamic factors and flow abnormal- in diastole (A) and systole (B) with ascending aortic dilation (C) in the ities is very likely to be responsible for the ultimate expression of bidimensional echocardiographic images. CT showed a mini-raphe the ascending aorta dilation.18 24 (arrow) between left and right coronary cusps (D) and confirmed Results regarding a potential risk of thoracic aortic aneu- ascending aortic dilation (E). 4D-flow MRI revealed the eccentric rysm in FDR with a TAV are controversial. Several authors direction of the aortic jet towards to the anterior wall of the ascending have suggested that ascending aortic dilation is one component aorta (F). BAV, bicuspid aortic valve; FDR, first-degree relative. of the bicuspid syndrome and is inherited together with BAV, 606 Galian-Gay L, et al. Heart 2019;105:603–608. doi:10.1136/heartjnl-2018-313802 Valvular heart disease Table 3 Heritability Heart: first published as 10.1136/heartjnl-2018-313802 on 15 October 2018. Downloaded from http://heart.bmj.com/ on January 31, 2022 by guest. Protected by copyright. BAV Dilation all siblings Dilation in siblings without BAV Dilation in siblings with BAV N 389 389 371 18 (153 probands and 236 siblings) (153 probands and 236 siblings) (144 probands and 227 siblings) (9 probands and nine siblings) Prevalence in siblings (%) 9.3 14.8 13.9 50 h2 0.47 0.30 0.31 0.68 SE 0.18 0.21 0.23 0.94 P value 0.002 0.06 0.08 0.24 h2 power >0.9 >0.9 >0.9 >0.9 BAV, bicuspid aortic valve; h2, heritability; h2power, heritability power calculation; N, number of analysed individuals. although both conditions do not necessarily appear together in complications occur in over one-third of cases, BAV has a high the same individual. Some data suggest that the risk of thoracic morbidity rate. Based on these data, guidelines recommend aortic aneurysm is higher in relatives of patients with BAV even echocardiographic evaluation of all FDR of patients with BAV in those individuals who have morphologically normal aortic as class IIaC in search of aortic dilation and/or BAV.16 Data valves. Loscalzo et al found a 22% prevalence of aortic dila- of the current study need to be considered in these screening tion in BAV families with or without BAV.7 Similarly, Biner et recommendations. al reported a 32% prevalence of aortic root dilation in FDR, and also that aorta elastic properties were more affected in FDR Strengths and limitations than in controls but less than in BAV probands.14 However, in This study was conducted in families of patients with BAV that study, 53% of patients with BAV index had a dilated aortic attending tertiary centres; thus, our population may have a selec- root. Dilation of the aortic root is described as relatively rare in tion bias. As described in other series,10 17 only a 30% of possible BAV and is proposed as the form of bicuspid aortopathy most candidates agreed to undergo family screening, probably due to likely to be associated with a genetic cause.2 7 13 21 25–27 FDRs of geographic reasons, lack of interest or considering BAV a benign young patients with BAV with aortic root dilation may have an abnormality. Pedigree was not obtained in all families and the increased risk of thoracic aortic aneurysm in absence of BAV.7 14 genetic effect size (heritability) could not be estimated. The aim However, other studies reported lower percentages of 3%–4% of the study was not to define mini-raphe prevalence. There- of aorta dilation in first-degree TAV relatives4 10 17 21 similar to fore, only one subgroup of FDR with aortic dilation at the coor- the general population. Interestingly, Dayan et al compared a dinator centre underwent CT study and this finding should be group of FDR of patients with BAV without aortic dilation with confirmed in further studies. a group of FDR of patients with TAV without aortic dilation and found no differences in aortic measurements between groups, Conclusions suggesting that aortic dilation in FDR should be assessed when The BAV prevalence rate in FDR in this large multicentre study the proband has aortic dilation.28 was 6.4%, with no concordance in valvular morphotype. Aortic In the present study, aortic dilation in TAV relatives was 9.6%, dilation was observed in 9.6% of FDR with TAV. The heritability mostly in the tubular part. This higher incidence of aortic dila- of BAV was high without concordance in valve morphotypes but tion may be due to a strict definition of aortic dilation using a aortic dilation heritability was not observed. Patients with BAV Z-score-based criterion, mean FDR age of 42 years and 14% of cases with arterial hypertension. However, aortic dilation was ≥45 mm in only 0.4% of FDR. In addition, aortic root dilation Key messages was significantly more infrequent than in the Biner et al’s series (2.1% vs 32%).14 What is already known on this subject? Though not the aim of the current study, mini-raphe (frustre ►► The prevalence of bicuspid aortic valve (BAV) in first-degree BAV) was identified by CT in 9 of 22 cases (41%) with aortic relatives (FDRs) varies from 4% to 11% in published dilation and apparent TAV by TTE. This interesting finding may series. While the presence of aortic dilation has also been widen our understanding of aortic dilation in FDR but should be documented, its inheritance pattern remains unknown. interpreted with caution, as this was not the aim of our study. We hypothesise that these mini-raphes may disturb ascending aorta What might this study add? flow in a similar way to BAV24 (see figure 2). In a recent publica- ►► The prevalence of BAV was 6.4% in FDR and aortic dilation tion, surgical inspection of aortic valves in the setting of thoracic appeared in 10% of FRD with tricuspid aortic valve, and this aneurysm and aortic insufficiency found very small raphes (ie, phenomenon was associated with arterial hypertension and 3–6 mm in length) in valves initially considered to be tri-leaflet. aortic regurgitation. The heritability of BAV is moderate and These may have represented the fruste BAV form in 18/61 suggests a mostly genetic pattern, which is also not subject (29.5%).29 Although these mini-raphes were not diagnosed by to BAV morphotype. Aortic dilation heritability was not TTE, some were identifiable with high-resolution true co-axial observed. imaging by TOE, CT or MRI. This fruste BAV form could play a role in the aortic dilation of FDR with TAV defined by TTE. How might this impact on clinical practice? Although BAV is often identified incidentally in otherwise ►► Aortic dilation is present not only in patients with BAV but healthy, asymptomatic patients, it is associated with serious also in their FDR. Patients with BAV should be made aware long-term health risks, including valvular dysfunction, infective of its familial pattern. These data need to be considered in endocarditis, significant aortic dilation and more exceptionally recommendations about screening. aortic.2 30 Given its prevalence, and the fact that significant Galian-Gay L, et al. Heart 2019;105:603–608. doi:10.1136/heartjnl-2018-313802 607 Valvular heart disease should be made aware of its familial pattern, and screening of 5 Cripe L, Andelfinger G, Martin LJ, et al. Bicuspid aortic valve is heritable. J Am Coll their FDR advised. Further studies by CT or MRI are required Cardiol 2004;44:138–43. Heart: first published as 10.1136/heartjnl-2018-313802 on 15 October 2018. Downloaded from http://heart.bmj.com/ on January 31, 2022 by guest. Protected by copyright. 6 Calloway TJ, Martin LJ, Zhang X, et al. Risk factors for aortic valve disease in bicuspid to elucidate the presence and implications of mini-raphe in FDR aortic valve: a family-based study. Am J Med Genet A 2011;155A:1015–20. with TAV and aortic dilation. 7 Loscalzo ML, Goh DL, Loeys B, et al. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Author affiliations Am J Med Genet A 2007;143A:1960–7. 1 Department of Cardiology, Hospital Universitari Vall d´Hebron, CIBER-CV, Universitat 8 Padang R, Bagnall RD, Semsarian C. Genetic basis of familial valvular heart disease. Autònoma de, Barcelona, Spain Circ Cardiovasc Genet 2012;5:569–80. 2 Department of Cardiology, Hospital Universitario Virgen de la Macarena. CIBER-CV, 9 Bm S, Lewin MB, Stout KK, et al Heart 2008;94:1634–8. Sevilla, Spain 10 Robledo-Carmona J, Rodríguez-Bailón I, Carrasco-Chinchilla F, et al. 3 Department of Cardiology, Xestión Integrada de Vigo Hospital Alvaro Cunqueiro, Hereditary patterns of bicuspid aortic valve in a hundred families. Int J Cardiol Vigo, Spain 2013;168:3443–9. 4 Department of Cardiology, Hospital General Universitario Gregorio Marañón, 11 Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 Facultad de Medicina, Universidad Complutense de Madrid and CIBER-CV, Madrid, surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226–33. Spain 12 Masri A, Svensson LG, Griffin BP, et al. Contemporary natural history of bicuspid aortic 5 Department of Cardiology, Hospital Universitario Virgen de la Victoria, CIBER-CV, valve disease: a systematic review. Heart 2017;103:1323–30. Málaga, Spain 13 Verma S, Siu SC. Aortic dilatation in patients with bicuspid aortic valve. N Engl J Med 6 Department of Cardiology, Hospital Universitario 12 de Octubre, CIBER-CV, Madrid, 2014;370:1920–9. Spain 14 Biner S, Rafique AM, Ray I, et al. Aortopathy is prevalent in relatives of bicuspid aortic 7 Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, valve patients. J Am Coll Cardiol 2009;53:2288–95. CIBER-CV, Murcia, Spain 15 Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular 8 Department of Cardiology, Hospital Clínico Universitario de Valladolid, CIBER-CV, heart disease (version 2012). Eur Heart J 2012;33:2451–96. Valladolid, Spain 16 Erbel R, Aboyans V, Boileau C, et al. ESC guidelines on the diagnosis and treatment of 9 Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), aortic diseases. Eur Heart J 2014 35:2873–926. Sevilla, Spain 17 Panayotova R, Macnab A, Waterworth PD. A pilot project of familial screening in patients with bicuspid aortic valve disease. J Heart Valve Dis 2013;22:150–5. Acknowledgements The authors would like to thank Christine O’Hara for help 18 Evangelista A, Gallego P, Calvo-Iglesias F, et al. Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease. Heart with the English language of the manuscript and Augusto Cesar Sao-Avilés for 2018;104:566–73. statistical analyses. 19 Campens L, Demulier L, De Groote K, et al. Reference values for echocardiographic Collaborators BICUSPID investigators (see online supplementary appendix). This assessment of the diameter of the aortic root and ascending aorta spanning all age research was possible thanks to the collaboration of patients with BAV, their families categories. Am J Cardiol 2014;114:914–20. and the staff of the following centres: Hospital Universitari Vall d’Hebron (Barcelona), 20 Della Corte A, Bancone C, Buonocore M, et al. Pattern of ascending aortic dimensions Hospital Universitario Virgen de la Macarena (Sevilla), Hospital Universitario predicts the growth rate of the aorta in patients with bicuspid aortic valve. JACC Cardiovasc Imaging 2013;6:1301–10. Virgen de la Victoria (Málaga), Hospital Alvaro Cunqueiro (Vigo), Hospital General 21 Martin LJ, Hinton RB, Zhang X, et al. Aorta Measurements are Heritable and Universitario Gregorio Marañón (Madrid), Hospital Clínico Universitario Virgen de la Influenced by Bicuspid Aortic Valve. Front Genet 2011;2. Arrixaca (Murcia), Hospital Univesitario 12 de Octubre (Madrid) and Hospital Clínico 22 Fernández B, Durán AC, Fernández MC, et al. Genetic contribution of bicuspid aortic Universitario de Valladolid (Valladolid). valve morphology. Am J Med Genet A 2011;155A:2897–8. Contributors All co-authors and collaborators agree with the final version of the 23 Keane MG, Wiegers SE, Plappert T, et al. Bicuspid aortic valves are associated manuscript submitted and in the information that I have included in the current with aortic dilatation out of proportion to coexistent valvular lesions. Circulation form. 2000;102:III-35–-30. 24 Rodríguez-Palomares JF, Dux-Santoy L, Guala A, et al. Aortic flow patterns and wall Funding This work was supported by the grant PI11/01081 (Instituto de Salud shear stress maps by 4D-flow cardiovascular magnetic resonance in the assessment Carlos III, Madrid). of aortic dilatation in bicuspid aortic valve disease. J Cardiovasc Magn Reson Competing interests None declared. 2018;20:28. 25 Girdauskas E, Rouman M, Disha K, et al. Aortopathy in patients with bicuspid aortic Patient consent Obtained. valve stenosis: role of aortic root functional parameters. Eur J Cardiothorac Surg Ethics approval CEIC Hospital Vall d’Hebron. 2016;49:635–44. 26 Tadros TM, Klein MD, Shapira OM. Ascending aortic dilatation associated with Provenance and peer review Not commissioned; externally peer reviewed. bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications. Circulation 2009;119:880–90. References 27 Della Corte A, Bancone C, Quarto C, et al. Predictors of ascending aortic dilatation 1 Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J with bicuspid aortic valve: a wide spectrum of disease expression. Eur J Cardiothorac Cardiol 1970;26:72–83. Surg 2007;31:397–405. 2 Michelena HI, Desjardins VA, Avierinos JF, et al. 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