Prevalence, clinical characterization, management and evolution of bicuspid aortic valve classified according to the 2021 International Consensus Statement in a tertiary care hospital

Abstract

OBJECTIVES

The 2021 International Consensus for the congenital bicuspid aortic valve (BAV) condition recognizes 3 morphologies of BAV (fused, two-sinus and partial-fusion) and 3 types of aortopathy (ascending, root and extended). The clinical impact of BAV phenotyping on aortopathy evolution has not been evaluated so far. The aims were to assess: (i) prevalence of BAV phenotypes; (ii) frequency of BAV-related aortic valve dysfunction and aortopathy; and (iii) inter-phenotypic differences in aortopathy progression in a real-world population.

METHODS

This was an observational cohort study on patients with BAV referred to our tertiary hospital between January 2018 and November 2022 to undergo a comprehensive transthoracic echocardiography. Baseline clinical, ultrasonographic and computed tomographic data were evaluated; even echocardiographic progression of aortic dilatation was assessed.

RESULTS

Three hundred and two patients were evaluated: 245 (81.1%) had fused, 41 (13.6%) two-sinus and 16 (5.3%) partial fusion BAV. Aortopathy was documented in 101 (33.6%) cases and it was prevalent among patients with the fused type. The prevalence of aortic valve dysfunction was instead similar among the 3 groups. Two hundred and twelve patients underwent invasive management of clinically relevant aortic valve or aortic disease. Non-operated fused type presented the highest progression rate of aortic dilatation, whilst, among the interventional subpopulation, a more pronounced evolution was observed in the two-sinus type, at a median follow-up of 2 years.

CONCLUSIONS

Fused type represented the BAV phenotype with the highest frequency and the most significant association with aortopathy. In terms of aortopathic progression, the mid-term growth rate of the thoracic aorta was more significant in the non-interventional fused BAVs.

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INTRODUCTION

Bicuspid aortic valve (BAV) is the most frequent congenital heart valve abnormality, affecting ∼1–2% of the general population [1]. It is associated to an increased risk of aortic valvular dysfunction, infective endocarditis and thoracic aorta aneurysms [2].

The recent International Consensus Classification and Nomenclature (ICCN) for the congenital BAV condition recognizes 3 types of BAVs: fused, two-sinus and partial-fusion type (forme fruste), with a prevalence of 90–95% and 5–7% for the former 2 types, unknown for the latter. The ICCN also defines 3 types of BAV-associated aortopathy: ascending phenotype (70% of cases, with dilatation of the tubular ascending aorta), root phenotype (20% of cases, with dilatation of the Sinuses of Valsalva) and extended phenotype (up to 10% of cases with concurrent dilatation of aortic root, ascending aorta and, occasionally, aortic arch) [3].

The multitude of BAV and aortopathy phenotypes described by Michelena et al. subtend substantial genetic and/or haemodynamic differences, which overcome the pure morphological assessment of previous classification systems proposed by other groups (e.g. Angelini et al. [4], Sievers and Schmidtke [5], Kang et al. [6]; however, the predictive role of ICCN-defined BAV phenotypes in terms of aortopathy incidence and evolution has not yet been evaluated yet.

The aims of this study were to assess:

• Prevalence of BAV phenotypes;

• Frequency of BAV-related aortic valve dysfunction and aortopathy;

• Aortopathy progression.

MATERIALS AND METHODS

Ethics statement

The study was approved by the local Institutional Review Board (protocol no. 185/INT/2020). All patients provided informed written consent to share their clinical data; a specific informed consent was signed by the prospectively enrolled patients in order to authorize their study enrolment.

Study design

A single-centre observational, cohort study was conducted on patients affected by BAV and extrapolated from the whole population referred to the Echo Laboratory at the San Raffaele Hospital (Milan, Italy) between January 2018 and November 2022 to undergo transthoracic echocardiography (TTE). Exclusion criteria were the following: age < 18 years, previous aortic valve or thoracic aortic surgery, evaluation in the context of urgent procedures (due to aortic dissection, aortic rupture or complicated infective endocarditis).

All patients performed a two-dimentional TTE using a Philips EPIQ 7 ultrasound system equipped with a 1.0–5.0 MHz xMATRIX Array Cardiac Transducer (Philips Medical Systems, Best, Netherlands). Echocardiographic images and clips were acquired, digitally stored and then analysed offline using Suitestensa Review software (Esaote SpA, Genoa, Italy) by a single experienced operator for each exam. The echocardiographic assessment was performed in accordance with the most recent scientific recommendations [7, 8]; BAV phenotypes and their related abnormalities were classified according to the ICCN nomenclature (Videos 1–3) [3]. The following features were also described:

• ‘Aortic valve dysfunction’: at least mild valvular regurgitation or stenosis. Aortic valve dysfunction was graded through a multiparametric approach using the most recent recommendations of the American Society of Echocardiography (ASE) [7, 8]. Combined aortic valve disease was defined as having concomitant at least mild aortic regurgitation and at least mild stenosis.

• ‘BAV-related aortopathy’: as stated in the ICCN, we defined ‘root aortopathy’ if only the aortic root was ≥45 mm, ‘ascending aortopathy’ if only the tubular ascending aorta was ≥45 mm and extended aortopathy if both the segments were ≥45 mm. Measures were obtained leading-edge to leading-edge, perpendicularly to the blood flow [9].

Baseline clinical, laboratory, and computed tomographic (CT) data of patients were collected. Subjects with significant aortic valve dysfunction, coronary artery disease and/or aortic aneurysm underwent interventional procedures [surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR), ascending aorta replacement (AAR), SAVR + coronary artery bypass grafting (CABG) or SAVR + AAR] in accordance with current guidelines and evidence-based literature [9–11].

The echocardiographic progression rate of aortopathy was assessed in all patients with at least 1 year follow-up (FU), excluding those who underwent thoracic aortic surgery. The progression rate of aortopathy was defined as: [delta between baseline and FU diameter of the aortic segment of interest (SOI)/FU time]. The aortic SOI was selected as the most grown segment among the aortic root and the tubular ascending aorta.

Statistical analysis

Non-parametric continuous variables were presented as median and interquartile range (IQR), whilst categorical variables were reported as absolute number and percentage. The Kruskal–Wallis H test and the Mann–Whitney U-test were used to compare independent variables, while the repeated measures ANOVA test was used to compare repeated measurements. In case of P-value statistical significance (<0.05) at the Kruskal–Wallis H test, multiple comparisons adjusted by Bonferroni were performed to assess the difference between 1 specific group and the others. Frequency distribution was tested using Fisher’s Exact test. Linear correlation between different measurements was evaluated using the Pearson correlation coefficient (r). At the multivariate analysis, results were presented as odds ratio with a 95% confidence interval: two-sided P-values <0.05 were considered statistically significant. Both inter-rater and intra-rater reproducibility in measuring aortic dimensions were evaluated in a random sample of 100 patients. The Bland–Altman analysis and the interclass correlation coefficient were used to test inter-rater reproducibility; the interclass correlation coefficient was also used to test the intra-rater reproducibility.

All statistical analyses were performed using the SPSS software (version 25.0, SPSS Inc., Chicago, IL, USA).

RESULTS

Among an original screened population of 385 patients with BAV, 83 were ruled out as they presented exclusion criteria (Supplementary Material, Fig. S1). The baseline clinical and echocardiographic characteristics of the study population are reported in Table 1.

Patients were predominantly male (214, 70.9%) with a median age of 53.5 years (IQR 43–63). The most prevalent BAV phenotype was the fused type (245, 81.1%) (Fig. 1).

Aortic regurgitation was the most common type of aortic valve dysfunction in the overall population (263 cases, 87%), whilst aortic valve stenosis was diagnosed in 189 cases (62.6%) (Table 2). Aortic regurgitation was severe in 63 patients (20.9%), whilst severe stenosis was present in 98 patients (32.5%). No significant difference among BAV categories in terms of severe valvular disease was observed. Conversely, two-sinus BAV had more frequently mild aortic regurgitation (58.5%, P = 0.041), and partial fusion presented more cases of moderate regurgitation (56.3%, P < 0.001): the frequency of mild and moderate aortic valve stenosis was not statistically different comparing BAV phenotypes. Combined aortic valve dysfunction was found in 150 cases (49.7%), with higher frequency in the partial fusion type (P = 0.023).

One hundred and one patients (33.5%) were diagnosed with aortopathy: 79 (77.5% of the sub-group) had an ascending phenotype, 5 (4.9%) a root phenotype and 17 (16.7%) an extended phenotype (Fig. 2).

Aortopathy was prevalent among fused BAVs, the group who additionally presented statistically higher values of both baseline aortic root and ascending aorta diameters (Table 2).

CT data were available for 97 patients (80, 14 and 3 subjects with, respectively, a TTE-based diagnosis of fused, two-sinus and partial fusion BAV): TTE-based valvular morphology was confirmed at the CT evaluation for all these patients. In terms of aortic diameters, TTE and CT measurements presented a very strong correlation for both aortic root (r = 0.984, P < 0.001) and ascending aorta (r = 0.946, P < 0.001; Supplementary Material, Fig. S2).

Like on TTE, even at the tomographic evaluation, both aortic root and ascending aorta diameters were numerically higher in the fused phenotype, but without achieving the statistical significance in this case (Supplementary Material, Table S1).

In our population, 212 patients underwent invasive procedures (SAVR, TAVR, AAR, SAVR + CABG or SAVR + AAR). SAVR was the most frequent intervention, involving 99 subjects (46.7% of the subgroup), with a significant prevalence among the fused phenotype (Supplementary Material, Table S2). Conversely, TAVR, AAR, SAVR + AAR and SAVR + CABG were performed with similar rates among the 3 BAV types.

Progression of the aortic dilatation

Progression rate of aortic dilatation was assessed in all 208 patients who did not undergo interventional procedures involving thoracic aorta and had an echocardiographic FU of at least 1 year. This subpopulation consisted of 90 non-operated subjects and 118 subjects who performed TAVR/SAVR ± CABG. Non-operated BAVs presented a higher progression rate of aortic dilatation (37.9, IQR 33.4–42.5 vs 39.51, IQR 34.5–44.2; P = 0.015) than the interventional subpopulation (38.2, IQR 34.6–42 vs 38.6, IQR 34.6–42.7; P = 0.023) after a median FU of 24 months (IQR 18–28). Non-operated fused-type BAVs exhibited the most significant increase of the aortic SOI (38.6, IQR 34.1–43.3 vs 40.8, IQR 35.3–44.9; P = 0.003), whilst, among the interventional group, a more pronounced aortopathic progression was observed in the two-sinus type (37.4, IQR 33.1–41.5 vs 39.2, IQR 34.7–42.8; P = 0.012) (Fig. 3). Baseline and FU diameters did not significantly differ in both interventional and non-interventional partial fusion BAVs. Figure 4 and Supplementary Material, Table S3 show in detail the median progression rate of the aortic SOI among the different phenotypes.

No patient developed a significant aortopathic progression to match an indication to a first surgical procedure or a reintervention after a median FU of 2 years. FU therapy did not differ between BAV phenotypes (Supplementary Material, Table S4).

Reproducibility

The inter-rater reproducibility was obtained with 2 trained echocardiographers independently evaluating aortic diameters; intra-rater reproducibility was assessed by the same reader re-assessing aortic diameters 2 weeks apart.

Measurements of the aortic dimensions revealed an optimal inter-rater reproducibility at both baseline and FU. Baseline Bland–Altman plot showed a mean difference of 0.02 ± 0.76 mm and 95% limits of agreement of −1.48 + 1.52 mm (Supplementary Material, Fig. S3); FU-Bland–Altman plot showed a mean difference of 0.14 ± 0.72 mm and 95% limits of agreement of −1.27 + 1.55 mm (Supplementary Material, Fig. S4).

Even interclass correlation coefficient measurements confirmed an optimal baseline and FU inter-/intra-rater reproducibility (Supplementary Material, Table S5).

DISCUSSION

Our study analysed the prevalence and clinical features of a real-word population of patients affected by BAV, referred to a Tertiary Care Hospital and classified according the 2021 International Consensus Statement. The fused type was the most frequent morphology. More specifically, the prevalences of fused, two-sinus and partial fusion BAVs were similar in comparison to the current literature data [3]. The two-sinus phenotype resulted clinically (even though not statistically) older than the fused type, an interesting finding because the two-sinus BAV is thought to represent a strong embryologic aberrancy potentially presenting with valvular/aortic complications that are diagnosed at a younger age: according to our study, this might not be necessarily true. More than one-third of the subjects exhibited aortopathy, and the ascending type was the most common one. Fused-type BAV resulted the phenotype with the highest association with aortopathy, as well as the non-operated fused BAVs presented the most significant progression of aortic dilatation at a 2-year FU.

Instead, in the subset of patients performing interventions not involving thoracic aorta, the two-sinus phenotype had a more pronounced aortopathic evolution at a mid-term FU. These results find a clear explanation in the pathophysiological basis of BAV-related aortopathy. In fact, in the context of BAVs, the 2 main enhancers of the aortopathic process are genetics and haemodynamics [12]. While fused, two-sinus and partial fusion phenotypes share a genetic background with mutations and polymorphisms predisposing to aortic dilatation, only patients with complete cusps fusion present an altered transaortic blood as 2nd major trigger of aortopathy. This haemodynamic aberration produces an asymmetrical deflection towards the outer curvature of the ascending aorta, increasing the local wall shear stress (WSS) [13–15]. Increased local WSS is associated to higher risk and higher progression rate of aortic dilatation in patients with BAV due to a significant fragmentation of the regional elastic fibres, which is more typical of fused BAVs [16, 17]. Cross-sectional analysis using four-dimentional cardiac magnetic resonance aortic flow pattern assessment demonstrated that the right-non cusp fusion BAV phenotype is associated to a higher incidence of ascending type aneurysms, because patients present an increased WSS on the outer curvature of the tubular aorta; instead, the right–left cusp fusion phenotype is characterized by a higher risk of root aneurysms, because the aortic flow is directed towards the outer curvature of the aortic root [13–15]. However, these studies had a major limitation: they enrolled only patients affected by fused-type BAV, so the risk of aortopathy related to the two-sinus or the partial-fusion phenotypes remains unclear.

Our study is the 1st one to investigate the aortopathic implications in a population including all the 3 ICCN-defined BAV phenotypes.

The haemodynamic abnormalities in patients with partial fused cusps were described by Guala et al. [18], who reported a higher cardiac magnetic resonance-assessed incidence of flow displacement in whole ascending aorta and vortexes in the distal ascending aorta and proximal aortic arch in comparison to tricuspid aortic valves. However, those 2 groups did not differ in terms of maximum aortic diameter: it seems probably that the impact of partial fused BAVs on WSS is not as remarkable as in the complete fusion; the two-sinus phenotype, instead, produces a more symmetrical transaortic flow with an aortic WSS, which is comparable with the physiological tricuspid valves [19].

These hydrodynamic differences between BAV phenotypes might be the reason why.

However, the two-sinus BAV presented a higher mid-term progression rate of aortic dilatation in the group of patients performing TAVR/SAVR ± CABG. Some studies reported that aortic valve replacement determines a normalization of the asymmetrical transaortic flow with a reduction of the aortic WSS [20]; this effect is more pronounced in patients with cusps fusion rather than the two-sinus phenotype [19]. Moreover, Michelena et al. [3] defined the two-sinus BAV ‘a more severe expression of the embryological mechanisms leading to the fused BAV’, being linked to abnormal endocardial cushion formation/positioning or abnormal outflow tract septation during embryogenesis. These patients frequently present variants and/or mutations on genes regulating connective tissue growth (e.g. NOTCH1, GATA4, SMAD6) [21], and thus the dilatation of the thoracic aorta is enhanced by the inherited laxity of the aortic media layer. Although there is no scientific evidence on possible genotypic differences between the BAV phenotypes, the more pronounced weight of the genetic factors rather than the haemodynamics may justify the stronger tendency of the aorta in the two-sinus group to dilatate in a setting of normalized transaortic blood flow following valvular procedures. This aspect might have some important clinical implications as it can be speculated that patients with two-sinus BAV would benefit from earlier AAR in comparison to the other phenotypes when a surgical indication for valve dysfunction has emerged.

Limitations

This study presents some limitations: (i) the mostly retrospective nature of the study performed on a population enrolled with a possible referral bias; (ii) the relatively short postprocedural FU time of the population used to investigate the aortopathy progression, although it achieved a median of 24 months; (iii) the absence of genetic, molecular and haemodynamic features of patients and ascending aorta flow patterns; (iv) the use of TTE to assess aortopathy incidence and progression, although optimal indices of inter-rater and intra-rater reproducibility were guaranteed; and (v) the availability of CT data only for a limited portion of subjects.

CONCLUSIONS

The recent ICCN classification provides standardized definitions of BAV phenotypes for clinical, interventional and research purposes. Phenotyping patients according to this recommendation, fused type presented the highest frequency and the most significant association with aortopathy. Non-operated fused-type BAV is associated to a higher rate of aortopathy progression as well as, in the subpopulation undergoing invasive aortic valve therapy, a more pronounced evolution was observed in the two-sinus phenotype. Further studies are necessary to confirm our preliminary data, refining the genetic and the haemodynamic assessment of the different BAV phenotypes in order to optimize patients’ clinical outcomes.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

FUNDING

None declared.

Conflict of interest: none declared.

DATA AVAILABILITY

The data underlying this article are available in the article and in its online supplementary material.

Author contributions

Vincenzo Rizza: Conceptualization; Writing—original draft; Writing—review & editing. Francesco Ancona: Writing—original draft; Writing—review & editing. Giacomo Ingallina: Writing—review & editing. Stefano Stella: Writing—review & editing. Davide Margonato: Writing—review & editing. Annamaria Tavernese: Writing—review & editing. Martina Belli: Writing—review & editing. Federico Biondi: Writing—review & editing. Giorgio Fiore: Writing—review & editing. Monica Barki: Writing—review & editing. Damiano Cecchi: Writing—original draft; Writing—review & editing. Alessandro Castiglioni: Supervision. Michele De Bonis: Supervision. Ottavio Alfieri: Supervision. Francesco Maisano: Supervision. Eustachio Agricola: Supervision.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Denis A. Berdajs and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• AAR

  Ascending aorta replacement

 
• ASE

  American Society of Echocardiography

 
• BAV

  Bicuspid aortic valve

 
• CABG

  coronary artery bypass grafting

 
• CT

  Computed tomographic

 
• FU

  Follow-up

 
• ICCN

  International Consensus Classification and Nomenclature

 
• IQR

  Interquartile range

 
• SAVR

  Surgical aortic valve replacement

 
• SOI

  Segment of interest

 
• TAVR

  Transcatheter aortic valve replacement

 
• TTE

  Transthoracic echocardiography

 
• WSS

  Wall shear stress