Clinical Characteristics of Korean Patients with Bicuspid Aortic Valve Who Underwent Aortic Valve Surgery

Bicuspid aortic valve (BAV) is one of the most common congenital cardiac anomalies that affects 1–2% of the global population.1), 2) BAV is defined as the morphological features of an aortic valve (AV) with “two cusps”, and is associated with a variety of clinical manifestations that include hemodynamic alteration, premature valvular failure, aortic pathologies such as aneurysm or dissection, and association with other complex congenital disorders.3), 4), 5) Little is known about the genetic components of BAV, as they range from single nucleotide polymorphisms to complex mutations, such as Notch homolog 1, translocation-associated (NOTCH1).6) Several clinical studies on overall survival, incidence of adverse cardiac events, and aortic complications have been published recently.7), 8), 9) Nevertheless, the current volume of evidence is insufficient, considering the many unanswered questions and clinical needs. A leading BAV research group recently suggested that current knowledge gaps need to be more clearly defined.10)

To-date, most large-sized clinical studies are from western countries;7), 8), 9) therefore, the possibility that ethnicity can be a potential disease modifier in BAV11) needs to be examined. Specifically, there is a need for large-scale clinical evidence for Asian subjects. The Korean Bicuspid Aortic Valve (KoBAV) registry was launched in 2014 with 2 study arms. The prospective arm was designed to construct a cohort of newly diagnosed BAV patients for observation of long-term clinical consequences, and the retrospective arm included patients with full-blown BAV disease, with particular focus on their clinical presentations and morphological features. In the present report, we describe a large-sized patient group with BAV in Korea in terms of clinical features, patterns of practice, and morphological phenotypes.

We described the clinical features, current practice patterns, and morphological phenotypes in a large patient group with BAV, which is the first report of this kind in Korea. BAV has historically been considered an ominous disease, which is likely due to sporadic reports on fatal infective endocarditis14) and aortic dissection or histologic similarity to Marfan's disease, based on an excised aorta.10) Recent representative clinical studies revealed that perceptions about the fatality of BAV have been biased or exaggerated, resulting from a lack of clinical evidence. Patients with BAV actually have similar overall survival rates compared to the general population.7), 8) Moreover, the risk of aortic dissection was found to be as low as 0.5% in a 25-year follow-up.9) Nevertheless, these clinical studies also provided information about the risk for aortic aneurysm, which was 26% in a 25-year follow-up,9) and approximately 27% of the patients underwent AV or aortic surgery during a 20-year follow-up.7) These findings are a reminder that development of valvular disease and aortic aneurysm that require surgery is an actual lifetime health risk. In this context, data focused on indications for AV surgery and clinical features in Korean patients with BAV are beneficial for improving patient care.

We have shown that development of valvular dysfunction (AS or AR) and infective endocarditis was the main cause of AV surgery, and AS was the predominant lesion for AV surgery (77% [892/1,160]). Interestingly, there was a unique relationship between age and predominant valvular lesions that required AV surgery. Surgery for AS before 60 years of age was reported to represent premature degeneration of BAV,15) and BAV is more frequent than tricuspid AV in younger ages based on data for AV replacement.16) However, in our study, surgery for AS due to BAV was mainly performed in the aged population and more than 90% (811/892) of patients who underwent surgery were older than 50 years. The second common cause of AV surgery in patients with BAV was development of AR and the mean age was significantly lower for those with AR than AS (47±14 vs. 62±10 years; p<0.001). More than 50% (104/199) underwent AV surgery due to AR before age 50. Infective endocarditis was the primary lesion for AV surgery in 6% of cases, comprising the smallest proportion. However, this number is not negligible, considering the prevalence of BAV in the general population and the volume of AV surgery. Infective endocarditis developed in relatively young patients and more than 60% of patients (43/69) underwent surgery before 50 years of age. Aortic root abscess was observed in 25% of patients with infective endocarditis, which is comparable with the previously reported frequency (22%) in patients with AV endocarditis17) but lower than that (50%) in specified BAV endocarditis groups.18) The relationship between age and predominant valvular lesions that required AV surgery in our patients with BAV is similar to that reported previously: In a surgical pathology study of 542 cases, the authors confirmed that AS surgery was predominantly performed in the aged population with the peak in the 60s.19)

Although BAV has unique morphological features with recognizable patterns, its clinical impact or significance has remained elusive. Different classification systems for BAV phenotypes have been reported since the 1970s.19^-21) The current representative classification was proposed by Sievers and Schmidtke,12) who applied a sophisticated method to 304 surgical reports and derived 3 main and 6 subcategories. This system was utilized by other researchers who demonstrated the feasibility of AV repair based on detailed anatomic features.22) However, such a classification process is difficult to reproduce in routine practice using non-invasive imaging studies alone, which are limited in their ability to document fused individual cusps; moreover, its benefit is doubtful as 95% of patients undergo AV replacement rather than repair surgery. Conversely, the influence of BAV phenotype on hemodynamics has been highlighted recently.23), 24), 25) Most of these studies, however, used magnetic resonance images for better spatial resolution, which is inconsistent with real clinical practice, in which echocardiography remains the mainstay of diagnosis. Therefore, we investigated the classification system presented by Schaefer et al.,13) in which echocardiographic images were used to derive 3 main patterns. In this study, due to the potential ambiguity of real images, we added a type 4 that represented indeterminate patterns between types 2 and 3.

We confirmed that type 1 (fusion between right and left coronary cusp) was the most frequent phenotype despite some variations in the frequency between the 4 institutions. Notably, the relative frequency of the type 1 phenotype in our study was lower compared to that reported in western countries, suggesting the possibility of ethnic differences in the frequency of different BAV phenotypes. The prevalence of the type 1 phenotype in western countries was over 70% (up to 86%), whereas that reported in Japan and Korea was less than 60% (Table 3 and Figure 5).7), 8), 12), 13), 26), 27), 28) One potential explanation for this difference is different study cohorts: our study included BAV patients with significant valvular dysfunction that needed AV surgery, whereas western reports based on imaging studies included variable degrees of valve dysfunction. Currently, the clinical impact of ethnic differences on the frequency of specific BAV phenotypes is unclear; however, considering the different embryologic pathogenesis of different BAV phenotypes,29) these could manifest in ethnically-based differences in clinical features or outcomes in patients with BAV. This hypothesis requires additional testing in future investigations.

Table 3
BAV phenotypes described in previous research

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Figure 5
BAV phenotypes described in previous research.

BAV = bicuspid aortic valve; Lat = lateral; LN = fusion between left and non-coronary cusps; RL = fusion between right and left coronary cusps; RN = fusion between right and non-coronary cusps.

^*Orange and blue bars present data from western and Asian countries, respectively; ^†Lat, BAV presenting with 2 even cusps, no raphe and right-left orientation.

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This study is limited in that we only included patients who underwent AV surgery in tertiary referral hospitals, and thus, the actual incidence of valvular dysfunction or aortic dissection/aneurysm in the general population cannot be accurately estimated based on these results. This selection bias may have also affected the frequency of BAV phenotypes in real clinical practice, which includes patients with mild or no valvular dysfunction. Moreover, although aortic complication is common in patients with BAV, our retrospective study was not ideal for adequately evaluating this important clinical outcome. Patients who underwent primary aortic surgery without AV surgery were not included in this study.

In summary, clinical characteristics of patients with BAV who underwent AV surgery were studied according to the 3 different valvular lesions for surgery (AS, AR, and infective endocarditis). We observed a possible ethnic difference in a specific BAV phenotype and a potential association with types of valvular dysfunction. Further investigations are necessary to evaluate whether these observations may be applied in daily clinical practice for the general population.