One disease, two phenotypes: should asymptomatic bicuspid and tricuspid aortic stenosis be treated differently?

The optimal timing of intervention in severe aortic stenosis (AS) remains a highly debated question in valvular heart disease. Current guidelines recommend intervention primarily after symptom onset or in selected truly asymptomatic patients with low procedural risk as an alternative to active surveillance.1 Whether this concept applies equally to patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) stenosis, however, remains uncertain. In this issue of the European Heart Journal – Valvular and Structural Heart Disease, Wedin et al.2 provide novel data suggesting that preoperative symptom burden carries different prognostic implications according to valve morphology. Using a large single-centre cohort of more than 1000 patients undergoing surgical aortic valve replacement (SAVR), the authors report that severe symptoms were independently associated with worse long-term survival in patients with bicuspid AS, whereas this relationship was considerably less pronounced in tricuspid disease. Particularly noteworthy is the use of relative survival analyses, demonstrating that mildly symptomatic BAV patients achieved survival comparable to that expected for the general population, whereas highly symptomatic BAV patients experienced excess long-term mortality. These observations raise the intriguing possibility that symptom progression may reflect more advanced myocardial injury in bicuspid AS than in tricuspid disease. Interestingly, the interaction was not limited to subjective symptom burden. Sensitivity analyses incorporating NT-proBNP demonstrated a similar pattern, with biomarker-defined disease severity carrying greater prognostic implications in BAV than in TAV. Although exploratory, these findings further support the hypothesis that myocardial adaptation differs according to valve phenotype. The biological rationale supporting these findings is also compelling. Previous imaging studies have consistently demonstrated differences in ventricular remodelling and atrial dysfunction between bicuspid and tricuspid AS.3,4 Patients with BAV frequently develop more pronounced hypertrophy, myocardial fibrosis, and adverse ventricular remodelling despite having fewer conventional cardiovascular risk factors. This aligns with the growing concept that prognosis in AS is determined less by valve obstruction itself than by the extent of cardiac damage.5 From this perspective, symptom progression in bicuspid AS may indeed represent a more advanced stage of myocardial disease than symptom progression in older patients with degenerative tricuspid AS, in whom multiple cardiovascular and non-cardiovascular comorbidities contribute substantially to long-term outcomes and may dilute the prognostic importance of symptom severity itself. The present study therefore reinforces the concept that bicuspid and tricuspid AS should not necessarily be regarded as biologically identical entities simply because they share the same valvular lesion. Rather, they appear to represent distinct biological phenotypes with different systemic and myocardial manifestations. Beyond valve morphology itself, these entities differ in genetic background, patient demographics, patterns of ventricular adaptation, myocardial remodelling, associated aortopathy, and likely the mechanisms driving disease progression and clinical outcomes. Furthermore, BAV is increasingly recognized not simply as a valve malformation but as a broader developmental condition in which endothelial-cell biology plays a central role. Recent studies show that patients with BAV have distinct endothelial-cell transcriptomic profiles and abnormalities in extracellular matrix organization and signalling pathways.6 These findings suggest that the underlying developmental abnormalities in BAV may affect not only valve formation and aortic disease but also myocardial remodelling and fibrosis through shared biological pathways. In this context, valve morphology may serve as a surrogate for a broader disease phenotype rather than simply describing the anatomy of the valve. Hence, the present study challenges one of the fundamental assumptions of current guidelines: that symptom onset carries equivalent biological significance across all patients with severe AS. However, as cardiovascular medicine continues to evolve towards a more personalized approach, future strategies for timing intervention may need to incorporate these phenotypic differences alongside traditional measures such as stenosis severity and symptom burden. Whether valve morphology itself, or the broader biological phenotype it represents, should influence clinical decision-making and intervention timing remains an important unanswered question. Interestingly, the present observations may also offer a potential explanation for the heterogeneous results of contemporary randomized trials evaluating early intervention in asymptomatic severe AS.7–10 The RECOVERY trial,7 which demonstrated a long-term survival benefit with early surgery, enrolled predominantly patients with BAV, whereas subsequent trials with neutral mortality results included relatively few BAV patients. Although entirely hypothesis-generating, the current study raises the possibility that valve phenotype may partly explain these apparently conflicting observations and should therefore be considered in the design and interpretation of future randomized trials. At the same time, caution is warranted when translating these observations into clinical practice. As with all observational studies, the reported associations cannot establish causality. Residual confounding remains an unavoidable consideration, even after multivariable adjustment and sensitivity analyses. The contribution of Wedin et al. lies less in changing current clinical practice than in challenging existing assumptions. Their findings suggest that symptom burden may not carry identical biological or prognostic meaning across different phenotypes of AS. Their work therefore provides an important rationale for designing dedicated prospective trials evaluating early surgery according to valve morphology, ideally integrating biomarkers, multimodality imaging, myocardial fibrosis assessment, and standardized functional testing. Ultimately, only a randomized comparison with prespecified analyses according to valve morphology could determine whether the benefit of early intervention truly differs between bicuspid and tricuspid AS. If confirmed in prospective studies, this observation could have important implications for future guideline recommendations and may represent another step towards a more individualized approach to the timing of intervention. Until such evidence becomes available, however, treatment decisions should continue to integrate symptom status with imaging findings, biomarkers, patient characteristics, and multidisciplinary heart team assessment. The assessment of symptom burden itself also illustrates one of the longstanding challenges in AS. Functional limitation remains inherently subjective, and the distinction between truly asymptomatic patients and those with subtle exertional symptoms is often difficult in routine clinical practice. In the present study, NYHA class I and II were grouped together as ‘mildly symptomatic’. While understandable from a statistical standpoint, these categories represent clinically distinct populations. Patients with NYHA class II symptoms already satisfy conventional indications for intervention, whereas the management of genuinely asymptomatic patients continues to generate considerable debate. Moreover, unless systematic exercise testing is routinely incorporated into patient evaluation, as recommended by current guidelines, symptom status may underestimate disease severity, particularly in individuals who have unconsciously reduced their physical activity due to their inherent valvular heart disease. Another important consideration concerns the growing role of objective indicators of myocardial damage. Contemporary management of AS increasingly relies not only on symptom status but also on biomarkers, advanced imaging, and measures of cardiac remodelling. Although the present study incorporates NT-proBNP analyses in a substantial subgroup and demonstrates findings that parallel those observed for symptom status, complete biomarker assessment was unavailable across the entire cohort. Likewise, detailed echocardiographic characterization beyond left ventricular ejection fraction was not consistently available. These parameters may represent the mechanistic link between valve morphology, symptom development, and long-term prognosis and deserve continued investigation in future prospective studies. These considerations also extend to the ongoing expansion of transcatheter aortic valve implantation (TAVI) into younger and lower-risk populations. If SAVR enables mildly symptomatic bicuspid AS patients to achieve a life expectancy comparable to that of the age- and sex-matched general population, this outcome establishes a remarkably high benchmark for any alternative treatment strategy. Whether TAVI can consistently deliver comparable lifetime outcomes in younger BAV patients remains unknown. Although indirect, the present study reinforces the continued importance of surgery in this population, where durability, lifetime management, and the cumulative consequences of future interventions are likely to outweigh short-term procedural advantages. Furthermore, the findings from this study reinforce the importance of considering lifetime management strategies in younger patients, where the first intervention is only one step in a sequence of future valve-related decisions. If the field moves towards earlier surgery in asymptomatic bicuspid AS, however, the surgical community must also accept an equally important responsibility. Lowering the threshold for intervention can only be justified if accompanied by the highest standards of surgical care and the lowest possible treatment burden. Young patients with preserved functional capacity should expect not only excellent long-term survival and valve durability but also minimal invasiveness, near-zero perioperative mortality and morbidity, short hospital stays, rapid recovery, and an early return to physical activity, professional life, and normal daily living. In this setting, continued refinement of minimally invasive surgical approaches, enhanced recovery pathways, and perioperative care is not merely desirable; it becomes an essential prerequisite for an early intervention strategy. Mateo Marin-Cuartas (Conceptualization, Investigation, Validation, Writing—original draft, Writing—review & editing [lead]), Jörg Kempfert (Formal analysis, Validation, Writing—review & editing [supporting]), and Volkmar Falk (Conceptualization, Supervision, Validation, Writing—review & editing [supporting]) No new data were generated or analysed in support of this manuscript. Nothing to disclose. All authors declare no funding for this contribution.