From Valve Anatomy to Molecular Trajectories: Integrating Proteomics into Precision Care for Bicuspid Aortic Valve Disease

Bicuspid aortic valve (BAV) disease is a lifelong disorder in which congenital anatomy, tissue susceptibility, abnormal flow, and acquired fibrocalcific remodeling produce heterogeneous valve and aortic outcomes. This narrative review examined peer-reviewed literature indexed in PubMed/MEDLINE through June 2026 to evaluate how circulating proteomics could complement established imaging-based risk assessment. Published studies of incident aortic stenosis consistently implicate integrated stress, inflammation, apoptosis, and extracellular-matrix remodeling, with recurrent signals including GDF15, MMP12, and natriuretic peptides. These data support a long preclinical molecular phase, but existing proteomic models were developed predominantly in general aortic stenosis populations and cannot be transferred directly to BAV. We propose a five-layer framework integrating valve morphology and function, aortic phenotype and growth, flow and wall mechanics, molecular activity, and patient-specific lifetime context. In the near term, proteomics is best used for cohort enrichment, mechanistic phenotyping, and trial design rather than intervention decisions. Prospective BAV-specific cohorts, standardized imaging, repeated sampling, competing-risk analysis, external calibration, and demonstration of management-changing utility are required before clinical implementation. Molecular phenotyping should refine, not replace, guideline-based imaging and shared decision-making.