Serum proteomics mirrors the histopathological changes underlying different etiologies of primary mitral valve disease

Mitral valve disease (MVD) is the most common valvulopathy and a frequent cause of heart failure and death. However, data regarding the molecular basis are scarce. We aimed to thoroughly explore and compare the circulating, molecular, and histopathological profiles in the main subtypes of primary chronic MVD. In total, 300 patients with chronic primary MVD undergoing mitral valve (MV) replacement were enrolled and classified in the four main etiologic subtypes: calcific mitral valve disease (CMVD, n = 81), rheumatic disease (RHVD, n = 114), Barlow’s disease (BD, n = 70), and fibroelastic deficiency (FED, n = 35). Discovery studies were performed using Olink Proteomics® technology in 80 serums from MVD patients (n = 20/etiology). Histopathologic study, ELISA, and zymography were performed on resected MVs to analyze extracellular matrix (ECM) composition and remodeling, inflammation, and calcification. Serum proteomics identified markers exclusively overexpressed in each MVD etiologic subtype. Further enrichment analyses revealed specific etiology-dependent pathways involving calcification, inflammation, or ECM remodeling. Such etiology-dependent differences were mirrored in the excised MVs both architecturally and compositionally. CMVD and RHVD valves had a marked ECM disorganization with increased collagen deposition and presence of nodular and diffuse calcification, respectively. Moreover, RHVD valves exhibited high levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and matrix degradation enzymes. BD valves showed enhanced inflammatory markers and infiltrates. Moreover, BD and FED valves presented marked proteoglycans deposition. Our study identified circulating markers involved in calcification, inflammation, and ECM remodeling, which may be associated with specific MVD etiologies. The differences in serum markers seem to mirror histopathologic and molecular alterations in the MVs with potential applications into the clinic as diagnosis biomarkers. Identification of underlying molecular mechanisms of each etiology is essential to discover new specific therapeutic targets.