Background
In severe aortic stenosis (AS), left ventricular (LV) cardiomyocytes hypertrophy to compensate pressure overload and reduce wall stress. After transcatheter aortic valve implantation (TAVI), reverse remodelling can restore LV integrity; however, this fails in a subgroup of normal ejection-fraction high-gradient (NEF-HG) AS patients who develop worsening heart failure. Chronic pressure overload may progress from compensated LV hypertrophy to dilation and dysfunction with interstitial fibrosis. In reduced ejection-fraction low-gradient (LEF-LG) AS, recovery of LV ejection fraction (LVEF) after TAVI occurs in only half of patients, often due to ischaemic heart disease but not exclusively.
Objectives
To identify molecular mechanisms of reversible versus fixed myocardial hypertrophy and improved versus limited LVEF recovery after TAVI, aiming to individualise treatment strategies in AS.
Methods
From the SFB1002 database, 90 NEF-HG AS and 32 LEF-LG AS patients were included. During TAVI, 20 LV biopsies and 45 serum samples from NEF-HG AS, and 19 biopsies and 24 serum samples from LEF-LG AS patients were obtained. Inclusion was based on guideline-defined AS subtypes. Biopsies were analysed using data-independent acquisition mass spectrometry (DIA-MS) and serum samples via Olink Target Cardiovascular II + III panels. Non-failing donor hearts served as controls. Cardiac magnetic resonance (CMR) imaging assessed myocardial fibrosis.
At six-month follow-up, NEF-HG patients were stratified by LV mass index regression (median −20.45 g/m²) and LEF-LG patients were grouped by LVEF recovery (median 10.3%) above vs. below the median.
Results
In NEF-HG AS, DIA-MS identified 3,732 LV proteins, with 24 showing significant differences between reversible and fixed hypertrophy. Gene ontology highlighted pathways of cell cycle regulation and cellular component disassembly (NRAP, STMN1, HSPA2). Targeted serum proteomics revealed regulated inflammatory proteins related to leukocyte–endothelial adhesion and cytokine receptor interaction. At follow-up, fixed hypertrophy was linked to higher NYHA class, worse Minnesota Living with Heart Failure Questionnaire scores, and reduced six-minute walk distance, despite similar extent of fibrosis (Extracellullar Volume Fraction, Late Gadolinium Enhancement).
In LEF-LG AS, DIA-MS detected 6,279 proteins, with 1,438 significantly altered versus non-failing controls. Calcineurin B homologous protein 1 (CHP-1) was upregulated in improved versus limited EF. Regression analysis of serum biomarkers and delta-LVEF showed enrichment in leukocyte migration and cell adhesion pathways. Moreover, improved LVEF patients had 77% lower cardiovascular mortality (HR 0.23, 95% CI 0.08–0.70, p = 0.02). Interestingly, CMR did not show significant difference regarding myocardial fibrosis between both LEF-LG AS cohorts.
Conclusions
Combined myocardial and serum proteomics provide novel insights into molecular determinants of LV hypertrophy regression and LVEF improvement after TAVI. These proteomic signatures associate with favourable remodelling and improved outcomes, providing implications for optimal valve replacement timing and adjunctive post-TAVI medical therapy.
