Prognostic validation and biomarker characterization of acute valve syndrome

Background A novel classification has recently been proposed to characterize the clinical presentation of severe aortic stenosis (AS) and its independent association with clinical outcomes. This framework categorizes patients into three clinical phenotypes: silent (or stable) valve syndrome (SVS), progressive valve syndrome (PVS), and acute valve syndrome (AVS). Purpose To validate in a large Canadian cohort the prognostic utility of this classification for long-term all-cause mortality and to derive a multimarker score associated with AVS. Methods Consecutive patients with severe AS who underwent transcatheter aortic valve replacement at our institution between May 2007 and June 2025 were included and prospectively followed. Baseline demographic, clinical, and echocardiographic data were collected. Patients were stratified into SVS, PVS, and AVS, and survival analyses were performed to assess their association with all-cause mortality. In a predefined subgroup with complete baseline circulating biomarker data, the relationship between individual biomarkers and AVS was further evaluated. Results A total of 3366 patients were included in the study: 50 (1.5%) presented with SVS, 679 (20.2%) with PVS, and 2637 (78.3%) with AVS. Patients classified as AVS exhibited a greater burden of comorbidities, with higher prevalence of hypertension, diabetes, atrial fibrillation, prior pacemaker implantation, history of myocardial infarction or coronary artery disease, stroke, chronic obstructive pulmonary disease, and renal failure. Although median left ventricular ejection fraction was 60% across categories, key measures of AS severity such as mean transvalvular gradient, indexed effective orifice area, and stroke volume index were lower in patients classified as AVS, who also showed impaired right ventricular function and a higher frequency of concomitant regurgitations. Over a follow-up period of up to 10 years, multivariable Cox regression analysis adjusted for relevant clinical covariates demonstrated that AVS was independently associated with a higher risk of all-cause mortality compared with PVS and SVS (HR [95%CI] 1.65, [1.42-1.92], p<0.001). In a subgroup analysis including 362 patients, multivariable logistic regression identified CA-125, GDF-15, and creatinine as independently associated with AVS. A multimarker model showed that a greater number of elevated biomarkers was associated with AVS and added incremental predictive value to the clinical model. Conclusion In this large validation cohort within the Canadian healthcare system, the majority of patients with severe AS presented with AVS and showed a higher burden of comorbidities along with more adverse echocardiographic features, which translated into worse long-term all-cause survival. A multimarker strategy may facilitate the identification of patients at increased risk of developing AVS.