Association of circulating procollagen 1 N-terminal pro-peptide (P1NP) with clinical outcomes in asymptomatic patients with non-severe aortic valve stenosis: a post-hoc study of the SEAS trial

Background Extracellular matrix remodelling plays a pivotal role in the pathogenesis of aortic valve stenosis (AS), driven by collagen synthesis-mediated cusp fibrosis and calcification, ultimately leading to left ventricular myocardial fibrosis and dysfunction. Studies imply associations between bone metabolism and AS progression in the elderly. Procollagen type 1 N-terminal pro-peptide (P1NP) is a proven biomarker of collagen synthesis and bone turnover. However, the impact of circulating P1NP on AS progression and clinical outcomes in patients with non-severe AS remains unexplored. Purpose To investigate if an elevated plasma P1NP concentration (above 95% reference interval specific for age and sex) is associated with the severity of AS and with an increased risk of clinical outcomes in asymptomatic patients with non-severe AS. Methods We analysed data of 1553 asymptomatic patients who had mild-to-moderate AS, preserved systolic and renal function, no manifest coronary artery disease (CAD), and remained event-free one year after inclusion in the randomised Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. We assessed the correlation of P1NP with clinical variables, echocardiographic AS severity, and echocardiographic markers of annual AS progression. Multivariable Cox proportional hazard models in competing risk analyses examined associations between elevated P1NP with a 4-year risk of the primary composite endpoint of aortic valve events (AVE), comprising the first event of cardiovascular death (CVD), hospitalisation with heart failure, or aortic valve replacement. Similarly, we defined the secondary endpoint of CAD as a composite of CVD, myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. Results Among 1553 included patients with a mean age of 67.5 (SD 9.7) years, 932 (60%) were men, 259 (17%) had moderate-severe AS, and 48 (3%) had elevated P1NP. These patients were older with higher Framingham risk scores, interleukin-6, and high-sensitivity Troponin T levels than patients with normal P1NP. During one year of follow-up, P1NP remained stable across AS severity groups. We found no correlation between annual P1NP change and annual changes in echo parameters of AS progression (Table 1). During the 4-year follow-up from landmark at year 1, 483 (32%) patients experienced an AVE-related event, and 220 (14%) experienced a CAD-related event. An elevated P1NP at baseline was associated with an increased 4-year CAD risk in moderate-severe AS (HR 2.84, 95% CI, 1.05-7.68; P=0.039) in adjusted Cox regression analyses (Figure 1). Conclusions Circulating P1NP remains stable within the reference range in 97% of asymptomatic patients with non-severe AS during a one-year follow-up, regardless of AS severity. An age- and sex-adjusted elevated P1NP was associated with a 2.8-fold increased 4-year CAD risk in patients with moderate-severe AS, supporting its further investigation as a potential therapeutic target.