Serum Pro‐N‐Cadherin Is a Marker of Subclinical Heart Failure in the General Population

BACKGROUND: We recently reported aberrant processing and localization of the precursor PNC (pro‐N‐cadherin) protein in failing heart tissues and detected elevated PNC products in the plasma of patients with heart failure. We hypothesize that PNC mislocalization and subsequent circulation is an early event in the pathogenesis of heart failure, and therefore circulating PNC is an early biomarker of heart failure. METHODS AND RESULTS: In collaboration with the Duke University Clinical and Translational Science Institute's MURDOCK (Measurement to Understand Reclassification of Disease of Cabarrus and Kannapolis) study, we queried enrolled individuals and sampled 2 matched cohorts: a cohort of individuals with no known heart failure at the time of serum collection and no heart failure development in the following 13 years (n=289, cohort A) and a matching cohort of enrolled individuals who had no known heart failure at the time of serum collection but subsequently developed heart failure within the following 13 years (n=307, cohort B). Serum PNC and NT‐proBNP (N‐terminal pro B‐type natriuretic peptide) concentrations in each population were quantified by ELISA. We detected no significant difference in NT‐proBNP rule‐in or rule‐out statistics between the 2 cohorts at baseline. In participants who developed heart failure, serum PNC is significantly elevated relative to those who did not report development of heart failure (P<0.0001). Receiver operating characteristic analyses of PNC demonstrate diagnostic value for subclinical heart failure. Additionally, PNC has diagnostic potential when comparing participants with no reported heart failure risk factors from cohort A to at‐risk participants from cohort B over the 13‐year follow‐up. Participants whose PNC levels measure >6 ng/mL have a 41% increased risk of all‐cause mortality independent of age, body mass index, sex, NT‐proBNP, blood pressure, previous heart attack, and coronary artery disease (P=0.044, n=596). CONCLUSIONS: These data suggest that PNC is an early marker of heart failure and has the potential to identify patients who would benefit from early therapeutic intervention.