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.

Pathologic Proteolytic Processing of N-Cadherin as a Marker of Human Fibrotic Disease.

Prior research has implicated the involvement of cell adhesion molecule N-cadherin in tissue fibrosis and remodeling. We hypothesize that anomalies in N-cadherin protein processing are involved in pathological fibrosis. Diseased tissues associated with fibrosis of the heart, lung, and liver were probed for the precursor form of N-cadherin, pro-N-cadherin (PNC), by immunohistochemistry and compared to healthy tissues. Myofibroblast cell lines were analyzed for cell surface pro-N-cadherin by flow cytometry and immunofluorescent microscopy. Soluble PNC products were immunoprecipitated from patient plasmas and an enzyme-linked immunoassay was developed for quantification. All fibrotic tissues examined show aberrant PNC localization. Cell surface PNC is expressed in myofibroblast cell lines isolated from cardiomyopathy and idiopathic pulmonary fibrosis but not on myofibroblasts isolated from healthy tissues. PNC is elevated in the plasma of patients with cardiomyopathy (p ≤ 0.0001), idiopathic pulmonary fibrosis (p ≤ 0.05), and nonalcoholic fatty liver disease with cirrhosis (p ≤ 0.05). Finally, we have humanized a murine antibody and demonstrate that it significantly inhibits migration of PNC expressing myofibroblasts. Collectively, the aberrant localization of PNC is observed in all fibrotic tissues examined in our study and our data suggest a role for cell surface PNC in the pathogenesis of fibrosis.