Serum Pro-N-Cadherin Correlates With Cardiac Injury in the Radiation Late Effects Cohort of Nonhuman Primates

BACKGROUND: The delayed effects of radiation exposure on the heart often manifest as cardiac fibrosis and diastolic dysfunction, which can develop years after exposure. However, no Food and Drug Administration-approved serological biomarker is available to assess an individual's risk of developing radiation-related heart disease (RRHD). OBJECTIVES: The authors hypothesize that the risk of RRHD can be assessed using serum pro-N-cadherin (PNC), a promising marker for predicting subclinical heart failure in the general population. METHODS: We examined 46 male nonhuman primates (NHPs) that survived total-body irradiation and 10 unirradiated controls. NHPs exhibited cardiac fibrosis scores ranging from less severe (F0-1) to more severe (F2-3). Cardiac tissue samples collected at necropsy, with a median of 6.8 years post-irradiation, were stained for PNC by immunohistochemistry. PNC was quantified in longitudinal serum samples collected 2, 1, and 0 years before necropsy. The associations of serum PNC levels with cardiac fibrosis scores and echocardiographic parameters were examined. RESULTS: Histological examinations showed aberrant localization of PNC in NHPs with cardiac fibrosis. Elevated serum PNC levels were associated with severe cardiac fibrosis (F2-3) (area under the curve = 0.81, P = 0.006) and echocardiogram parameters of diastolic dysfunction, including lateral e' and lateral E/e' (P < 0.05). Cardiac fibrosis was associated with the greatest elevation in serum PNC among measured comorbidities. CONCLUSIONS: Our findings from this radiation late effects cohort of NHPs reveal a strong association between elevated serum PNC and cardiac injury. These findings pave the way for future clinical studies to develop serum PNC as a biomarker of RRHD in humans.