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

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).

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.

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.

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.

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.