Serum pro-N-cadherin: a biomarker of cardiac fibrosis and diastolic dysfunction in irradiated non-human 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 FDA-approved serological biomarker is available to assess the risk of individuals for developing radiation-related heart disease (RRHD).

Objectives

Serum pro-N-cadherin (PNC) has shown promise as a marker for predicting the onset of heart failure in the general population. We hypothesize that serum PNC levels will correlate with the risk of RRHD following radiation exposure.

Methods

We examined male non-human primates (NHPs) exposed to total-body irradiation (TBI) and unirradiated controls from the Wake Forest University radiation late effects cohort. NHPs exhibited cardiac fibrosis scores ranging from less severe (F0-1) to more severe (F2-3). Cardiac tissue samples collected at necropsy, median 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 significantly correlated with severe cardiac fibrosis (AUC = 0.81, p = 0.006) and echocardiogram parameters of diastolic dysfunction. Cardiac fibrosis was the only measured comorbidity with a significant difference in serum PNC.

Conclusions

Our results demonstrate that serum PNC significantly correlates with cardiac fibrosis and diastolic dysfunction in irradiated NHPs. These findings pave the way for future clinical studies to develop serum PNC as a biomarker of RRHD in humans.

HIGHLIGHTS

• Radiation-related heart disease is an often under-recognized complication of radiation exposure and radiation therapy, which has no FDA-approved biomarkers for assessing risk.

• Our results reveal that serum pro-N-cadherin is a biomarker of cardiac fibrosis and diastolic dysfunction in non-human primates that survived radiation exposure.

• This study lays the foundation for further research into the development of serum pro-N-cadherin as a biomarker for assessing the risk of radiation-related heart disease in humans.