Biology subjects

Kitzman, D. W.

Publications and source records attributed to Kitzman, D. W..

3 recordsLinked to original sources

bioRxiv2026

Serum pro-N-cadherin: a biomarker of cardiac fibrosis and diastolic dysfunction in irradiated non-human primates

BackgroundThe 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). ObjectivesSerum 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. MethodsWe 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. ResultsHistological 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. ConclusionsOur 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. HIGHLIGHTSO_LIRadiation-related heart disease is an often under-recognized complication of radiation exposure and radiation therapy, which has no FDA-approved biomarkers for assessing risk. C_LIO_LIOur results reveal that serum pro-N-cadherin is a biomarker of cardiac fibrosis and diastolic dysfunction in non-human primates that survived radiation exposure. C_LIO_LIThis 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. C_LI

physiology↗

bioRxiv2026

Genetic demultiplexing and transcript start site identification from nanopore sequencing of 10x Genomics multiome libraries

Short-read Illumina sequencing of 10x Genomics single-nucleus multiome libraries captures only the 3 end of RNA transcripts, losing transcription start site (TSS) information. Here we demonstrate nanopore sequencing of 10x multiome libraries, which enables the profiling of full length transcripts. We show concordance with common short-read sequencing based workflows including successful genetic demultiplexing of nanopore data despite its higher error rate. We compare TSS identified using nanopore sequencing of multiome cDNA to those identified using a short-read 5 assay, and provide an optimized approach for the preprocessing of nanopore reads prior to TSS identification. We find that nanopore sequencing of multiome cDNA captures a median of 63% of the TSS detected by the 5 assay.

bioinformatics↗

bioRxiv2020

Diastolic Dysfunction Accompanies Alterations in Myocardial Structure, Cellular Composition and Macrophage Polarization in Survivors of Ionizing Radiation Exposure

RationaleRadiation induced heart disease (RIHD) is a significant delayed/late effect of ionizing radiation exposure. ObjectiveTo determine the cardiac effects of total body irradiation (TBI) in male rhesus macaques, a translational non-human primate (NHP) model. Methods and ResultsEchocardiography was performed on survivors of a single dose (6.4-8.5 Gy) of TBI (n=34) and non-irradiated controls (n=26) divided into longer (LT IRR) and shorter term (ST IRR) survivors and controls to assess the effects of time since TBI on phenotypes. LT IRR had increased Doppler transmitral early filling velocities (E), decreased early mitral annular descent velocities (e), and higher E/e ratio compared to LT CTL (all p[≤]0.05), indicating left ventricular (LV) diastolic dysfunction. Echocardiographic stroke volume, cardiac output, and end-diastolic and systolic volumes were also lower in LT IRR than controls (all p [≤] 0.05). ST IRR had similar alterations in LV diastolic function but not in cardiac volumetric measures. Analyses of LV, interventricular septum (IVS), and right ventricle (RV) myocardium from deceased irradiated animals (n=17) exposed to a single dose (6.9-8.05 Gy) TBI and non-irradiated controls (n=12) showed that IRR animals had decreased LV and IVS capillary density, and increased LV fibrosis, pan-cardiac fibroblast and macrophage staining, LV and IVS M2 macrophages, and pan-cardiac M1 macrophages (all p<0.05). While M2 predominated over M1 macrophages in both groups, M1 showed greater increases than M2 in IRR. ConclusionsLV diastolic dysfunction due to radiation exposure may be due to a combination of capillary rarefication, activation and expansion of fibroblasts, and increased accumulation of both pro-fibrotic and pro-inflammatory macrophages, all of which lead to increased myocardial stiffness due to fibrosis. Collectively, these findings provide insights into the delayed effects of acute ionizing radiation exposure and suggest that therapies targeting macrophage regulation of fibrosis may mitigate radiation induced heart disease.

pathology↗