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

Abstract

Rationale: Radiation induced heart disease (RIHD) is a significant delayed/late effect of ionizing radiation exposure. Objective: To determine the cardiac effects of total body irradiation (TBI) in male rhesus macaques, a translational non-human primate (NHP) model. Methods and Results: Echocardiography 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 deceasedirradiated 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.