Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques

Abstract

Heart disease is an increasingly recognized, serious late effect of radiation exposure, most notably among breast cancer and Hodgkin’s disease survivors, as well as the Hiroshima and Nagasaki atomic bomb survivors. The purpose of this study was to evaluate the late effects of total-body irradiation (TBI) on cardiac morphology, function and selected circulating biomarkers in a well-established nonhuman primate model. For this study we used male rhesus macaques that were exposed to a single total-body dose of ionizing gamma radiation (6.5–8.4 Gy) 5.6–9.7 years earlier at ages ranging from ~3–10 years old and a cohort of nonirradiated controls. Transthoracic echocardiography was performed annually for 3 years on 20 irradiated and 11 control animals. Myocardium was examined grossly and histologically, and myocardial fibrosis/collagen was assessed microscopically and by morphometric analysis of Masson’s trichrome-stained sections. Serum/plasma from 27 irradiated and 13 control animals was evaluated for circulating biomarkers of cardiac damage [N-terminal pro B-type natriuretic protein (nt-proBNP) and troponin-I], inflammation (CRP, IL-6, MCP-1, sICAM) and microbial translocation [LPS-binding protein (LBP) and sCD14]. A higher prevalence of histological myocardial fibrosis was observed in the hearts obtained from the irradiated animals (9/14) relative to controls (0/3) (P = 0.04, χ2). Echocardiographically determined left ventricular end diastolic and systolic diameters were significantly smaller in irradiated animals (repeated measures ANOVA, P < 0.001 and P < 0.008, respectively). Histomorphometric analysis of trichrome-stained sections of heart tissue demonstrated ~14.9 ± 1.4% (mean ± SEM) of myocardial area staining for collagen in irradiated animals compared to 9.1 ± 0.9 % in control animals. Circulating levels of MCP-1 and LBP were significantly higher in irradiated animals (P < 0.05). A high incidence of diabetes in the irradiated animals was associated with higher plasma triglyceride and lower HDLc but did not appear to be associated with cardiovascular phenotypes. These results demonstrate that single total-body doses of 6.5–8.4 Gy produced long-term effects including a high incidence of myocardial fibrosis, reduced left ventricular diameter and elevated systemic inflammation. Additional prospective studies are required to define the time course and mechanisms underlying radiation-induced heart disease in this model.

Nonhuman primates as models for the discovery and development of radiation countermeasures

“…Heart disease is an increasingly recognized, serious late effect of radiation exposure. A recent study conducted in NHPs demonstrated that single total-body doses of 6.5 – 8.4 Gy produced long-term effects including a high incidence of myocardial fibrosis, reduced left ventricular diameter, and elevated systemic inflammation [54]. Also, the kidney has been shown to be one of the most radiosensitive late-responding organs in humans with chronic renal injuries occurring after single doses as low as 4–6 Gy.…”

Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

“…We screened serum samples for a panel of markers of microbial translocation, as myeloablative conditioning can trigger gut damage and microbial translocation (28)(29)(30) (Figure 7, A-C). Zonulin, a marker of gut epithelium tight junctions and gut integrity, was significantly increased during transplant recovery, and remained higher following cART withdrawal (P = 0.0159 at post-transplant time point I [post-Tx I], P = 0.031 at post-Tx II, P = 0.028 at cART withdrawal (ART WD in figure), and P = 0.057 at necropsy) ( Figure 7A).…”

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…Other large animals such as non-human primates and pigs have been used by a few groups to study RIHD [146][147][148], but these are uncommon given the high cost and low throughput nature of large animal models.…”