Michalson, K. T. | bioRxiv Science

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↗

bioRxiv2020

Divergent effects of Western and Mediterranean diets on behavior and monocyte polarization.

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an "evolutionary mismatch," between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism - inflammatory polarization of monocytes - that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR<0.05). Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered animal behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets generate inflammation and disease.

genomics↗