Experimental cardiac radiation exposure induces ventricular diastolic dysfunction with preserved ejection fraction

Abstract

Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (I) measurement of cardiac iodine uptake allowed calculation of the I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak +dP/d Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.

MicroRNA‐155 inhibits dengue virus replication by inducing heme oxygenase‐1‐mediated antiviral interferon responses

“…Deregulation of miR‐155 is associated with different kinds of cancer, inflammation, cardiovascular disease, and viral infections . These diseases are highly correlated with oxidative stress . DENV infection results in the intracellular accumulation of reactive oxygen species which induced damage that has been associated with increased disease severity in DENV‐infected patients .…”

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212

“…Premature coronary heart disease, electrical conduct defects or valve abnormalities are often associated with RIHD (4–6). In the early phase, RIHD often presents as heart failure with preserved ejection fraction (HFpEF), characterized by LVH and diastolic dysfunction (1, 7, 8). Radiotherapy significantly improves cancer patient survival; however, in the long-term, patients are at risk of RIHD and subsequent heart failure which becomes a major health issue affecting outcome, quality of life and health care costs (1).…”

“…They have been shown to be mediated by oxidative stress, the activation of pathologic NO-cGMP-PKG signaling, cytokine and growth factor cascades such as IL-4, IL-13, Rho/ROCK pathway and transforming growth factor beta (TGF-β) (1, 7, 9, 13, 14). Histopathological examination of cardiac lesions of RIHD shows hypertrophic cardiomyocytes, inflammatory cells, fibroblasts, and excessive deposition of collagens (1, 7, 14). Radiation-induced hypertrophy and fibrosis of the myocardium ultimately leads to a decrease in elasticity, ductility, and the development of diastolic heart failure.…”

Macrophage migration inhibitory factor serves a pivotal role in�the regulation of radiation-induced cardiac senescencethrough rebalancing the microRNA-34a/sirtuin 1 signaling pathway

“…Randomized trials have reported that radiotherapy can substantially reduce cancer recurrence and moderately reduce cancer mortality; however, cardiac radiation exposure increases the risk of heart failure, thus limiting the use of radiotherapy (1,2). Cardiac radiation exposure in a rodent model resulted in cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, oxidative stress and myocardial fibrosis (3). However, the mechanisms responsible for these effects of radiotherapy remain unclear.…”