Abstract
ABSTRACTCardiac disease is a frequent and significant adverse event associated with radiotherapy for cancer. Identifying the underlying mechanism responsible for radiation injury to the heart will allow interventions to be developed. In the present study, we tested if local kidney irradiation results in remodeling of the shielded, nontargeted heart. One kidney, two kidneys, or the total body of male WAG and Dahl SS rats were irradiated with 10 Gy of X‐rays. Local kidney irradiation resulted in systemic hypertension, increased BUN, infiltration of T lymphocytes, natural killer cells, and macrophages into the renal cortex and medulla, and renal fibrosis. Local irradiation of kidneys in WAG rats resulted in remodeling in the nontargeted heart after 120 days, manifested by perivascular fibrosis and increased interventricular septal thickness, but was not seen in Dahl SS rats due to a high baseline level of fibrosis in the sham‐irradiated animals. Genetic depletion of T cells mitigated the nephropathy after local kidney irradiation, indicating a role for the immune system in mediating this outcome. Local kidney irradiation resulted in a cascade of pro‐inflammatory cytokines and low‐molecular weight metabolites into the circulation associated with transmission of signals resulting in pathologic remodeling in the nontargeted heart. A new model is proposed whereby radiation‐induced cardiac remodeling in susceptible animals is indirect, with lower hemi body organs such as the kidney exporting factors into the circulation that cause remodeling outside of the irradiated field in the shielded, nontargeted heart. This nontargeted effect appears to be mediated, in part, by the immune system.
Highlights
Radiation is a cornerstone of successful cancer treatment, with over one-half of all cancer patients receiving radiotherapy.[1]
Our study demonstrates that local kidney irradiation can result in T cell activation that is associated with pathologic remodeling in the nontargeted heart in a susceptible rat strain
Results from the present study demonstrate local irradiation of the kidneys results in WAG rats results in a late pathology in the nontargeted heart, manifest as increased perivascular collagen deposition in the smaller diameter coronary vessels and increased interventricular septal thickness at end diastole, indicative of early onset left ventricular hypertrophy
Summary
Radiation is a cornerstone of successful cancer treatment, with over one-half of all cancer patients receiving radiotherapy.[1]. The kidney is known to be a highly radiosensitive organ susceptible to the development of nephropathy, proteinuria, and hypertension after irradiation.[6] Historically, pelvic or abdominal radiotherapy resulted in exposure of kidneys in the irradiation field to a dose that could reach 10 Gy,[7] a dose that is known to cause renal injury.[8,9] Renal dysfunction has been proposed as part of the mechanism causing increased cardiac disease in cancer survivors treated with TBI10 and in survivors of atomic bombs.[11] Dysfunction in the kidney inducing cardiac dysfunction was described as early as 1836 by Richard Bright.[12] Shielding of the rat kidneys during irradiation prevents the increase in risk factors for cardiac disease and kidney injury in this experimental animal model, indicating the importance of the kidney in mechanisms that underlie radiation-induced cardiac disease.[5] These findings suggest injury to the heart from irradiation can be indirect, supporting the notion that injury to an abdominal organ such as the kidney plays a role in the occurrence of cardiac disease after irradiation below the diaphragm This hypothesis can be directly tested by locally irradiating the kidney and determining whether there is disease in the nontargeted heart. Our study demonstrates that local kidney irradiation can result in T cell activation that is associated with pathologic remodeling in the nontargeted heart in a susceptible rat strain
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