Radiation-induced Heart Disease: Review of Experimental Data on Dose Reponse and Pathogenesis

Abstract

Clinical and experimental heart irradiation can cause a variety of sequelae. A single dose of greater than or equal to 15 Gy leads to a reversible exudative pericarditis, occurring in dogs, rabbits or rats at around 100 days. Its time-course is very similar in all species investigated, but there are considerable species and strain differences in severity and incidence. After longer, dose-dependent latency times chronic congestive myocardial failure develops. At histological examination myocardial degeneration and necrosis is observed, which in some species is accompanied by a variable degree of interstitial fibrosis. In rabbits and rats, myocardial degeneration becomes apparent at around 70 days after 20 Gy and is preceded by a marked reduction in capillary density as well as ultrastructural endothelial cell degeneration. Simultaneously to structural capillary damage, a focal loss of the endothelial marker enzyme alkaline phosphatase was observed in rats in areas with subsequent myocardial degeneration. Cell kinetic studies in rabbits and rats revealed a radiation-induced wave of increased endothelial cell proliferation at 30-100 days postirradiation. In the rat it is exclusively seen in conjunction with alteration of endothelial cell marker enzymes. The temporal and spatial pattern of proliferative response exludes endothelial cell death in mitosis as the sole pathogenetic mechanism causing capillary loss and myocardial degeneration. Parallel to development of morphological damage, haemodynamic studies in various rats strains revealed a drop in cardiac output and left ventricular ejection fraction to about 64% of normal values after 20 Gy. In vivo, this slightly reduced cardiac function was then maintained in a steady state for many weeks, probably due to a compensatory up-regulation of cardiac beta-adrenergic receptors. In denervated working heart preparations in vitro, however, these compensatory mechanisms are not effective and stroke volume as well as cardiac contractility show a rapid and steady deterioration. In many respects radiation-induced heart disease conforms to radiobiological concepts of late-responding tissues, showing a chronic progressive time-course and a very pronounced fractionation effect. However, pathogenesis cannot be understood in terms of target cell depletion alone, and experimental evidence indicates the importance of alterations of regulatory mechanisms.

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

“…Irradiation of the thorax for diagnostic or therapeutic reasons includes exposure of the lungs, myocardium, pericardium, great vessels and coronary circulation. Radiation-induced effects on any of these components can cause feedback into others in a decompensating feedback loop, resulting in failure (58). We anticipate that future studies will further detail the role of endothelial dysfunction in radiation-induced heart disease and that additional sub-compartments of the heart will be assessed for their respective radiation sensitivities.…”

Pulmonary Radiation Injury: Identification of Risk Factors Associated with Regional Hypersensitivity

“…During the intermediate phase, the influence of the heart irradiation disappeared (OR < 1). An explanation of this phenomenon may be derived from observations of early decline in cardiac function after heart irradiation followed by a period of recovery (likely coinciding with the intermediate phase) that precedes the onset of late symptoms reported for rats (43)(44)(45), dogs (38), and even humans (46,47). If true, this would change the traditional view of heart as a late-reacting organ and may bear relevance for clinical practice where the combination of subclinical injuries to lung and heart may give rise to unexpected toxicity, both early and late after the radiation treatment.…”

“…Redistribution of perfusion to, or a compensatory expansion of, previously underused alveoli may maintain an adequate gas exchange after destruction of irradiated regions (41). Also in the case of failing cardiac function, compensatory abilities have been shown either on the level of the heart itself or on the level of regulatory mechanisms of the entire cardiovascular system (42,43). Thus, it is plausible that limited damage to each of the two organs separately would remain subclinical, but its combination will exceed compensatory abilities and translate into clinically manifest symptoms.…”

Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors

“…Radiation therapy to the chest wall may directly cause cardiac toxicity or augment the effects of chemotherapy. [22][23][24] Potentially cardiotoxic effects of the transplant itself, 25 and the use of the preservative dimethyl sulfoxide (DMSO) 26 have also been reported. Risk factors other than these are less clear.…”