Structural changes in the auricles of the rat heart after local ionizing irradiation.
OBJECTIVE
Irradiation of the heart may lead to late cardiovascular complications and depending on the dose to cardiac-related death. There is increasing evidence that left atrial appendages play an important role in left ventricular filling especially in cardiac disease. The aim of the present study was to investigate the radiation response of the atria of the rat heart (auricles in particular) at morphological, histological and transcriptional level.


METHODS
Sprague-Dawley rats were irradiated with a single dose locally on the heart (0-22.5 Gy). End-diastolic diameters of left auricles were measured during evaluation of cardiac function. Histopathological evaluations were performed at various time points up to 16 months post irradiation. Changes in mRNA expression of procollagen types I and III and pro-fibrogenic cytokines (TGF-beta1 and IL-1beta) were investigated using competitive PCR.


RESULTS
Irradiation leads to a dose-dependent decrease in end-diastolic diameter of the left auricles. This decrease was observed at 4 months post-irradiation, where no gross damage of the ventricle has been reported. Histologically, epicardial fibrosis was found already 1 month post irradiation, and the frequency/severity of the structural changes appeared to be dose-dependent and progressive with time post irradiation. At 9 months, fibrosis was observed in all three layers (epicardium, myocardium and endocardium) of both auricles. On the level of gene expression, increases in procollagen types I and III were observed at 12 and 3 months post irradiation, respectively. Increases in IL-1beta and TGF-beta1, cytokines known to influence collagen deposition at different levels, preceded the upregulation of procollagen mRNA.


CONCLUSIONS
Auricles of the rat heart show a marked pathological response to ionizing radiation, characterized by generalized accumulation of collagen (fibrosis) and a reduction of end-diastolic diameter. The reduction of auricular volume and loss of elasticity will negatively contribute to the pump function of the irradiated ventricle.
Department of Clinical Oncology, University Hospital Leiden (LUMC), Leiden, The Netherlands.
J J
JJ
Krüse
C
C
Zurcher
E G
EG
Strootman
C I
CI
Bart
N
N
Schlagwein
J W
JW
Leer
J
J
Wondergem
D000818:Animals; D020517:Atrial Appendage / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D003094:Collagen / Q000032:analysis; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005355:Fibrosis; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007375:Interleukin-1 / Q000032:analysis; D009206:Myocardium / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011347:Procollagen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011829:Radiation Dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000032:analysis
D007375:Interleukin-1; D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen