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J Am Coll Cardiol, 2007; 49:2457-2464, doi:10.1016/j.jacc.2007.02.060 (Published online 7 June 2007).
© 2007 by the American College of Cardiology Foundation
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Potentiation of Doxorubicin Cardiotoxicity by Iron Loading in a Rodent Model

Gurusher S. Panjrath, MD*, Virender Patel, MD*, Carolina I. Valdiviezo, MD{ddagger}, Navneet Narula, MD{dagger}, Jagat Narula, MD, PhD, FACC* and Diwakar Jain, MD, FACC*,*

* Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania
{dagger} Pathology Department, University of Pennsylvania, Philadelphia, Pennsylvania
{ddagger} Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, New York.


Figure 1
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  		Figure 1 Experimental Protocol

Four animals were included in each experimental as well as control group. DOX = doxorubicin.

 

Figure 2
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  		Figure 2 Weight Change

Both iron-rich chow and regular chow fed control animals gained weight. Regular chow fed animals treated with doxorubicin (DOX) showed a progressive weight loss. Weight loss in iron-rich chow group treated with DOX was significantly higher compared with that in other groups.

 

Figure 3
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  		Figure 3 99mTc Annexin-V Imaging

Planar whole body (top) and ex-vivo images of heart (bottom) of animals from each subgroup on 99mTc annexin-V imaging. There is intense Annexin uptake in liver (L) and spleen (S) with variable uptake in the heart (arrows). No myocardial uptake seen in control group (A and B). Regular chow and iron-rich chow fed animals treated with doxorubicin (DOX) show intense cardiac uptake (C and D).

 

Figure 4
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  		Figure 4 Percent ID/g of Myocardial 99mTc Annexin-V Uptake

Highest uptake in iron-rich chow fed animals treated with doxorubicin (DOX). ID = injected dose.

 

Figure 5
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  		Figure 5 Myocardial Iron

A mild increase in myocardial iron content is seen in iron-rich chow fed animals in both control and doxorubicin (DOX)-treated groups. *p < 0.05 compared with DOX and saline.

 

Figure 6
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  		Figure 6 Light Microscopy

Light microscopy of hematoxylin- and eosin-stained myocardial tissue shows no signs of myocyte injury in (A) regular chow fed animals treated with saline, (B) iron-rich chow fed animals treated with saline, (C) regular chow fed animals treated with DOX, and (D) iron-rich chow fed animals treated with doxorubicin (DOX).

 

Figure 7
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  		Figure 7 Electron Microscopy

(A) No loss of myofilaments is seen in regular chow fed saline-treated animal. (B) Minimal myofilament loss in iron-rich chow fed animal treated with saline. (C) Regular chow fed doxorubicin-treated animal showed infrequent areas of myofilament loss (arrow) without any sarcoplasmic swelling. (D) Larger areas of myofilament loss (arrow) seen in iron-rich chow fed animals treated with doxorubicin. Iron-rich chow fed animals treated with doxorubicin show frequent and large areas of myofilament loss (arrow) accompanied by swelling of sarcoplasmic reticulum, which are characteristic changes seen in doxorubicin cardiotoxicity. N = nucleus.

 

Figure 8
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  		Figure 8 Activated Caspase-3 Immunohistochemistry of Myocardial Specimens

Activated caspase-3 was present in the cytoplasm of cells with morphology consistent with apoptosis. Positive staining is seen in myocardium of animals treated with doxorubicin (C and D). No staining is seen in control animals fed (A) regular chow or (B) iron-rich chow. Iron-rich chow fed animals treated with doxorubicin (D) show a greater area of staining involving higher number of myocytes compared with regular chow fed animals treated with doxorubicin (C).

 




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Copyright © 2007 by the American College of Cardiology Foundation.