Cardiac function and cytotoxic aldehyde production in a murine model of chronic iron-overload.
OBJECTIVE
To determine the relationship between the total chronic dose of iron administered, ex-vivo cardiac function and the concentrations of cytotoxic aldehydes in heart tissue of a murine model.


METHODS
In the first experiment, 34 male B6D2F1 mice were randomized to receive intraperitoneal injections of 5, 10 or 20 mg of iron dextran for three weeks, or a placebo control. The mice were subsequently randomized to undergo ex-vivo assessment of cardiac function. In the second experiment, free radical generation, quantified by the presence of 20 separate cytotoxic aldehydes, was assessed in heart tissue of 40 mice that were randomized to receive chronic treatment with various concentrations of iron dextran (100 mg to 300 mg total chronic dose administered), placebo treatment with saline, or no treatment at all (baseline).


RESULTS
Iron-loaded groups displayed dose-dependent depressions of heart rate, systolic pressure, developed pressure, coronary pressure, -dP/dt and +dP/dt, and increases in diastolic pressure. Monotonic dose-dependent increases in total heart aldehydes were observed in the iron-treated groups (r-0.97, p < 0.0001), whereas no significant differences were observed between baseline or time-placebo control groups.


CONCLUSIONS
While no single mechanism is likely to account for the complex pathophysiology of iron-induced heart failure, our findings show that chronic iron-loading in a murine model results in dose-dependent alterations to cardiac function; and results in free radical mediated damage to the heart, as measured by excess concentrations of cytotoxic aldehyde-derived peroxidation products. This is the first description of the effects of excess iron on cardiac function assessed by an ex-vivo Langendorff technique in a murine model of chronic iron-overload.
Bartfay
W J
WJ
Heart and Stroke/Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Ontario, Canada.
Dawood
F
F
Wen
W H
WH
Lehotay
D C
DC
Hou
D
D
Bartfay
E
E
Luo
X
X
Backx
P H
PH
Liu
P P
PP
D000447:Aldehydes / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D007501:Iron / Q000494:pharmacology*; D019190:Iron Overload / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D011897:Random Allocation; D017725:Ventricular Pressure / Q000187:drug effects
D000447:Aldehydes; D007501:Iron