Original Articles
Bimodal cardiac dysfunction in an animal model of iron overload,☆☆

https://doi.org/10.1067/mlc.2002.127725Get rights and content

Abstract

Iron-overload cardiomyopathy is the most common cause of death in patients with thalassemia major, yet the associated changes in cardiac function have not been quantified. We studied the effects of iron overload on cardiac function in Mongolian gerbils, a species that responds to iron overload in the same manner as human beings. We injected iron-dextran or dextran alone at low subcutaneous doses (200 mg/kg/wk) for 20 to 60 weeks and at high doses (800 mg/kg/wk) for 6 to 20 weeks. At shorter durations for either dose, the mean values of cardiac work, coronary flow, left ventricular (dP/dt)max and left ventricular (dP/dt)min in isolated perfused hearts were significantly greater than control values; at longer durations, these values were significantly less than control values. Echocardiography in intact animals showed eccentric cardiac hypertrophy, increased cardiac output, and normal exercise tolerance at shorter durations of dosage. At longer durations, concentric cardiac hypertrophy developed, and cardiac output and exercise capacity were impaired. The response to iron overload in Mongolian gerbils progresses from an initial state of high cardiac output to a subsequent state of low-output failure similar to the course of cardiomyopathy that has been inferred in patients with transfusional iron overload. (J Lab Clin Med 2002;140:263-71)

Section snippets

Methods

Experiments were conducted in 2-month-old female Mongolian gerbils. The investigation conformed to the “Guide for the Care and Use of Laboratory Animals” published by the National Institutes of Health (NIH publication no. 85-23, revised 1996). A low dose (200 mg iron/kg/week) and a high dose (800 mg iron/kg/week) of iron-dextran (ferric hydroxide-dextran complex, 100 mg/mL; Sigma Chemical Co, St Louis, Mo) were used in this study. The doses were injected subcutaneously; control animals were

Results

Table I shows that iron loading in accordance with low-dose (200 mg/kg/week) and high-dose (800 mg/kg/week) protocols resulted in greater terminal weights of the heart, liver, and body than those seen controls. Table II shows that both protocols resulted in dose- and time-dependent increases in cardiac and liver iron per gram of dry tissue. The iron levels measured in our experimental conditions were similar to those reported in autopsies of human beings with transfusional iron overload11, 19

Discussion

The progressive increase in cardiac iron content in our experiments was associated with a bimodal change in cardiac performance. Relatively short periods of iron overloading tend to enhance cardiac performance, whereas relatively long periods tend to impair cardiac performance. In the isolated working heart preparations derived from those animals that received the low-dose iron regimen for 20 weeks, the values of cardiac work and coronary flow were significantly greater than the corresponding

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      However, they did not find rats and mice to be suitable models for prolonged iron overload as they do not develop the same pathology as seen in man [31]. Subsequently many studies on the use of iron dextran subcutaneously in Mongolian gerbils to produce severe iron overload have been done to investigate a new iron chelator or to produce pathology similar to that seen in humans with iron overload [32,33]. This was later challenged by Kaiser et al. in 2003 where the literature showed that when the human and gerbil iron content in the liver and heart tissues in the iron overloaded state was compared, the hepatic and cardiac iron content in all gerbils was found to be higher than the similar human iron content [34].

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      Gerbils were weighed weekly, and the injected dose was based on the body weight of the previous week. The literature describes various iron dosing protocols for gerbils, which include the original protocol of Carthew15 (1 g/kg followed by 6 weekly doses of 500 mg/kg) and the Brittenham groups high-dose protocol16-19 (800 mg/kg/week to 16 g). In preliminary experiments, we could not reproduce any of these protocols without rapid and severe morbidity requiring euthanasia.

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    Supported by United States Public Health Service grants HL61642, HL62882 and HL61642-S1.

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    Reprint requests: Arthur M Brown, MD, PhD, Rammelkamp Center for Education and Research, 2500 MetroHealth Drive, R301, Cleveland, OH 44109-1998; e-mail: [email protected].

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