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Bimodal cardiac dysfunction in an animal model of iron overload
Tianen Yang1, Wei-Qiang Dong, Yuri A Kuryshev
1Rammelkamp Center for Education and Research, MetroHealth Campus, 2500 MetroHealth Drive R301, Cleveland, OH 44109-1998, USA.
Insights
Iron overload causes progressive heart damage, initially increasing cardiac function and output, then leading to heart failure. This study in gerbils models human iron-overload cardiomyopathy progression.
Area of Science:
- Cardiology
- Hematology
- Toxicology
Background:
- Iron-overload cardiomyopathy is a major cause of mortality in thalassemia major.
- Cardiac function changes in iron overload are not fully quantified.
- Mongolian gerbils serve as a relevant animal model for human iron overload responses.
Purpose of the Study:
- To quantify the effects of iron overload on cardiac function in Mongolian gerbils.
- To characterize the progression of cardiac dysfunction due to iron overload.
- To compare gerbil cardiac response to iron overload with human conditions.
Main Methods:
- Gerbils received subcutaneous injections of iron-dextran or dextran alone at low (200 mg/kg/wk) and high (800 mg/kg/wk) doses for varying durations.
- Isolated perfused hearts were used to measure cardiac work, coronary flow, and left ventricular pressure changes (dP/dt).
- Echocardiography was performed on intact animals to assess cardiac hypertrophy, output, and exercise tolerance.
Main Results:
- Short-term iron overload led to increased cardiac work, coronary flow, and ventricular contractility/relaxation.
- Long-term iron overload resulted in decreased cardiac function parameters.
- Echocardiography revealed a progression from eccentric to concentric cardiac hypertrophy, with initial increases in cardiac output followed by impairment.
Conclusions:
- Iron overload in gerbils mimics the progression of human iron-overload cardiomyopathy.
- The study demonstrates a transition from a high-output state to low-output heart failure.
- Findings provide quantitative insights into the cardiac effects of iron overload.
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.