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Cardiac magnetic resonance detection of dynamic apoptotic signaling in vivo following anti-apoptotic therapy

Background

Doxorubicin (DOX) is a widely used chemotherapy drug that causes irreversible cardiomyopathy in a growing number of patients. An early detection method for this side effect could positively impact patient care. Previous work validated a molecular MRI probe that linked human Annexin V (ANX), a protein that binds strongly to early apoptotic cells, to superparamagnetic iron oxide (SPIO). T2 weighted (T2W) cardiac MRI of ANX-SPIO was found to detect DOX-induced cardiac apoptosis in mice. Alpha-1AR adrenergic stimulation with A61603 (A6) has been shown to prevent DOX-induced apoptosis and cardiac dysfunction in mice.

Hypothesis

T2-weight (T2W) MRI of an ANX-SPIO molecular probe will detect reductions in DOX-induced apoptosis following cardioprotective A6 therapy.

Methods

FVB/n mice were administered DOX (25 mg/kg, intraperitoneally) plus a subcutaneous mini-osmotic pump secreting saline or A6 (10 ng/kg/day). Fractional shortening was assessed by echocardiography at day 0 and day 6 (Siemens Acuson, Inc.). ANX-SPIO was injected by tail vein 2 days after DOX, and animals were imaged by T2W cardiac MRI 24 hours later (3 Tesla GE Signa Excite T2W GRE sequence: GRE TR 100/TE 10-20 ms/FA 60/FOV 4/matrix 256 × 256/ST 0.8 mm/NEX 6). Ejection fraction was also analyzed by cardiac MRI (Ziosoft, Inc.). Hearts were excised and assayed for Caspase activity (Promega, Inc.) to determine apoptosis signaling.

Results

DOX+A6 mice had preserved fractional shortening (FS%) after 1 week compared to DOX+VEH mice and preliminary T2* decay in mice receiving ANX-SPIO revealed reduced myocardial iron uptake in DOX+A6 vs DOX+VEH (see Figure 1 and Table 1). Preliminary ejection fractions (EF) by cardiac MRI tended to be higher in DOX+A6 mice compared to DOX+VEH. Decreased uptake of ANX-SPIO into DOX+A6 myocardium was associated with a blunted increase in Caspase 3/7 activation, indicating reduced cardiac apoptosis.

Figure 1
figure1

Short-Axis MRI from mice treated with DOX+VEH (top) or DOX+A6 (bottom) and then administered ANX-SPIO by tail vein. Echo time (TE) of 10 ms (left) vs 15 ms (right) is shown. Note rapid T2* signal loss in DOX+VEH hearts, indicating increased ANX-SPIO uptake.

Table 1 Echo, MRI, and Caspase Data

Conclusion

T2W MRI of ANX-SPIO can non-invasively detect cardioprotection by an alpha-1A adrenergic receptor agonist A6 at an early timepoint. MRI of ANX-SPIO may be useful in monitoring apoptotic signaling during therapy for other cardiac disease states.

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Correspondence to Rajesh Dash.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dash, R., Chung, J., Barral, J. et al. Cardiac magnetic resonance detection of dynamic apoptotic signaling in vivo following anti-apoptotic therapy. J Cardiovasc Magn Reson 12, P99 (2010). https://doi.org/10.1186/1532-429X-12-S1-P99

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Keywords

  • Cardiac Magnetic Resonance
  • Myocardial Iron
  • Adrenergic Receptor Agonist
  • Cardiac Apoptosis
  • Impact Patient Care