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  • Open Access

In vivo detection and treatment of ischemia-induced cardiac apoptosis using an MRI-detectable molecular probe and an alpha-adrenergic receptor agonist

  • 1,
  • 1,
  • 2,
  • 3, 4,
  • 2,
  • 1 and
  • 1
Journal of Cardiovascular Magnetic Resonance201214 (Suppl 1) :P67

https://doi.org/10.1186/1532-429X-14-S1-P67

  • Published:

Keywords

  • Ischemic Cardiomyopathy
  • Superparamagnetic Iron Oxide
  • Post Myocardial Infarction
  • Apoptotic Cell Population
  • Cardiac Apoptosis

Summary

A novel anti-apoptotic alpha-adrenergic agonist preserves left ventricular ejection fraction in mice following myocardial infarction. This therapeutic effect is able to be detected and quantified non-invasively, using T2* signal loss assessment of an Annexin-SPIO molecular apoptosis probe.

Background

Myocardial infarction (MI) leads to cardiomyopathy through a combination of programmed cell death (re: apoptosis) and necrotic cell death. The relative contribution of apoptosis to ischemic cardiomyopathy and the effect of targeting apoptosis specifically to prevent MI-induced damage is unknown. Our laboratory previously developed and validated an in vivo, MRI-detectable apoptosis probe. Annexin-V (ANX), which binds to cells in the earliest stages of apoptosis, was conjugated to superparamagnetic iron oxide (SPIO) nanoparticles, allowing for the non-invasive detection of early apoptotic cell populations (ANX-SPIO r1: 8.6 ± 0.61 mM-1 s-1 and r2: 326 ± 16 mM-1 s-1). To test the effect of apoptosis reversal in an MI model, we employed A61603 (A6), an α1-adrenergic receptor agonist, which was previously shown to rescue cardiac cells from Doxorubicin-induced cardiac apoptosis through activation of the cardio-protective ERK pathway. Our hypothesis is that A6 therapy will protect against MI-induced cardiomyopathy, and that cardiac MRI of systemic ANX-SPIO will detect and longitudinally monitor this therapeutic effect in vivo.

Methods

Mice underwent MI (via LAD ligation) along with a subcutaneous pump implant that delivered A6 or vehicle (VEH) solution at a rate of 10 ng/kg/day over a course of two weeks. Cardiac MRI (CMR) was performed at 2 days, 1 week, and 2 weeks post MI. ANX-SPIO was delivered via tail vein one day prior to CMR to simultaneously assess left ventricular function and apoptosis (using T2* signal loss as a marker of apoptotic activity) in vivo.

Results

Although A6-treated (39±5%, n=3) and VEH-treated (38±10%, n=6) mice exhibited identical ejection fractions (EFs) 2 days post-MI, A6-treated mice exhibited significantly (p<0.05) higher ejection fractions (EFs) versus their VEH-treated counterparts at both 1 week (A6, n=6: 37±9%; VEH, n=5: 18±4%) and 2 weeks (A6, n=5: 33±10%; VEH, n=6: 14±7%) post-MI (Figure 1). Upon T2* quantification, A6-treated mice showed significantly (p<0.05) less T2* signal loss after ANX-SPIO delivery compared to VEH-treated mice at 1 week post MI (A6 T2*: 19±2ms; VEH T2*: 14±1, n=3), reflecting less myocardial uptake of ANX-SPIO and therefore less cardiac cell apoptosis in A6-treated hearts (Figure 2).
Figure 1
Figure 1

Graph of EFs for A6-treated vs VEH-treated mice over a two week period. Note the significant preservation of EFs in A6-treated hearts at 1 and 2 weeks.

Figure 2
Figure 2

a) CMR images of an infarcted mouse heart showing T2* signal loss from ANX-SPIO; b) CMR of A6-treated, infarcted mouse heart showing a visibly reduced degree of T2* signal loss, compared to VEH control hearts; c) T2* signal loss curves for control animals, as well as MI+A6-treated and MI+VEH hearts. The steeper decay curve of MI+VEH hearts reflects the increased apoptosis and subsequent ANX-SPIO uptake, compared to A6-treated hearts.

Conclusions

These results suggest that cardiomyocyte apoptosis is a prominent contributor to the functional impairment of ischemic cardiomyopathy and that A6-mediated cardioprotection from MI-induced apoptosis preserves cardiac function. Moreover, ANX-SPIO can non-invasively detect and monitor A6’s therapeutic effect longitudinally.

Funding

NIH-NHLBI K08 (RD), R01 (PY).

Authors’ Affiliations

(1)
Cardiovascular Medicine, Stanford University, Stanford, CA, USA
(2)
Cardiac Surgery, Stanford University Medical Center, Stanford, CA, USA
(3)
Medicine and Cardiology, University of California, San Francisco, CA, USA
(4)
Medicine and Cardiology, San Francisco VA Medical Center, San Francisco, CA, USA

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