Preclinical Investigation
Delayed Echo Enhancement Imaging to Quantify Myocardial Infarct Size

https://doi.org/10.1016/j.echo.2021.02.019Get rights and content

Highlights

  • Perfluoropropane droplets can be activated to produce myocardial ultrasound contrast.

  • Transmission electron microscopy detected droplets within myocardial scar zones.

  • Fundamental nonlinear imaging resulted in selective enhancement of the infarct zone.

Background

Perfluoropropane droplets formulated from commercial microbubbles exhibit different acoustic characteristics than their parent microbubbles, most likely from enhanced endothelial permeability. This enhanced permeability may permit delayed echo-enhancement imaging (DEEI) similar to delayed enhancement magnetic resonance imaging (DE-MRI). We hypothesized this would allow detection and quantification of myocardial scar.

Methods

In 15 pigs undergoing 90 minutes of left anterior descending ischemia by either balloon (n = 13) or thrombotic occlusion (n = 2), DE-MRI was performed at 2-24 days postocclusion. Delayed echo-enhancement imaging was performed at 2-4 minutes following an intravenous injection of 1 mL of 50% Definity (Lantheus Medical) compressed into 180 nm droplets; DEEI was attempted in all pigs with single-pulse harmonic imaging at 1.7 transmit/3.4 MHz receive. Myocardial defects observed with DEEI were quantified (percentage of infarct area) and compared with DE-MRI as well as postmortem staining. In six pigs, multipulse low–mechanical index (MI) fundamental nonlinear imaging (FNLI) with intermittent high-MI impulses was performed to determine whether droplet activation within the infarct zone was achievable with a longer pulse duration.

Results

The range of infarct size area by DE-MRI ranged from 0% to 46% of total left ventricular area. Single-pulse harmonic imaging detected a contrast defect that correlated closely with infarct area by DE-MRI (r = 0.81, P = .0001). The FNLI high-MI impulses resulted in droplet activation in both the infarct and normal zones. Harmonic subtraction of the FNLI images resulted in infarct zone enhancement that also correlated closely with infarct size (r = 0.83; P = .04). Droplets were observed on postmortem transmission electron microscopy within myocytes of the infarct and remote normal zone.

Conclusion

Intravenously Definity nanodroplets can be utilized to detect and quantify infarct zone at the bedside using DEEI techniques.

Section snippets

Definity Droplet Formulation

Definity (Lantheus Medical, North Billerica, MA) was used in all the studies.13 Definity microbubbles were activated via mechanical agitation (Vialmix shaker, Bristol-Myers-Squibb, New York, NY) for 45 seconds. Definity nanodroplets (DD) were then formulated according to a previously described protocol.1, 2, 3 A 1:1 (with normal saline) dilution of one vial of Definity (total volume 5 mL) was drawn into a 10 mL syringe and cooled in an isopropyl alcohol bath (–10°C) for 3 minutes. The cooled

Definity Droplet Size and Concentration

The mean size of the DD (prior to 1:1 dilution) was 180 ± 70 nm, with over 90% of the droplets being <275 nm. The mean concentration prior to the 1:1 dilution (using the Nanosight N5300 Particle Analyzer) was 8.1 × 1010 droplets/mL.

Hemodynamic Effects of Droplet Injection and Activation

Table 2 depicts mean arterial pressure (MAP), heart rate (HR), and oxygen saturation following IVI of droplets. There were no changes in any of these parameters following droplet injections.

Acoustic Activation Imaging

There was a wide range of infarct size noted by DE-MRI, ranging from 0% to

Discussion

Using an “activate-image” sequence on the same diagnostic transducer, we observed delayed echo myocardial contrast enhancement at 2-4 minutes following IVI of perfluoropropane droplets. At this time period post-IVI, there were minimal residual left ventricular cavity droplets, indicating the contrast emanated from activation of droplets within extravascular spaces. The presence of droplets within these extravascular spaces was confirmed by TEM. With SPHI-induced activation, we observed

Conclusion

Using FNLI with harmonic subtraction, we were able to selectively enhance and quantify the infarct zone with acoustic activation imaging of extravascular DD. Delayed enhancement of the infarct zone was achieved with FNLI, while only viable myocardial segments were enhanced with SPHI. The mechanism for this different droplet acoustic response within the scar zone needs to be further elucidated, in order to utilize this technique for both targeted imaging and targeted therapy.

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    This study was supported by National Institutes of Health, United States Application 1 RO1 HL 146489-01A1 with additional support from the Theodore F. Hubbard Foundation.

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