Microbubbles as Contrast Agents in CMR: Preclinical Assessment of Sensitivity with Myocardial R2* Mapping

Presenting Author(s)

• 

  Ayda Arami, MSc

  PhD Candidate
  Delft University of Technology, Leiden University Medical Center (LUMC)
  Delft, Zuid-Holland, Netherlands

Primary Author(s)

• 

  Ayda Arami, MSc

  PhD Candidate
  Delft University of Technology, Leiden University Medical Center (LUMC)
  Delft, Zuid-Holland, Netherlands

Co-Author(s)

• MC

  Milo Commandeur, BSc

  BSc.
  Delft University of Technology, Netherlands
• YZ

  Yi Zhang

  PhD candidate
  Delft University of Technology, Netherlands
• QT

  Qian Tao, PhD

  Assistant Professor
  Delft University of Technology
  Delft, Zuid-Holland, Netherlands
• 

  Hildo J. Lamb, MD, PhD

  Professor of Radiology
  Leiden University Medical Center
  Leiden, Zuid-Holland, Netherlands
• 

  Elias Ylä-Herttuala, PhD

  Post-Doctoral Researcher
  Univeristy of Eastern Finland
  Kuopio, Pohjois-Savo, Finland
• 

  Sebastian Weingärtner, PhD

  Associate Professor
  Delft University of Technology
  Delft, Zuid-Holland, Netherlands

Background: Gas-filled microbubbles (MBs) are widely used for contrast-enhanced echocardiography. Due to its volume magnetic susceptibility, MBs induce magnetic field distortions1, giving rise to a potential use in MRI. Spin diffusion through these distortions causes dephasing, which affects both R₂ and R₂^*. However, the relatively small susceptibility difference and the microscopic size of the MBs hamper the effect size. Thus, its use in cardiac MR remains largely unexplored. In this study, we evaluated R₂^* mapping for the detection of MBs in the myocardium using simulations, phantom and animal experiments.

Methods: A 3D Krogh model4 with impermeable spheres (MBs) and cylinders (vessels) was used to simulate MB distribution and local field distortions (Fig.1a). Signal dynamics were simulated using random walks of hydrogen spins (D=2.2µm²/ms,n=20,000). Mono-exponential fits were used to derive R₂^*. Effects of vessel size, susceptibility, and MB size on R₂^* were studied for oxy- and deoxygenated blood across MB concentrations (Fig.1b). Phantom experiments with Optison MBs (0.19 mg/mL, GE Healthcare), diluted to 1.2% with saline in 2mL-tubes, were at 3T (Ingenia, Philips) using spGRE (TR/TE/ΔTE=1000/2/1.8ms, 10 echoes). Two anesthetized mice (1.5% isoflurane) were imaged at 9.4T (Bruker BioSpin). After reference scans (t0), 200 µL of MB solution (3.5% SonoVue, Bracco, 1:1 saline) was injected via the tail vein. Five consecutive acquisitions (t1–t5) were performed per mouse after injection, using a segmented ECG-triggered GRE (res=0.16×0.16×1mm³, TE/TR/ΔTE=3/1600/3.9ms, 12 echoes, FOV=30×15mm²). Images were registered, and R₂^*maps generated using a 2-parameter exponential fit. ΔR₂^* was evaluated in 4 myocardial ROIs relative to the pre-contrast scan.

Results: Simulated R₂^* was substantially different for oxy- and deoxygenated blood, as expected due to the difference in susceptibilities (Fig.1b). R₂^*was strongly dependent on the volume fraction of MBs, with a greater effect size for larger Δ𝝌 (Fig.1b). R₂^* showed no size-selectivity for either R_v or R_mb. In phantoms, MB migration to the top produced concentration variation. Progressively lower R₂^* was measured for decreasing concentration: 62±8.82 vs 12±4.59s-1 (Fig.2). In vivo, the effect of MBs on the R₂^* was readily observed in major vessels (e.g. caudal vena cava ΔR₂^*:15.76±7.15%). However, in the myocardium, inconsistent changes were observed across ROIs after contrast injection. A slight overall trend of decreased R₂^* was measured, albeit with very high variability (t1:7.9±13.8%, min:-24.78%, max:+20.51%). Despite the ~5 min circulation time of MBs, very high variability (28.30±33%) remained at t5 (15min) (Fig.3b). This suggests physiological effects with larger effect sizes than MBs.

Conclusion: Myocardial R₂^* mapping showed poor sensitivity to MBs, likely due to their small effect size. Subtle changes were more consistent with physiological confounders, including stress or residual motion, than with true MBs detection.

Fig. 1. (a) Simulation setup showing field distortions from MBs and a vessel. For MBs (⍵mbs), δ⍵ is the equatorial field shift, determined by the susceptibility difference between MBs and blood; Rmb is the MB radius; r is the position relative to the MB; and θ is the angle between r and B0. For vessels (⍵v), δ⍵, Rv, and r have analogous meaning for a cylinder, while θ is the angle between the cylinder axis and B0, and φ is the angle between r and the cylinder axis. b) Simulation parameters: R2* is highly sensitive to MB concentration and differs between oxygenated and deoxygenated blood due to susceptibility contrast (–9.15 and –5.72 ppm, respectively5). Effect size increases with increasing susceptibility difference between MB and surrounding medium (Δ𝝌) (I), while R2* shows no dependence on the size of the MBs (Rmb )or vessel (Rv), which is shown in I and II, respectively.
Fig 2: a) Phantom setup (bottom) and T2* -weighted image (top, TE = 18 ms) showing saline with 20.41 ± 19.92 s–1 in the absence of MBs. b) R2* decreases over time as MBs migrate upward, reducing their concentration within the slice. Shaded areas indicate ROI standard deviation per time point.
Fig. 3. (a) T2*w images used for R2* map extraction. (b) Myocardial R2* maps from two mice (M1, M2), acquired before MB injection (t0) and five times consecutively over ~20 min after injection (scan duration ~2.5 min each). An inconsistent trend with high variability was observed across myocardial regions, likely reflecting cardiac motion or other physiological confounders (anterior:3.8%; lateral: -12.19%; posterior: -17.16%; septum: -6.11%). Caudal vena cava (The purple arrow) showing clear MB presence, with R2* increase immediately after injection compared to baseline (ΔR2*: -15.76 ± 7.15 %).