INTRODUCTION:

Asthma is typically characterized by airway abnormalities,^1,2 including inflammation, smooth muscle hyper-responsiveness and occlusions. Abnormal alveolar collagen deposits have also been described in poorly-controlled asthma, suggesting that inflammation may extend beyond the airways.³ Previous work also demonstrated pulmonary vascular remodeling in severe asthma,⁴ but it remains poorly understood.
Hyperpolarized ¹²⁹Xe MRI provides a way to quantify inhaled gas distribution (ventilation) as well as transmembrane diffusion (perfusion) into the alveolar-capillary interface and the red-blood-cells (RBC) via MR spectroscopy (MRS).⁵ Preliminary investigations using ¹²⁹Xe MRS measurements identified gas-exchange abnormalities in chronic lung disease.⁶ Until now, these measurements have not yet been investigated in patients with mild or moderate asthma. Hence, here we aimed to acquire ¹²⁹Xe MRS gas-exchange measurements in patients with moderate and severe asthma for direct comparison and with the same measurements in healthy volunteers.

METHODS:

Study Participants:
We evaluated participants without chronic lung disease (n=24) and participants with asthma (n=45), who provided written informed consent to spirometry⁷ and ¹²⁹Xe MRI/MRS. Participants with asthma were classified by Global Initiative for Asthma (GINA) report.⁸
MRI Acquisition:
Anatomical ¹H and hyperpolarized ¹²⁹Xe MRI/MRS were acquired using a whole-body 3T Discovery MR750 (GE Healthcare, Milwaukee, USA) with broadband imaging capabilities and a whole-body radiofrequency coil, as previously described.^9-11 Anatomical ¹H images were acquired using a fast-spoiled gradient-recalled echo (FGRE) sequence with a partial-echo (total acquisition time=8s; TR msec/TE msec=4.7/1.2; flip-angle=30°; FOV=40×40cm²; bandwidth=24.4kHz; 128×80 matrix, zero-padded to 128×128; partial echo percentage=62.5%; 15-17 slices; slice thickness=15mm; no gap). Static ventilation images were acquired using a three-dimensional FGRE sequence (total acquisition time=14s; TR msec/TE msec=6.7/1.5; variable flip-angle; FOV=40×40cm²; bandwidth=15.63kHz; 128×128 matrix, zero-padded to 128×128; 14 slices; slice thickness, 15mm; no gap). ¹²⁹Xe MRS was acquired using a whole-lung free-induction-decay spectroscopy sequence (200 dissolved-phase spectra, TR msec/TE msec=15/0.7, flip-angle=40°, BW=31.25kHz, 600μs 3-lobe Shinnar-Le Roux pulse). Participants were instructed to inhale and hold 1.0L of gas (100% N₂ for anatomical scan; 400mL hyperpolarized ¹²⁹Xe + 600mL ⁴He for static ventilation; 200mL hyperpolarized ¹²⁹Xe + 800mL ⁴He for spectroscopy).
Data Analysis:
MRS peaks were fit to a three-component Lorentzian model in MATLAB (2021b, Mathworks) to determine component full-width half maximum, phase, and frequency. RBC:membrane ratio was calculated as the ratio of RBC area-under-the-curve and membrane area-under-the-curve. MRI data reconstruction was performed by re-gridding radial k-space data to a Cartesian representation (kernel sharpness=0.32, over-gridding=3).¹² Receiver phase-offset and local phase inhomogeneity were corrected.¹³ Intergroup differences were evaluated using analysis-of-variance (ANOVA) and univariate relationships were determined using Spearman (ρ) correlations. Results were considered statistically significant when the probability of making a type I error was less than 5% (p<.05).

RESULTS:

Table 1 provides demographic and imaging measurements for healthy volunteers (n=24), moderate (GINA-4, n=27), and severe (GINA-5, n=18) asthma. There were significant differences (p<.05) between the three subgroups in all measurements, except for blood eosinophil count and MRS membrane:gas ratio. There was a difference between GINA-4 and GINA-5 participants for RBC:membrane (p=.048). As shown in Figure 1, in healthy volunteers, RBC:membrane correlated with FEV₁ (ρ=.63, p=.001), forced-vital-capacity (FVC; ρ=.62, p=.001), body-mass-index (BMI; ρ=.49, p=.04) and diffusing-capacity-of-the-lungs-for-carbon-monoxide (DL_CO; ρ=.80, p<.001). In GINA-4 asthma, (Figure 2) RBC:membrane was correlated with FEV₁/FVC (ρ=-.36, p=.04) and age (ρ=-.50, p=.005), and in GINA-5 with FVC (ρ=.48, p=.047) (Figure 3).

DISCUSSION:

¹²⁹Xe MRS measurements of alveolar gas-exchange were significantly different between healthy volunteers, moderate and severe asthma patients. RBC:membrane ratio was the only measurement that was different between asthma participants when grouped by GINA steps. The interpretability of RBC:membrane can be challenging, due to abnormalities in either the RBC or membrane compartment contributing to an impaired ratio. However, these differences appeared to be driven by RBC abnormalities, as there was no difference in membrane:gas signal between groups.
The RBC:membrane ratio is believed to sensitively reflect abnormal gas-exchange,¹⁴ where abnormally low RBC:membrane has been reported in non-specific interstitial pneumonia,¹⁵ and was related to FVC in idiopathic pulmonary fibrosis.¹⁶ We extend these findings to asthma patients, where RBC:membrane was abnormally low and correlated with global measurements of airflow obstruction (FEV₁, FVC, and FEV₁/FVC) in asthma patients.
¹²⁹Xe MRS provides sensitive measurements to interrogate individual components of the alveolar gas-exchange process and better understand the underlying pathophysiology that may drive symptoms and outcomes in patients with asthma.

CONCLUSIONS:

To our knowledge, this is the first demonstration of differences in ¹²⁹Xe MRS gas-exchange measurements between healthy volunteers, mild-moderate and severe asthma. These ¹²⁹Xe MRS findings agree with previous work suggesting pulmonary vascular remodeling in asthma.⁴ Thus, abnormal pulmonary gas-exchange may play a role in asthma regardless of GINA disease classification.

Acknowledgements

No acknowledgement found.

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