Synopsis

Keywords: Lung, Hyperpolarized MR (Gas)

Large and small airway-wall and lumen abnormalities and occlusion are hallmark findings in asthma, but pathologic abnormalities have also been reported in the pulmonary vasculature. ¹²⁹Xe MR-spectroscopy provides a way to quantify ¹²⁹Xe gas in the airways and as it diffuses through the alveolar tissue-membrane and binds to red-blood-cells in the pulmonary capillaries. Static and dynamic ¹²⁹Xe MR-spectroscopy were undertaken in participants with poorly controlled asthma in whom there was significantly different ¹²⁹Xe MR RBC:membrane ratio compared to healthy-volunteers. Cardiopulmonary oscillations were observed in all ¹²⁹Xe compartments; the oscillation amplitude in the gas-compartment was related to oscillometry airways impedance measurements.

PURPOSE:

In patients with asthma, lung findings include airway wall thickening, airway lumen obstruction and airway wall smooth muscle dysfunction. Other abnormalities have been observed, including collagen deposits in alveolar walls in uncontrolled asthma¹ and pulmonary vascular pruning.^{2 129}Xe MRS can probe the alveolar-capillary interface where these abnormalities may be occurring by measuring the spectral properties of ¹²⁹Xe dissolved in the alveolar membrane and bound to red-blood-cells (RBC). The temporal variability of the RBC and alveolar membrane ¹²⁹Xe MRS signal, referred to as cardiogenic oscillations, are thought to be driven by blood pulsation.³ Investigations in patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) have uncovered RBC:membrane signal differences and oscillation amplitude differences compared to healthy participants.⁴ Similar investigations have not been undertaken in patients with asthma, in whom both airways disease and pulmonary vascular pruning has been demonstrated. Therefore, we endeavored to examine both static and dynamic spectroscopy measurements in people with asthma and to compare them with clinical and pulmonary function test measurements.

METHODS:

Participants:
Participants with severe asthma were recruited from a quaternary care Asthma clinic and provided written informed consent to an approved protocol (NCT02351141 or NCT 03733535) to undertake pulmonary function tests, oscillometry, thoracic CT, ¹²⁹Xe MRI, and static and dynamic MRS. Healthy volunteers were recruited from the local general population and performed static and dynamic MRS. Participants were coached to inhale 1.0 L of gas (1/5 mixture by volume of ¹²⁹Xe/⁴He) from functional residual capacity.

Data Acquisition:
Pulmonary function tests were performed using a MedGraphics Elite Series plethysmograph (MGC Diagnostics Corporation). Oscillometry measurements were acquired using a TremoFlo C-100 Airwave Oscillometer (Thorasys) at multiple frequencies and reported at 5 and 19Hz frequencies.
MRI and MRS were acquired using a whole-body 3.0T Discovery MR 750 system (General Electric Healthcare, USA) with broadband imaging capabilities and a flexible vest transmit-receive coil (Clinical MR Solutions, USA). ¹²⁹Xe MRS was obtained using a whole-lung free-induction-decay sequence (500 spectra, TR-15ms, TE=0.7ms, flip=40^o, BW=31.25kHz, 600μs 3-lobe Shinnar-Le Roux pulse). ¹²⁹Xe ventilation MRI were acquired with a fast spoiled gradient recalled echo sequence (TR=3.8ms, TE=1.0ms, flip angle=7^o, FOV=40x40cm²; BW=48.8kHz; matrix=128x80 zero-padded to 128x128; number of slices=15-18, slice thickness=15mm).

Data Analysis:
¹²⁹Xe MRS peaks were fit to a three-component Lorentzian model in Matlab (2021a, Mathworks) to determine component magnitude, phase, and frequency. Each peak was then fit to sinusoids to measure cardiogenic oscillations in peak magnitude, phase and chemical shift. Oscillations were normalized to peak height at start time. RBC:membrane ratio was calculated as the ratio of RBC area-under-the-curve and membrane area-under-the-curve.

RESULTS:

21 participants with asthma (age=60±15, 18/21 female) and 16 healthy volunteers (age=37±17 years, 5/16 female) were enrolled. Table 1 shows participant demographic, pulmonary function test, imaging and MRS measurements for healthy volunteers and participants with asthma. RBC:membrane and RBC:Gas measurements were significantly lesser in participants with asthma (0.29±0.08) compared to healthy volunteers (0.44±0.09, p<.001), however there was no significant difference in membrane:gas (healthy=0.93±0.26, asthma=0.94±0.18, p=.93). Figure 1 shows representative dynamic spectroscopy waterfall plots in a healthy volunteer and a participant with asthma. In addition to previously described RBC oscillations, we observed oscillations in the membrane and gas signals in both healthy volunteers and participants with asthma. There were no significant differences between oscillation amplitudes in healthy participants (12±5%) and participants with asthma (15±12%, p=.33), however there were significantly greater phase oscillations in all three ¹²⁹Xe compartments. Figure 2 shows RBC:membrane correlated with age in both healthy volunteers (r=.67, p=.008) and participants with asthma (r=.52, p=.02), however asthma measurements were lesser across ages. Gas oscillation amplitudes were correlated with airway oscillometry measurements.

DISCUSSION:

The RBC:membrane ratio was diminished in participants with asthma independent of age. These changes appeared to be driven by RBC abnormalities, as there was no difference in membrane:gas signal observed. We also observed significant differences between RBC and membrane resonant frequencies, however the magnitude of these differences was small. These differences may have been due to differences in the mean age and sex distribution between the healthy and asthma subgroups or because of pathophysiology inherent in long-standing severe asthma. We also observed cardiopulmonary oscillations in both the membrane and gas compartments. Gas oscillations were related to airway oscillometry measurements of airway resistance and reactance, suggesting that this may be related to gas redistribution in the airways as the heart muscle contraction compressed surrounding elastic tissue. There were no significant differences between amplitude oscillations, however there were significant differences in phase oscillations.

CONCLUSIONS:

To our knowledge, this is the first report in asthma of ¹²⁹Xe MR RBC:membrane ratio abnormalities alongside abnormalities in RBC:gas ratio but not the membrane:gas ratio. Taken together, these findings suggest that this specific gas-exchange abnormality originates in the pulmonary vasculature, not the alveolar wall tissue and that asthma patholophysiologic abnormalities involve the pulmonary capillaries. We also observed cardiogenic oscillations in the gas component which may stem from cardiac muscle contraction and its compression of surrounding lung tissue.

Acknowledgements

No acknowledgement found.

References

1. Weitoft, M, et al. Respir Res 2014.

2. Ash, SY, et al. Am J Respir Crit Care Med 2018.

3. Bier, EA, et al. NMR Biomed 2019.

4. Wang, Z, et al. Eur Respir J 2019.