Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker

Abstract

Background: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects.

Methods: We studied 5 controls and 4 subjects with PAH using HRCT and ¹³NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV²_Qtotal) and its components in the vertical (CV²_Qvgrad) and cranio-caudal (CV²_Qzgrad) directions, and the residual heterogeneity (CV²_Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O₂ + iNO). The length scale spectrum of CV²_Qr was determined from 10 to 110 mm, and the response of regional perfusion to O₂ + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Q_vgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of ¹³NN washout kinetics.

Results: O₂ + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O₂ + iNO, CV²_Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10^-3 (2 × 10^-4-0.02), p < 0.001) with a considerable gap between groups. Q_vgrad and CV²_Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV²_Qvgrad had the largest effect size among the primary parameters during O₂ + iNO. CV²_Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant.

Conclusions: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

Keywords: Functional imaging; Inhaled nitric oxide; Perfusion distribution; Positron emission tomography; Pulmonary circulation; Vascular physiology; Ventilation.

Fig. 1

Perfusion heterogeneity profiling distinguished PAH subjects and control subjects. The total spatial heterogeneity of perfusion (CV²_Qtotal) [27] (A) is comprised of the heterogeneity of the vertical (dorsoventral) gradient in perfusion (CV²_Qvgrad) (B), the heterogeneity of the craniocaudal (z-axis) gradient in perfusion (CV²_Qzgrad) (C), and the heterogeneity of the residual (or remaining) perfusion (CV²_Qr) (D). PAH subjects demonstrated very low CV²_Qvgrad due to attenuated vertical gradients in perfusion (Q_vgrad) (E) that were not responsive to O₂ + iNO, distinguishing this cohort from their control counterparts. Note that imaging noise is excluded from all CV² parameters

Fig. 2

Cohen’s d effect size estimates and 95% confidence intervals of the primary parameters. The effect sizes for PAH vs. control were substantially larger for O₂ + iNO compared to baseline. CV²_Qvgrad had the most significant effect size and a 95% confidence interval not crossing zero, followed by Q_vgrad and CV²_Qtotal. The relatively large effect sizes for O₂ + iNO vs. baseline in the control group are indicators of the magnitude of the response

Fig. 3

Perfusion-height maps for PAH subjects and controls. The greatest perfusion heterogeneity, including the largest range of perfusion values at any given height, was present in PAH subjects, followed by controls. The vertical gradient in perfusion (represented by the slope of the black-and-white dashed line) increased in magnitude in controls but not PAH subjects breathing O₂ + iNO. In contrast to controls, several PAH subjects had no vertical gradient in perfusion in the lower or dependent part of the lung (dorsal in the supine position), as if the hydrostatic pressure, which increases towards the dependent regions, had no effect on perfusion. Surprisingly, there was no substantial fraction of voxels with very low or zero perfusion in any PAH subject, suggesting there was no severe or complete obstruction of blood vessels. The only confirmed responder of the PAH group is shown in the second row

Fig. 4

Difference maps of the perfusion-height distribution visualizing the changes in mean normalized perfusion vs. height in response to the administration of O₂ + iNO in PAH subjects and controls. Note that all subjects had regional responses to breathing O2 + iNO, including PAH subjects who had no discernible change in mean pulmonary arterial pressures with vasodilator challenge during cardiac catheterization. In controls, the changes in perfusion show a substantial spatial heterogeneity with an overall trend towards an increased vertical gradient during O2 + iNO and more uniform perfusion in the dependent (dorsal) regions (see also Fig. 2). In contrast, there are substantial changes in regional perfusion in PAH but not associated with a shift in the vertical gradient except for the confirmed responder among the PAH subjects shown in the second row. All panels use the same scale greyscale for the magnitude of differences

Fig. 5

3D renderings and animations of perfusion distributions. A Representative 3D renderings of the mean-normalized distribution of perfusion for PAH and healthy control subjects at baseline and after O₂ + iNO (animated in Videos V1 (https://doi.org/10.6084/m9.figshare.12442589) and V2 (https://doi.org/10.6084/m9.figshare.12442784)) showing the effects of the administration of O₂ + iNO based on PET-CT imaging in supine position. The patchy areas of high perfusion illustrate the size and location of regional variations behind the representations in perfusion-height maps (Fig. 2). B 3D renderings of the regional changes in perfusion corresponding to the perfusion distributions in panel A (animated in Videos V3 (https://doi.org/10.6084/m9.figshare.12442787) and V4 (https://doi.org/10.6084/m9.figshare.12442790)). The web-like structure of perfusion increases (yellow) and decreases (blue) instead of gradual changes in perfusion among different regions illustrates the spatial variations behind the difference maps of the perfusion-height distribution (Fig. 3). The relatively small sizes suggest the involvement of smaller anatomical structures together with larger anatomical structures linked to the average changes in larger regions. In all 3D renderings, the orientation of the lungs is shown by a small mannequin. Color scales are fully transparent either for average perfusion (A, V1, and V2) or zero change (B, V3, and V4), opaqueness increases with the deviation from these values, and differences in color between PAH and controls are differences in magnitude. Rotating 3D renderings with periodic switching between air and O2 + iNO show the location and changes in high and low perfusion areas. This provides a spatial perception of their location and their magnitude lacking in the still images – video download provides the highest resolution and allows playback in loop mode

Fig. 6

$\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ distributions in PAH subjects and controls. The distributions of $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ ratios at baseline in PAH subjects were overall broader than in controls at baseline, approaching statistical significance, consistent with moderate degrees of vascular disease, causing a mismatch. There was no difference in the $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ distribution among groups while breathing O₂ + iNO, in large part due to the widening of the $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ distribution in controls. $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ distributions while breathing O₂ + iNO were unimodal in all subjects, including those with a bimodal distribution prior to the intervention