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

Tilo Winkler; Puja Kohli; Vanessa J Kelly; Ekaterina G Kehl; Alison S Witkin; Josanna M Rodriguez-Lopez; Kathryn A Hibbert; Mamary T Kone; David M Systrom; Aaron B Waxman; Jose G Venegas; Richard N Channick; R Scott Harris

doi:10.1186/s12931-022-02239-8

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

Respir Res. 2022 Dec 1;23(1):325. doi: 10.1186/s12931-022-02239-8.

Affiliations

¹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. twinkler@mgh.harvard.edu.
² Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

^# Contributed equally.

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.

MeSH terms

Biomarkers
Cohort Studies
Familial Primary Pulmonary Hypertension
Healthy Volunteers
Humans
Nitric Oxide
Oxygen
Perfusion Imaging
Pulmonary Arterial Hypertension*

Substances

Nitric Oxide
Biomarkers
Oxygen