Noninvasive wave intensity analysis predicts functional worsening in children with pulmonary arterial hypertension

Abstract

The purpose of the present study was to characterize pulmonary vascular stiffness using wave intensity analysis (WIA) in children with pulmonary arterial hypertension (PAH), compare the WIA indexes with catheterization- and MRI-derived hemodynamics, and assess the prognostic ability of WIA-derived biomarkers to predict the functional worsening. WIA was performed in children with PAH ( n = 40) and healthy control subjects ( n = 15) from phase-contrast MRI-derived flow and area waveforms in the main pulmonary artery (MPA). From comprehensive WIA spectra, we collected and compared with healthy control subjects forward compression waves (FCW), backward compression waves (BCW), forward decompression waves (FDW), and wave propagation speed ( c-MPA). There was no difference in the magnitude of FCW between PAH and control groups (88 vs. 108 mm⁵·s^-1·ml^-1, P = 0.239). The magnitude of BCW was increased in patients with PAH (32 vs. 5 mm⁵·s^-1·ml^-1, P < 0.001). There was no difference in magnitude of indexed FDW (32 vs. 28 mm⁵·s^-1·ml^-1, P = 0.856). c-MPA was increased in patients with PAH (3.2 vs. 1.6 m/s, P < 0.001). BCW and FCW correlated with mean pulmonary arterial pressure, right ventricular volumes, and ejection fraction. Elevated indexed BCW [heart rate (HR) = 2.91, confidence interval (CI): 1.18-7.55, P = 0.019], reduced indexed FDW (HR = 0.34, CI: 0.11-0.90, P = 0.030), and increased c-MPA (HR = 3.67, CI: 1.47-10.20, P = 0.004) were strongly associated with functional worsening of disease severity. Our results suggest that noninvasively derived biomarkers of pulmonary vascular resistance and stiffness may be helpful for determining prognosis and monitoring disease progression in children with PAH. NEW & NOTEWORTHY Wave intensity analysis (WIA) studies are lacking in children with pulmonary arterial hypertension (PAH) partially because WIA, which is necessary to assess vascular stiffness, requires an invasive pressure-derived waveform along with simultaneous flow measurements. We analyzed vascular stiffness using WIA in children with PAH who underwent phase-contrast MRI and observed significant differences in WIA indexes between patients with PAH and control subjects. Furthermore, WIA indexes were predictive of functional worsening and were associated with standard catheterization measures.

Keywords: magnetic resonance imaging; pediatric pulmonary arterial hypertension; vascular stiffness.

Fig. 1.

Wave intensity analysis workflow. A and B: segmented magnitude and phase images from acquired phase-contrast MRI (A) were required to create flow and area waveforms (B), which were further interpolated to achieve 5-ms temporal resolution. C: flow-area diagrams were reconstructed to calculate main pulmonary arterial wave speed (pulse wave velocity) by means of linear regression of noninterpolated data points (red) sampled during early systole. D: wave intensity spectra were then generated from separated flow and area waveforms. E: compression or decompression nature of the forward and backward waves was determined from separated area differential waveforms. c-MPA or c, wave speed/pulse wave velocity in the main pulmonary artery; dA₊ and dA₋, forward-positive and backward-negative components of area differential waveform, respectively; dI₊ and dI₋, forward-positive and backward-negative components of intensity differential waveform, respectively; dQ, flow differential waveform.

Fig. 2.

Comparison of wave intensity analysis in typical patient with pulmonary arterial hypertension (PAH; A–C) and control subject of similar age and size (D–F). Flow waveform in patient with pulmonary arterial hypertension shows characteristic late systolic notch (A). Wave intensity pattern in patient with PAH shows prominent backward compression wave (BCW; B), which positively identified by parallel analysis of separated differential area waveforms (C). In comparison, wave intensity analysis in control subject does not have backward compression wave (E). Furthermore, wave intensity analysis spectra do not show significant differences between forward compression waveform (FCW) typically associated with dP/dt and right ventricular contraction, and similarly, forward decompression wave (FDW) reflective of right ventricular diastolic function appears to have similar magnitude. dA₊ and dA₋, forward-positive and backward-negative components of area differential waveform, respectively; dI₊ and dI₋, forward-positive and backward-negative components of intensity differential waveform, respectively.

Fig. 3.

Graphical summary of observed correlations between indexed indexed backward compression wave [BCW_(i)] magnitude with catheterization-derived mean pulmonary arterial pressure (mPAP; A) and right ventricular ejection fraction (B). Similarly, wave speed (pulse wave velocity) measured in the main pulmonary artery (c-MPA) correlated with mPAP (C) and right ventricular ejection fraction (D).

Fig. 4.

Forest plot summarizing the univariate Cox proportional hazard analysis investigating the prognostic ability of wave intensity analysis, catheterization, and MRI hemodynamic indexes to depict clinical functional worsening. Increased indexed backward compression wave [BCW_(i)] and elevated wave speed/pulse wave velocity measured in the main pulmonary artery (c-MPA) were prognostic of functional deterioration. Additionally, reduced indexed forward decompression wave [FDW_(i)] was prognostic of functional worsening. All typical catheterization markers and MRI-derived right ventricular ejection fraction (EF) were prognostics of functional worsening. CI, cardiac index; EDP, end-diastolic pressure; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; FCW_(i), indexed forward compression wave; mPAP, mean pulmonary arterial pressure; PVRi, pulmonary vascular resistance index; RAC-MPA, relative area change of the main pulmonary artery; WRI, wave reflection index.

Fig. 5.

Kaplan-Meier curves depicting the prognostic potential of noninvasive wave intensity analysis metrics. Indexed backward compression wave [BCW_(i), A], indexed forward decompression wave [FDW_(i), B], and wave speed propagation (pulse wave velocity) measured in the main pulmonary artery (c-MPA, C). TTE, time to event.