Arterial vascular volume changes with haemodynamics in schistosomiasis-associated pulmonary arterial hypertension

To the Editor:

Schistosomiasis is a prevalent cause of pulmonary arterial hypertension (PAH), currently classified as group 1 pulmonary hypertension (PH) [1]. In comparison to other aetiologies of PAH, such as idiopathic PAH, schistosomiasis-associated PAH (Sch-PAH) has not been extensively studied. Potential mechanisms of PAH development in schistosomiasis include systemic and localised lung inflammation, involvement of other organs, such as the liver and spleen, and direct blockage of precapillary vessels from parasite egg embolisation. Currently, the diagnosis of Sch-PAH relies on haemodynamic assessment using right heart catheterisation. In several aetiologies of PH, loss of visualised distal vascular volume has been quantified from pulmonary angiography [2, 3] and computed tomography (CT) of the lungs [4–6]. Additionally, loss of distal vascular volume has been shown to be associated with loss of vascular cross-sectional area histologically [7]. In this pilot study, we hypothesised that relative loss of arterial pulmonary vascular volume differentially correlates with haemodynamics in Sch-PAH patients, compared to a group of control subjects.

12 patients with Sch-PAH who had thin-slice chest CT were retrospectively identified at three PH centres where schistosomiasis is prevalent (Federal University of São Paulo, São Paulo, Brazil; Federal University of Minas Gerais, Belo Horizonte, Brazil; Santa Casa of Salvador, Bahia, Brazil). The diagnosis of Sch-PAH was established by: 1) significant exposure to an endemic region, history of treatment for schistosomiasis, or history of presence of Schistosoma mansoni eggs on stool examination or rectal biopsy; 2) presence of hepatosplenic disease on imaging (periportal fibrosis, or enlargement of the left lobe of the liver); 3) no other apparent cause of group 1 PAH; and 4) PAH haemodynamic criteria, including mean pulmonary arterial pressure (mPAP) ≥25 mmHg, pulmonary arterial wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance (PVR) ≥3 Wood units (WU) (observed ranges: mPAP, 36–86 mmHg; PAWP, 4–15 mmHg; and PVR, 5.7–36.8 WU). 17 control subjects with thin-slice chest CT were identified from a cohort of patients who previously underwent invasive cardiopulmonary exercise testing (CPET) [8] for dyspnoea at Brigham and Women's Hospital (Boston, MA, USA) and were found to have no evidence of PH (observed ranges: mPAP, 9–21 mmHg; PAWP, 7–14 mmHg; PVR, 0.2–2.1 WU) and a normal physiological limit to exercise (IRB#2018P000419).

Automated vascular reconstructions and computation of the vascular volumes by cross-sectional area were performed using the Chest Imaging Platform (www.chestimagingplatform) [9], with the separation of the arteries and veins performed using a convolutional neural network algorithm [10]. All vascular volumes reported were normalised by lung volume (yielding a unitless index representing millilitres of vessel volume per litre of lung volume). We focused on the fraction of blood volume in arteries of area <5 mm² (“small vessel volume”) relative to total arterial volume, termed arterial small vessel fraction (arterial BV5%), in relation to log(PVR index). Data are represented as median with interquartile range by group (compared using Wilcoxon rank-sum test) with the exception of gender, reported as percentage (p-value from Fisher's exact test). Analyses were conducted using SAS version 9.4 (Cary, NC, USA).

The Sch-PAH group was similar in age to the control group (54 (46–59) versus 52 (44–71) years; p=0.63) but included fewer women (58% versus 88%; p=0.09). In addition to higher mPAP and PVR, and similar PAWP, subjects with Sch-PAH had higher pulmonary vascular stiffness (1.8 (1.1–2.6) versus 0.3 (0.3–0.4) mmHg·mL⁻¹; p=0.0001), lower pulmonary arterial compliance (PAC) (1.0 (0.59–1.73) versus 5.5 (4.1–6.6) mL·mmHg⁻¹; p=0.0001) and lower stroke volume (SV) index (25.4 (21.0–38.6) versus 42.3 (35.8–51.9) mL·m⁻²; p=0.005) compared to controls. The subgroup of Sch-PAH who underwent CPET (n=6) had a reduced peak oxygen consumption compared to controls (62 (49–69) versus 101 (91–106)% predicted; p=0.003). Pairwise correlations among the haemodynamic metrics stratified by group showed that log(PVR index) was more strongly correlated with log(PAC) and SV index within the Sch-PAH group (R=0.85 and 0.87, respectively) than among controls (R=−0.54 and −0.12, respectively).

The pulmonary vasculature was reconstructed from the chest CT scans, with an example from each group shown in figure 1. There was no statistically significant difference between whole lung volume (3.5 (2.6–4.6) versus 4.0 (2.2–4.7) L; p=0.62) or total arterial volume (28.0 (26.9–36.1) versus 29.5 (24.6–38.3); p=0.42) between Sch-PAH and control groups. However, there was significantly lower arterial small vessel volume (10.7 (9.0–12.6) versus 16.6 (15.2–19.0); p<0.0001) in the Sch-PAH cohort, compensated for by higher large vessel volume (18.1 (13.9–26.2) versus 11.7 (7.9–19.9); p=0.03), as shown in figure 1. We quantified this shift of volume from small to large vessels by the arterial small vessel fraction (arterial BV5%), with the median percentage being 35% in Sch-PAH compared to 60% in controls (p=0.0003).

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1

a) Representative vascular reconstructions from a control subject (left; subject ranked eighth amongst controls based on arterial BV5%) and a patient with schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) (right, subject ranked seventh amongst Sch-PAH patients based on arterial BV5%) showing comparative loss of distal small vessels and dilation of proximal vessels. b) Relative distribution of arterial small vessel volume (top) and arterial large vessel volume (bottom) showing a decrease in arterial small vessel volume (defined as volume in vessels with cross sectional area ≤5 mm²) and an increase in arterial large vessel volume (defined as volume in vessels with cross sectional area >5 mm²) in patients with Sch-PAH. c) The graph shows each subject's arterial small-vessel fraction (arterial BV5%; defined as arterial small vessel volume divided by total vascular volume) in relation to their log(PVR index), with subjects ranked by group and by arterial BV5%. Arterial BV5% is negatively correlated with log(PVR index) in the Sch-PAH group, showing that loss of small arterial vessel volume relates to greater pulmonary vascular resistance (PVR) (Spearman's correlation, ρ=−0.50). There is no evidence of this link in the control group, where the correlation is positive and weaker (ρ=0.31).

We additionally plotted each individual's arterial BV5% in relation to their log(PVR index) (figure 1). In general, the arterial BV5% was negatively associated with log(PVR index) among Sch-PAH patients (Spearman's correlation, ρ=−0.50) and positively associated among controls (ρ=0.31). Arterial BV5% values were nearly distinct between groups: three Sch-PAH patients had arterial BV5% >42% and only one control had arterial BV5% <42%.

To further quantify the association of arterial small-vessel fraction with log(PVR index), we modelled arterial BV5% as a function of log(PVR index), group, and their interaction using a generalised linear model with log-binomial inference. Per 1-point increase in log(PVR index), the arterial small-vessel fraction declined 0.72-fold (95% CI 0.50 to 1.03) among Sch-PAH patients (e.g. as log(PVR index) increased from 7 to 8, arterial BV5% decreased by a factor of 0.72=28%/39%) but rose 1.13-fold (95% CI 0.95 to 1.34) among controls (e.g. as log(PVR index) increased from 4 to 5, arterial BV5% increased by a factor of 1.13=56%/49%). Comparison of the relative effects between groups identified a clinically and statistically significant greater reduction in arterial BV5% per 1-point increase in log(PVR index) among Sch-PAH patients compared with controls: 0.64 (95% CI 0.43 to 0.94; p=0.026), where 0.64=0.72/1.13.

Relating haemodynamics to the physical pulmonary vascular structure, quantified by CT imaging of the lungs, extends our understanding of Sch-PAH disease. The current findings support the hypothesis that pulmonary vascular remodelling severity, as measured by higher PVR index in Sch-PAH, reflects arterial small vessel loss. Insofar as blood gas exchange occurs in the small arterial vessels of the lungs, this loss helps to explain the devastating experience of PAH progression. Our evidence suggests that Sch-PAH-related loss of distal arterial volume may be due to blood volume shifting from smaller to larger vessels and/or to narrowing of the distal arterial lumen. Proximal dilation of the pulmonary arteries has been observed in other forms of PH [4, 11] and may be an adaptation to higher pressure. In Sch-PAH, previously described [12] arterial aneurysmal dilation may also play a role, which may result from more focal extreme dilations of the spatially uniform proximal dilation we observed. While obstruction of the arterial lumen by Schistosoma eggs has been reported, PH persistence despite effective anthelmintic treatment (as was the case in the Sch-PAH cohort) and modern autopsy studies finding Schistosoma eggs absent from the lungs [13] make it unlikely that egg obstruction is causing the observed decrease in arterial small vessel volume. Rather, it is more likely that a persisting inflammatory response cascade, or the persisting effect of the initial vascular injury, lead to progression of arterial remodelling and development of PAH [14]. The relatively small size of the eggs (short axis diameter 50 µm) is below the resolution of conventional CT imaging (0.5–1 mm), and none of the patients in this study had active infection. To further explore this question, our future studies will compare other biomarkers in conjunction with imaging, as well Sch-PAH to other aetiologies of PAH.

This study is limited by the retrospective nature of the data collection, small sample sizes, limitations inherent to CT imaging resolution, and variations in image acquisition between different sites. Nonetheless, this is the first study, to our knowledge, characterising the pulmonary vascular structure in Sch-PAH, adding to the framework of our understanding of Sch-PAH pathophysiology.

In conclusion, the current pilot study findings suggest that arterial small vessel volume is reduced and inversely associated with PVR index in Sch-PAH. Validation of these methods involving larger prospective cohorts is necessary to evaluate their potential for non-invasive screening, diagnosis, and monitoring in Sch-PAH.

Shareable PDF