Figures
- FIGURE 1
Flow diagram for search and selection of included studies [27].
- FIGURE 2
Main pathophysiologic pathways in schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH). Schematic diagram depicting the main pathophysiologic mechanisms involved in Sch-PAH, which have been described previously in idiopathic pulmonary arterial hypertension. ALK: activin receptor-like kinase; BMP: bone morphogenetic protein; BMP-R: bone morphogenetic protein receptor; cGMP: cyclic guanosine monophosphate; EC: endothelial cell; GMP: guanosine monophosphate; GTP: guanosine triphosphate; HIF: hypoxia-inducible factor; IL: interleukin; IL-13R: IL-13 receptor; IL-4R: IL-4 receptor; JAK: Janus kinase; NO: nitric oxide; NOS: nitric oxide synthase; PASMC: pulmonary arterial smooth muscle cell; sGC: soluble guanylate cyclase; STAT: signal transducer and activator of transcription; TGF-β: transforming growth factor β; TGF-βR: TGF-β receptor; TYK: tyrosine kinase; VEGF: vascular endothelial growth factor.
Tables
- TABLE 1
Comparison of pathophysiological mechanisms in idiopathic pulmonary arterial hypertension (iPAH) and schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH)
Molecules Expression Pathways affected Vascular cells affected Targeted therapies for iPAH Similarities with Sch-PAH Study designs in Sch-PAH studies [Ref] BMPR-II ↓ Cell apoptosis ↓
Inflammation ↑EC, SMC FK506# indirectly by IL-2 inhibition + Animal study, Database study [30, 42, 43, 44–48] Caveolin-1 ↓ Cell proliferation ↑ EC − − Animal study [39, 43, 49] Endothelin-1 ↑ Cell apoptosis ↓
Cell proliferation ↑EC, SMC, AF ERA (bosentan, macitentan, ambrisentan) NA − [43, 50] HIF-1α ↑ Cell proliferation ↑
Cell apoptosis ↓EC, SMC, AF − + Animal study [28, 43, 51] IL-6 ↑ Inflammation ↑ EC Tocilizumab# +/− Animal study [36, 43, 52–54] [K+] channels ↓ Cell apoptosis ↓
Vasoconstriction ↑SMC − NA − [43, 87, 55] MIP-1α ↑ Inflammation ↑ Macrophage − NA − [43, 56] MMP-2 ↑ Cell proliferation ↑ SMC − NA − [43, 57, 58] MT-MMP1 ↑ Cell proliferation ↑ SMC − NA − [43] Nitric oxide ↓ Cell proliferation ↑
Clotting ↑
Inflammation ↑EC, SMC PDE5i (sildenafil, tadalafil)
Soluble guanylate cyclase stimulators (riociguat)+ Animal study [39, 43, 50, 59] PDGF ↑ Cell proliferation ↑ EC, SMC, AF PDGFR inhibitor (imatinib¶) +/− Case–control study [43, 60–62] E-selectin ↑ Cell proliferation ↑ EC − + Case–control study [62] P-selectin ↑ Cell proliferation ↑ EC − + Case–control study [62] Prostacyclin ↓ Cell proliferation ↑
Clotting ↑EC, SMC Prostacyclin analogues (e.g. epoprostenol, treprostinil)
Prostacyclin receptor stimulator (selexipag)NA − [43, 63–65] CCL5/RANTES ↑ Inflammation ↑ Macrophage − NA −− [43, 66] TGF-β ↑ Cell proliferation ↑ SMC, AF + Case–control study, human necropsy study, animal study, in vitro study [31, 32, 35, 38, 40, 43, 67, 68] TGF-βR2 ↓ Cell apoptosis ↓
Inflammation ↑EC, SMC − + in vitro study [41, 43, 68, 69] TIMP-1 ↑ Cell proliferation ↑ SMC − NA − [43, 57, 70] VEGF ↑ Cell apoptosis ↓
Cell proliferation ↑
Clotting ↑
Inflammation ↑EC, SMC + Animal study [28, 29, 43, 71] vWF ↑ Clotting ↑
Inflammation ↑EC, SMC − NA − [43, 72] 5-HT transporter/
receptor↑ Cell proliferation ↑
Vasoconstriction ↑SMC NA − [44, 73] Selected pathophysiological patterns for iPAH as presented at WSPH 2018 [42], sought for similarities in Sch-PAH. BMPR-II: bone morphogenetic protein receptor type 2; HIF-1α: hypoxia-inducible factor 1-α; IL: interleukin; MIP-1α: macrophage inflammatory protein 1-α; MMP-2: matrix metalloproteinase-2; MT-MMP1: membrane-type MMP-1; PDGF: platelet-derived growth factor; TGF-β: transforming growth factor β; TGF-βR2: transforming growth factor β receptor 2; TIMP-1: tissue inhibitor of metalloproteinases-1; VEGF: vascular endothelial growth factor; vWF: von Willebrand factor; 5-HT: serotonin; EC: endothelial cell; SMC: smooth muscle cell; AF: adventitial fibroblast; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor; NA: not applicable. −: different in iPAH and Sch-PAH; +: similar in iPAH and Sch-PAH. #: drugs currently under investigation, that are not yet approved for therapy of iPAH; ¶: negative trials in humans. Data from [43].
- TABLE 2
Comparison of haemodynamics of patients with schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) and (idiopathic pulmonary arterial hypertension) iPAH
Haemodynamic variable Sch-PAH iPAH p-value n mean±sd n mean±sd CO L·min−1 181 4.4±1.3 144 4.1±1.4 0.046 CI L·min−1·m−2 104 2.6±0.7 3388 2.3±0.8 <0.001 mRAP mmHg 277 11±5 3532 10±6 0.007 mPAP mmHg 277 54±17 3532 55±15 0.290 mPAWP mmHg 193 12±4 3142 10±4 <0.001 PVR WU 277 10±6 1396 13±7 <0.001 CO: cardiac output; CI: cardiac index; mRAP: mean right atrial pressure; mPAP: mean pulmonary artery pressure; mPAWP: mean pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance. Bold in p-values idicates significance.
- TABLE 3
Comparison of survival of patients with schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) and idiopathic pulmonary arterial hypertension (iPAH)
Survival Sch-PAH iPAH p-value n mean±sd n mean±sd 1-year 191 91.0±9.9 3653 86.1±9.7 <0.001 2-year 191 84.3±20.8 1644 75.7±11.7 <0.001 3-year 191 73.0±26.8 3653 67.3±14.1 <0.001 5-year 102 79.0±14.1 2630 52.5±19.9 <0.001 Bold in p-values indicates significance.
Supplementary Material
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ERR-0089-2019_Supplementary material ERR-0089-2019_Supplementary_material
