Details

Autor(en) / Beteiligte

• Knutsen, Russell H.
• Gober, Leah M.
• Kronquist, Elise K.
• Kaur, Maninder
• Donahue, Danielle R.
• Springer, Danielle
• Yu, Zu Xi
• Chen, Marcus Y.
• Fu, Yi-Ping
• Choobdar, Feri
• Nguyen, My-Le
• Osgood, Sharon
• Freeman, Joy L.
• Raja, Neelam
• Levin, Mark D.
• Kozel, Beth A.

Titel

Elastin Insufficiency Confers Proximal and Distal Pulmonary Vasculopathy in Mice, Partially Remedied by the KATP Channel Opener Minoxidil: Considerations and Cautions for the Treatment of People With Williams-Beuren Syndrome

Ist Teil von

• Frontiers in cardiovascular medicine, 2022-05, Vol.9, p.886813-886813

Ort / Verlag

Frontiers Media S.A

Erscheinungsjahr

2022

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Background Williams Beuren syndrome (WBS) is a recurrent microdeletion disorder that removes one copy of elastin ( ELN ), resulting in large artery vasculopathy. Early stenosis of the pulmonary vascular tree is common, but few data are available on longer-term implications of the condition. Methods Computed tomography (CT) angiogram ( n = 11) and echocardiogram ( n = 20) were performed in children with WBS aged 3.4–17.8 years. Controls ( n = 11, aged 4.4–16.8 years) also underwent echocardiogram. Eln +/− mice were analyzed by invasive catheter, echocardiogram, micro-CT (μCT), histology, and pressure myography. We subsequently tested whether minoxidil resulted in improved pulmonary vascular endpoints. Results WBS participants with a history of main or branch pulmonary artery (PA) stenosis requiring intervention continued to exhibit increased right ventricular systolic pressure (RVSP, echocardiogram) relative to their peers without intervention ( p < 0.01), with no clear difference in PA size. Untreated Eln +/− mice also show elevated RVSP by invasive catheterization ( p < 0.0001), increased normalized right heart mass ( p < 0.01) and reduced caliber branch PAs by pressure myography ( p < 0.0001). Eln +/− main PA medias are thickened histologically relative to Eln +/+ ( p < 0.0001). Most Eln +/− phenotypes are shared by both sexes, but PA medial thickness is substantially greater in Eln +/− males ( p < 0.001). Eln +/− mice showed more acute proximal branching angles ( p < 0.0001) and longer vascular segment lengths ( p < 0.0001) (μCT), with genotype differences emerging by P7. Diminished PA acceleration time ( p < 0.001) and systolic notching ( p < 0.0001) were also observed in Eln +/− echocardiography. Vascular casting plus μCT revealed longer generation-specific PA arcade length ( p < 0.0001), with increased PA branching detectable by P90 ( p < 0.0001). Post-weaning minoxidil decreased RVSP ( p < 0.01) and normalized PA caliber ( p < 0.0001) but not early-onset proximal branching angle or segment length, nor later-developing peripheral branch number. Conclusions Vascular deficiencies beyond arterial caliber persist in individuals with WBS who have undergone PA stenosis intervention. Evaluation of Eln +/− mice reveals complex vascular changes that affect the proximal and distal vasculatures. Minoxidil, given post-weaning, decreases RVSP and improves lumen diameter, but does not alter other earlier-onset vascular patterns. Our data suggest additional therapies including minoxidil could be a useful adjunct to surgical therapy, and future trials should be considered.