title: Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow.
abstract: Congenital heart disease with increased blood flow commonly leads to the development of increased pulmonary vascular reactivity and pulmonary arterial hypertension by mechanisms that remain unclear. We hypothesized a shear stress paradigm of hemodynamic reactivity and network remodeling via the persistence and/or exacerbation of a fetal diameter bifurcation phenotype [parent diameter d(0) and daughters d(1) >or= d(2) with alpha < 2 in (d(1)/d(0))(alpha) + (d(2)/d(0))(alpha) and area ratio beta < 1 in beta = (d(1)(2)+ d(2)(2))/ d(0)(2)] that mechanically acts as a high resistance magnifier/shear stress amplifier to blood flow. Evidence of a hemodynamic influence on network remodeling was assessed with a lamb model of high-flow-induced secondary pulmonary hypertension in which an aortopulmonary graft was surgically placed in one twin in utero (Shunt twin) but not in the other (Control twin). Eight weeks after birth arterial casts were made of the left pulmonary arterial circulation. Bifurcation diameter measurements down to 0.010 mm in the Shunt and Control twins were then compared with those of an unoperated fetal cast. Network organization, cumulative resistance, and pressure/shear stress distributions were evaluated via a fractal model whose dimension D(0) approximately alpha delineates hemodynamic reactivity. Fetus and Control twin D(0) differed: fetus D(0)=1.72, a high-resistance/shear stress amplifying condition; control twin D(0) = 2.02, an area-preserving transport configuration. The Shunt twin (D(0)=1.72) maintained a fetal design but paradoxically remodeled diameter geometry to decrease cumulative resistance relative to the Control twin. Our results indicate that fetal/neonatal pulmonary hemodynamic reactivity remodels in response to shear stress, but the response to elevated blood flow and pulmonary hypertension involves the persistence and exacerbation of a fetal diameter bifurcation phenotype that facilitates endothelial dysfunction/injury.
authors.affiliation: Department of Pediatrics, University of California, Davis, CA 95616, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Ghorishi
authors.forename: Jay M
authors.initials: JM
authors.lastname: Milstein
authors.forename: Francis R
authors.initials: FR
authors.lastname: Poulain
authors.forename: Anita
authors.initials: A
authors.lastname: Moon-Grady
authors.forename: Theresa
authors.initials: T
authors.lastname: Tacy
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Bennett
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Fineman
authors.forename: Marlowe W
authors.initials: MW
authors.lastname: Eldridge
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D016319:Corrosion Casting; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000098:blood supply / Q000601:surgery; D017709:Fractals; D006330:Heart Defects, Congenital / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D007091:Image Processing, Computer-Assisted; D018715:Microscopy, Video; D008955:Models, Cardiovascular; D011247:Pregnancy; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D011652:Pulmonary Circulation; D012756:Sheep; D013314:Stress, Mechanical; D014655:Vascular Resistance; D014656:Vascular Surgical Procedures