In Utero Placement of Aortopulmonary Shunts

Reddy, V. Mohan; Meyrick, Barbara; Wong, Jackson; Khoór, András; Liddicoat, John R.; Hanley, Frank L.; Fineman, Jeffrey R.

doi:10.1161/01.cir.92.3.606

Cited by 137 publications

(84 citation statements)

References 24 publications

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“…At 1 month of age, these lambs have a pulmonary-to-systemic blood flow ratio of Ϸ2:1, a mean pulmonary arterial pressure that is 50% to 75% of mean systemic arterial pressure, and pulmonary vascular remodeling characteristic of children with pulmonary hypertension and increased pulmonary blood flow. 12 Previously, we demonstrated that these lambs display alterations in the ET-1 cascade at 4 weeks of age. These include increased plasma ET-1 levels, decreased ET B receptor protein with loss of ET B receptor-mediated vasodilation, and increased ET A receptor protein with augmentation of ET A receptor-mediated vasoconstriction.…”

mentioning

confidence: 86%

“…[12][13][14] Through a left lateral fetal thoracotomy, an 8.0-mm Gore-tex vascular graft (Ϸ2 mm long) (W.L. Gore and Associates) was anastomosed between the ascending aorta and main pulmonary artery of the fetus with 7.0 proline (Ethicon Inc) with a continuous-suture technique.…”

Section: Ewesmentioning

confidence: 99%

“…Eight weeks after spontaneous delivery, 35 lambs (18 shunted and 17 age-matched controls) were anesthetized with ketamine hydrochloride, diazepam, and fentanyl citrate, mechanically ventilated, and instrumented to measure vascular pressures and flow as previously described [12][13][14] Twenty-three lambs (12 shunted and 11 age-matched controls; Pozzi Livestock, Valley Ford, Calif) then underwent a hemodynamic study as described below. After the last protocol, the lambs were killed by an intravenous injection of pentobarbital sodium (Euthanasia CII, Central City Medical), followed by bilateral thoracotomy.…”

Section: Lambsmentioning

confidence: 99%

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Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

et al. 2003

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Background-Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-monthold lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results-Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2Ϯ113.8 versus 209.8Ϯ61.8 pg/g, PϽ0.05). In shunt lambs (nϭ9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ET A receptor antagonist PD 156707 (nϭ3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ET B receptor agonist, and was blocked by the ET B receptor antagonist BQ 788 (nϭ3). However, in control lambs (nϭ7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ET B receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions-Over

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mentioning

confidence: 86%

Section: Ewesmentioning

confidence: 99%

Section: Lambsmentioning

confidence: 99%

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Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

et al. 2003

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“…Eight pregnant, mixed-breed Western ewes (135-140 days gestation; term ϭ 145 days) were operated on under sterile conditions. Through a left lateral fetal thoracotomy, an 8.0-mm Gore-Tex vascular graft (2-mm length; W. L. Gore, Milpitas, CA) was anastomosed between the ascending aorta and main pulmonary artery, as previously described in shunted lambs (52). After the surgery, the ewes were returned to the cage with free access to food and water.…”

Section: Surgical Preparations and Carementioning

confidence: 99%

Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Lee¹,

Ovadia²,

Azakie³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Neonates and infants with congenital heart disease with increased pulmonary blood flow suffer morbidity from poor oxygenation and decreased lung compliance. In a previous experiment involving 4-wk-old lambs with pulmonary hypertension secondary to increased pulmonary blood flow following an in utero placement of an aortopulmonary vascular graft, we found a decrease in surfactant protein (SP)-A gene expression as well as a decrease in SP-A and SP-B protein contents. To determine the timing of these changes, the objective of the present study was to characterize the effect of increased pulmonary blood flow and pulmonary hypertension on SP-A, -B, and -C gene expressions and protein contents within the first week of life. Of eight fetal lambs that underwent the in utero placement of the shunt, there was no difference in the expression of SP-A, -B, and -C mRNA levels or SP-A and -B protein contents compared with age-matched controls. The results showed that, in this model of congenital heart disease with pulmonary hypertension and increased pulmonary blood flow, the effect of the shunt on SP gene expression and protein content was not apparent within the first week of life.congenital heart disease AMONG NEONATES AND INFANTS with congenital heart disease with increased pulmonary blood flow, the presence of the systemicto-pulmonary communication often leads to progressive structural and functional changes in the pulmonary vascular bed, leading to pulmonary hypertension. The structural changes include increased muscularity of small pulmonary arteries with early distal extension, intimal hyperplasia, scarring and thrombosis, and a reduction in the number of intra-acinar arteries, as well as the arterial-to-alveolar ratio. These vascular changes result in eventual obliteration of the pulmonary vascular bed with elevation in pulmonary vascular resistance and extreme sensitivity to vasoconstricting stimuli. If uncorrected, these children will suffer from morbidity from cyanosis and myocardial failure (12,34,49).Multiple studies have shown that increased pulmonary blood flow and/or pressure affect endothelial cell functions within the alveolar space. Grigg et al. (22) found elevated levels of endothelin-1 (ET-1) in bronchoalveolar lavage in children with congenital heart disease with increased pulmonary blood flow. Ishikawa et al. (36) found elevated plasma ET-1 levels in children with ventricular septal defects who had both volume and pressure overload to the pulmonary circulation but not in children with atrial septal defects who had only volume overload. In cultured human vascular endothelial cells, shear stress stimulated the synthesis of mRNA for platelet-derived growth factors-A and -B (48), tissue plasminogen activator (20), and intercellular adhesion molecule-1 (46).Recently, increased pulmonary blood flow and/or pressure has also been shown to affect pulmonary epithelial cell functions. Wang et al. (59) showed that, in an isolated, constantly inflated, blood-perfused rat lung, increased left atrial pressure increa...

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“…One important form of nonsprouting angiogenesis is intussusception, first described by Burri and coworkers (Caduff et al, 1986;Burri and Tarek, 1990) in the capillaries of the pulmonary circulation. At certain periods of postnatal pulmonary development, and in instances of pathophysiological increase of blood flow, the pulmonary circulation demonstrates an intrinsic capacity to increase arterial and venous vessel number by an unknown mechanism of angiogenesis (Reid and Davies, 1988;Reddy et al, 1995). Another important process that is not presently understood, especially during stages of pulmonary hypertension development, is the phenomenon of "pruning," i.e., obliteration and removal of branches from a bifurcation (Reid and Davies, 1988).…”

Section: Introductionmentioning

confidence: 99%

Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism

Djonov

Kurz

Burri

2002

Developmental Dynamics

189

218

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The theory of bifurcating vascular systems predicts vessel diameters that are related to optimality criteria like minimization of pumping energy or of building material. However, mechanisms for producing the postulated optimality have not been described so far, and quantitative data on bifurcation diameters during development are scarce. We used an embryonic vascular bed that rapidly grows and adapts to changing hemodynamic conditions, the chicken chorioallantoic membrane (CAM), and correlated vascular cast and tissue section morphology with in vivo time-lapse video monitoring. The bifurcation exponent ⌬ and associated parameters were quantitatively assessed in arterial and venous microvessels ranging in diameter from 30 to 100 m. We observed emergence of optimality by means of intussusception, i.e., formation of transvascular tissue pillars. In addition to intussusceptive microvascular growth (IMG ‫؍‬ expansion of capillary networks) and intussusceptive arborization (IAR ‫؍‬ formation of feeding vessels from capillaries) the observed intussusception at bifurcations represents a third variant of nonsprouting angiogenesis. We call it intussusceptive branching remodeling (IBR). IBR occurred in vessels of considerable diameter by means of two alternative mechanisms: either through pillars arising close to a bifurcation, which increased in girth until they merged with the connective tissue in the bifurcation angle; or through pillars arising at some distance from the bifurcation point, which then expanded by formation of ingrowing tissue folds until they became connected to the tissue of the bifurcation angle. Morphologic evidence suggests that IBR is a wide-spread phenomenon, taking place also in lung, intestinal, kidney, eye, etc., vasculature. Irrespective of the mode followed, IBR led to a branching pattern close to the predicted optimum, ⌬ ‫؍‬ 3.0. Significant differences were observed between ⌬ at arterial bifurcations (2.70 to 2.90) and ⌬ at venous bifurcations (2.93 to 3.75). IBR, by means of eccentric pillar formation and fusion, was also involved in vascular pruning. Experimental changes in CAM hemodynamics (by locally increasing blood flow) induced onset of IBR within less than 1 hr. Our study provides morphologic and quantitative evidence that a similar cellular machinery is used for all three variants of vascular intussusception, IMG, IAR, and IBR. It thus provides a mechanism of efficiently generating complex blood transport systems from limited genetic information. Differential quantitative outcome of IBR in arteries and veins, and the experimental induction of IBR strongly suggest that hemodynamic factors can instruct embryonic vascular remodeling toward optimality.

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In Utero Placement of Aortopulmonary Shunts

Cited by 137 publications

References 24 publications

Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism

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