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J Thorac Cardiovasc Surg 2000;120:55-65
© 2000 The American Association for Thoracic Surgery

SURGERY FOR CONGENITAL HEART DISEASE

Remodeling of the porcine pulmonary autograft wall in the aortic position

From the Departments of Cardiothoracic Surgery,^a Anatomy,^b and Pathology,^c Leiden University Medical Center, The Netherlands.

Address for reprints: P. H. Schoof, MD, Department of Cardiothoracic Surgery, D6-50, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands (E-mail: PSchoof{at}thorax.AZL.NL ).

	Abstract

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Objective: Dilatation and valve regurgitation are disturbing sequelae of the pulmonary root functioning at systemic pressures. We tried to characterize the histologic mode of adaptation of the neoaortic wall.
Methods: We compared routine histologic studies, immunohistochemical staining, and computer-assisted morphometric analysis of aortic, pulmonary autograft, and native pulmonary wall specimens from pigs in which, as a newborn, a valveless pulmonary autograft had been implanted in the aorta.
Results: Histologic examination of the pulmonary autograft revealed a viable, normally revascularized wall without degenerative phenomena. Smooth muscle cells were enlarged and rearranged. The characteristic "pulmonary" medial elastin lamellar structure was retained, which was confirmed by morphometry. Immunohistochemistry of the autograft revealed relatively strong staining of type III collagen and alpha smooth muscle actin, exclusive staining of basic fibroblast growth factor, and no staining of proliferation markers proliferating cell nuclear antigen and Ki67.
Conclusion: The developing pulmonary autograft in the aortic position becomes normally revascularized, lacks major degenerative phenomena, and retains its own typical pulmonary morphologic features. Remodeling is accomplished by increased extracellular matrix deposition with collagen as an important constituent. The marked expression of growth factors in the autograft suggests the persistence of increased metabolic activity.

	Introduction

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Dilatation of the pulmonary autograft after the Ross operation in adults has become a matter of serious concern. ^1,2 Disproportionate enlargement of the neoaortic root has been documented in children after the Ross operation ³ and after the arterial switch operation and has been related to neoaortic valve regurgitation. ⁴ Additionally, pulmonary valve regurgitation is commonly found in the pulmonary root at systemic pressures after the Norwood and Damus-Kaye-Stansel operations. ^5,6

These observations have excited the interest about how histologic adaptation of the pulmonary root to systemic pressures is accomplished. Clarification of this issue may help to understand late neoaortic valve failures. This was the aim of our study. We focused on the pulmonary arterial wall, assuming that pulmonary (neoaortic) root dilatation is a major determinant of neoaortic valve regurgitation. For this purpose, we characterized the adaptive histologic responses in vascular wall explants of mature pigs in which, as newborns, a valveless pulmonary autograft had been implanted in the aorta.

	Methods

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Animal model
Five Dutch Landrace piglets (age, 2-3 weeks; weight range, 9.3 ± 0.7 kg) underwent the operation. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" as published by the National Academy Press, 1996. The study protocol was approved by the Animal Experimentation Committee of the Leiden University.

Surgery
The operation has been detailed previously. ⁷ The (valveless) pulmonary artery main stem was excised and transplanted to the transected ascending aorta. Before reconstruction, transverse segments of approximately 5-mm height of both pulmonary and aortic wall were excised and fixed in paraformaldehyde (3.6%) at room temperature. Pulmonary artery continuity was reestablished by end-to-end anastomosis.

The animals were allowed to thrive until maturity and were killed 10 months after the operation. At autopsy, transverse segments of the proximal great vessels that contained the pulmonary autograft–to–aorta transition area and the remaining native pulmonary artery, distal from the anastomosis, were harvested.

Tissue preparation
Operative specimens were fixed in paraformaldehyde, embedded in paraffin, and stained with hematoxylin-eosin and elastin–van Gieson stains. Autopsy specimens of pulmonary autograft–to–aorta transition area and native pulmonary artery were divided into 2 segments. One part was frozen for immunohistochemical studies, and the other part was fixed in paraformaldehyde for hematoxylin-eosin and van Gieson stains. Sections were made longitudinally to allow the assessment of the pulmonary autograft–to–aorta anastomotic area.

Light microscopy
Hematoxylin-eosin and elastin–van Gieson stains were applied to paraffin sections for routine histologic assessment.

Immunohistochemistry
Frozen tissue sections (4 µm) were fixed with acetone and incubated for 1 hour with goat–anti-type I, III, IV, and VI collagen (Harlan Sera-lab, Sussex, England), goat–anti-fibronectin and mouse–anti-alpha-smooth muscle actin (Sigma, St Louis, Mo), rabbit–anti-EHS laminin (E-Y Labs, San Mateo, Calif), rabbit–anti-factor VIII and mouse–anti–proliferating cell nuclear antigen (PCNA; DAKO, Copenhagen, Denmark), mouse–anti–basic fibroblast growth factor (bFGF; Upstate Biotechnology, Lake Placid, NY), mouse–anti-Ki67 (Immunotech, Marseille, France), and rabbit–anti-transforming growth factor-ß₁ (TGF-ß₁). Secondary incubation was performed with the horseradish peroxidase–conjugated antibodies: rabbit–anti-mouse immunoglobulin, rabbit–anti-goat immunoglobulin, or swine–anti-rabbit immunoglobulin (DAKO). Diaminobenzidine-developed slides were counterstained with hematoxylin. Light microscopic findings were semiquantitatively scored by 2 investigators.

Morphometry
Medial elastin density, fiber number, and mean size of the nonfiber area were determined by computer-assisted image analysis on a Zeissvision KS400 system (Zeiss, Göttingen, Germany). A software program was developed by us to select elastin fibers by color, intensity, and saturation of the signal. Elastin density was measured as a percentage of the total field area. Fiber numbers were counted after they were digitally skeletonized, and mean nonfiber area was determined as the mean area of gaps between elastin fibers in van Gieson–stained sections by random selection of 5 circular fields within the media of each vessel wall specimen.

Statistics
The average elastin density, fiber count, and mean nonfiber area were compared between aorta, pulmonary autograft, and native pulmonary wall specimens with analysis of variance. Analysis was performed with SPSS version 9 (SPSS, Inc, Chicago, Ill).

	Results

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All animals were healthy and had attained a 19.4-fold mean increase of body weight (mean ± SD, 179.2 ± 10.4 kg; range, 161 to 186 kg) when put to death.

Gross inspection
Growth of the pulmonary autograft paralleled the anatomic development of the animal. ⁷ The diameter of the vessel lumen was slightly larger than that of the aorta in 3 of 5 specimens. There was no anastomotic narrowing; the luminal aspect of the autograft wall looked healthy, and the wall felt thinner and more pliable than the aortic wall. On transverse sections, the autograft exhibited less wall thickness than the aorta (Fig 1).

View larger version (28K): [in this window] [in a new window]   Fig. 1. Transverse sections of mature wall of native aorta (left) and pulmonary autograft (right). Note the relatively thin wall and large diameter of the autograft.

The medial elastin lamellar structure of the autograft resembled that of the native pulmonary artery, although elastin lamellae of the autograft appeared to be arranged in a more orderly fashion. Additionally, smooth muscle cells in the autograft media were oriented more longitudinally.

Contrary to the autograft media, the aortic media was thicker with more numerous elastin lamellae well-organized in concentric layers (Fig 2).

View larger version (127K): [in this window] [in a new window]   Fig. 2. Longitudinal microscopic section of pulmonary autograft to aorta transition area (top). (Elastin–van Gieson stain; original magnification, x5). Scar tissue is covered by neointima. The aortic media (bottom right) is thicker and shows more numerous and organized elastin layers on detail (original magnification, x100) than does the pulmonary autograft (bottom left; original magnification, x100.)

The adventitia of the autograft showed the presence of normal vasa vasorum and appeared to stain more densely in hematoxylin-eosin sections than in native pulmonary artery.

The anastomotic scar between the autograft and aorta showed large numbers of vasa vasorum and was virtually devoid of elastin.

Immunohistochemistry
The results of staining scores are summarized in Table I. Among the tested collagen antibodies, the expression of collagen I was slightly more in the autograft than in the aorta but was not different from that of native pulmonary artery. Collagen III, which was strongly expressed in the anastomotic scar, also showed a relatively strong expression in the autograft. In the media, expression was confined to interlamellar spaces, whereas in the adventitia the staining was more diffuse (Fig 3). The expression of other collagen types (IV and VI) was generally restricted to endothelial cells of the vascular luminal side and vasa vasorum of the various wall specimens. Laminin was faintly stained between medial smooth muscle cells and in scar tissue and more pronounced in basal lamina. Fibronectin was strongly expressed in the anastomotic scar and moderately expressed in both media and adventitia of all specimens. Factor VIII exclusively stained vasa vasorum within the vascular wall. Without background staining, the number and distribution of vasa vasorum in the autograft were shown to be similar to those in the native pulmonary artery (Fig 3). Alpha smooth muscle actin expression seemed particularly strong in the autograft and apparently related to medial smooth muscle cells with large nuclei. It was absent in the anastomotic scar. The pattern of expression was generally coarse in the autograft and native pulmonary artery, whereas in the aorta it had a much finer structure (Fig 4). Compared with the native pulmonary artery, the autograft exhibited more numerous large smooth muscle cells with large nuclei that were frequently arranged in longitudinal fashion, which indicated a change of phenotype. Fibronectin was particularly strongly expressed in the anastomotic scar tissue and equally moderate in the media and adventitia of all specimens. TGF-ß, although faintly expressed in the inner one third of the native pulmonary and aortic media, was more strongly expressed throughout the media of the autograft, with focal condensations at the adventitial-medial interface. A patchy staining pattern was found in the scar. bFGF was exclusively expressed in the autograft and was confined to smooth muscle cells between the elastic lamellae (Fig 3). A patchy staining pattern was present in the anastomotic scar.

View larger version (97K): [in this window] [in a new window]   Fig. 3. Micrographs of pulmonary autograft show immunohistochemical localization of collagen III (top): high density, particularly in the adventitia. bFGF (center three panels): large nuclei of autograft smooth muscle cells. Middle (original magnification, x100) and left panels (original magnification, x200) exhibit a peripheral dark shade that is absent in the native pulmonary artery (right; original magnification, x100). Factor VIII (bottom): vasa vasorum in autograft adventitia and outer media.

View larger version (144K): [in this window] [in a new window]   Fig. 4. Micrographs of pulmonary autograft (top) and native aortic media (bottom) show immunohistochemical localization of -smooth muscle actin (original magnification, x100); a coarse pattern of expression particularly related to large nuclei in the autograft compared with the native aorta.

Morphometry
Medial elastin density in the aortic wall of newborn pigs did not differ from the pulmonary wall (P = .25). By 10 months of age, in the adult pig, a significant difference in elastin density had evolved between the native aortic and pulmonary walls (P = .007) and the autograft wall (P = .018), whereas no difference could be demonstrated between the native pulmonary artery and the autograft (P = .63; Fig 5).

View larger version (13K): [in this window] [in a new window]   Fig. 5. Results of morphometric analysis of elastin density in the aortic wall (a ) and native pulmonary artery (b ). At operation (T 0), no difference between aortic and pulmonary density (a vs b ; P = .25). At autopsy (T 1), there was a significant difference between native aortic and pulmonary wall (* a' vs b'; P = .007) and native aortic wall and autograft (**a' vs c; P = .018), whereas no difference was observed between the native pulmonary artery and the autograft (b' vs c; P = .63).

View larger version (13K): [in this window] [in a new window]   Fig. 6. Results of morphometric analysis of the number of elastin fiber fragments. The mean number was not different in wall segments of newborns (a vs b; P = .31), whereas at autopsy it was significantly less in the aorta than in the pulmonary artery (*a' vs b'; P = .030) and in the aorta than in the autograft (**a' vs c; P = .012). No difference was observed between the autograft and the native pulmonary artery (b' vs c; P = .64).

View larger version (13K): [in this window] [in a new window]   Fig. 7. Results of morphometric analysis of the nonfiber area. The mean size of the nonfiber area was not different in wall segments of newborns (P = .23), whereas at autopsy it was significantly larger in the autograft (**a' vs c; P = .021) and in the native pulmonary artery (a' vs b'; P = .032) than in the aorta. No difference was found between the autograft and the native pulmonary artery (b' vs c; P = .81).

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Basic morphologic features
We were surprised to find that, by light microscopy in the autograft, the medial elastin lamellar pattern of the pulmonary wall had been preserved. Maintenance and development of an aortic type of medial pattern would have seemed more appropriate and in accordance with older literature ⁸; however, despite early transplantation and development at systemic pressures, the basic morphologic condition of the pulmonary autograft was still characteristically "pulmonary." We considered this to be an important finding and therefore extended our study by performing morphometric measurements to see whether these light microscopic findings could be substantiated. These results confirmed our impression. The characteristic medial pattern of the pulmonary wall is apparently not altered by transplantation to the aortic position and may be genetically predetermined, which would be in accordance with experimental data on the developmental accumulation of vascular elastin, which suggests that factors other than blood pressure contribute to determine vascular morphologic features. ^9,10 Genetic information on dimensional position of the vessel within the body and embryologic origin of vessel wall smooth muscle cells seem to play a critical role in this process. ^11,12

Consequentially, the normal quantitative relationship that exists between vascular structure and mechanical properties according to Wolinsky and Glagov ¹³ and Glagov and colleagues ¹⁴ would not be applicable in the pulmonary autograft in the aortic position because the number of elastin lamellae is not in proportion to the pressure that is distending the wall. When the autograft does not acquire the architecture of the aortic wall, normal systemic blood pressures could be considered an unphysiologic mechanical load for the pulmonary autograft. Adaptation of the pulmonary wall to systemic hemodynamics is apparently accomplished in a different way.

Remodeling
A vascular wall adapts to excessive mechanical stress by the reorganization of wall constituents to maintain wall integrity and restore baseline conditions of wall stress. ¹⁵ The mode of this remodeling is well known in systemic arteries, pulmonary arteries, and veins at hypertension and is primarily characterized by an increased matrix deposition that results in a thicker wall. ^15-17 The features of remodeling that we observed in the pulmonary autograft were similar. However, macroscopically, adaptation did not result in a wall thickness that matched the thickness of the aortic wall. This is not in accordance with the principle that vascular walls, subject to hypertension, thicken until normal wall stress is reestablished (radius/thickness ratio conservation). ¹⁸ Additionally, the autograft had acquired a relatively large circumference in 3 of 5 specimens, which suggested dilatation (Fig 1).

At microscopic examination, the autograft was found to be viable and revascularized without degenerative phenomena in the wall segment. Autocrine growth factors TGF-ß and bFGF, which are normally not or only faintly expressed in mature quiescent arterial wall, ¹⁹ were found to be expressed in the pulmonary autograft wall, which indicated growth activity. As potent stimulators of smooth muscle cell growth and differentiation, ^19,20 both these factors are probably responsible for the observed change in muscle cell phenotype and increased alpha smooth muscle actin immunoreactivity of the autograft. The observed enlargement and rearrangement may indicate an acquired synthetic phenotype of smooth muscle cells that are stimulated to produce extracellular matrix proteins, such as collagen and elastin. Because collagen III reactivity seemed to be strongest in the autograft, this may be an important matrix constituent that is involved in pulmonary autograft remodeling. It seems logical because collagen has the highest tensile force of vascular matrix components and therefore seems to be an obvious constituent for fortification of the vessel wall against the mechanical injury of excessive tensile stress.

Although growth factors were determined in the autograft, cell division could not be detected in any of the mature vessel wall specimens with the use of the proliferation markers PCNA and Ki67. Maybe we missed the cellular replication spurt in the autograft if it was confined to the early postoperative period, as in venous grafts in the systemic circulation ¹⁸ and should the presence of growth factors be explained by an increased metabolic demand. This may be caused by increased matrix turnover in the autograft wall and interpreted as an ongoing activity to re-establish wall stress homeostasis.

Dilatation
Our findings do not clarify the propensity of the pulmonary root to dilate at systemic pressures. Nevertheless, dilatation of the unsupported pulmonary autograft seems conceivable when the low elastic modulus of the adult pulmonary wall is considered (one fifth of that of the aortic wall) ²¹ and when the much higher tensile stress of systemic blood pressure is exerted on the neoaortic wall (8- to 10-fold, according to the LaPlace law). Furthermore, the tendency to dilate was shown both clinically after pulmonary artery banding and in in vitro experiments in porcine pulmonary roots. ^22-24

Our findings suggest that dilatation is not compensated for by a significant increase in wall thickness, although it would be expected considering the principle of r/t ratio conservation. ¹⁸ Instead, it seems that collagen is deposited to bear the increased mechanical load. Fortifying the wall in this way will probably also make it stiffen. This occurs in a wall that is already stiffer than the normal pulmonary artery wall because of excessive stretch as the result of systemic blood pressures. ²⁵ Theoretically, therefore, systemic pressures may cause loss of distensibility and cause the pulmonary root to become a frozen root. The functional implications of this stiffening, ²⁶ in addition to changes in root geometry because of dilatation, may both contribute to early and late neoaortic valve regurgitation.

Pathologic features
The most important question remains: What will be the long-term consequences of these findings? Should pulmonary wall remodeling be considered as a benign form of scar formation, which, like a dermal scar, will not fail and maintain life-long integrity or should it be viewed as a potential initiation of degenerative vascular disease with a possibility of secondary structural wall failure, as in hypertensive native pulmonary vascular disease? ²⁷ Long-term function of the neoaortic root, however, is probably not determined by wall integrity but rather by the secondary effects of altered dynamic properties and geometry of the neoaortic root on neoaortic valve function.

Study limitations
Our findings are based on an animal study. Therefore, the results may not accurately simulate the human process of pulmonary wall remodeling.

Light microscopic findings were derived from longitudinal tissue sections, whereas routine vascular wall sections are usually performed in transverse direction.

The results of the immunohistochemical study were semiquantitatively scored. Quantitative assessment of changes of the various matrix components should be performed to verify our findings.

The documented remodeling response is derived from a pulmonary autograft that was transplanted as a free graft very early in life. The results therefore may not represent the response that may occur later in life nor the remodeling that may occur in the orthotopic pulmonary root at systemic pressures. Furthermore, the study focuses on supracommissural wall specimens. Therefore, the observed changes may not represent the changes that occur below, in the sinus walls.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
The developing pulmonary autograft in the aortic position becomes normally revascularized, lacks major degenerative phenomena, and retains its own typical pulmonary morphologic features. Remodeling is accomplished by the increased deposition of extracellular matrix constituents, with collagen being an important component. The marked expression of growth factors in the autograft suggests the persistence of increased metabolic activity.

	Acknowledgments

 
We thank the animal laboratory technicians for their skilled assistance during the study, Hans Baelde for assistance on tissue specimen processing, Jan Schutrups for the morphometry, Klaas van der Ham for the photography, Evelien van Westerop and Piet van Sighem for the secretarial work, and Koos Zwinderman for the statistics.

	References

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