同种带瓣心外管道的临床应用

目的 探讨同种带瓣主动脉和肺动脉心管道治疗复杂先天性心脏病的临床效果。方法 应用深低温保存同种带瓣主动脉或肺动脉心外管道重建右心室流出道治疗复杂先天性心脏病6例，其中，右心室双出口4例，法氏氏四联症1例，完全型大动脉位1例。应用同种带瓣主动脉4例，同种带带瓣动脉2例。结果 手术死亡1例，余5例术后同种管道吻合口通道，无压差、扭曲和受压，同种瓣膜活动良好。随访9个月－2．5年，效果良好。结论 同种带瓣主动脉和肺动脉心外管道具有生物活性和完整的瓣膜功能，是矫正复杂先天性心脏病的理想材料。     

Ultrastructural features of the distended pulmonary arteries of the normal rat.

Detailed study has been made of the structure of the normal pulmonary artery of rat by both light (1-micrometer sections) and electron microscopy. After tying the pulmonary veins at the hilum, the lungs were fixed by simultaneous injection of glutaraldehyde into the pulmonary trunk and trachea. Study of distended arteries allows precise measurement and assessment of normal lung structure. Four regions of the pulmonary artery can be identified by wall structure and are described here--muscular, partially muscular, non-muscular and the newly described thick-walled oblique muscular. Electron microscopid examination has demonstrated in the non-muscular regions of the partially muscular arteries, an "intermediate" cell and in the non-muscular arteries, a pericyte. The intermediate cell lies internal to the single elastic lamina but external to the endothelial cell, is surrounded by its own basement membrane and contains filaments mainly along the adluminal region of the cell. The pericyte also lies internal to the single elastic lamina, is within the basement membrane of the adjacent endothelial cell and has previously been reported in the lung only in the walls of alveolar capillaries. The structure of the intermediate cell and its position suggest it is a transitional stage between the pericyte and smooth muscle cell.     

Ultrastructural features of the distended pulmonary arteries of the normal rat

Detailed study has been made of the structure of the normal pulmonary artery of rat by both light (1-μ sections) and electron microscopy. After tying the pulmonary veins at the hilum, the lungs were fixed by simultaneous injection of glutaraldehyde into the pulmonary trunk and trachea. Study of distended arteries allows precise measurement and assessment of normal lung structure. Four regions of the pulmonary artery can be identified by wall structure and are described here-muscular, partially muscular, non-muscular and the newly described thick-walled oblique muscular. Electron microscopic examination has demonstrated in the non-muscular regions of the partially muscular arteries, an “intermediate” cell and in the non-muscular arteries, a pericyte. The intermediate cell lies internal to the single elastic lamina but external to the endothelial cell, is surrounded by its own basement membrane and contains filaments mainly along the adluminal region of the cell. The pericyte also lies internal to the single elastic lamina, is within the basement membrane of the adjacent endothelial cell and has previously been reported in the lung only in the walls of alveolar capillaries. The structure of the intermediate cell and its position suggest it is a transitional stage between the pericyte and smooth muscle cell.     

Identification of host and donor cells in porcine homograft heart valve explants by fluorescence in situ hybridization

The pathogenesis of the primary tissue degeneration that limits the life-span of aortic and pulmonary homografts has still not been revealed. Histopathological studies on homograft explants have not given definitive insight into the eventual fate of donor cells, nor have they demonstrated the assumed importance of host cell ingrowth into the graft tissue. In this experimental study, fluorescence in situ hybridization (FISH) is introduced as a new approach to examine the distribution of host and donor cells in homograft explants. Aortic valve replacement was performed with a cryopreserved porcine aortic homograft in three pigs; donor and recipient were of opposite sex. After 4 months, the grafts were explanted and examined by FISH using a biotinylated porcine Y-chromosome-specific library probe. Following probe detection with FITC-conjugated avidin, a clear distinction could be made between cells of host and donor origin without distorting the histological integrity of the explants. There was ingrowth of donor cells into the graft aortic wall and into the valve leaflet, to some extent. In all explants, remaining donor cells were present, though decreased in number. The introduction of FISH in homograft heart valve research provides a powerful tool to study the fate of recipient and donor cellular elements in situ, and may therefore contribute to a better understanding of the histopathological processes that take place in transplanted homograft valves. © 1997 by John Wiley & Sons, Ltd.     

Remodelling of the pulmonary arteries during recovery from pulmonary hypertension induced by neonatal hypoxia

Little is understood of the mechanisms involved in reducing pulmonary arterial wall thickness on recovery from pulmonary hypertension and the present study sought to clarify the events that occur. Piglets were exposed to hypobaric hypoxia for 3 days, either from birth or from 3 days of age, and others were exposed for 11 days starting at 3 days. All recovered in room air for up to 6 days. Using light and electron microscopy, the pulmonary artery wall thickness, the relative contribution of smooth muscle and matrix, smooth muscle cell replication, and apoptosis were assessed after hypoxic exposure and during recovery from hypoxic exposure. In elastic arteries, after 6 days' recovery in room air, a reduction in wall thickness to normal was associated with a similar reduction in proportional area of smooth muscle cells and matrix (p < 0.05), increased apoptosis (p < 0.05), and an abnormally low replication rate (p < 0.05). In peripheral muscular arteries, an increase in external diameter, and wall thinning on recovery, was achieved by smooth muscle cell remodelling and a reduction in cell replication (p < 0.05). Apoptosis did not contribute. Thus, different mechanisms are involved in recovery from hypoxia-induced pulmonary hypertension in elastic and muscular pulmonary arteries. Recovery is slower in animals exposed from birth rather than from 3 days of age.     

A quantitative histomorphologic analysis of lymph node granulomas in sarcoidosis in relation to radiological stage I and II

A decrease in numbers of pulmonary arteries has been implicated in various forms of both human and experimental pulmonary hypertension. However, data in support of this hypothesis have not been conclusive. Especially, intravascular fixation under pressure and the size of the areas of lung tissue subjected to quantitation, may have influenced the results. In order to investigate these factors, we fixed lungs of ten normal rats in three different ways, i.e. by perfusion of the pulmonary vasculature, by immersing collapsed lungs and by instilling the fixative through the trachea with intact thoracic cavity. Subsequently, blood vessels were counted in histological sections. Our study illustrates that perfusion of vessels under pressure decreases the number of recognizable arteries. Also the small areas, used in previous studies for counting vessels, produce unreliable results. Our conclusion is that a decreased number of lung vessels as a factor in pulmonary resistance has not been conclusively demonstrated.     

Hypoxic induction of cox-2 regulates proliferation of human pulmonary artery smooth muscle cells

Chronic hypoxia-induced pulmonary hypertension results partly from proliferation of smooth muscle cells in small peripheral pulmonary arteries. Therefore, we examined the effect of hypoxia on growth of pulmonary artery smooth muscle cells (PASMCs) from human distal pulmonary arteries. Initial studies identified that serum-induced proliferation of explant-derived PASMCs was inhibited under hypoxic conditions (3-4 kPa in medium). However, selection of hypoxia-stimulated cells was achieved by culturing cells at low density under conditions of prolonged hypoxia (1-2 wk). In hypoxia-inhibited and -stimulated cells, Western blotting revealed hypoxic induction of cyclooxygenase (COX)-2, which was dependent on the activation of p38(MAPK), but not COX-1, inducible nitric oxide synthase (iNOS), or hemoxygenase-1 (HO-1). Hypoxic induction of COX-2 was also observed in the media of pulmonary arteries in lung organ culture. Hypoxia induced a 4- to 5-fold increase (P < 0.001) in prostaglandin (PG)E(2), PGD(2), PGF(2alpha), and 6-keto-PGF(1alpha) release from PASMCs. Hypoxic inhibition of proliferation was attenuated by incubation with indomethacin (10 micro M), or the COX-2 antagonist, NS398 (10 micro M), but not by the COX-1 antagonist, valeryl salicylate (0.5 mM). In conclusion, we have isolated cells from human peripheral pulmonary arteries that are either inhibited or stimulated by culture under hypoxic conditions. In both cell types hypoxia modulates cell proliferation by induction of COX-2 and production of antiproliferative prostaglandins. Induction of COX-2 may contribute to the inhibition of hypoxia-induced pulmonary vascular remodeling.     

Plexiform Lesions in the Lungs of Domestic Fowl Selected for Susceptibility to Pulmonary Arterial Hypertension: Incidence and Histology

Plexiform lesions develop in the pulmonary arteries of humans suffering from idiopathic pulmonary arterial hypertension (IPAH). Plexogenic arteriopathy rarely develops in existing animal models of IPAH. In this study, plexiform lesions developed in the lungs of rapidly growing meat‐type chickens (broiler chickens) that had been genetically selected for susceptibility to IPAH. Plexiform lesions developed spontaneously in: 42% of females and 40% of males; 35% of right lungs, and 45% of left lungs; and, at 8, 12, 16, 20, 24, and 52 weeks of age the plexiform lesion incidences averaged 52%, 50%, 51%, 40%, 36%, and 22%, respectively. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries exhibiting intimal proliferation. Perivascular mononuclear cell infiltrates consistently surrounded the affected arteries. Proliferating intimal cells fully or partially occluded the arterial lumen adjacent to plexiform lesions. Broilers reared in clean stainless steel cages exhibited a 50% lesion incidence that did not differ from the 64% incidence in flock mates grown on dusty floor litter. Microparticles (30 μm diameter) were injected to determine if physical occlusion and focal inflammation within distal pulmonary arteries might initiate plexiform lesion development. Three months postinjection no plexiform lesions were observed in the vicinity of persisting microparticles. Broiler chickens selected for innate susceptibility to IPAH represent a new animal model for investigating the mechanisms responsible for spontaneous plexogenic arteriopathy. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Crotalaria-induced pulmonary hypertension. Uptake of 3H-thymidine by the cells of the pulmonary circulation and alveolar walls.

Feeding with Crotalaria spectabilis seeds induces structural changes in the pulmonary arterial circulation characteristic of pulmonary hypertension: increased medial and adventitial thickness, the appearance of muscle in smaller arteries than normal, and reduction in the number of peripheral arteries. By autoradiographic techniques, after injection of 3H-thymidine into rats fed Crotalaria for 3, 7, 14, 21, 28, or 35 days, the contribution of hyperplasia to these changes has been assessed at two levels of the pulmonary artery--the hilum and the periphery. In the hilar pulmonary artery, a biphasic increase in labeling index (LI) is seen in each cell type. After 3 days of feeding, the medial smooth muscle cells show a slight but significant increase (1.5 times the control value), and, after 7 days, so do the adventitial fibroblasts (3 x) and the endothelial cells (EC) (2 x). After 14 days LI for all three cell types is again at control values, but after 21 days (wall thickness is no increased) each cell type shows at least a fivefold increase; by 35 days all are again near control levels. In the intra-acinar region, by 14 days, "newly" muscularized arteries are identified and increase in number and proportion up to 35 days; 3H-thymidine uptake is not evident in this cell type until 35 days have passed. The ECs of these arteries, however, show a striking increase in LI after 14 days as do those of the alveolar capillaries. The ECs of the intra-acinar veins show a biphasic response being increased after 7, 28, and 35 days. The present study has shown that Crotalaria ingestion induces hyperplasia and hypertrophy of pulmonary arterial cells at pre- and intra-acinar levels. The early increase in LI probably represents a response to the original cell injury, the later changes, a response to continuing damage or, in part, adaptation to the pulmonary hypertension now present.     

Mechanical environment,donor age,and presence of endothelium interact to modulate porcine artery viability ex vivo

Though ex vivo culture of arteries is a widely used model of native arteries and is closely aligned with efforts to generate tissue-engineered arteries, the effects of culture conditions on artery viability are poorly characterized. To investigate factors regulating long-term viability of cultured arteries, carotid arteries from neonatal and adolescent pigs were perfused for up to 27 days with steady laminar flow ranging from 2% to 200% of physiological flow rates. Arteries from neonatal animals (2 weeks old, 5 kg) were susceptible to spontaneous progressive endothelial denudation followed by deterioration of the vessel wall that spread from luminal to abluminal regions. Subphysiological levels of flow and pressure abrogated this deterioration. Arteries harvested from adolescent (6 months old, 100 kg) animals maintained viability and retained structure for at least 9 days as assessed by normal histology, presence of intact endothelium, normal mitochondrial activity, and low levels of cell death and proliferation, unless the vessels were subjected to superphysiological levels of flow or the endothelium was intentionally denuded. Adolescent arteries perfused at subphysiological, but not physiological, flow rates maintained viability and normal structure for at least 27 days. These data indicate that under the appropriate conditions, arteries may be cultured long term but careful attention to the viability is merited. © 2002 Biomedical Engineering Society. PAC2002: 8780Rb, 8719Tt, 8719Uv, 8768+z     

Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries.

Lobar pulmonary arteries from patients with unexplained pulmonary hypertension were obtained at the time of single-lung transplantation to determine the response of large elastic vessels to increased intraluminal pressure. Specifically, human pulmonary arteries were examined to determine if remodeling remained active at the time of surgery and whether remodeling was similar to previously reported remodeling observed in several animal models. Grossly, the hypertensive vessels appeared atherosclerotic. Histochemical stains revealed a thick, diffuse neointima in hypertensive vessels compared with normal vessels. Immunohistochemistry demonstrated elastin protein in the neointima and in situ hybridization studies demonstrated tropoelastin mRNA largely in the neointima. Similarly, immunohistochemistry and in situ hybridization detected cellular fibronectin, thrombospondin and type I collagen protein and mRNA within the thickened intima from hypertensive vessels. These studies provide evidence that hypertensive vessels in patients with severe chronic pulmonary hypertension are actively remodeling but that the pattern of remodeling is different from previously described animal models.     

深低温保存同种瓣移植后的免疫排斥反应及临床意见

深低温保存技术的出现使同种瓣更广泛地应用于各种心脏外科手术.深低温很大程度上保持了同种瓣的生物活性,这是它能够在体内保持耐久性的重要条件,但随之产生的特异性免疫排斥反应不容忽视.本文讨论了深低温技术对同种瓣抗原性的影响以及移植后的免疫排斥现象、发生机制及其意义.     

A comparative analysis of glycosaminoglycans from human umbilical arteries in normal subjects and in pathological conditions affecting pregnancy.

BACKGROUND: Vascular cells express different phenotypes in adult and fetal vessels, and the extracellular matrix they synthesize should reflect these differences. Alterations of vascular proteoglycan/glycosaminoglycan is verified in disorders such as hypertension and diabetes, and when occurring during pregnancy, they bring about structural changes to fetal vessels that often lead to impaired fetus growth. Yet there is little data about the extracellular matrix of an important human fetal vessel, the umbilical artery. EXPERIMENTAL DESIGN: This study involved the biochemical characterization of the extracellular matrix of normal umbilical arteries, umbilical arteries from complicated pregnancies (maternal hypertension and diabetes and intrauterine growth retardation syndrome), and, for purpose of comparison, normal adult arteries (aorta and iliac and pulmonary arteries). Although the collagen types I:III ratio was determined in some cases, emphasis was placed on analysis of glycosaminoglycans. RESULTS: Normal umbilical arteries differ from normal adult arteries in that they contain greater concentrations of hyaluronic acid and lesser concentrations of heparan sulfate and chondroitin 4- and 6-sulfate. The umbilical artery also differs from adult arteries in the disaccharide composition of its chondroitin and heparan sulfates and in the molecular weight of this latter glycosaminoglycan. The glycosaminoglycan distribution in umbilical arteries derived from complicated pregnancies is roughly similar to that of controls. However, total glycosaminoglycan and collagen were significantly reduced, and the collagen I:III ratio was increased in the umbilical arteries from hypertension-complicated pregnancies. CONCLUSIONS: The glycosaminoglycan composition of the normal umbilical artery, a fully differentiated tissue, differs in many aspects from that of normal adult arteries. Of the cases of complicated pregnancies studied, the extracellular matrix of umbilical arteries was altered only in maternal hypertension. The changes, notably a mild fibrosis, were not very pronounced and should not impair hemodynamic properties of the vessel.     

Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

BACKGROUND: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. METHODS: The localisation of VEGFs A-C and their receptors (VEGFRs 1-3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. RESULTS: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominantly localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. CONCLUSION: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A-C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.     

Effect of Norcantharidin on the Human Breast Cancer Bcap-37 Cells

Norcantharidin (NCTD), a chemically modified form of cantharidin, is a potential anticancer drug. In this study, the effects of NCTD on the cellular viability, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and DNA damage in the human breast cancer cell line Bcap-37 were investigated with confocal and fluorescence microscopy. The cell cycle was further analyzed using the CellQuest software of a Becton-Dickinson FACS flow cytometer. The results indicated that the cellular viability was decreased with the growing concentrations of NCTD and time exposure. Moreover, the fluorescence intensity of ROS was increased, whereas the MMP was decreased in Bcap-37 cells with the growing concentrations of NCTD. NCTD induced a dose-dependent DNA damage and reduced the G1 peak in Bcap-37 cells. The G2/M peak of Bcap-37 was also decreased by the higher concentration of NCTD.     

Pulmonary thrombotic arteriopathy in patients with sickle cell disease.

BACKGROUND: Shortened life expectancy due to pulmonary hypertension (PH) is seen in 5% to 10% of patients with sickle cell disease. The principal factors suspected of causing PH are pulmonary thromboemboli (PE) and in situ arterial thrombosis. OBJECTIVE: To investigate the possible role that PE or in situ arterial thrombosis play in the development of PH in sickle cell disease. METHODS: Autopsies of 12 patients with sickle cell disease were correlated with clinical data from medical records. RESULTS: Right ventricular hypertrophy was present in 9 of 12 patients. Six patients with right ventricular hypertrophy had thrombi in large elastic pulmonary arteries. All patients with elastic artery thrombi had fresh or organized thrombi in small muscular pulmonary arteries. Hypertensive small arterial changes were present in 5 of these 6 patients. Six patients showed no thrombi in elastic arteries. Among these 6 patients, 3 had right ventricular hypertrophy and recent and organized thrombi, as well as hypertensive changes in small arteries. One of these 3 patients demonstrated plexiform-like lesions and fibrinoid necrosis of small arteries. Three patients without right ventricular hypertrophy had pneumonia or pulmonary edema with no identifiable pulmonary artery pathology. CONCLUSIONS: Arterial thrombosis with PH and cor pulmonale was regarded as the cause of death among most of these patients. Elastic artery thrombi are pulmonary thromboemboli, but pulmonary thromboemboli are always associated with widespread thrombosis of small arteries. Widespread thrombosis of small arteries alone was associated with PH in some cases. This finding suggests that pulmonary thromboemboli may be a late complication of PH and cor pulmonale and that an in situ thrombotic arteriopathy underlies the development of PH in most patients with sickle cell disease.     

Preclinical evaluation of ice-free cryopreserved arteries: structural integrity and hemocompatibility

Objective: Arterial allografts are routinely employed for reconstruction of infected prosthetic grafts. Usually, banked cryopreserved arteries are used; however, existing conventional freezing cryopreservation techniques applied to arteries are expensive. In contrast, a new ice-free cryopreservation technique results in processing, storage and shipping methods that are technically simpler and potentially less costly. The objective of this study was to determine whether or not ice-free cryopreservation causes tissue changes that might preclude clinical use. Methods: Conventionally frozen cryopreserved porcine arteries were compared with ice-free cryopreserved arteries and untreated fresh controls using morphological (light, scanning electron and laser scanning microscopy), viability (alamarBlue assay) and hemocompatibility methods (blood cell adhesion, thrombin/antithrombin-III-complex, polymorphonuclear neutrophil-elastase, β-thromboglobulin and terminal complement complex SC5b-9). Results: No statistically significant structural or hemocompatibility differences between ice-free cryopreserved and frozen tissues were detectable. There were no quantitative differences observed for either autofluorescence (elastin) or second harmonic generation (collagen) measured by laser scanning microscopy. Cell viability in ice-free cryopreserved arteries was significantly reduced compared to fresh and frozen tissues (p < 0.05). Conclusions: The formation of ice in aortic artery preservation did not make a difference in histology, structure or thrombogenicity, but significantly increased viability compared with a preservation method that precludes ice formation. Reduced cell viability should not reduce in vivo performance. Therefore, ice-free cryopreservation is a potentially safe and cost-effective technique for the cryopreservation of blood vessel allografts.     

Arterial Wall Adaptation under Elevated Longitudinal Stretch in Organ Culture

Arteries in vivo are subjected to large longitudinal stretch which may change significantly due to vascular disease and surgery. However, little is known about the effect of longitudinal stretch on vascular function and wall remodeling, although the effects of tensile and shear stress from blood pressure and flow have been well documented. To study the effect of longitudinal stretch on vascular function and wall remodeling, porcine carotid arteries were longitudinally stretched 20% more than in vivo for 5 days while being maintained in an ex vivo organ culture system under conditions of pulsatile flow at physiologic pressure. Vessel viability was demonstrated by strong vasomotor responses to norepinephrine (NE, 10^-6M), carbachol (10^-6M), and sodium nitroprusside (10^-5M), as well as by dense staining for mitochondrial activity and a low occurrence of cell necrosis. Cell proliferation was examined by incorporation of bromodeoxyuridine (BrdU). Results showed that arteries maintain normal structure and viability after 5 days in organ culture. Both the stretched and control arteries demonstrated significant contractile responses. For example, both stretched and control arteries showed approximately 10% diameter contraction in response to NE. Stretched arteries contained 8% BrdU-positive cells compared to 5% in controls (p < 0.05). These results indicate that longitudinal stretch promotes cell proliferation in arteries while maintaining arterial function. © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8717Ee, 8719Uv     

Application of stereolithography for scaffold fabrication for tissue engineered heart valves

A crucial factor in tissue engineering of heart valves is the functional and physiologic scaffold design. In our current experiment, we describe a new fabrication technique for heart valve scaffolds, derived from x-ray computed tomography data linked to the rapid prototyping technique of stereolithography. To recreate the complex anatomic structure of a human pulmonary and aortic homograft, we have used stereolithographic models derived from x-ray computed tomography and specific software (CP, Aachen, Germany). These stereolithographic models were used to generate biocompatible and biodegradable heart valve scaffolds by a thermal processing technique. The scaffold forming polymer was a thermoplastic elastomer, a poly-4-hydroxybutyrate (P4HB) and a polyhydroxyoctanoate (PHOH) (Tepha, Inc., Cambridge, MA). We fabricated one human aortic root scaffold and one pulmonary heart valve scaffold. Analysis of the heart valve included functional testing in a pulsatile bioreactor under subphysiological and supraphysiological flow and pressure conditions. Using stereolithography, we were able to fabricate plastic models with accurate anatomy of a human valvular homograft. Moreover, we fabricated heart valve scaffolds with a physiologic valve design, which included the sinus of Valsalva, and that resembled our reconstructed aortic root and pulmonary valve. One advantage of P4HB and PHOH was the ability to mold a complete trileaflet heart valve scaffold from a stereolithographic model without the need for suturing. The heart valves were tested in a pulsatile bioreactor, and it was noted that the leaflets opened and closed synchronously under subphysiological and supraphysiological flow conditions. Our preliminary results suggest that the reproduction of complex anatomic structures by rapid prototyping techniques may be useful to fabricate custom made polymeric scaffolds for the tissue engineering of heart valves.     

Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats

Tyrosine kinase inhibitors are promising for the treatment of severe pulmonary hypertension. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases and attenuation of vascular remodeling. Their potential vasodilatory activities have not been explored. Vasorelaxant effects of the tyrosine kinase inhibitors imatinib, sorafenib, and nilotinib were examined in isolated pulmonary arterial rings from normal and pulmonary hypertensive rats. Phosphorylation of myosin light chain phosphatase and myosin light chain was assessed by Western blots. Acute hemodynamic effects of imatinib were tested in the pulmonary hypertensive rats. In normal pulmonary arteries, imatinib reversed serotonin- and U46619-induced contractions in a concentration-dependent and endothelium-independent manner. Sorafenib and nilotinib relaxed U46619-induced contraction. Imatinib inhibited activation of myosin phosphatase induced by U46619 in normal pulmonary arteries. All three tyrosine kinase inhibitors concentration-dependently and completely reversed the spontaneous contraction of hypertensive pulmonary arterial rings unmasked by inhibition of nitric oxide synthase. Acute intravenous administration of imatinib reduced high right ventricular systolic pressure in pulmonary hypertensive rats, with little effect on left ventricular systolic pressure and cardiac output. We conclude that tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their long-term beneficial effect against pulmonary hypertension. Vascular smooth muscle relaxation mediated via activation of myosin light chain phosphatase (Ca(2+) desensitization) appears to play a role in the imatinib-induced pulmonary vasodilation.