Medial Hypertrophy Of Pulmonary Arteries Research Articles

Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts.

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units × m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p = 0.045), particularly in the high-PVR group (n = 16) (p = 0.022) and in subjects with the AC CPSI T1405N genotype (n = 16) compared to those with the CC genotype (n = 25) (p = 0.017). Patients with high-PVR/AC-genotype profile (n = 9) had the highest MIF levels (p = 0.030 compared with the high-PBF/CC-genotype subgroup, n = 18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p = 0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.

Metabonomics Profiling Reveals Biochemical Pathways Associated with Pulmonary Arterial Hypertension in Broiler Chickens.

Pulmonary arterial hypertension (PAH) is the major cause of death in fast growing meat-type chickens (broiler chickens). At present, the underlying mechanisms that give rise to PAH are not fully understood. To identify the metabonomics profiles characterizing the process, we conducted a comprehensive gas chromatography-mass spectrometry (GC-MS)-based metabolic profiling of lung tissues from PAH broilers and age-matched controls. PAH was induced by excess salt in drinking water. Medial hypertrophy of pulmonary arteries was present in PAH birds as compared with controls. The metabonomics profiles of lung tissues well distinguished PAH broilers from control subjects. Significant changes in the levels of 41 metabolites were detected in PAH vs normal birds. Aside from the metabolic alterations indicating a status of oxidative stress and inflammation, evidence of reduced cellular uptake of arginine due to increased lysine biosynthesis and of a shift of arginine metabolism to arginase pathway were observed. In addition, PAH birds showed increased biosynthesis of fatty acids, which may be associated with excessive proliferation of vascular cells during pulmonary vascular remodeling. Furthermore, we observed significant changes in pentose phosphate pathway and increased aminomalonic acid in PAH broilers. These results provide additional biochemical insights into the pathogenesis of the PAH. Our data may lead to the development of new strategies to control PAH in broilers.

Repair of Borderline Operable Atrial Septal Defect with Severe Pulmonary Hypertension–after Medical Management

Large left to right shunt across an atrial septal defect results in volume overload and dilatation of the right atrium and ventricle. As a result of increased flow into the lungs, the pulmonary arteries, capillaries & the veins are dilated & there can be flow related pulmonary artery hypertension. Overtime this can lead to medial hypertrophy of pulmonary arteries & muscularization of arterioles resulting in pulmonary vascular obstructive disease. Once PAH develops, it is challenging to determine operability and predict outcomes after repair in borderline situations. We report a woman with large atrial septal defect and severe pulmonary hypertension 9.84 wood units /m2 of indexed total pulmonary vascular resistance. She underwent successful corrective repair of atrial septal defect after 4 months of medical management. This case supports that careful evaluation of reversibility of borderline pulmonary arterial hypertension associated with atrial septal defect and pre operative medical management with advanced pulmonary vasodilator therapy can modify a life to normal following closure of ASD. DOI: http://dx.doi.org/10.3329/pulse.v6i1-2.20349 Pulse Vol.6 January-December 2013 p.44-47

ClC‐3 chloride channel is upregulated by hypertrophy and inflammation in rat and canine pulmonary artery

Cl- channels have been implicated in essential cellular functions including volume regulation, progression of cell cycle, cell proliferation and contraction, but the physiological functions of the ClC-3 channel are controversial. We tested the hypothesis that the ClC-3 gene (ClCn-3) is upregulated in hypertensive pulmonary arteries of monocrotaline-treated rats, and upregulated ClC-3 channel aids viability of pulmonary artery smooth muscle cells (PASMCs). Experimental pulmonary hypertension was induced in rats by a single subcutaneous administration of monocrotaline (60 mg kg(-1)). Injected animals developed characteristic features of pulmonary hypertension including medial hypertrophy of pulmonary arteries and right ventricular hypertrophy. Reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and Western immunoblot analysis indicated that histopathological alterations were associated with upregulation of the ClC-3 mRNA and protein expression in both smooth muscle cells of hypertensive pulmonary arteries and in cardiac myocytes. RT-PCR analysis of mRNA, extracted from canine cultured PASMCs, indicated that incubation with the inflammatory mediators endothelin-1 (ET-1), platelet-derived growth factor (PDGF), interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF alpha), but not transforming growth factor beta (TGFbeta), upregulated ClC-3 mRNA. Adenovirus-mediated delivery and overexpression of ClC-3 in canine PASMCs improved cell viability against increasing concentrations of hydrogen peroxide (H2O2, range 50-250 microM). In conclusion, upregulation of ClC-3 in rat hypertensive lung and heart is a novel observation. Our functional data suggest that upregulation of ClC-3 is an adaptive response of inflamed pulmonary artery, which enhances the viability of PASMCs against reactive oxygen species.

Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats

Hepatocyte growth factor (HGF) is a multi-potent growth factor, which has anti-fibrotic effects for lung injuries. In this study, we investigated whether human HGF gene transfer may attenuate the medial hypertrophy of pulmonary arteries and enhance the ameliorating effect of prostacyclin in monocrotaline (MCT)-induced pulmonary hypertension in rats. The day before MCT injection, HVJ-liposome complex with the cDNA encoding HGF gene (H group), PGIS gene (P group), and both HGF and PGIS gene (HP group) were transfected to the liver of rats as drug delivery system for the lung. Rats transfected with control vector served as controls (C group). Twenty-eight days after MCT injection, histological examination showed marked thickening of medial wall of pulmonary arteries and right ventricular hypertrophy. Percent medial wall thickness (%WT) of peripheral pulmonary arteries, pressure ratio of the right ventricle (RV) to the left ventricle (LV), and weight ratio of the RV to the LV plus septum were significantly increased in the control. Percent medial wall thickness was significantly ameliorated in H group and HP group in comparison with C group. Pressure and weight ratio of RV to LV was significantly ameliorated in P group and HP group in comparison with C group, and was significantly ameliorated in HP group than P group. In vivo gene transfection with HGF gene attenuated the medial hypertrophy of pulmonary arteries and enhanced the ameliorating effect of prostacyclin for pulmonary hypertension in MCT rats. Thus, gene therapy with HGF and PGIS may be a promising strategy for severe pulmonary hypertension.

Inhaled nitric oxide versus prostacyclin in chronic shunt-induced pulmonary hypertension

Objective Cardiac surgery for congenital heart defects is commonly complicated by shunt-induced chronic pulmonary hypertension and associated acute hypertensive crises. To investigate the effects of vasodilators in chronic and acute pulmonary hypertension, we used the innominate artery to create a growing aortopulmonary shunt in young piglets. Methods Pulmonary hemodynamics and right ventricular function and their responses to hypoxia, intravenous prostacyclin, and inhaled nitric oxide were investigated after closure of the shunt by using pulmonary flow-pressure relationships, pulmonary vascular resistance partitioning, pulmonary vascular impedance, and ventriculoarterial coupling expressed as the ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance. Results Shunt-induced pulmonary hypertension was associated with medial hypertrophy of pulmonary arteries, increased resistance, increased elastance, increased wave reflection, and preserved ventriculoarterial coupling. Hypoxic pulmonary vasoconstriction was blunted in the shunt group. Compared with prostacyclin, inhaled nitric oxide was a more effective vasodilator in the shunt group and in hypoxia. Effective pulmonary arterial elastance and right ventricular end-systolic elastance increased in chronic (shunt) and acute (hypoxic) hypertension and decreased with vasodilators, preserving a normal coupling. Conclusions A growing aortopulmonary shunt in the young pig is a reliable model of chronic pulmonary hypertension, with medial hypertrophy, increased resistance, and increased elastance. In this model inhaled nitric oxide is a better pulmonary vasodilator than intravenous prostacyclin, with neither drug having a specific inotropic effect, and normal coupling is preserved in chronic and acute pulmonary hypertension.

An Improved Mathematical Approach for the Assessment of the Medial Thickness of Pulmonary Arteries

Medial hypertrophy of pulmonary arteries is caused by different acute and chronic diseases complicated by pulmonary hypertension and malformations of the lung. Thus the precise assessment of external radius and relative medial thickness are of importance for clinical and experimental pathology. Different concepts have been proposed to solve this problem. Wall thickness methods which can be applied to obliquely cut arteries suffer from the disadvantage that they require prior injection of vessels. Planimetric methods can be applied to not injected vessels but they fail in assessing the medial thickness of obliquely cut arteries. We describe a mathematical approach which renders even obliquely cut and simultaneously not injected pulmonary arteries able to be assessed accurately for medial thickness and external vessel radius. This method combines the advantages of wall thickness and planimetric methods. This new method and the established wall thickness and planimetric methods were applied to 178 rat pulmonary arteries and 412 injected and 401 not injected human pulmonary arteries. The statistical analysis revealed a satisfying reproducibility (Coefficient of correlation: 0.70-0.90) of the new method. The data assessed by the new method are similar to those of the established methods. We conclude our new method to be a significant tool for the assessment of vessel parameters even in small specimens including only few not injected vessels.

Open lung biopsies in congenital heart disease for evaluation of pulmonary vascular disease. Predictive value with regard to corrective operability.

For evaluation of pulmonary vascular disease 140 open lung biopsies were performed in 137 patients with congenital heart disease in order to decide whether the state of the lung vessels would allow corrective surgery. As far as possible follow-up was obtained in patients who underwent a cardiac repair. From the study of these biopsy specimens it appeared that medial hypertrophy of pulmonary arteries and changes in pulmonary veins should not be considered an impediment for a corrective operation as long as more advanced changes are absent. The same is true for intimal thickening due to longitudinal smooth muscle, post-thrombotic changes or cellular proliferation. Concentric-laminar intimal fibrosis forms no contra-indication as long as it is mild but, if severe, it is likely that hypertensive pulmonary vascular disease will progress in spite of cardiac repair. In the presence of fibrinoid necrosis or plexiform lesions correction of a cardiac anomaly should not be attempted. The presence of dilatation lesions is more disputable but probably, as long as they are scarce and not accompanied by fibrinoid necrosis or plexiform lesions, corrective surgery may be attempted. This becomes very dubious when they are more numerous.

Effect of fulvine on pulmonary arteries and veins of the rat.

Wagenvoort, C. A., Wagenvoort, N., and Dijk, H. J. (1974).Thorax, 29, 522-529. Effect of fulvine on pulmonary arteries and veins of the rat. Fulvine, one of the pyrrolizidine alkaloids from the Crotalaria group, was administered to rats in a single dose. Vasoconstriction and medial hypertrophy of pulmonary arteries and right ventricular hypertrophy developed gradually, starting after one week. Smooth muscle fibres developed in the arterial adventitia. Fibrinoid necrosis and arteritis of these arteries were common. In addition, however, changes were observed in pulmonary veins and venules which showed thickening of their walls by constriction, proliferation of muscle fibres, and increase of collagen, leading to luminal occlusion. Apparently fulvine is angiotoxic not only for pulmonary arteries but also for pulmonary veins. This detracts from the usefulness of fulvine in the experimental production of pulmonary arterial hypertension.