Pulmonary Vasculature In Patients Research Articles

Iron lung? New ideas about hypoxic pulmonary vasoconstriction

Iron lung? New ideas about hypoxic pulmonary vasoconstriction

Human Herpesvirus-8 Infection of Primary Pulmonary Microvascular Endothelial Cells

Human herpesvirus-8 (HHV-8) is the causative agent of Kaposi's sarcoma and is associated with the angioproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Evidence of HHV-8 infection within the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH) has been described. We hypothesize that HHV-8 infection of pulmonary microvascular endothelial cells results in an apoptotic-resistant phenotype characteristic of severe pulmonary arterial hypertension. Our objective was to investigate the ability of HHV-8 to infect human pulmonary microvascular endothelial cells in vitro and characterize the phenotypic effect of this infection. Human pulmonary microvascular endothelial cells were exposed to HHV-8 using two methods (direct virus and co-culture technique). The presence of lytic and latent infection was confirmed. Changes in endothelial cell gene and protein expression and effects on cellular apoptosis were measured. HHV-8 can both lytically and latently infect primary human pulmonary microvascular endothelial cells in vitro. HHV-8 infection results in significant changes in gene expression, including alterations of pathways important to cellular apoptosis. HHV-8 infection also alters expression of genes integral to the bone morphogenic protein pathway, including down-regulation of bone morphogenic protein-4. Other genes previously implicated in the development of PAH are affected by HHV-8 infection, and cells infected with HHV-8 are resistant to apoptosis.

Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension

Mutations in the bone morphogenetic protein type II receptor gene (BMPR2) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation contributes to the vascular remodeling observed in PAH, the role of BMPs in this process and the impact of BMPR2 mutation remains unclear. Studies involving normal human pulmonary artery smooth muscle cells (PASMCs) suggest site-specific responses to BMPs. Thus, BMP-4 inhibited proliferation of PASMCs isolated from proximal pulmonary arteries, but stimulated proliferation of PASMCs from peripheral arteries, and conferred protection from apoptosis. These differences were not caused by differential activation of BMP signaling pathways because exogenous BMP-4 led to phosphorylation of Smad1, p38(MAPK), and ERK1/2 in both cell types. However, the proproliferative effect of BMP-4 on peripheral PASMCs was found to be p38MAPK/ERK-dependent. Conversely, overexpression of dominant-negative Smad1 converted the response to BMP-4 in proximal PASMCs from inhibitory to proliferative. Furthermore, we confirmed that proximal PASMCs harboring kinase domain mutations in BMPR2 are deficient in Smad signaling and are unresponsive to the growth suppressive effect of BMP-4. Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1. We conclude that defective Smad signaling and unopposed p38(MAPK)/ERK signaling, as a consequence of mutation in BMPR2, underlie the abnormal vascular cell proliferation observed in familial PAH.

Correlation between pulmonary vascular change and hemodynamics in patients with complete atrioventricular septal defect.

The study of the pulmonary vasculature in Taiwanese with atrioventricular septal defect has not been reported previously. This study investigated the correlation between pulmonary vascular change and hemodynamics in these patients. Ten children with complete atrioventricular defect, 8 of whom had Down syndrome, underwent open lung biopsy. Their age ranged from 8 months to 6 years (mean, 2 years 7 months). Cardiac catheterization was performed and the systolic pressures of pulmonary and systemic arteries were measured immediately before cardiopulmonary bypass (CPB) and immediately after cardiac repair in 9 patients, and expressed as a ratio of pulmonary to systemic systolic pressure (Pp/Ps). Medial hypertrophy and intimal proliferation were prominent in 7 patients with pulmonary hypertension. The alveolar wall muscular arteries and percent arterial medial thickness increased significantly with increasing post-repair Pp/Ps, preoperative Pp/Ps, pulmonary arteriolar resistance index and pre-CPB Pp/Ps (p < 0.02). The arteries present per 100 alveoli were inversely correlated with the above mentioned hemodynamic parameters (p < 0.02). The results of qualitative and quantitative analyses of the pulmonary vasculature in patients with complete atrioventricular defect correlated well with pre-and postoperative pulmonary arterial pressure and can be used to predict the postoperative pulmonary arterial pressure.

Endothelial function following the Fontan operation

Outcomes for children with most forms of congenital heart disease continue to improve. Nonetheless, long-term morbidity—such as progressive ventricular dysfunction and congestive heart failure—for patients with single ventricular lesions remains high. 1 Gentles T.L. Gauvreau K. Mayer Jr, J.E. Fishberger S.B. Burnett J. Colan S.D. Newburger J.W. Wernovsky G. Fontan operation in five hundred consecutive patients factors influencing early and late outcome. J Thorac Cardiovasc Surg. 1997; 114: 376-391 Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar The factors that contribute to hemodynamic compromise are incompletely understood. Although abnormal mechanics of the single ventricle have been well documented, recent evidence suggests that there may be a complex interplay between the heart and the peripheral and pulmonary vasculature in patients after the Fontan operation. 2 Yang S.G. Rychik J. Mesenteric blood flow patterns a link to protein-losing enteropathy after the Fontan operation. Am J Cardiol. 2002; 90: 672-674 Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar , 3 Hiramatsu T. Imai Y. Takanashi Y. Seo K. Terada M. Aoki M. Nakazawa M. Time course of endothelin-1 and adrenomedullin after the Fontan procedure. Ann Thorac Surg. 1999; 68: 169-172 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar In adults with congestive heart failure, endothelial dysfunction is common. 4 Katz S.D. Biasucci L. Sabba C. Strom J.A. Jondeau G. Galvao M. Solomon S. Nikolic S.D. Forman R. LeJemtel T.H. Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol. 1992; 19: 918-925 Abstract Full Text PDF PubMed Scopus (372) Google Scholar Perturbations of the nitric oxide pathway are believed to play a critical role in endothelial dysfunction in these patients, and therapies directed at enhancing nitric oxide production have been proposed. 5 Kubo S.H. Rector T.S. Bank A.J. Williams R.E. Heifetz S.M. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991; 84: 1589-1596 Crossref PubMed Scopus (700) Google Scholar , 6 Drexler H. Kästner S. Strobel A. Studer R. Brodde O.E. Hasenfuss G. Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart. J Am Coll Cardiol. 1998; 32: 955-963 Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Several previous studies have suggested that the nitric oxide pathway is also abnormal in patients after the Fontan procedure. 3 Hiramatsu T. Imai Y. Takanashi Y. Seo K. Terada M. Aoki M. Nakazawa M. Time course of endothelin-1 and adrenomedullin after the Fontan procedure. Ann Thorac Surg. 1999; 68: 169-172 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar , 7 Gorenflo M. Zheng C. Werle E. Fiehn W. Ulmer H.E. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol. 2001; 37: 489-492 Crossref PubMed Scopus (134) Google Scholar These findings have particular importance because improving the endothelial response in Fontan patients has the potential to reduce of the risk of developing congestive heart failure. In the present study, we studied the endothelial function in a group of asymptomatic patients who underwent the Fontan operation. In addition, we examined factors that influence endothelial function, including abnormalities of the nitric oxide pathway.

Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management.

Pulmonary vascular resistance is frequently elevated in patients with chronic left ventricular failure as a result of dysregulation of vascular smooth muscle tone and structural remodeling. The former is reversible over a period of minutes to days by pharmacological vasodilators, whereas the latter is relatively fixed and may resolve only slowly, over months to years. These abnormalities are due, at least in part, to pulmonary vascular endothelial dysfunction that results in impaired nitric oxide availability and increased endothelin expression. In patients with chronic heart failure, the resulting pulmonary hypertension directly affects right ventricular function and may affect exercise capacity, morbidity, and mortality. New treatment strategies, which include the use of agents that increase nitric oxide availability or oppose the actions of endothelin, may improve the structure and function of the pulmonary vasculature in patients with chronic heart failure.

Median sternotomy single stage complete unifocalization for pulmonary atresia, major aorto-pulmonary collateral arteries and VSD-early experience.

It is a prospective study to assess the results of median sternotomy, single stage complete unifocalization and repair for ventricular septal defect (VSD), pulmonary atresia and major aorto pulmonary collateral arteries (MAPCAs). From June 97 to August 98, 20 patients were treated with single stage complete unifocalization and repair. Their ages ranged from 6 months to 11 years. Through median sternotomy, all MAPCAs were dissected and looped. On cardiopulmonary bypass, MAPCAs were anastomosed to native pulmonary arteries (PAs) or to MAPCAs. VSD was closed if possible and RV to PA continuity was established with a homograft conduit. If complete repair was not suitable, central shunt was done from ascending aorta to reconstructed PA with a polytetrafluroethylene graft. The patients were divided into three groups according to the arborization pattern in the lungs. Group 1 had well formed native PAs with MAPCAs, group 2 had hypoplastic PAs with MAPCAs and group 3 had only MAPCAs. Twenty patients had 21 procedures. All MAPCAs were unifocalized with tissue-to-tissue anastomosis for future growth, except one in whom polytetrafluroethylene tube graft was used to attain the confluence. In group 1, all seven patients had complete unifocalization and repair. In group 2, four patients had RV to PA conduit and two patients had central shunt. In group 3, three patients had complete repair, three patients had RV to PA conduit and one patient had central shunt. There were three deaths, two in group 2 and one in group 3. The first patient died due to a wrong decision to close the VSD, the second patient died due to missed large MAPCA in preoperative angio and the third patient was a 7-year-old boy who died with irreversible pulmonary vascular changes due to unprotected MAPCAs. To conclude, complete repair/RV-PA conduit/central shunt should be done according to the size of the total pulmonary vasculature in patients with group 1, 2 and 3 with protected PAs/MAPCAs and in hypoplastic or absent PAs with unprotected MAPCAs (less than 1 year) and protected MAPCAs. We are yet to determine the surgical procedure to be performed in hypoplastic/absent PAs with unprotected MAPCAs more than 1 year. It is very essential to delineate all the MAPCAs up to the level of the diaphragm preoperatively.

The spectrum of pulmonary input impedance in children with complete transposition after the arterial switch operation

AbstractWe evaluated the physical characteristics of the pulmonary trunk in 32 patients with complete transposition after the arterial switch operation, calculating the pulmonary input impedance. In 6 of the patients, the characteristic impedance was equal to, or less than, the value in patients with ventricular septal defect. In those patients with an intact ventricular septum, or those with a ventricular septal defect who had undergone the arterial switch operation or banding of the pulmonary trunk before 3 months age, the frequency of the first modulus minimum also agreed with the values obtained in patients with ventricular septal defect. The value was high, however, in patients with complete transposition with ventricular septal defect who had undergone an arterial switch operation or banding of the pulmonary trunk after 4 months of age. Our data suggest decreased distensibility of the proximal pulmonary trunk after the arterial switch operation, and mild changes in the pulmonary vasculature in patients with complete transposition with ventricular septal defect who had undergone either an arterial switch operation or banding of the pulmonary trunk after 4 months of age. Long-term follow-up is needed clarify whether or not these features affect right ventricular function by means of an increase in afterload.

Histological diagnosis of amniotic fluid embolism by monoclonal antibody TKH-2 that recognizes NeuAc α 2–6GaINAc epitope

This study evaluates whether immunohistochemical staining using antibody TRH-2 is presented as a sensitive method for the histological diagnosis of amniotic fluid embolism (AFE). TKH-2 is the sensitive antibody clearly directed to sialyl Tn, NeuAc α 2–6GaINAc and reacts with meconium- and amniotic fluid-derived mucin-type glycoprotein. Formalin-fixed, paraffin-embedded maternal lung tissue sections were obtained from four cases of patients showing AFE, and four women uninvolved with AFE served as control. Specimens were stained using the streptavidin-biotin-immunoperoxidase method. The results of immunostaining were compared with those of hematoxylin-eosin (H&E) or a conventional Alcian blue stain. Remarkable positive TKH-2 stainings were observed easily within the pulmonary vasculature in patients with AFE syndrome. AFE can be easily missed on H&E sections. Compared with TKH-2 staining, Alcian blue staining also may be insufficient to show intravascular mucin in the maternal lung sections. TKH-2 immunostaining is the sensitive method to detect meconium-and amniotic fluid-derived mucin in the lung sections of patients with AFE syndrome.

994-97 Quantitating Pulmonary Capillary Volume Using Digital Parametric Angiographic Analysis

Assessment of the distal pulmonary vasculature in patients with pulmonary hypertension has been limited to qualitative description of pulmonary arteriograms. Digital parametric imaging, using contrast density and transit time, has been used to qualitative blood volume and flow in the coronary and renal vascular beds. This study was performed to determine whether digital parametric imaging can quantitate vascular volume in the distal pulmonary capillary bed with pulmonary flow intact. Two digital angiograms of the pulmonary vasculature were acquired in 11 patients with varying degrees of pulmonary hypertension. A balloon flotation catheter was advanced distally into the pulmonary artery. The first angiogram (static image) was performed with blood flow occluded by inflation of the catheter balloon. Non-ionic contrast was then hand injected to completely fill the vasculature beyond the balloon occlusion. The second angiogram (flow image) was performed with the balloon deflated and blood flow preserved. A hand injection of a rapid bolus of contrast, 1–2 cc, was given. Digital subtraction image data were obtained at 15 frames/sec at end expiration for both angiograms. Contrast density measurements of the distal pulmonary vasculature were determined from the static images in various 2 × 2 mm areas using digital parametric imaging. The maximum density in these same areas was similarly determined from the flow images. The correlation of the density measurements between the static and the flow images in 64 regions of interest was excellent (R = 0.92, regression slope = 0.98). This correlation was similar to that observed for repeated injections using the same technique (flow image) (R = 0.97, regression slope = 0.97). Digital parametric measurements of pulmonary capillary volume obtained with blood flow preserved are the same as those obtained with flow occluded and the entire bed replaced by contrast. This method allows quantitation of pulmonary vascular volume and flow using a simple, single contrast injection in the distal pulmonary artery.

The pulmonary circulation in essential systemic hypertension

Seventy-one men, ages 16 to 59 years, were referred for systemic hypertension, which was without detectable cause and with limited organ damage (World Health Organization stages I to II). They performed a graded exercise test on the bicycle ergometer in the sitting position. Mean brachial intraarterial pressure, mean pulmonary artery and wedge pressures and cardiac output (Fick method) were measured. At rest mean brachial artery pressure ranged from 72 to 168 mm Hg. Mean pulmonary wedge pressure was significantly (p < 0.05) related to mean brachial artery pressure at rest, at submaximal work (50 watts) and at the end of exercise (161 ± 42 [standard deviation] watts). In each subject pulmonary vascular resistance was calculated as the slope of the relation between the pressure gradient across the pulmonary circulation and cardiac output from data at rest, at 50 watts and at the end of exercise; mean critical closing pressure was calculated as the intercept of this relation. Pulmonary vascular resistance averaged 0.63 ± 0.37 mm Hg/liter/min and was significantly related to age (r = 0.28, p < 0.05) but not to rest brachial artery pressure (r = 0.14) or pulmonary wedge pressure (r = 0.09, difference not significant for both). The mean critical closing pressure averaged 6.1 ± 4.0 mm Hg and was not related to brachial artery pressure (r = −0.08) or to age (r = −0.18, difference not significant for both). It is concluded that there is neither a primary nor a secondary effect of systemic hypertension on the pulmonary vasculature in patients with World Health Organization stages I to II essential hypertension.

Quantitative analysis of postoperative changes in the pulmonary vasculature of patients with complete transposition of the great arteries and pulmonary hypertension

Postoperative changes in the medial thickness of the small pulmonary arteries and the degree of pulmonary vascular disease were estimated histometrically and histopathologically in three cases of late death after total corrrection of complete transposition of the great arteries with large ventricular septal defect and pulmonary hypertension. In the postoperative course of two of the three cases extreme medial hypertrophy of the small pulmonary arteries as well as severe pulmonary vascular disease were found. In the third case, the thickening of the media was mild and pulmonary vascular disease had not progressed owing to a residual ventricular septal defect. Examination of three additional cases of late death and 15 autopsy cases of complete transposition of the great arteries revealed that hypertrophy of pulmonary arterial media after radical surgery for complete transposition of the great arteries is a common phenomenon. In cases of complete transposition of the great arteries with severe pulmonary hypertension, the development of marked hypertrophy of the media accompanied by pulmonary vascular disease after total correction is usually seen and seems to be the most likely cause of death in the postoperative period.

Distribution of pulmonary blood flow after myocardial ischemia and infarction.

Regional distribution of pulmonary blood flow and ventilation was determined with the 133 xenon technic in the erect position at the bedside in 15 patients an average of 6 days after uncomplicated myocardial infarction (MI) and in five patients with severe angina in the same coronary care unit. Follow-up studies were repeated within 3 to 25 weeks on six of the patients with MI. There was marked reduction in perfusion to the lung base after myocardial infarction. Patients with severe angina showed some underperfusion of the lower lung zones, but to a much less degree than those with acute MI. The pattern of pulmonary perfusion reverted toward that seen in angina in the follow-up studies of patients with MI. Distribution of ventilation was normal in all patients. The results of the study suggest that there are probably chronic changes in the pulmonary vasculature of patients with arteriosclerotic heart disease which lead to redistribution of pulmonary blood flow toward the apex, and that the marked under-perfusion of the lung base demonstrated following acute myocardial infarction reflects an acute increase in the pulmonary venous and interstitial pressures most likely due to occult left ventricular failure.