Showing papers on "Pulmonary artery published in 2003"

Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease.

Abstract: Doppler echocardiography is commonly used to estimate systolic nose PH in patients with advanced lung disease is preferable. pulmonary artery pressure and to diagnose pulmonary hypertension, Doppler echocardiography (DE) has gained popularity in but data relating to its utility in patients with advanced lung disease the last 2 decades for noninvasive estimation of systolic pulare limited. In a cohort study of 374 lung transplant candidates, the monary artery pressure (sPAP) from the peak velocity of a performance characteristics of echocardiography compared with tricuspid regurgitant jet. Studies in patients with cardiac disright heart catheterization in the determination of systolic pulmo- ease have revealed a significant statistical correlation benary artery pressure and diagnosis of pulmonary hypertension were tween sPAP estimated by DE and that measured by RHC investigated. The prevalence of pulmonary hypertension was 25% (6‐9). However, in patients with chronic pulmonary disease, in the study population. Estimation of systolic pulmonary artery pres- DE has been reported to perform variably in the assessment sure by echocardiography was possible in 166 patients (44%). The of sPAP (10‐12). Despite a close correlation between DEcorrelation between systolic pulmonary artery pressure estimated estimated and directly measured sPAP, several studies have by echocardiography and measured by cardiac catheterization was revealed that such estimations were possible in only a minorgood (r 0.69, p 0.0001). However, 52% of pressure estimations ity of patients with chronic lung disease (11‐14). More imporwere found to be inaccurate (more than 10 mm Hg difference tantly, by focusing exclusively on the correlation between compared with measured pressure), and 48% of patients were mis- estimated and measured pressures, previous studies have classified as having pulmonary hypertension by echocardiography. largely ignored the important issue of the true accuracy of Sensitivity, specificity, and positive and negative predictive values DE estimation of sPAP. That is, if DE were to consistently of systolic pulmonary artery pressure estimation for diagnosis of overestimate or underestimate sPAP by a constant value, pulmonary hypertension were 85%, 55%, 52%, and 87%, respectively. correlation would be high, but the accuracy of the estimation In conclusion, despite a statistically significant correlation with directly measured values, estimation of systolic pulmonary artery pres- would be dictated by the magnitude of discrepancy. It is the sure by echocardiography is frequently inaccurate in patients with accuracy of estimation that defines the clinical utility of DE in advanced lung disease and leads to considerable overdiagnosis of such circumstances as evaluation of patients for lung volume pulmonary hypertension. reduction surgery or lung transplantation. Patients with advanced lung disease referred for lung

Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach

Abstract: Objective: To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort. Methods: A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (Tlco) 20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice. Results: The prevalence of PAH was 12% (89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure—raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3). Conclusions: The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.

Pulmonary hypertension in chronic obstructive pulmonary disease

Abstract: Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). Its presence is associated with shorter survival and worse clinical evolution. In COPD, pulmonary hypertension tends to be of moderate severity and progresses slowly. However, transitory increases of pulmonary artery pressure may occur during exacerbations, exercise and sleep. Right ventricular function is only mildly impaired with preservation of the cardiac output. Structural and functional changes of pulmonary circulation are apparent at the initial stages of COPD. Recent investigations have shown endothelial dysfunction and changes in the expression of endothelium-derived mediators that regulate vascular tone and cell growth in the pulmonary arteries of patients with mild disease. Some of these changes are also present in smokers with normal lung function. Accordingly, it has been postulated that the initial event in the natural history of pulmonary hypertension in COPD could be the lesion of pulmonary endothelium by cigarette-smoke products. Long-term oxygen administration is the only treatment that slows down the progression of pulmonary hypertension in chronic obstructive pulmonary disease. Nevertheless, with this treatment pulmonary artery pressure rarely returns to normal values and the structural abnormalities of pulmonary vessels remain unaltered. Vasodilators are not recommended on the basis of their minimal clinical efficacy and because they impair pulmonary gas exchange. Recognition of the role of endothelial dysfunction in the physiopathology of pulmonary hypertension in chronic obstructive pulmonary disease opens new perspectives for the treatment of this complication.

Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease.

Abstract: Background Acute cellular rejection is the mechanism of most immune-related injury in cardiac transplant recipients. However, antibody-mediated humoral rejection (HR) has also been implicated as an important clinical entity following orthotopic heart transplantation. Humoral rejection has been reported to play a role in graft dysfunction in the early post-transplant period, and to be a risk factor for the development of transplant coronary artery disease. Some involved in transplantation pathology doubt the existence of clinically significant humoral rejection in cardiac allografts. Those who recognize its existence disagree on its possible role in graft dysfunction or graft coronary artery disease. In this study, we report clinical features of patients with the pathologic diagnosis of HR at our institution since July 1997, when we began systematic surveillance for humoral rejection. Methods We reviewed medical records of patients with the pathologic diagnosis of HR without concurrent cellular rejection between July 1997 and January 2001. Diagnosis was based on routine histology (“swollen cells” distending capillaries, interstitial edema and hemorrhage) and immunofluorescence (capillary deposition of immunoglobulin and complement with HLA-DR positivity), or immunoperoxidase staining of paraffin-embedded tissue (numerous CD68-positive macrophages and fewer swollen endothelial cells distending capillaries). Results A total of 44 patients (4 to 74 years old) showed evidence of HR without concurrent cellular rejection at autopsy or on one or more biopsies. Although females comprised only 26% of our transplant population, 23 patients (52%) with HR were female. A positive peri-operative flow cytometry T-cell crossmatch was observed in 32% of HR patients compared with 12% of controls ( p = 0.02). Hemodynamic compromise consisting of shock, hypotension, decreased cardiac output/index and/or a rise in capillary wedge or pulmonary artery pressure was observed in 47% of patients at the time of diagnosis of HR. Six patients (5 females) died (14% mortality) with evidence of HR at or just before autopsy, 6 days to 16 months after transplantation. The incidence of transplant coronary artery disease was 10% greater at 1 year, and 36% greater at 5 years, in patients with HR when compared with non-HR patients. Conclusion Humoral rejection was associated with acute hemodynamic compromise in 47% of patients, and was the direct cause of death in 6 patients (13%). Humoral rejection is a clinicopathologic entity with a high incidence in women and is associated with acute hemodynamic compromise, accelerated transplant coronary artery disease and death.

Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension

Abstract: Primary pulmonary hypertension is a fatal disease causing progressive right heart failure within 3 years after diagnosis. We describe a new concept for treatment of the disease using vasoactive intestinal peptide, a neuropeptide primarily functioning as a neurotransmitter that acts as a potent systemic and pulmonary vasodilator. Our rationale is based on the finding of a deficiency of the peptide in serum and lung tissue of patients with primary pulmonary hypertension, as evidenced by radioimmunoassay and immunohistochemistry. The relevance of this finding is underlined by an upregulation of corresponding receptor sites as shown by Northern blot analysis, Western blot analysis, and immunological techniques. Consequently, the substitution with the hormone results in substantial improvement of hemodynamic and prognostic parameters of the disease without side effects. It decreased the mean pulmonary artery pressure in our eight study patients, increased cardiac output, and mixed venous oxygen saturation. Our data provide enough proof for further investigation of vasoactive intestinal peptide and its role in primary pulmonary hypertension.

Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease?

Abstract: Pulmonary hypertension is a life-threatening complication of sickle cell disease. L-Arginine is the nitrogen donor for synthesis of nitric oxide, a potent vasodilator that is deficient during times of sickle cell crisis. This deficiency may play a role in pulmonary hypertension. The enzyme arginase hydrolyzes arginine to ornithine and urea, and thus, it may compete with nitric oxide synthase, leading to decreased nitric oxide production. Nitric oxide therapy by inhalation has improved pulmonary hypertension associated with acute chest syndrome in sickle cell disease, and several studies demonstrate therapeutic benefits of arginine therapy for primary and secondary pulmonary hypertension. We sought to determine the effects of arginine therapy on pulmonary hypertension in patients with sickle cell disease. Arginase activity was also determined. Oral arginine produced a 15.2% mean reduction in estimated pulmonary artery systolic pressure (63.9 +/- 13 to 54.2 +/- 12 mm Hg, p = 0.002) after 5 days of therapy in 10 patients. Arginase activity was elevated almost twofold (p = 0.07) in patients with pulmonary hypertension and may limit arginine bioavailability. With limited treatment options and a high mortality rate for patients with sickle cell disease who develop pulmonary hypertension, arginine is a promising new therapy that warrants further investigation.

Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.

Abstract: Background Bosentan, a dual endothelin-receptor antagonist, is registered for the treatment of pulmonary arterial hypertension. Little is known about the effects of bosentan in children. This study was conducted to investigate the pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Methods In this 2-center, open-label study, 19 pediatric patients with pulmonary arterial hypertension were enrolled and stratified for body weight and epoprostenol use. Patients weighing between 10 and 20 kg, between 20 and 40 kg, or greater than 40 kg received a single dose of 31.25, 62.5, or 125 mg, respectively, on day 1, followed by 4 weeks of treatment with the initial dose. The dose was then up-titrated to the target dose (31.25, 62.5, or 125 mg twice daily). Pharmacokinetic and hemodynamic parameters were obtained at baseline and after 12 weeks of treatment. Six-minute walk distance and cardiopulmonary exercise testing results were measured at baseline and at week 12 in children aged 8 years or older. Results The variability in exposure among the 3 groups was less than 2-fold after single- and multiple-dose administration. The exposure to bosentan decreased over time in all groups. The covariates body weight, gender, age, and the use of epoprostenol had no significant effect on the pharmacokinetics of bosentan. Bosentan produced hemodynamic improvement and was well tolerated. The mean change from baseline in mean pulmonary artery pressure was −8.0 mm Hg (95% confidence interval, −12.2 to −3.7 mm Hg), and that in pulmonary vascular resistance index was −300 dyne · s · m2/cm5 (95% confidence interval, −576 to −24 dyne · s · m2/cm5). Conclusions The pharmacokinetics of bosentan in pediatric patients with pulmonary arterial hypertension and healthy adults are similar, and treatment with bosentan resulted in hemodynamic improvement. These results suggest that the applied dosing regimens may be appropriate to treat pediatric patients. Clinical Pharmacology & Therapeutics (2003) 73, 372–382; doi: 10.1016/S0009-9236(03)00005-5

Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia

Abstract: Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2alpha is a homologue of HIF-1alpha and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2alpha-deficient (Hif2alpha(+/-)) mice after exposure to 10% O(2) for 4 weeks. In contrast to WT mice, Hif2alpha(+/-) mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2alpha in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2alpha(+/-) mice after hypoxia, suggesting that HIF-2alpha-mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

Severity of acute pulmonary embolism: evaluation of a new spiral CT angiographic score in correlation with echocardiographic data.

Abstract: The purpose of this study was to investigate whether the severity of acute pulmonary embolism (PE) could be quantitatively assessed with spiral CT angiography (SCTA). Thirty-six consecutive patients without underlying cardiopulmonary disease and high clinical suspicion of PE underwent prospectively thin-collimation SCTA and echocardiography at the time of the initial diagnosis (T0) and after initial therapy (T1; mean interval of time T1-T2: 32 days). The CT severity score was based on the percentage of obstructed surface of each central and peripheral pulmonary arterial section using a 5-point scale (1: 40 mm Hg). The SCTA depicted acute PE in all patients at T0 with complete resolution of endovascular clots in 10 patients at T1. At T0, the mean percentage of obstruction of the pulmonary arterial bed was significantly higher in the 22 patients with echocardiographic signs of severity (56+/-13 vs 28+/-32%; p<0.001). A significant reduction in the mean percentage of pulmonary artery obstruction was observed in the 19 patients with resolution of echocardiographic criteria of severity between T0 and T1 T0: 57+/-14%; T1: 7+/-11%; p<0.001). The threshold value for severe PE on CT angiograms was 49% (sensitivity: 0.773; specificity: 0.214). The mean (+/-SD) pulmonary artery pressure was significantly higher in the 26 patients with more than 50% obstruction of the pulmonary artery bed (45+/-15 mm Hg) than in the 10 patients with less than 50% obstruction of pulmonary artery bed at T0 (31+/-11 mm Hg; p<0.01). The CT severity score evaluated in the present study enables quantitative assessment of acute PE severity on spiral CT angiograms, readily applicable in routine clinical practice.

In Vivo Gene Transfer of the O2-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

Abstract: Background— Alveolar hypoxia acutely elicits pulmonary vasoconstriction (HPV). Chronic hypoxia (CH), despite attenuating HPV, causes pulmonary hypertension (CH-PHT). HPV results, in part, from inhibition of O2-sensitive, voltage-gated potassium channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). CH decreases Kv channel current/expression and depolarizes and causes Ca2+ overload in PASMCs. We hypothesize that Kv gene transfer would normalize the pulmonary circulation (restore HPV and reduce CH-PHT), despite ongoing hypoxia. Methods and Results— Adult male Sprague-Dawley rats were exposed to normoxia or CH for 3 to 4 weeks and then nebulized orotracheally with saline or adenovirus (Ad5) carrying genes for the reporter, green fluorescent protein reporter±human Kv1.5 (cloned from normal PA). HPV was assessed in isolated lungs. Hemodynamics, including Fick and thermodilution cardiac output, were measured in vivo 3 and 14 days after gene therapy by use of micromanometer-tipped catheters. Transgene e...

Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells.

Abstract: Background—Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. Methods and Results—Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg 1 ·d 1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP36 mm Hg) and 6 weeks (mPAP24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor- and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. Conclusions—Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury. (Circulation. 2003;108:1640-1645.)

Pulmonary embolism: optimization of small pulmonary artery visualization at multi-detector row CT.

Abstract: PURPOSE: To compare the frequency of well-visualized pulmonary arteries according to anatomic level by using different collimation with single– and multi–detector row computed tomography (CT) in patients suspected of having acute pulmonary embolism. MATERIALS AND METHODS: Sixty patients were examined with one of three techniques (20 patients each). Group 1 was examined with single–detector row CT with 3-mm collimation and 1.3–1.6 pitch; groups 2 and 3, with multi–detector row CT with 2.5- and 1.25-mm collimation, respectively. Three thoracic radiologists independently reviewed examination findings to determine if each main, lobar, segmental, and subsegmental artery was well visualized for presence of pulmonary embolism. χ2 tests were performed. For well-visualized vessels, the presence and/or absence of pulmonary embolism was recorded and κ statistic was determined. RESULTS: Reader 1 scored 95% (114 of 120), 96% (115 of 120), and 99% (119 of 120) of lobar arteries (P > .05); 76% (304 of 400), 86% (346 of ...

Phosphodiesterase Type 5 as a Target for the Treatment of Hypoxia-Induced Pulmonary Hypertension

Abstract: Background— Phosphodiesterase type 5 (PDE5) is a novel therapeutic target for the treatment of pulmonary hypertension. This study examined the distribution of PDE5 in normal and hypoxic lung and the effect of chronic PDE5 inhibition with sildenafil, initiated before and during exposure to hypoxia, on pulmonary artery pressure (PAP) and structure. Methods and Results— Sprague-Dawley rats were exposed to hypoxia (10% O2) for up to 42 days. PAP, measured continuously by telemetry, increased gradually by 20 to 40 mm Hg, reaching a plateau between 10 and 14 days, and declined to normal levels on return to normoxia. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal lung and in distal muscularized arteries (<25 μm diameter) after hypoxia-induced pulmonary hypertension. Sildenafil (25 or 75 mg · kg−1 · d−1) given before hypoxia produced marked dose-dependent inhibition in the rise of PAP (60% to 90% reduction; P<0.0001) and vascular muscul...

Polymorphism of the Serotonin Transporter Gene and Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Abstract: Background— The serotonin transporter (5-HTT) is involved in the pulmonary artery smooth muscle hyperplasia that leads to pulmonary hypertension (PH). Because hypoxia and 5-HTT gene polymorphism control 5-HTT expression, we examined 5-HTT gene polymorphism and PH in hypoxemic patients with advanced chronic obstructive pulmonary disease (COPD). Methods and Results— In 103 patients with COPD recruited in France (n=67) and the UK (n=36), we determined 5-HTT gene polymorphism and pulmonary artery pressure (PAP) measured during right heart catheterization (France) or Doppler echocardiography (UK). Ninety-eight subjects from the 2 countries served as control subjects. The distribution of 5-HTT gene polymorphism did not differ between patients and control subjects. In patients carrying the LL genotype, which is associated with higher levels of 5-HTT expression in pulmonary artery smooth muscle cells than the LS and SS genotypes, PH was more severe than in LS or SS patients. Mean PAP values in patients from Franc...

Severity assessment of acute pulmonary embolism: evaluation using helical CT

Abstract: The objective was to evaluate the helical CT (HCT) criteria that could indicate severe pulmonary embolism (PE). In a retrospective study, 81 patients (mean age 62 years) with clinical suspicion of PE explored by HCT were studied. The patients were separated into three different groups according to clinical severity and treatment decisions: group SPE included patients with severe PE based on clinical data who were treated by fibrinolysis or embolectomy (n=20); group NSPE included patients with non-severe PE who received heparin (n=30); and group WPE included patients without PE (n=31). For each patient we calculated a vascular obstruction index based on the site of obstruction and the degree of occlusion in the pulmonary artery. We noted the HCT signs, i.e., cardiac and pulmonary artery dimensions, that could indicate acute cor pulmonale. According to multivariate analysis, factors significantly correlated with the severity of PE were: the vascular obstruction index (group SPE: 54%; group NSPE: 24%; p<0.001); the maximum minor axis of the left ventricle (group SPE: 30.2 mm; group NSPE: 40.4 mm; p<0.001); the diameter of the central pulmonary artery (group SPE: 32.4 mm; group NSPE: 28.3 mm; p<0.001); the maximum minor axis of the right ventricle (group SPE: 47.5 mm; group NSPE: 42.7 mm; p=0.029); the right ventricle/left ventricle minor axis ratio (group SPE: 1.63; group NSPE: 1.09; p<0.0001). Our data suggest that hemodynamic severity of PE can be assessed on HCT scans by measuring four main criteria: the vascular obstruction index; the minimum diameter of the left ventricle; the RV:LV ratio; and the diameter of the central pulmonary artery.

Right Ventricle to Pulmonary Artery Conduit Improves Outcome After Stage I Norwood for Hypoplastic Left Heart Syndrome

Abstract: Background— Diastolic run off into the pulmonary circulation and labile coronary perfusion are thought to contribute to morbidity and mortality after the Norwood procedure (NP). We compared outcomes from the use of a RV to PA conduit (RV/PA) or a modified Blalock-Taussig shunt (BTS), physiologically distinct sources of pulmonary blood flow. Methods and Results— Review of 56 consecutive patients who underwent a Norwood procedure with a RV/PA (n=36) or a BTS (n=20) between 2000 and 2002. Median age was 4.5 days (range 1 to 40) and median weight was 3.1 kg (range 1.8 to 4.1). The RV/PA was constructed with a 5-mm conduit. Patients in the BTS group received a 4-mm shunt. Comparisons between RV/PA and BTS groups showed no difference for weight, gestational age, prenatal diagnosis, HLHS variant, associated diagnoses, ascending aortic size, ventricular function, AV valve function, and pulmonary venous obstruction. Operative survival was higher with RV/PA [33/36 (92%) versus 14/20 (70%); P=0.05]. Patients with RV...

Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease.

Abstract: Chronic obstructive pulmonary disease (COPD) is associated with structural and functional changes in the pulmonary circulation that commence at an early stage. To investigate whether vascular endothelial growth factor (VEGF) might be implicated as a mediator in COPD-associated pulmonary vascular changes, we studied surgical specimens obtained from 19 nonsmokers, 21 smokers with normal lung function, 28 patients with moderate COPD, and 10 patients with severe emphysema. The expression of VEGF in pulmonary muscular arteries was evaluated by immunohistochemistry, its protein content in lung tissue by Western blot analysis, and VEGF mRNA and its isoforms were analyzed by reverse transcription-polymerase chain reaction. The immunohistochemical expression of VEGF was increased in pulmonary arteries of smokers (median, 68% [interquartile range, 60–88]) and patients with moderate COPD (77% [63–82]), compared with nonsmokers (53% [40–63]) (p < 0.05 each). The expression of VEGF in smooth muscle cells correlated wi...

Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease

Abstract: Background— Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra™) in pre- and postoperative children with increased PVR because of CHD. Methods and Results— 12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3±1.0 Wood Units*m2) were studied during cardiac catheterization (“cath laboratory”), or within...

Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure.

Abstract: Aims: To test the hypothesis that during acute heart failure endotoxin might be increased in hepatic veins as a sign of bacterial or endotoxin translocation from the bowel into the blood stream. Methods and results: In patients with acute heart failure (NYHA IV; n=17) levels of endotoxin, soluble (s) CD14, tumor necrosis factor α (TNFα and interleukin 6 (IL6)) were measured in blood drawn from an antecubital vein on admission and compared with age-matched patients with stable chronic heart failure (n=21) and healthy volunteers (n=9). All levels were systemically elevated during acute heart failure (all P<0.05); once patients were stable enough to undergo cardiac catheterization, endotoxin was found to be significantly higher in hepatic veins (0.62±0.05 EU/ml) than left ventricles (0.46±0.04 EU/ml; P<0.05), whereas sCD14, TNFα and IL6 were not different between these sites. At follow-up (29±6 days) endotoxin but not sCD14, TNFα or IL-6 was significantly lower as compared to baseline (P<0.05). Conclusions: Higher levels of endotoxin in hepatic veins as compared to the left ventricle during acute heart failure are suggestive of bacterial or endotoxin translocation from the bowel into the blood stream. This may lead to new treatment strategies. The lack of difference in TNFα levels between the pulmonary artery and the left ventricle sheds doubt on the heart as a source of systemically elevated TNFα levels.

Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension

Abstract: Angiopoietin-1 (Ang-1), a newly discovered ligand of the endothelial-specific tyrosine kinase receptor Tie-2, has been found to promote cell survival, vascular maturation, and stabilization. We hypothesized that Ang-1 gene transfer to the pulmonary microcirculation would improve pulmonary hemodynamics and vascular remodeling in experimental pulmonary hypertension. Rat pulmonary artery smooth muscle cells were transfected with Ang-1 cDNA or null (pFLAG-CMV-1) vector. Syngeneic Fisher 344 rats were treated with monocrotaline (MCT) (75 mg/kg IP) with or without delivery of 5×105 Ang-1–transfected cells into the right jugular vein. After 28 days, plasmid-derived Ang-1 mRNA was consistently and robustly detected by reverse transcriptase–polymerase chain reaction in lungs from all animals receiving Ang-1 gene therapy. Tie-2 receptor expression was markedly downregulated in rats treated with MCT, and this was partially restored by gene therapy with Ang-1. Animals receiving MCT exhibited 77% mortality by 28 days....

Portopulmonary hypertension in decompensated cirrhosis with refractory ascites

Abstract: Background: The prevalence of portopulmonary hypertension (PPHTN) in patients with cirrhosis and refractory ascites is unknown Its presence may preclude patients from receiving a transjugular intrahepatic portosystemic shunt or liver transplantation as a definitive treatment for their end stage cirrhosis Purpose: To determine the prevalence, possible aetiological factors, and predictive factors for the development of PPHTN in these patients Methods: Sixty two patients (53 males, nine females; mean age 545 (14) years) with biopsy proven cirrhosis and refractory ascites underwent angiographic measurements of pulmonary and splanchnic haemodynamics Endothelin 1 levels were measured from the pulmonary artery Forty nine patients underwent radionuclide angiography for measurements of central blood volume, pulmonary vascular, and cardiac chamber volumes Forty seven patients also underwent two dimensional echocardiography for measurements of cardiac structural and functional parameters Cardiac output, and systemic and pulmonary vascular resistance were calculated Results: Ten patients (161%) fulfilled the criteria for PPHTN (mean pulmonary artery pressure ≥25 mm Hg and pulmonary vascular resistance ≥120 dyn×s/cm5), with significantly higher mean right atrial (154 (12) v 79 (05) mm Hg; p<0001), and right ventricular pressures (247 (15) v 147 (06) mm Hg; p<0001), and endothelin 1 levels (304 (040) v 198 (012) pg/ml; p=002) No significant differences in any of the other parameters measured were detected between the two groups A right atrial pressure of ≥14 mm Hg had a 83% positive predictive value for the presence of PPHTN Conclusions: Portopulmonary hypertension is common in cirrhosis with refractory ascites, possibly due to excess endothelin 1 in the pulmonary circulation An elevated right atrial pressure ≥14 mm Hg predicts the presence of PPHTN, which may be helpful in deciding management options in these patients

Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD

Abstract: Background: Pulmonary hypertension is a frequent complication of severe chronic obstructive pulmonary disease (COPD) and a major cause of morbidity and mortality in this condition. Based on the improved survival of these patients due to long term oxygen therapy and the potent and selective pulmonary vasodilation by inhaled nitric oxide, the safety and effectiveness of the combined inhalation of these two gases over a 3 month period was assessed. Methods: Forty patients with secondary pulmonary hypertension due to COPD were randomly assigned to receive either oxygen alone or "pulsed" inhalation of nitric oxide with oxygen over a period of 3 months. "Pulsed" inhalation of nitric oxide was used to reduce pulmonary ventilation-perfusion mismatch and formation of toxic reaction products of nitric oxide and oxygen. Results: Compared with oxygen alone, the combined inhalation of nitric oxide and oxygen caused a significant decrease in mean (SE) pulmonary artery pressure (from 27.6 (4.4) mm Hg to 20.6 (4.9) mm Hg, p<0.001) and pulmonary vascular resistance index (from 569.7 (208.1) to 351.3 (159.9) dyne•s-1•cm-5•m-2, p<0.001) without decreasing arterial oxygenation. Cardiac output increased by 0.5 litres (from 5.6 (1.3) l/min to 6.1 (1.0) l/min, p=0.025). Systemic haemodynamics and left heart function remained unchanged during this period and no increase in toxic reaction products of nitric oxide was observed. Conclusions: This is the first controlled trial indicating that the "pulsed" inhalation of nitric oxide together with oxygen may be safely and effectively used for the long term treatment of severe COPD.

Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus.

Abstract: Platelet-derived growth factor (PDGF) is a potent smooth muscle cell mitogen that may contribute to smooth muscle hyperplasia during the development of chronic pulmonary hypertension (PH). We studied changes in PDGFalpha- and beta-receptor and ligand expression in lambs with chronic intrauterine PH induced by partial ligation of the ductus arteriosus (DA) at gestational age 124-128 days (term = 147 days). Western blot analysis performed on whole lung homogenates from PH animals after 8 days of DA ligation showed a twofold increase in PDGFalpha- and beta-receptor proteins compared with age-matched controls (P < 0.05). Lung PDGF-A and -B mRNA expression did not differ between PH and control animals. We treated PH animals with NX1975, an aptamer that selectively inhibits PDGF-B, by infusion into the left pulmonary artery for 7 days after DA ligation. NX1975 reduced the development of muscular thickening of small pulmonary arteries by 47% (P < 0.05) and right ventricular hypertrophy (RVH) by 66% (P < 0.02). Lung PDGFalpha- and beta-receptor expression is increased in perinatal PH, and NX1975 reduces the increase in wall thickness of small pulmonary arteries and RVH in this model. We speculate that PDGF signaling contributes to structural vascular remodeling in perinatal PH and that selective PDGF inhibition may provide a novel therapeutic strategy for the treatment of chronic PH.

Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension.

Abstract: BACKGROUND: The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET(B) receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET(A) receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. CONCLUSIONS: Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan.