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Pulmonary Arterial Hypertension (pulmonary + arterial_hypertension)
Selected AbstractsCONTINUOUS FLUOXETINE ADMINISTRATION PREVENTS RECURRENCE OF PULMONARY ARTERIAL HYPERTENSION AND PROLONGS SURVIVAL IN RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009Shao-Ping Zhu SUMMARY 1The serotonin transporter (SERT) is strongly implicated in the pathogenesis of pulmonary arterial hypertension (PAH) in patients and animal models. Inhibitors of SERT have been reported to attenuate or reverse experimental PAH, which makes them potential therapeutic options for the treatment of PAH in humans. However, little is known about pathophysiological features after reversal or attenuation of PAH; moreover, the long-term therapeutic effects of SERT inhibitors on PAH remain undetermined. Thus, the aim of the present study was to investigate the short- and long-term effects of fluoxetine on monocrotaline (MCT)-induced PAH and associated pathophysiological changes in PAH models. 2Rats were randomly divided into four groups as follows: (i) an M + F group, in which rats received a single injection of MCT (60 mg/kg, s.c.) and then after 3 weeks were given fluoxetine (10 mg/kg) once daily by gavage from Week 4 to Week 12; (ii) an M/F group, in which 3 weeks after a single MCT (60 mg/kg, s.c.) injection, rats were given fluoxetine (10 mg/kg) by daily gavage from Week 4 to Week 6 and were then given an equivalent volume of saline once daily by gavage from Week 7 to Week 12; (iii) an MCT group, in which 3 weeks after a single MCT (60 mg/kg, s.c.) injection rats were given an equivalent volume of saline by gavage from Week 4 to Week 12; and (iv) a saline group, in which rats received an equivalent volume of saline injection or gavage over the 12 week treatment period. Morphometric changes, pulmonary arterial pressure, percentage wall thickness, right ventricular hypertrophy index and SERT expression were detected at various times during the 12 week treatment period. Survival analysis was performed in each group. 3After 12 weeks treatment, it was found that even through fluoxetine treatment resulted in complete reversal of PAH, PAH recurred after fluoxetine withdrawal. In contrast, continuous administration of fluoxetine prevented the recurrence of PAH and prolonged survival. Analysis of SERT protein levels in rat lung indicated that, compared with values obtained at Week 0, SERT protein increased significantly after discontinuation of fluoxetine but continuous fluoxetine administration inhibited this increase. 4In conclusion, SERT overexpression correlates with the recurrence of PAH after withdrawal of fluoxetine in rats. Continuous fluoxetine administration prevents recurrence of PAH and prolongs survival. [source] Usefulness of B-Type Natriuretic Peptide as a Predictor of Treatment Outcome in Pulmonary Arterial HypertensionCONGESTIVE HEART FAILURE, Issue 5 2004Myung H. Park MD We examined the utility of early modulation B-type natriuretic peptide (BNP) levels in 20 pulmonary arterial hypertension patients as a marker of response to epoprostenol therapy. The baseline BNP level was 828±217 pg/mL. A total of 19 hospitalizations and one death occurred in nine patients during 11.0±1.8 months. At baseline, a trend toward higher BNP level was observed among the event-free (Group A) as compared with clinical event patients (Group B) (1090±372 vs. 510±235 pg/mL, respectively; p=0.08). After 3 months on epoprostenol, a significant reduction among Group A occurred while Group B demonstrated an increase (288±92 vs. 610±121 pg/mL, p=0.04). A comparison of percent reduction in BNP level demonstrated a ,70±7% change among Group A and an 11±19% increase in Group B (p=0.005). A decrease in BNP level of ,50% during the first 3 months on epoprostenol was strongly predictive of event-free survival (p=0.003). This investigation establishes the utility of BNP for predicting response to epoprostenol therapy in pulmonary arterial hypertension. [source] Comparison of Impedance Cardiography to Direct Fick and Thermodilution Cardiac Output Determination in Pulmonary Arterial HypertensionCONGESTIVE HEART FAILURE, Issue 2004Gordon L. Yung MD Cardiac output (CO) is an important diagnostic and prognostic tool for patients with ventricular dysfunction. Pulmonary hypertension patients undergo invasive right heart catheterization to determine pulmonary vascular and cardiac hemodynamics. Thermodilution (TD) and direct Fick method are the most common methods of CO determination but are costly and may be associated with complications. The latest generation of impedance cardiography (ICG) provides noninvasive estimation of CO and is now validated. The purpose of this study was to compare ICG measurement of CO to TD and direct Fick in pulmonary hypertension patients. Thirty-nine enrolled patients were analyzed: 44% were male and average age was 50.8±17.4 years. Results for bias and precision of cardiac index were as follows: ICG vs. Fick (,0.13 L/min/m2 and 0.46 L/min/m2), TD vs. Fick (0.10 L/min/m2 and 0.41 L/min/m2), ICG vs. TD (respectively, with a 95% level of agreement between ,0.72 and 0.92 L/min/m2; CO correlation of ICG vs. Fick, TD vs. Fick, and ICG vs. TD was 0.84, 0.89, and 0.80, respectively). ICG provides an accurate, useful, and cost-effective method for determining CO in pulmonary hypertension patients, and is a potential tool for following responses to therapeutic interventions. [source] The Role of K+ Channels in Determining Pulmonary Vascular Tone, Oxygen Sensing, Cell Proliferation, and Apoptosis: Implications in Hypoxic Pulmonary Vasoconstriction and Pulmonary Arterial HypertensionMICROCIRCULATION, Issue 8 2006ROHIT MOUDGIL ABSTRACT Potassium channels are tetrameric, membrane-spanning proteins that selectively conduct K+ at near diffusion-limited rates. Their remarkable ionic selectivity results from a highly-conserved K+ recognition sequence in the pore. The classical function of K+ channels is regulation of membrane potential (EM) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K+ egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a EM of about ,60 mV. It has been recently discovered that K+ channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage-gated (Kv), inward rectifier (Kir), calcium-sensitive (KCa), and two-pore (K2P) channels. Certain K+ channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen-sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits Kv1.5, which depolarizes EM, opens voltage-sensitive, L-type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia-inhibited K+ currents are not seen in systemic arterial SMCs. Kv expression is also transcriptionally regulated by HIF-1, and NFAT. Loss of PASMC Kv1.5 and Kv2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K+, thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring Kv expression (via Kv1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kv current (including an oxygen-sensitive component), whereas conduit PASMC current is a Kv/KCa mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K+ channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH. [source] Bridge to Thoracic Organ Transplantation in Patients with Pulmonary Arterial Hypertension Using a Pumpless Lung Assist DeviceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009M. Strueber We describe a novel technique of pumpless extracorporeal life support in four patients with cardiogenic shock due to end-stage pulmonary hypertension (PH) including patients with veno-occlusive disease (PVOD) using a pumpless lung assist device (LAD). The device was connected via the pulmonary arterial main trunk and the left atrium, thereby creating a septostomy-like shunt with the unique addition of gas exchange abilities in parallel to the lung. Using this approach, all four patients were successfully bridged to bilateral lung transplantation and combined heart,lung transplantation, respectively. Although all patients presented in cardiogenic shock, hemodynamic unloading of the right ventricle using the low-resistance LAD stabilized the hemodynamic situation immediately so that no pump support was subsequently required. [source] REVIEW: Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension: An OverviewCARDIOVASCULAR THERAPEUTICS, Issue 5 2010Shahzad G. Raja The last decade has seen major advances in the pharmacotherapy of pulmonary arterial hypertension (PAH). One of these advances has been the discovery of endothelin receptor antagonists (ERAs). ERAs are a class of potent vasodilators and antimitotic substances, which could specifically dilate and remodel pulmonary arterial system, and have been proposed as an alternative to traditional therapies for PAH. Current available evidence suggests that ERAs improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening for patients with PAH. This review attempts to provide an overview of the pharmacology, therapeutic benefits, and safety profile of ERAs in patients with PAH. [source] Inflammatory Signaling in Pulmonary Arterial Hypertension: The Controversial Role of CRP, and the Search for New TherapiesCARDIOVASCULAR THERAPEUTICS, Issue 1 2010Paul M. Maciocia A greater understanding of the mechanisms behind the development of Pulmonary Arterial Hypertension remains crucial [source] Bosentan treatment of portopulmonary hypertension related to liver cirrhosis owing to hepatitis CEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006W. Grander Abstract Pulmonary arterial hypertension (PAH) with coexisting portal hypertension has been defined as portopulmonary hypertension (PPHTN). It is often related to liver cirrhosis of various aetiologies and is associated with a high mortality rate. Endothelin-1 (ET) is supposed to play an important role in the pathogenesis of PAH as well as portal hypertension. Therefore, therapy with an ETA/ETB receptor antagonist might be of use in the treatment of PPHTN. We report the case of a 76-year-old male with liver cirrhosis owing to chronic hepatitis C virus infection and PPHTN who was treated with the dual ETA/ETB receptor antagonist bosentan. The patient showed remarkable improvement of 6-min walking distance from 300 to 480 m after 2 weeks and to 540 m after 14 weeks, respectively. In addition, a significant decline of N-terminal pro B-type natriuretic peptide fraction (NT-proBNP) from 4928 ng mL,1 to 640 ng mL,1 was observed. Bosentan might be a promising new therapeutical option for patients suffering from PPHTN. [source] Pulmonary hypertension in pregnancy: two cases and review of the literatureINTERNAL MEDICINE JOURNAL, Issue 11 2009A. M. Higton Abstract Pulmonary arterial hypertension (PAH) in pregnancy carries a mortality of 30,56%. There are few published data to guide clinicians in its management. Two pregnant women with severe PAH have been treated at Royal Perth Hospital with a successful result in both. Their presentation and management are described. We review the physiological changes in pregnancy, pathophysiology in PAH, and review the literature describing treatment of PAH in pregnancy. [source] Current treatment strategies for pulmonary arterial hypertensionJOURNAL OF INTERNAL MEDICINE, Issue 3 2005S. H. LEE Abstract., Lee SH, Rubin LJ (University of California, San Diego, La Jolla, CA, USA). Current treatment strategies for pulmonary arterial hypertension (Review). J Intern Med 2005; 258: 199,215. Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, exercise tolerance, functional class, haemodynamics, echocardiographic parameters and quality of life measures. Since the introduction of continuous intravenous prostacyclin, the treatment armamentarium of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Selective endothelin-A receptor antagonists have shown promise in clinical trials and are likely to be added to the list of options. As the number of medications available for PAH continues to increase, treatment decisions regarding first-line therapy, combination treatments, and add-on strategies are becoming more complex. This article reviews the current treatments strategies for PAH and provides guidelines for its management. [source] Retrospective Evaluation of Sildenafil Citrate as a Therapy for Pulmonary Hypertension in DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2006Jonathan F. Bach DACVIM (SA-IM) Pulmonary arterial hypertension (PH) is a pathologic condition in dogs characterized by abnormally high pressures in the pulmonary circulation and has been associated with a poor outcome. Sildenafil is a type V phosphodiesterase inhibitor that produces nitric oxide-mediated vasodilatation. Sildenafil treatment decreases pulmonary arterial pressure and pulmonary vascular resistance in people with PH. The purpose of this study was to describe the clinical characteristics and outcome of dogs with PH treated with sildenafil. The cardiology database was searched for dogs with PH treated with sildenafil. PH was defined as systolic pulmonary arterial pressure (PAPS) 25 mmHg at rest. Medical records were reviewed for the following information: signalment, duration and type of clinical signs before treatment, underlying disease, estimated or measured PAPS, dosage and dosing interval of sildenafil, and the effect of treatment on clinical signs and pulmonary arterial pressure and survival time. Thirteen affected dogs were identified. Clinical signs included collapse, syncope, respiratory distress, and cough. Duration of clinical signs before presentation ranged from 3 days to 5 months. An underlying cause was identified in 8 dogs. The median sildenafil dosage was 1.9 mg/kg. Ten dogs received concurrent medications. Median PAPS was 90 mmHg; 8 dogs were reevaluated after therapy, and the median decrease in PAPS was 16.5 mmHg. The median survival time of all dogs was 91 days. Sildenafil appeared to be well tolerated in dogs with PH and was associated with decreased PAPS and amelioration of clinical signs in most. Sildenafil represents a reasonable treatment option for dogs with pulmonary hypertension. [source] Pulmonary arterial hypertension in childrenPEDIATRIC PULMONOLOGY, Issue 1 2004Erika Berman Rosenzweig MD Abstract Pulmonary arterial hypertension is a serious progressive condition with a poor prognosis if not identified and treated early. Because the symptoms are nonspecific and the physical findings can be subtle, the disease is often diagnosed in its later stages. Remarkable progress has been made in the field of pulmonary arterial hypertension over the past several decades. The pathology is now better defined, and significant advances have occurred in understanding the pathobiologic mechanisms. Risk factors have been identified, and the genetics have been characterized. Advances in technology allow earlier diagnosis as well as better assessment of disease severity. Therapeutic modalities such as new drugs, e.g., epoprostenol, treprostinil, and bosentan, and surgical/interventional options, e.g., transplantation and atrial septostomy, which were unavailable several decades ago, have had a significant impact on prognosis and outcome. Thus, despite our inability to cure pulmonary arterial hypertension, advances in medical treatments over the past two decades have resulted in significant improvement in outcomes for children with various forms of pulmonary arterial hypertension. This report is a review the current state of the art for pulmonary arterial hypertension in 2004, with an emphasis on childhood pulmonary arterial hypertension and specific recommendations for current practice and future directions. Pediatr Pulmonol. 2004; 38:2,22. © 2004 Wiley-Liss, Inc. [source] Emerging treatments for pulmonary arterial hypertensionTHE CLINICAL RESPIRATORY JOURNAL, Issue 3 2008Dermot S. O'Callaghan Abstract Introduction:, Pulmonary arterial hypertension (PAH) is a rare, progressive disease for which no cure exists. However, improved understanding of underlying pathophysiological mechanisms has led to the development of several effective treatments that improve haemodynamics and functional status. Objective:, An overview of emerging pharmacological approaches to the management of PAH is presented. Materials and methods:, A Medline search was performed for studies describing novel treatments and potential therapeutic targets relevant to PAH. Results:, Several different treatments that modulate abnormalities in the prostacyclin, endothelin and nitric oxide pathways have shown efficacy in randomised, controlled studies and are now licensed for use for PAH patients with advanced disease. Furthermore, there is now encouraging long-term survival data associated with use of these agents. A number of other targets with therapeutic potential have also been identified, such as serotonin, platelet-derived growth factor and vasoactive intestinal peptide. Recently, strategies involving combinations of different PAH-specific agents have emerged as a promising approach for those failing monotherapy. Conclusion:, The therapeutic options available for PAH has improved considerably in recent years and is likely to expand in the future. Please cite this paper as: O'Callaghan DS. Emerging treatments for pulmonary arterial hypertension. The Clinical Respiratory Journal 2008; 2: 132,140. [source] Association of a KCNA5 gene polymorphism with systemic sclerosis,associated pulmonary arterial hypertension in the European Caucasian populationARTHRITIS & RHEUMATISM, Issue 10 2010J. Wipff Objective Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor , receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. Methods Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. Results The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48,0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13,0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21,0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. Conclusion Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc. [source] Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertensionBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009C Agard Background and purpose:, Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH. Experimental approach:, Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells. Key results:, In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg·kg,1·day,1). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth. Conclusions and implications:, Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier. [source] Pulmonary arterial hypertension and right heart failure,A late-onset complication after cardiac catheterization,CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS, Issue 7 2009Beate Koch MD Abstract Arteriovenous fistula is a possible complication of diagnostic procedures requiring arterial femoral catheterization. Late onset manifestation is reported rarely. An impressive case of severe pulmonary arterial hypertension and consecutive right heart failure caused by an arteriovenous fistula between the common iliac artery and the distal inferior caval vein manifesting four years after cardiac catheterization in described. © 2009 Wiley-Liss, Inc. [source] Usefulness of B-Type Natriuretic Peptide as a Predictor of Treatment Outcome in Pulmonary Arterial HypertensionCONGESTIVE HEART FAILURE, Issue 5 2004Myung H. Park MD We examined the utility of early modulation B-type natriuretic peptide (BNP) levels in 20 pulmonary arterial hypertension patients as a marker of response to epoprostenol therapy. The baseline BNP level was 828±217 pg/mL. A total of 19 hospitalizations and one death occurred in nine patients during 11.0±1.8 months. At baseline, a trend toward higher BNP level was observed among the event-free (Group A) as compared with clinical event patients (Group B) (1090±372 vs. 510±235 pg/mL, respectively; p=0.08). After 3 months on epoprostenol, a significant reduction among Group A occurred while Group B demonstrated an increase (288±92 vs. 610±121 pg/mL, p=0.04). A comparison of percent reduction in BNP level demonstrated a ,70±7% change among Group A and an 11±19% increase in Group B (p=0.005). A decrease in BNP level of ,50% during the first 3 months on epoprostenol was strongly predictive of event-free survival (p=0.003). This investigation establishes the utility of BNP for predicting response to epoprostenol therapy in pulmonary arterial hypertension. [source] Correlation between Right Ventricular Indices and Clinical Improvement in Epoprostenol Treated Pulmonary Hypertension PatientsECHOCARDIOGRAPHY, Issue 5 2005Jayant Nath M.D. The aim of this study was to evaluate which parameter of right ventricular (RV) echocardiographic best mirrors the clinical status of patients with pulmonary arterial hypertension. Patients with pulmonary arterial hypertension on epoprostenol therapy were identified via hospital registry. Twenty patients, (16 females, 4 males) were included in the study, 9 with primary pulmonary hypertension and 11 with other diseases. Echocardiograms before therapy and at 22.7 (±9.3) months into therapy were compared. The right ventricular myocardial performance index (RVMPI) was measured as the sum of the isometric contraction time and the isometric relaxation time divided by right ventricular ejection time. Other measures included peak tricuspid regurgitation jet velocity (TRV), pulmonary artery systolic pressure (PASP), pulmonary valve velocity time integral (PVVTI), PASP/PVVTI (as an index of total pulmonary resistance) and symptoms by New York Heart Association (NYHA) functional class. Echo parameters of right ventricular function were analyzed in patients, before and during therapy. There was significant improvement of NYHA class in patients following epoprostenol therapy (P < 0.0001). Peak tricuspid regurgitant jet velocity (pre 4.2 ± 0.6 m/sec, post 3.8 ± 0.7 m/sec, P = 0.02) and PASP/PVVTI (pre 6.7 ± 3.3 mmHg/m per second, post 4.8 ± 2.2 mmHg/m per second, P < 0.0001) were significantly improved during treatment. RVMPI did not improve (pre 0.6 ± 0.3, post 0.6 ± 0.3, P = 0.54). Changes in NYHA class did not correlate with changes in RVMPI (P = 0.33) or changes in PASP/PVVTI (P = 0.58). Despite significant improvements in TRV, PASP/PVVTI, and NYHA class, there was no significant change in RVMPI on epoprostenol therapy. Changes in right ventricular indices were not correlated with changes in NYHA class. [source] The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009N. J. Davie Abstract Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ETA or nonselective ETA/ETB blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease. [source] Dual ETA/ETB vs. selective ETA endothelin receptor antagonism in patients with pulmonary hypertensionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006C. F. Opitz Abstract Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ETA/ETB and selective ETA receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ETA receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ETB receptors has been more complex. It has been shown that there is a subpopulation of ETB receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ETB receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ETA receptor antagonism. [source] Bosentan therapy for pulmonary arterial hypertension associated with hereditary haemorrhagic telangiectasiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006D. Bonderman Abstract Hereditary haemorrhagic telangiectasia (HHT) is a disorder of arteriovenous malformations and telangiectases. In rare cases affected individuals may develop typical pulmonary arterial hypertension (PAH). Vasodilator therapy has not been recommended because of a potential increase in arteriovenous shunt volume. This report is on two patients with severe HHT-associated PAH who were treated with bosentan, an oral endothelin ETA/ETB receptor antagonist. After 1 year, symptomatic and functional improvements were confirmed by haemodynamic evaluation demonstrating a significant decrease of mean pulmonary artery pressures and an increase in cardiac index, without evidence for an increase in effective shunt volume. [source] Dual endothelin receptor antagonism in pulmonary arterial hypertension (PAH)EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2005Article first published online: 10 MAR 200 No abstract is available for this article. [source] Metalloproteinase-9 in circulating monocytes in pulmonary hypertensionFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2006Caroline Cantini-Salignac Abstract The role of matrix metalloproteinases (MMPs) in pulmonary hypertension (PH) is complex as MMPs are involved in both the vascular and cardiac remodelling associated with PH. To gain insight into this problem, monocytes were isolated from pulmonary arterial blood in patients suffering from PH, related to chronic obstructive pulmonary disease (n = 6), chronic pulmonary thromboembolism (n = 3) or pulmonary arterial hypertension (n = 8). The severity of PH was associated with decreases in cardiac index (CI) and mixed venous blood oxygen saturation (SO2), and an increase in right atrial pressure (). Monocyte pro-MMP-9 content (zymography) was positively correlated with SO2 (r = 0.73, P < 0.05) and CI (r = 0.66, P < 0.05), and negatively with (r = 0.54, P < 0.05); there was no significant correlation with pulmonary vascular resistance. In conclusion, the pro-MMP-9 content of circulating monocytes was lower in the more severe forms of PH which showed heart failure suggesting that such MMP enzymatic activity reflects heart failure following pulmonary vascular and myocardial remodelling in PH. [source] The six-minute walk test: a useful metric for the cardiopulmonary patientINTERNAL MEDICINE JOURNAL, Issue 8 2009T. Rasekaba Abstract Measurement of exercise capacity is an integral element in assessment of patients with cardiopulmonary disease. The 6-min walk test (6MWT) provides information regarding functional capacity, response to therapy and prognosis across a range of chronic cardiopulmonary conditions. A distance less than 350 m is associated with increased mortality in chronic obstructive pulmonary disease, chronic heart failure and pulmonary arterial hypertension. Desaturation during a 6MWT is an important prognostic indicator for patients with interstitial lung disease. The 6MWT is sensitive to commonly used therapies in chronic obstructive pulmonary disease such as pulmonary rehabilitation, oxygen, long-term use of inhaled corticosteroids and lung volume reduction surgery. However, it appears less reliable to detect changes in clinical status associated with medical therapies for heart failure. A change in walking distance of more than 50 m is clinically significant in most disease states. When interpreting the results of a 6MWT, consideration should be given to choice of predictive values and the methods by which the test was carried out. [source] Intravenous catheter infections in pulmonary arterial hypertensionINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2008S. Gaine No abstract is available for this article. [source] Current treatment strategies for pulmonary arterial hypertensionJOURNAL OF INTERNAL MEDICINE, Issue 3 2005S. H. LEE Abstract., Lee SH, Rubin LJ (University of California, San Diego, La Jolla, CA, USA). Current treatment strategies for pulmonary arterial hypertension (Review). J Intern Med 2005; 258: 199,215. Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, exercise tolerance, functional class, haemodynamics, echocardiographic parameters and quality of life measures. Since the introduction of continuous intravenous prostacyclin, the treatment armamentarium of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Selective endothelin-A receptor antagonists have shown promise in clinical trials and are likely to be added to the list of options. As the number of medications available for PAH continues to increase, treatment decisions regarding first-line therapy, combination treatments, and add-on strategies are becoming more complex. This article reviews the current treatments strategies for PAH and provides guidelines for its management. [source] Feasibility study of aerosolized prostaglandin E1 microspheres as a noninvasive therapy for pulmonary arterial hypertensionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2010Vivek Gupta Abstract This study was designed to test the feasibility of polymeric microspheres as an inhalable carrier for prostaglandin E1 (PGE1) for treatment of pulmonary arterial hypertension. Poly(lactic- co -glycolic acid) (PLGA) microspheres were prepared by a double emulsion,solvent evaporation method. Six different microspheric formulations were prepared using two different blends of PLGA (50:50 and 85:15) and varying concentrations of polyvinyl alcohol (PVA) in the external aqueous phase (EAP). The particles were characterized for morphology, size, aerodynamic diameter, entrapment efficiency, release patterns, and metabolic stability. Pulmonary absorption was studied in a rat model, and safety of the formulations was evaluated by measuring cytotoxicity in Calu-3 cells and assessing injury markers in bronchoalveolar lavage (BAL) fluid. Both actual particle size and aerodynamic diameter of the formulations decreased with increasing PVA concentration. The mass median aerodynamic diameter of the particles was within the respirable range. Entrapment efficiency increased with increasing PVA concentration; PLGA 85:15 showed better entrapment due to hydrophobic interactions with the drug. Compared to intravenously administered PGE1, microspheres prepared with PLGA 85:15 produced a 160-fold increase in the half-life of PGE1 following pulmonary administration. Although plain PGE1 showed rapid degradation in rat lung homogenate, PGE1 entrapped in the particles remained intact for about 8,h. Optimized formulations were demonstrated to be safe, based on analysis of cytotoxicity and lung-injury markers in BAL fluid. Overall, the data suggest that microspheric PGE1 formulations have the potential to be used as a noninvasive and controlled-release alternative to the current medications used for treatment of pulmonary arterial hypertension that are administered by continuous infusion or require multiple inhalations. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1774,1789, 2010 [source] The Role of K+ Channels in Determining Pulmonary Vascular Tone, Oxygen Sensing, Cell Proliferation, and Apoptosis: Implications in Hypoxic Pulmonary Vasoconstriction and Pulmonary Arterial HypertensionMICROCIRCULATION, Issue 8 2006ROHIT MOUDGIL ABSTRACT Potassium channels are tetrameric, membrane-spanning proteins that selectively conduct K+ at near diffusion-limited rates. Their remarkable ionic selectivity results from a highly-conserved K+ recognition sequence in the pore. The classical function of K+ channels is regulation of membrane potential (EM) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K+ egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a EM of about ,60 mV. It has been recently discovered that K+ channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage-gated (Kv), inward rectifier (Kir), calcium-sensitive (KCa), and two-pore (K2P) channels. Certain K+ channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen-sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits Kv1.5, which depolarizes EM, opens voltage-sensitive, L-type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia-inhibited K+ currents are not seen in systemic arterial SMCs. Kv expression is also transcriptionally regulated by HIF-1, and NFAT. Loss of PASMC Kv1.5 and Kv2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K+, thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring Kv expression (via Kv1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kv current (including an oxygen-sensitive component), whereas conduit PASMC current is a Kv/KCa mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K+ channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH. [source] Anesthetic management of children with pulmonary arterial hypertensionPEDIATRIC ANESTHESIA, Issue 6 2008Dario Galante md No abstract is available for this article. [source] Pulmonary arterial hypertension in childrenPEDIATRIC PULMONOLOGY, Issue 1 2004Erika Berman Rosenzweig MD Abstract Pulmonary arterial hypertension is a serious progressive condition with a poor prognosis if not identified and treated early. Because the symptoms are nonspecific and the physical findings can be subtle, the disease is often diagnosed in its later stages. Remarkable progress has been made in the field of pulmonary arterial hypertension over the past several decades. The pathology is now better defined, and significant advances have occurred in understanding the pathobiologic mechanisms. Risk factors have been identified, and the genetics have been characterized. Advances in technology allow earlier diagnosis as well as better assessment of disease severity. Therapeutic modalities such as new drugs, e.g., epoprostenol, treprostinil, and bosentan, and surgical/interventional options, e.g., transplantation and atrial septostomy, which were unavailable several decades ago, have had a significant impact on prognosis and outcome. Thus, despite our inability to cure pulmonary arterial hypertension, advances in medical treatments over the past two decades have resulted in significant improvement in outcomes for children with various forms of pulmonary arterial hypertension. This report is a review the current state of the art for pulmonary arterial hypertension in 2004, with an emphasis on childhood pulmonary arterial hypertension and specific recommendations for current practice and future directions. Pediatr Pulmonol. 2004; 38:2,22. © 2004 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||