Hypertension: Barst RJ

McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Anonymous00029, Anonymous00030, Anonymous00031, Anonymous00032, Anonymous00033. · No affiliation provided · J Am Coll Cardiol. · Pubmed #19389575 No free full text.

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Doran AK, Ivy DD, Barst RJ, Hill N, Murali S, Benza RL, Anonymous00263. · Pulmonary Hypertension Program, The Children's Hospital, 13123 East 19th Avenue, Aurora, CO 80045, USA. · Int J Clin Pract Suppl. · Pubmed #18638170 No free full text.

Abstract: Intravenous prostanoids are the backbone of therapy for advanced pulmonary arterial hypertension (PAH) and have improved long-term outcome and quality of life. Currently, two prostanoids are approved by the US Food and Drug administration for parenteral administration: epoprostenol (Flolan) and treprostinil (Remodulin). Chronic intravenous therapy presents considerable challenges for patients and caregivers who must learn sterile preparation of the medication, operation of the pump, and care of the central venous catheter. Patients are routinely counseled and advised regarding the risks of CR-BSIs and catheter care before central line insertion. Central line infections as well as bacteremia are well documented risks of chronic intravenous therapy and may significantly contribute to morbidity and mortality. Recent reports have suggested a possible increase in CR-BSI; therefore, the Scientific Leadership Council of the Pulmonary Hypertension Association decided to provide guidelines for good clinical practice regarding catheter care. Although data exits regarding patients with central venous catheters and the risk of blood stream infections in patients with cancer or other disorders, there is little data regarding the special needs of patients with pulmonary arterial hypertension requiring central venous access. These guidelines are extrapolated from the diverse body of literature regarding central venous catheter care.

Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, McLaughlin VV, Anonymous00036. · University of Colorado Health Sciences Center, Denver, CO 80262, USA. · Chest. · Pubmed #15249494 links to  free full text

Abstract: Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

Barst RJ. · No affiliation provided · Am J Med. · Pubmed #15006594 No free full text.

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McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ, Anonymous00037. · No affiliation provided · Circulation. · Pubmed #19332472 No free full text.

This publication has no abstract.

Rosenzweig EB, Barst RJ. · Columbia University College of Physicians & Surgeons, New York, NY 10032, USA. · Curr Opin Pediatr. · Pubmed #18475097 No free full text.

Abstract: PURPOSE OF REVIEW: With rapid advances in the understanding and treatment of pulmonary arterial hypertension, navigating the pediatric literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations will provide insight into the current management of pediatric pulmonary hypertension patients. RECENT FINDINGS: Recent therapeutic advances have significantly improved the prognosis for children with pulmonary arterial hypertension. Pediatric pulmonary arterial hypertension continues to be a serious condition, however, which is extremely challenging to manage. There are also new target groups, such as those with sickle cell disease, congenital diaphragmatic hernia and Eisenmenger syndrome who may be candidates for treatments previously used for idiopathic pulmonary arterial hypertension patients. SUMMARY: The data in children are often limited to case reports as many of those described here. Thus, the reader needs to be cautious about the interpretation of such small uncontrolled studies. While many of these data support the rationale for using novel agents for children with pulmonary arterial hypertension, further controlled and well designed studies are necessary to assess the true impact of these agents on various subgroups of children with pulmonary arterial hypertension.

Barst RJ. · New York Presbyterian Pulmonary Hypertension Center, Columbia University College of Physicians & Surgeons, 3959 Broadway, BHN 2-255, NewYork, NY 10032, USA. · Vasc Health Risk Manag. · Pubmed #17583171 links to  free full text

Abstract: Pulmonary arterial hypertension (PAH) is a rare fatal disease. Current disease-specific therapeutic interventions in PAH target 1 of 3 established pathways in disease pathobiology: prostacyclin, nitric oxide, and endothelin-1. Endothelin receptor antagonists (ERAs) act on the endothelin pathway by blocking binding of endothelin-1 to its receptors (endothelin type-A [ET(A)] and/or type-B [ET(B)]) on the surface of endothelial and smooth muscle cells. Ambrisentan is an oral, once-daily, ET(A)-selective ERA in development for the treatment of PAH. In Phase 3 clinical trials in patients with PAH, ambrisentan (2.5-10 mg orally once-daily) improved exercise capacity, Borg dyspnea index, time to clinical worsening, WHO functional class, and quality of life compared with placebo. Ambrisentan provided durable (at least 2 years) improvement in exercise capacity in a Phase 2 long-term extension study. Ambrisentan was well tolerated with a lower incidence and severity of liver function test abnormalities compared with the ET(A)/ET(B) ERA, bosentan, and the ET(A)-selective ERA, sitaxsentan. Ambrisentan does not induce or inhibit P450 enzymes; therefore, ambrisentan is unlikely to affect the pharmacokinetics of P450-metabolized drugs. The demonstration of clinical efficacy, low incidence of acute hepatic toxicity, and low risk of drug-drug interactions support the role of ambrisentan for the treatment of PAH.

Barst RJ. · Columbia University College of Physicians and Surgeons, 3959 Broadway, BHN 2-255, New York, NY 10032, USA. · Expert Opin Pharmacother. · Pubmed #17163810 No free full text.

Abstract: Pulmonary arterial hypertension (PAH) is a progressive, life-threatening condition. Sitaxsentan, a selective endothelin-A receptor antagonist, is an effective, safe and well-tolerated endothelin receptor antagonist for the treatment of PAH in adult patients. Multi-center, randomized, placebo-controlled clinical trials have demonstrated that sitaxsentan has beneficial effects on exercise capacity (i.e., 6-min walk distance), functional class and hemodynamic parameters in PAH patients. Sitaxsentan has a low incidence of acute hepatotoxicity. Patients on concomitant warfarin require a decrease in warfarin dose to maintain a therapeutic international normalized ratio. The demonstration of clinical efficacy and low incidence of acute hepatotoxicity support the potential use of sitaxsentan for the treatment of PAH.

Widlitz AC, Barst RJ, Horn EM. · Pulmonary Hypertension Center, Columbia University College of Physicians and Surgeons, BHN 2-255, New York, NY 10032, USA. · Expert Rev Cardiovasc Ther. · Pubmed #16292989 No free full text.

Abstract: Sitaxsentan is an orally active, selective endothelin-A receptor antagonist that may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictive effects of endothelin-A receptors, while maintaining the vasodilator and endothelin-1 clearance functions of the endothelin-B receptors. In its first randomized, placebo-controlled study, sitaxsentan improved exercise capacity assessed by the 6-min walk test, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association Class II, III and IV patients with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension related to connective tissue disease or congenital heart disease. Although doses of 100 and 300 mg once daily demonstrated equivalent efficacy, the lower dose had a better safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg once-daily dosing. The most common side effects include rhinitis, headache, peripheral edema, chest pain, nausea, constipation, increased prothrombin time/international normalized ratio (in patients on warfarin), flushing and insomnia. As with other endothelin receptor antagonists, increases in hepatic transaminases have been observed with sitaxsentan. Initial studies using the selective oral endothelin-A receptor antagonist sitaxsentan in pulmonary arterial hypertension patients have revealed a favorable risk-benefit therapeutic profile with the 100 mg once-daily dose.

Barst RJ. · New York Presbyterian Pulmonary Hypertension Center, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA. · J Clin Invest. · Pubmed #16200204 links to  free full text

Abstract: The pathobiology of pulmonary arterial hypertension (PAH) includes endothelial cell dysfunction and proliferation and migration of VSMCs. As PDGF has been implicated in these processes, Schermuly et al. hypothesized that altered PDGF signaling may be involved in the vascular remodeling observed in PAH. To explore this notion further, the authors evaluated the effects of the PDGF receptor inhibitor STI571 in 2 different animal models of pulmonary hypertension. In both models, after development of pulmonary vascular disease, administration of STI571 reversed pulmonary vascular changes. These studies provide preclinical proof of concept for the clinical development of a PDGF inhibitor as a targeted therapy for PAH patients.

Rosenzweig EB, Barst RJ. · Department of Pediatrics, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA. · Curr Opin Pediatr. · Pubmed #15891429 No free full text.

Abstract: PURPOSE OF REVIEW: Until recently, the diagnosis of idiopathic pulmonary arterial hypertension was virtually a death sentence, particularly for children. Although there is no cure for idiopathic pulmonary arterial hypertension, recent medical advances have dramatically changed the course of this disease in children. A review of some of the latest medical advances will provide the reader with a better understanding of the most current treatment options for children with idiopathic pulmonary arterial hypertension. RECENT FINDINGS: The literature reviewed demonstrate sustained clinical and hemodynamic improvement in children with various types of pulmonary arterial hypertension as well as increased survival in patients with idiopathic pulmonary arterial hypertension using current treatment strategies. SUMMARY: This article will provide an overview of how the current diagnostic and treatment strategies of idiopathic pulmonary arterial hypertension in children have advanced over the last several years and how this impacts on clinical practice.

Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. · Pulmonary and Critical Care Division, University of California, San Diego, California, USA. · J Am Coll Cardiol. · Pubmed #15194180 No free full text.

Abstract: Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation.

Badesch DB, McLaughlin VV, Delcroix M, Vizza CD, Olschewski H, Sitbon O, Barst RJ. · University of Colorado Health Sciences Center, Denver, Colorado, USA. · J Am Coll Cardiol. · Pubmed #15194179 No free full text.

Abstract: Prostanoids have played a prominent role in the treatment of pulmonary arterial hypertension (PAH). Several compounds and methods of administration have been studied: chronic intravenously infused epoprostenol, chronic subcutaneously infused treprostinil, inhaled iloprost, and oral beraprost. Chronic intravenous epoprostenol therapy has had a substantial impact on the clinical management of patients with severe PAH. It improves exercise capacity, hemodynamics, and survival in patients with idiopathic pulmonary arterial hypertension (IPAH). It also improves exercise capacity and hemodynamics in patients with PAH occurring in association with scleroderma. The complexity of epoprostenol therapy (chronic indwelling catheters, reconstitution of the drug, operation of the infusion pump, and others) has led to attempts to develop other prostanoids with simpler modes of delivery. Treprostinil, a stable prostacyclin analogue with a half-life of 3 h, has been developed for subcutaneous delivery. It has beneficial effects on exercise and hemodynamics, which depend somewhat on the dose achieved. This, in turn, is determined by the patient's ability to tolerate the drug's side effects, including pain and erythema at the infusion site. Inhaled iloprost therapy may provide selectivity of the hemodynamic effects to the lung vasculature, thus avoiding systemic side effects. In a randomized and controlled trial, iloprost resulted in improvement in a combined end point incorporating the New York Heart Association functional class, 6-min walk test, and deterioration or death. Beraprost is the first orally active prostacyclin analogue. In the first of two randomized controlled trials, beraprost increased exercise capacity in patients with IPAH, with no significant changes in subjects with associated conditions. Hemodynamics did not change significantly, and no difference in survival was detected between the two treatment groups. The second study showed that beraprost-treated patients had less disease progression at six months and confirmed the results of the previous trial. However, this improvement was no longer present at 9 or 12 months. In conclusion, though treatment with prostanoids is complicated by their generally short half-lives and complicated drug delivery systems, they continue to play an important role in the treatment of PAH.

Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S. · Columbia University College of Physicians and Surgeons, New York, New York, USA. · J Am Coll Cardiol. · Pubmed #15194177 No free full text.

Abstract: Pulmonary arterial hypertension (PAH) is diagnosed by various investigations that are essential for making the diagnosis, and by additional tests to clarify the category of pulmonary hypertension (PH). A diagnostic algorithm can guide the evaluation of PH, but like all guidelines the algorithm can be modified according to specific clinical circumstances. Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed during screening of asymptomatic populations at risk. Right heart catheterization (RHC) must be performed in patients with suspected PH to establish the diagnosis and document pulmonary hemodynamics. Before initiation of medical therapy, assessment of acute vasoreactivity (during catheterization) is necessary to determine the appropriate therapy for an individual patient. An acute response is generally defined as a decrease in mean pulmonary arterial pressure of at least 10 mm Hg with the mean pulmonary arterial pressure decreasing to 40 mm Hg or below, accompanied by a normal or high cardiac output. After PAH is diagnosed, disease severity should be assessed in order to accurately determine risk:benefit profiles for various therapeutic options. Useful tools to predict outcome include functional class, exercise capacity, pulmonary hemodynamics, acute vasoreactivity, right ventricular function, as well as brain natriuretic peptide, endothelin-1, uric acid, and troponin levels. Repeating these tests serially on treatment is useful for monitoring the response to a given therapy. Close follow-up at a center specializing in management of PH is recommended, with careful periodic reassessment and adjustment of therapy.

Rosenzweig EB, Widlitz AC, Barst RJ. · Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10027, USA. · Pediatr Pulmonol. · Pubmed #15170869 No free full text.

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.

Widlitz A, Barst RJ. · Dept of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA. · Eur Respir J. · Pubmed #12570125 links to  free full text

Abstract: For physicians to admit that a group of patients remains for whom no cure is available in modern medicine is intellectually unsatisfying. Pulmonary arterial hypertension is a rare condition. Because the symptoms are nonspecific and the physical finding can be subtle, the disease is often diagnosed in its later stages. The natural history of pulmonary arterial hypertension is usually progressive and fatal. At the 1998 Primary Pulmonary Hypertension World Symposium, clinical scientists from around the world gathered to review and discuss the future of pulmonary arterial hypertension. Bringing together experts from a variety of disciplines provided the opportunity for a better understanding of the pathology, pathobiology, risk factors, genetics, diagnosis and treatment for pulmonary arterial hypertension. 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 pathobiological mechanisms. Risk factors have been identified and the genetics have been characterised. 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 interventions, e.g. transplantation and blade septostomy, which were unavailable several decades ago, have had a significant impact on prognosis and outcome. Thus, despite the inability to really cure pulmonary arterial hypertension, therapeutic advances over the past two decades have resulted in significant improvements in the outcome for children with various forms of pulmonary arterial hypertension. This review of pulmonary arterial hypertension will highlight the key features of pulmonary hypertension in infants and children and the current understanding of pulmonary arterial hypertension with specific recommendations for current practice and future directions.

Horn EM, Barst RJ. · Departments of Medicine and Pediatrics, New York Presbyterian Pulmonary Hypertension Center, New York, NY, USA. · Expert Opin Investig Drugs. · Pubmed #12437507 No free full text.

Abstract: Pulmonary artery hypertension is a life-threatening disease characterised by a pulmonary vasculopathy and progressive right ventricular failure. Major advances were made with the development of continuous intravenous epoprostenol (Flolan trade mark ) as a treatment modality. Nevertheless, it is far from ideal as treatment for this disease. Subcutaneous treprostinil has been FDA approved for the treatment of New York Heart Association Functional Class II - IV pulmonary artery hypertension. It is a longer acting subcutaneous prostacyclin analogue that offers an additional mode of therapy for this disease. A discussion of the pharmacology of this prostacyclin analogue as compared to its related compounds, the clinical studies which led to its approval, a review of some additional basic studies and the practical use of this drug in the treatment modalities for precapillary pulmonary artery hypertension in 2002 in light of other available therapies is discussed.

Berman EB, Barst RJ. · Division of Pediatric Cardiology, Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, NY, USA. · Prog Cardiovasc Dis. · Pubmed #12411974 No free full text.

Abstract: Eisenmenger's syndrome describes the elevation of pulmonary arterial pressure to the systemic level caused by increased pulmonary vascular resistance with reversal or bi-directional shunting through a large intracardiac or extracardiac congenital heart defect. This article reviews the natural history and pathophysiology of Eisenmenger's syndrome untreated and medical and surgical treatment options presently available. Although there is no cure for this condition at present, recent advances in management have improved the quality of life for many patients with Eisenmenger's syndrome.

Barst RJ. · Department of Pediatrics, Columbia University College of Physicians and Surgeons, Division of Pediatric Cardiology, Pulmonary Hypertension Center, New York Presbyterian Hospital, New York, New York, USA. · Clin Chest Med. · Pubmed #11590844 No free full text.

Abstract: Therapeutic medical advances over the past two decades have resulted in significant improvements in the outcome for patients with various forms of pulmonary arterial hypertension. As the current understanding of the pathology and pathobiology of pulmonary arterial hypertension has moved forward, rationale for additional therapeutic modalities with novel therapeutic agents has led to increased clinical investigations. A brief overview of the pathology and pathobiology is presented as background for an introduction to the current medical therapy for pulmonary arterial hypertension as well as the goals for future treatment.

Berman Rosenzweig E, Barst RJ. · New York Presbyterian Hospital, Division of Pediatric Cardiology, 3959 Broadway, Babies and Children's Hospital of New York, New York, NY 10032, USA. · Expert Opin Investig Drugs. · Pubmed #11322859 No free full text.

Abstract: The treatment of paediatric pulmonary arterial hypertension is challenging due to the serious nature of the disease, its rapid progression and the limited treatment options available. However, recent advances in the treatment of pulmonary arterial hypertension may offer significant improvements for patients suffering from this condition. Novel treatment options include prostacyclin analogues and endothelin receptor antagonists. A comprehensive review of the newer agents, with an emphasis on the pathobiology/pathophysiology of pulmonary arterial hypertension provides insight into future management of paediatric pulmonary arterial hypertension.

Frantz RP, Benza RL, Kjellström B, Bourge RC, Barst RJ, Bennett TD, McGoon MD. · Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · J Heart Lung Transplant. · Pubmed #18582809 No free full text.

Abstract: BACKGROUND: The purpose of this study was to determine whether an implantable hemodynamic monitor (IHM) could be used to judge the response of pulmonary arterial hypertension (PAH) patients to changes in therapy. METHODS: A prospective, non-randomized, multi-center study evaluated physical examination, functional class, echocardiography, brain natriuretic peptide (BNP) levels, exercise capacity assessed by 6-minute walk and cardiopulmonary exercise tests, and quality of life at baseline and at 12 weeks. IHM measurements were continuously available to clinicians between clinic visits. Based on a priori, pre-specified analyses, the relationships between hemodynamic values, PAH treatments and clinical parameters were tracked in an observational fashion. RESULTS: Twenty-four PAH patients underwent IHM implantation prior to a change in PAH therapy. IHM data identified 13 of the 15 patients who improved their 6-minute walk distance by >30 m at 12 weeks (+48 +/- 65 m, p < 0.05), whereas the others walked less (-78 +/- 115 m, not statistically significant). In addition, peak Vo(2), BNP levels and Minnesota Living with Heart Failure Questionnaire scores only improved in the former group. The change in mean pulmonary artery pressure correlated with the change in 6-minute walk distance at 12 weeks (r = -0.71, p < 0.001). Device-related adverse events were comparable to those known to occur with a pacemaker-like device. CONCLUSIONS: Changes in ambulatory continuous hemodynamic measurements predicted changes in 6-minute walk distance after the start or addition of PAH therapy. The IHM also identified patients who had improved exercise tolerance, BNP levels and quality of life. The IHM appeared to be well tolerated and allowed rapid hemodynamic feedback between clinic visits.

Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galiè N, Simonneau G, Anonymous00349. · Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. · J Rheumatol. · Pubmed #17985403 No free full text.

Abstract: OBJECTIVE: Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is difficult to manage, and has a poor prognosis. The phosphodiesterase-5 inhibitor sildenafil citrate enhances vasodilatation, has antiproliferative effects, and is effective in the treatment of PAH. We examined the efficacy and safety of oral sildenafil in patients with PAH-CTD. METHODS: In a 12-week, double-blind study (SUPER-1), 278 patients with PAH were randomized to oral placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg 3 times daily (tid). In a post-hoc subgroup analysis of 84 patients with PAH-CTD, exercise capacity, hemodynamic measures, World Health Organization functional class, and tolerability were assessed. RESULTS: Forty-five percent of the patients had scleroderma, 23% had systemic lupus erythematosus, and the rest (32%) were categorized as other. Patients were predominantly functional class II (38%) or III (61%) at baseline. Sildenafil-treated patients exhibited mean increases in 6-minute walk distance at Week 12 of 42 m (95% CI 20, 64) for 20 mg, 36 m (95% CI 14, 58) for 40 mg, and 15 m (95% CI -24, 54) for 80 mg, while placebo-treated patients exhibited a mean decrease of 13 m (95% CI -36, 10). Improvement of at least 1 functional class occurred in 29%-42% of sildenafil-treated patients, compared to 5% for placebo. Significant improvements in mean pulmonary arterial pressure and pulmonary vascular resistance were observed with sildenafil 20 mg, and sildenafil was generally well tolerated. CONCLUSION: In patients with PAH-CTD, sildenafil improves exercise capacity, hemodynamic measures (at the 20 mg dose), and functional class after 12 weeks of treatment.

Gomberg-Maitland M, Huo D, Benza RL, McLaughlin VV, Tapson VF, Barst RJ. · Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. · J Heart Lung Transplant. · Pubmed #17613405 No free full text.

Abstract: BACKGROUND: The 6-minute walk test (6MWT) is the current standard to assess exercise capacity in pulmonary arterial hypertension (PAH). We compared the Naughton-Balke treadmill test reported in exercise metabolic equivalents (METs) with the 6MWT to evaluate whether MET could be a useful tool to assess exercise capacity. METHODS: Serial 6MWTs followed by Naughton-Balke treadmill tests were performed in 47 PAH patients initiating a change in PAH therapy at baseline (i.e., Time 0) and Weeks 6, 12, 24 and 48; New York Heart Association (NYHA) functional class (FC) was also assessed. Hemodynamics data were recorded at baseline and Weeks 12 and 48. Treadmill time was converted to MET. Generalized estimating equation models, receiver-operating characteristic curves and fixed-effect linear models were utilized to create a model comparing 6MWT to MET. RESULTS: MET correlated with 6MWT (r = 0.62). Piecewise linear function described the relationship between 6MWT and MET. 6MWT and MET were both associated with FC (p < 0.001) with similar ability to discriminate FC. Changes in hemodynamics in response to a change in PAH therapy correlated with changes in both 6MWT and MET. In less sick patients (i.e., FC II), the changes in 6MWT were less pronounced than with MET. CONCLUSIONS: MET appears to be a reliable measure of exercise capacity in PAH, and correlates with 6MWT. MET can be used in clinical assessment and is helpful in demonstrating improvements in exercise capacity in less sick patients.

Karamanoglu M, McGoon M, Frantz RP, Benza RL, Bourge RC, Barst RJ, Kjellström B, Bennett TD. · NT & D Research, Medtronic Inc, 7000 Central Ave NE, CW320, Fridley, MN 55432, USA. · Chest. · Pubmed #17505045 links to  free full text

Abstract: BACKGROUND: Cardiac index is an important determinant of outcome in patients with idiopathic pulmonary artery hypertension (IPAH). An implantable hemodynamic monitor (IHM) [Chronicle; Medtronic; Minneapolis, MN; a system limited to investigational use only] that records right ventricular (RV) pressure waveforms continuously may increase our understanding of IPAH and improve therapeutic selections and outcomes. The aim of this study was to investigate whether the RV pressure waveform utilizing an IHM can be used to estimate the magnitude of pressure wave reflection and cardiac index in patients with IPAH in acute settings. METHODS: In eight patients with pulmonary arterial hypertension, RV pressure waveforms were recorded utilizing the IHM, and breath-by-breath cardiac index was recorded during acute IV epoprostenol infusion at 3, 6 and 9 ng/kg/min. Late systolic pressure augmentation and cardiac index were estimated using the RV pressure waveforms and correlated with direct measurement of cardiac index. RESULTS: At baseline, the cardiac index was 2.1 +/- 0.2 L/min/m(2), total pulmonary resistance index was 38 +/- 2 Wood U/m(2), and RV systolic pressure was 92 +/- 4 mm Hg. Wave reflection accounted for 29 +/- 1 mm Hg of the RV systolic pressure. During epoprostenol infusion, total pulmonary resistance index and wave reflection decreased (- 15 +/- 4 Wood U/m(2), p < 0.001, and - 5 +/- 2 mm Hg, p < 0.05, respectively). The breath-by-breath cardiac index correlated with the RV pressure waveform cardiac index estimates (r(2) = 0.95). CONCLUSIONS: RV pressure waveform analysis provides continuous hemodynamic assessments including cardiac index in acute settings. Once confirmed in long-term settings, this information may prove useful in optimizing a treatment regimen in patients with IPAH.

Tapson VF, McLaughlin VV, Gomberg-Maitland M, Widlitz AC, Krichman AD, Laliberte KJ, Zaccardelli DS, Barst RJ. · Duke University Medical Center, Durham, NC 27710, USA. · J Vasc Access. · Pubmed #17019662 No free full text.

Abstract: PURPOSE: Treprostinil is approved for the treatment of pulmonary arterial hypertension (PAH) via continuous intravenous (IV) infusion. Treprostinil's anti-platelet aggregation characteristics and stability at room temperature may allow for low infusion rates (0.1-0.2 mL/hr) using a miniaturized infusion pump. METHODS: A 12-week, multi-center, open-label study in 12 adult PAH patients, evaluated the feasibility and safety of low-flow IV treprostinil administration via the 407C miniaturized pump. Patients receiving IV treprostinil at a stable dose were transitioned from their current CADD-Legacy pump to the 407C and were assessed for adverse events including catheter occlusions, pump alarms, and efficacy (six minute walk distance (6MWD), Borg Dyspnea Score (BDS), NYHA functional class, and PAH signs/symptoms). All patients were also maintained on therapeutic doses of warfarin, heparin or low molecular weight heparin throughout the study. RESULTS: Baseline mean (+/-SD) 6MWD was 477 +/- 76 m (n = 9) with mean BDS of 2.1 +/- 1.2 (n = 9). Week 12 mean 6MWD and BDS were 500 +/- 92 m and 2.3 +/- 1.7, respectively (n = 9). Four patients discontinued the study prematurely (3 AEs and 1 consent withdrawn). Adverse events included headache, flushing, and nausea. Pump complications occurred in 5 of 12 patients, and although no catheter occlusions occurred in any patient during the 12-week study, further study is needed regarding pump complications. CONCLUSION: This study demonstrates that treprostinil can be administered intravenously at infusion rates as low as 0.1 mL/hr for 12 weeks without catheter occlusions. Further studies are warranted because the potential for adverse events is of some concern.