Hypertension: Badesch DB

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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Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. · University of Colorado Health Sciences Center, Box C-272, 4200 E. Ninth Ave, Denver, CO 80262, USA. · Chest. · Pubmed #17565025 links to  free full text

Abstract: A consensus panel convened by the American College of Chest Physicians developed guidelines for the treatment of pulmonary arterial hypertension (PAH) that were published in 2004. Subsequently, several important clinical trials have been published, and new treatments have received regulatory approval. In addition, add-on and combination therapy are being explored, which promise to open new therapeutic avenues. This article, taking into consideration studies published prior to September 1, 2006, provides an update to the previously published guidelines. The original guidelines have been summarized, a discussion of new studies has been added, and the treatment algorithm has been revised to take into account recent developments in therapy. This update provides evidence-based treatment recommendations for physicians involved in the care of patients with PAH. Due to the complexity of the diagnostic evaluation required and the treatment options available, referral of patients with PAH to a specialized center continues to be strongly recommended.

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.

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.

Ventetuolo CE, Benza RL, Peacock AJ, Zamanian RT, Badesch DB, Kawut SM. · Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Proc Am Thorac Soc. · Pubmed #18625754 links to  free full text

Abstract: Pulmonary arterial hypertension is a rare and often devastating disease, although various effective therapies are now available. Clinical trials have used hemodynamic, cardiac imaging, laboratory, and exercise measurements as surrogate and intermediate end points in pulmonary arterial hypertension. Yet, based on the current literature, it is difficult to surmise which of these (if any) have been definitively validated. In addition, investigators have advocated the use of combined clinical end points in future clinical trials. The dependence of clinical trials and clinical management on such end points warrants a review of their use.

Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. · Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. · Eur Respir J. · Pubmed #16319344 links to  free full text

Abstract: The association between autoimmunity and pulmonary arterial hypertension (PAH) has been appreciated for >40 yrs, but how autoimmune injury might contribute to the pathogenesis of this disease has only been examined in a case-specific manner. It is becoming increasingly clear that a variety of diverse clinical diseases, ranging from viral infections to connective tissue disorders, can culminate in pulmonary vascular pathology that is indistinguishable. Is there a hitherto unappreciated biology that unites these seemingly unrelated conditions? The answer to this question may come from the increasing body of evidence concerned with the central importance of regulatory T-cells in preventing inappropriate B-cell activity. Two striking similarities between conditions associated with severe angioproliferative pulmonary hypertension are a defect in the CD4 T-cell compartment and auto-antibody production. Pathogenic auto-antibodies targeting endothelial cells are capable of inducing vascular endothelial apoptosis and may initiate the development of PAH. The present review will focus on what is known about autoimmune phenomena in pulmonary arterial hypertension patients, in order to better consider whether an early loss of self-tolerance followed by autoimmune injury could influence the early development of severe angioproliferative pulmonary hypertension.

Rubin LJ, Badesch DB. · University of California, San Diego, Medical Center, La Jolla, California 92037-7381, USA. · Ann Intern Med. · Pubmed #16103472 links to  free full text

Abstract: Increased pressure in the pulmonary circulation, or pulmonary hypertension, is a common disorder that may complicate various cardiopulmonary conditions, including severe obstructive airways disease and left ventricular dysfunction. An increase in pulmonary arterial pressure that is not due to coexistent cardiopulmonary disease, known as pulmonary arterial hypertension, may occur in the absence of a demonstrable cause (idiopathic or familial); as a complication of systemic conditions, such as connective tissue disease, HIV infection, or chronic liver disease; or as a result of the use of fenfluramine anorexigens, amphetamines, or cocaine. The development of disease-specific therapies for pulmonary arterial hypertension over the past decade underscores the importance of diagnosing pulmonary hypertension early in the course of the condition and implementing a treatment strategy that is based on the condition's cause and severity. In this review, the authors present approaches to the diagnosis and management of pulmonary arterial hypertension, using a hypothetical case to highlight the key management points.

Bull TM, Fagan KA, Badesch DB. · Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, University of Colorado School of Medicine, 4200 East Ninth Avenue, Box C-272, Denver, CO 80262, USA. · Rheum Dis Clin North Am. · Pubmed #16084318 No free full text.

Abstract: Mixed connective tissue disease (MCTD) refers to a disease process with combined clinical features characteristic of systemic lupus erythematous, scleroderma, and polymyositis-dermatomyositis. This article focuses on the pulmonary vasculature manifestations of MCTD. We briefly discuss associations between MCTD and interstitial lung disease, pleural disease, and alveolar hemorrhage.

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.

Fagan KA, Badesch DB. · Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, CO, USA. · Prog Cardiovasc Dis. · Pubmed #12525998 No free full text.

Abstract: Pulmonary arterial hypertension is a life threatening complication of several connective tissue diseases including scleroderma (both diffuse and limited scleroderma, or the CREST syndrome--calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangectasia), systemic lupus erythomatosis (SLE), mixed connective tissue disease (MCTD), and less commonly, rheumatoid arthritis (RA) and dermatomyositis/polymyositis. This report reviews the occurrence of this complication, potential etiologies, clinical presentation, and treatment options.

McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin VV, Gerber MJ, Dufton C, Despain DJ, Rubin LJ. · Mayo Clinic, Rochester, MN 55905, USA. · Chest. · Pubmed #18812445 No free full text.

Abstract: BACKGROUND: Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. METHODS: Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs. RESULTS: Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. CONCLUSIONS: Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. Trial registration: Clinicaltrials.gov Identifier NCT00423592.

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.

McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, Rainisio M, Simonneau G, Rubin LJ. · University of Michigan, 1500 East Medical Center Drive, Women's Hospital, Room L3119, Ann Arbor, MI, USA. · Eur Respir J. · Pubmed #15684287 links to  free full text

Abstract: Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, Robbins IM, Tapson VF, McGoon MD, Badesch DB, Sigman J, Roscigno R, Blackburn SD, Arneson C, Rubin LJ, Rich S, Anonymous00171. · Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA. · J Cardiovasc Pharmacol. · Pubmed #12548091 No free full text.

Abstract: Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension, but it requires intravenous infusion and is associated with adverse effects. The objective of this study was to evaluate the effects of an epoprostenol analog, treprostinil, for management of pulmonary hypertension. Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials. In the first trial, intravenous epoprostenol and intravenous treprostinil were compared. In the second trial, intravenous treprostinil and subcutaneous treprostinil were compared. In the third trial, subcutaneous treprostinil was compared with placebo infusion during an 8-week period. Intravenous epoprostenol and intravenous treprostinil resulted in a similar reduction in pulmonary vascular resistance acutely (22% and 20%, respectively). Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance (23% and 28%, respectively). The placebo-controlled 8-week trial demonstrated a mean improvement of 37 +/- 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 +/- 28 m reduction in those receiving placebo. There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group. Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term. Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system.

Langleben D, Christman BW, Barst RJ, Dias VC, Galiè N, Higenbottam TW, Kneussl M, Korducki L, Naeije R, Riedel A, Simonneau G, Hirsch AM, Rich S, Robbins IM, Oudiz R, McGoon MD, Badesch DB, Levy RD, Mehta S, Seeger W, Solèr M. · Jewish General Hospital, McGill University, Montreal, Quebec, Canada. · Am Heart J. · Pubmed #12040360 No free full text.

Abstract: BACKGROUND: Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH). METHODS: To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied. RESULTS: Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P <.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites. CONCLUSION: Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered.

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. · Division of Pulmonary and Critical Care Medicine, University of California at San Diego, La Jolla 92037-1330, USA. · N Engl J Med. · Pubmed #11907289 links to  free full text

Abstract: BACKGROUND: Endothelin-1 is a potent vasoconstrictor and smooth-muscle mitogen. In a preliminary study, the orally administered dual endothelin-receptor antagonist bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension. The present trial investigated the effect of bosentan on exercise capacity in a larger number of patients and compared two doses. METHODS: In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening. RESULTS: At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening. CONCLUSIONS: The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension.

Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. · Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA, USA. · Lancet. · Pubmed #11597664 No free full text.

Abstract: BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galiè N, Gibbs JS, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. · Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0273, USA. · J Am Coll Cardiol. · Pubmed #19555863 No free full text.

Abstract: New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. · Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80045, USA. · J Am Coll Cardiol. · Pubmed #19555859 No free full text.

Abstract: The diagnosis and assessment of pulmonary arterial hypertension is a rapidly evolving area, with changes occurring in the definition of the disease, screening and diagnostic techniques, and staging and follow-up assessment. The definition of pulmonary hypertension has been simplified, and is now based on currently available evidence. There has been substantial progress in advancing the imaging techniques and biomarkers used to screen patients for the disease and to follow up their response to therapy. The importance of accurate assessment of right ventricular function in following up the clinical course and response to therapy is more fully appreciated. As new therapies are developed for pulmonary arterial hypertension, screening, prompt diagnosis, and accurate assessment of disease severity become increasingly important. A clear definition of pulmonary hypertension and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to deriving maximal benefit from our expanding therapeutic armamentarium.

Jing ZC, Xu XQ, Badesch DB, Jiang X, Wu Y, Liu JM, Wang Y, Pan L, Li HP, Pu JL, Zhang ZL, Yang YJ. · Shanghai Pulmonary Hospital, Tongji University, Shanghai, China. · Respir Med. · Pubmed #19403296 No free full text.

Abstract: BACKGROUND: Although previous studies have shown that peripheral airway obstruction can occur in idiopathic PAH (IPAH), pulmonary function tests have not been well-studied in patients with PAH associated with congenital heart disease (CHD-PAH) and connective tissue disease (CTD-PAH). METHODS: A multicenter prospective study was performed in PAH patients in China. Pulmonary function tests were evaluated in 190 PAH patients. RESULTS: Total lung capacity (TLC), residual volume (RV) and total airway resistance (Rtot) were similar in PAH patients and controls. However, measures of airflow, including vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1s (FEV(1)), FEV(1)/FVC and MEF(50) were decreased in PAH group. Single-breath diffusion capacity for carbon monoxide (DL(CO)) was also decreased in PAH patients. Expiratory flow-volume curves showed reduction and a curvilinear appearance in patients with PAH. Similar changes were observed among the various subgroups of IPAH, CHD-PAH, and CTD-PAH patients. More CTD-PAH patients had abnormal DL(CO). CONCLUSIONS: Airway obstruction is common in IPAH, CHD-PAH and CTD-PAH patients. CTD-PAH patients have lower DL(CO). Hemodynamics, serum markers and exercise capacity parameters did not correlate well with pulmonary function indices.

Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, Tighiouart H, Knowles JA, Rabinowitz D, Benza RL, Badesch DB, Taichman DB, Horn EM, Zacks S, Kaplowitz N, Kawut SM, Anonymous00040. · Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA. · Am J Respir Crit Care Med. · Pubmed #19218192 No free full text.

Abstract: RATIONALE: Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood. OBJECTIVES: To identify genetic risk factors for PPHTN in patients with advanced liver disease. METHODS: We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dynes.s(-1).cm(-5), and pulmonary capillary wedge pressure < or =15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient. MEASUREMENTS AND MAIN RESULTS: The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P < 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels. CONCLUSIONS: Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.

Roberts KE, Fallon MB, Krowka MJ, Benza RL, Knowles JA, Badesch DB, Brown RS, Taichman DB, Trotter J, Zacks S, Horn EM, Kawut SM, Anonymous00078. · Department of Medicine, Tufts Medical Center, Boston, MA, USA. · Chest. · Pubmed #19141529 No free full text.

Abstract: BACKGROUND: The long allele of a functional promoter polymorphism in the serotonin transporter (SERT) is associated with an increased risk of some forms of pulmonary arterial hypertension. We hypothesized that the long allele or other polymorphisms in SERT would be associated with an increased risk of portopulmonary hypertension (PPHTN) in patients with advanced liver disease. METHODS: We performed a multicenter case-control study. Subjects undergoing liver transplant evaluation at seven centers were prospectively screened for the presence of PPHTN using transthoracic echocardiography. PPHTN was confirmed by right heart catheterization using standard criteria. RESULTS: The study sample included 30 case patients with PPHTN and 109 control subjects with advanced liver disease. There was no significant association between the long allele and case status in an adjusted additive model (odds ratio, 0.63; 95% confidence interval, 0.33 to 1.21; p = 0.17). If anything, LL genotype tended to be associated with a lower risk of PPHTN. There were no associations between other SERT polymorphisms and PPHTN. CONCLUSIONS: SERT polymorphisms are not associated with the risk of PPHTN in patients with advanced liver disease. Other clinical or genetic risk factors may play a role in this complication of portal hypertension.

Simonneau G, Rubin LJ, Galiè N, Barst RJ, Fleming TR, Frost AE, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch DB, Anonymous00031. · Service de Pneumologie, Hôpital Antoine Béclère, Université Paris-Sud, Clamart, France. · Ann Intern Med. · Pubmed #18936500 links to  free full text

Abstract: BACKGROUND: Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension. OBJECTIVE: To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension. DESIGN: A 16-week, double-blind, placebo-controlled, parallel-group study. SETTING: Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006. PATIENTS: 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy. INTERVENTION: Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study. MEASUREMENTS: Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points). RESULTS: A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]). LIMITATIONS: The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis. CONCLUSION: In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.

Benza RL, Barst RJ, Galie N, Frost A, Girgis RE, Highland KB, Strange C, Black CM, Badesch DB, Rubin L, Fleming TR, Naeije R. · University of Alabama at Birmingham, 1900 University Blvd, Tinsley Harrison Towers, Room 328A, Birmingham, AL 35294, USA. · Chest. · Pubmed #18625676 No free full text.

Abstract: BACKGROUND: Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study. METHODS: The present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve Impaired Exercise-2 trial. All-cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan at 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods, and treatment effects are evaluated using the Cox proportional hazards model. RESULTS: Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels > 3 x upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels > 3 x ULN at 1 year and a 30% risk of discontinuation due to adverse events. CONCLUSIONS: At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.

Kawut SM, Krowka MJ, Trotter JF, Roberts KE, Benza RL, Badesch DB, Taichman DB, Horn EM, Zacks S, Kaplowitz N, Brown RS, Fallon MB, Anonymous00073. · Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, 622 West 168th Street, PH 8E, Room 101, New York, NY 10032, USA. · Hepatology. · Pubmed #18537192 No free full text.

Abstract: Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case-control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes x second x cm(-5), and pulmonary capillary wedge pressure < or = 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right-sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio = 2.90, 95% confidence interval 1.20-7.01, P = 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio = 4.02, 95% confidence interval 1.14-14.23, P = 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio = 0.24, 95% confidence interval 0.09-0.65, P = 0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension. CONCLUSION: Female sex and autoimmune hepatitis were associated with an increased risk of portopulmonary hypertension, whereas hepatitis C infection was associated with a decreased risk in patients with advanced liver disease. Hormonal and immunologic factors may therefore be integral to the development of portopulmonary hypertension.