Robyn J Barst

Publications (116)920.42 Total impact

• Source

  Available from: Peter Dorfmuller

  Dataset: Germain-2013-NG(1)

  Marine Germain, Mélanie Eyries, David Montani, Odette Poirier, Barbara Girerd, Peter Dorfmüller, Florence Coulet, Sophie Nadaud, Svetlana Maugenre, Christophe Guignabert, [......], Ivan M Robbins, Anna R Hemnes, James E Loyd, Erika Berman-Rosenzweig, Robyn J Barst, Wendy K Chung, Gerald Simonneau, David A Trégouët, Marc Humbert, Florent Soubrier
• Source

  Available from: David Montani

  Dataset: GWAS CBLN2 - Germain - Nature Genetics 2013 online first

  Marine Germain, Mélanie Eyries, David Montani, Odette Poirier, Barbara Girerd, Peter Dorfmüller, Florence Coulet, Sophie Nadaud, Svetlana Maugenre, Christophe Guignabert, [......], Ivan M Robbins, Anna R Hemnes, James E Loyd, Erika Berman-Rosenzweig, Robyn J Barst, Wendy K Chung, Gerald Simonneau, David A Trégouët, Marc Humbert, Florent Soubrier
• Source

  Available from: Marion Delcroix

  Article: Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension.

  Marine Germain, Mélanie Eyries, David Montani, Odette Poirier, Barbara Girerd, Peter Dorfmüller, Florence Coulet, Sophie Nadaud, Svetlana Maugenre, Christophe Guignabert, [......], Ivan M Robbins, Anna R Hemnes, James E Loyd, Erika Berman-Rosenzweig, Robyn J Barst, Wendy K Chung, Gerald Simonneau, David A Trégouët, Marc Humbert, Florent Soubrier
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  ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.
  Nature Genetics 03/2013; · 35.53 Impact Factor
• Article: Functional Class Improvement and Three-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry.

  Robyn J Barst, Lorinda Chung, Roham T Zamanian, Michelle Turner, Michael D McGoon
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  ABSTRACT: ABSTRACT OBJECTIVE: New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival versus patients who remain at FC III or worsen to FC IV. METHODS: Patients aged ≥19 years with FC III PAH from the REVEAL Registry (N=982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-minute walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by etiology (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly and previously diagnosed [diagnostic right heart catheterization within or ≥3 months of enrollment, respectively]). RESULTS: Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84%±2%; n=263) versus those who remained unchanged (66%±2%; n=645) or worsened (29%±6%; n=74) (all P<.001). Survival was also better in patient subgroups whose FC improved versus those who remained unchanged (idiopathic/familial [P<.001], CTD-associated PAH [P=.009], whether newly [P=.004] or previously diagnosed [P<.001]. 6MWD improvements were greater in patients whose FC improved versus those who remained unchanged in the overall (P<.001) and CTD (P=.028) cohorts. CONCLUSION: Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH etiology, have better survival versus patients who remain FC III.ClinicalTrials.gov Registration Number: NCT00370214.
  Chest 02/2013; · 5.25 Impact Factor
• Article: Imatinib Mesylate as Add-On Therapy for Pulmonary Arterial Hypertension: Results of the Randomized IMPRES Study.

  Marius M Hoeper, Robyn J Barst, Robert C Bourge, Jeremy Feldman, Adaani E Frost, Nazzareno Galié, Miguel Angel Gómez-Sánchez, Friedrich Grimminger, Ekkehard Grünig, Paul M Hassoun, Nicholas W Morrell, Andrew J Peacock, Toru Satoh, Gérald Simonneau, Victor F Tapson, Fernando Torres, David Lawrence, Deborah A Quinn, Hossein-Ardeschir Ghofrani
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  ABSTRACT: BACKGROUND: By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: IMPRES, a randomized, double-blind, placebo-controlled 24-week trial evaluated imatinib in patients with pulmonary vascular resistance (PVR) ≥800 dynes•sec•cm(-5) symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance (6MWD). Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide (NT-proBNP), and time to clinical worsening (TTCW). After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment-effect on 6MWD was 32 m (95% confidence interval [CI], 12, 52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. PVR decreased by 379 dynes•sec•cm(-5) (95% CI: -502, -255; P<0.001; between-group difference). Functional class, TTCW and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30%, 33% versus 18% respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. CONCLUSIONS: Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Identifier: NCT00902174 (core study); NCT01392495 (extension).
  Circulation 02/2013; · 14.74 Impact Factor
• Article: Clinical trials in neonates and children: Report of the pulmonary hypertension academic research consortium pediatric advisory committee.

  Ian Adatia, Sheila G Haworth, Max Wegner, Robyn J Barst, Dunbar Ivy, Kurt R Stenmark, Abraham Karkowsky, Erika Rosenzweig, Christopher Aguilar
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  ABSTRACT: Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal.
  Pulmonary circulation. 01/2013; 3(1):252-66.
• Article: Congenital heart disease and pulmonary hypertension: pharmacology and feasibility of late surgery.

  Erika B Rosenzweig, Robyn J Barst
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  ABSTRACT: Pulmonary arterial hypertension (PAH) with increased pulmonary vascular resistance (PVR), previously termed pulmonary vascular obstructive disease or pulmonary vascular disease is a frequent complication of congenital heart disease (CHD).While there have been advances in the medical treatments available for classic Eisenmenger syndrome patients who are not suitable for repair, the sub-group of patients with moderate sized congenital systemic to pulmonary shunts and mild to moderately elevated PVR remains challenging. With the development of targeted medical treatments for pulmonary arterial hypertension (PAH), the concept of a combined medical and interventional/surgical approach for patients with PAH associated with CHD (APAH-CHD) has emerged. Careful evaluation and an understanding of the predominant physiologic features will help guide the management of these complex patients and whether late surgical repair is feasible.
  Progress in cardiovascular diseases 09/2012; 55(2):128-33. · 4.25 Impact Factor
• Article: Bloodstream Infections in Patients With Pulmonary Arterial Hypertension Treated With Intravenous Prostanoids: Insights From the REVEAL REGISTRY(®).

  Natalie Kitterman, Abby Poms, Dave P Miller, Sandra Lombardi, Harrison W Farber, Robyn J Barst
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  ABSTRACT: To evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY(®), which provides current information about patients with PAH. Patients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk. Of 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol. Compared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors. clinicaltrials.gov Identifier: NCT00370214.
  Mayo Clinic Proceedings 08/2012; 87(9):825-34. · 5.70 Impact Factor
• Article: Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study.

  Ronald J Oudiz, Bruce H Brundage, Nazzareno Galiè, Hossein Ardeschir Ghofrani, Gerald Simonneau, Fady T Botros, Melanie Chan, Anthony Beardsworth, Robyn J Barst
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  ABSTRACT: The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension. Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening. Eligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated. The safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events. Long-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302).
  Journal of the American College of Cardiology 07/2012; 60(8):768-74. · 14.16 Impact Factor
• Article: Demographics and Outcomes of Patients Diagnosed With Pulmonary Hypertension With Pulmonary Capillary Wedge Pressures of 16-18 mmHg: Insights From REVEAL.

  Adaani E Frost, Harrison W Farber, Robyn J Barst, Dave P Miller, C Gregory Elliott, Michael D McGoon
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  ABSTRACT: ABSTRACT BACKGROUND:The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL) is a multicenter, US-based, observational study of patients diagnosed with group 1 pulmonary hypertension enrolled consecutively from March 2006-December 2009. Of 3128 patients in this analysis, inclusion criteria permitted enrollment of 268 patients with mean pulmonary capillary wedge pressure (PCWP) of 16-18 mmHg at diagnostic right heart catheterization (RHC) (above currently accepted PAH diagnostic criteria). This study compared the demographics and outcomes of those 268 patients with an elevated mean PCWP to patients with a mean PCWP ≤15 mmHg. METHODS:Demographic characteristics and outcomes were compared for patients with mean PCWP ≤12, 13-15, and 16-18 mmHg at diagnostic and follow-up RHC. RESULTS:At diagnostic RHC, patients with PCWP 16-18 mmHg were older, had more severe hemodynamic impairments, were more likely to be obese, and have other comorbidities than patients with PCWP ≤15 mmHg. There were no clinically relevant differences in 5-year survival from diagnostic RHC regardless of PCWP at diagnosis (≤15 vs 16-18 mmHg; P=0.07). Two-year survival of 108 PAH patients whose PCWP increased to ≥19 mmHg (regardless of PCWP at diagnosis) was significantly poorer than that of PAH patients with PCWP ≤18 mmHg at subsequent RHC. CONCLUSION:Patients with PCWP 16-18 mmHg who were diagnosed and treated for PAH were older, heavier, and more likely to have comorbidities associated with left ventricular diastolic dysfunction at diagnosis than those with PCWP ≤15 mmHg. Five-year survival was similarly poor for all PCWP subgroups.ClinicalTrials.gov Registration Number: NCT00370214.
  Chest 05/2012; · 5.25 Impact Factor
• Article: Vasodilator Testing with Nitric Oxide and/or Oxygen in Pediatric Pulmonary Hypertension

  Robyn J. Barst, Gabriella Agnoletti, Alain Fraisse, James Baldassarre, David L. Wessel, For the NO Diagnostic Study Group
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  ABSTRACT: The objective of this study was to determine whether a combination of inhaled nitric oxide (iNO) and O2 is more effective than 100% O2 or iNO alone for acute vasodilator testing in children. An open, prospective, randomized, controlled trial was conducted at 16 centers. Subjects were children 4weeks to 18years of age with pulmonary hypertension (PH) and increased pulmonary vascular resistance (PVR) undergoing right heart catheterization for acute vasodilator testing. All patients were tested with each of three agents (80ppm iNO, 100% O2, combination of 80ppm iNO/100% O2) in three 10-min treatment periods, and hemodynamic measurements obtained. Primary outcome measures were percentages of acute responders with O2 alone vs. iNO/O2 and iNO alone vs. iNO/O2. More patients on the combination were acute responders compared with O2 or iNO alone (26% vs. 14%, P=0.019, and 27% vs. 24%, P=0.602, respectively). Changes in PVR index and mean pulmonary arterial pressure vs. baseline were greater with iNO/O2 vs. either O2 or iNO alone (P<0.001). Survival at 1-year follow-up included (1) 90.9% of acute responders to the combination, compared with 77.8% of nonresponders to the combination, and (2) 85.7% of acute responders to O2 alone, compared with 80.6% of nonresponders to O2. Key conclusions are as follows. In children with PH and increased PVR, more acute responders were identified with the iNO/O2 combination vs. O2 alone. While there was no significant difference in acute responder rate with iNO alone vs. iNO/O2, the combination improved pulmonary hemodynamics acutely better than iNO alone. One-year survival data show similar rates between the iNO/O2 and the O2 alone groups; however, the combination may be more effective than O2 alone in discriminating survivors versus nonsurvivors at long-term follow-up. Keywords(MeSH headings) Nitric oxide-Diagnostic techniques-Cardiovascular-Hypertension-Pulmonary
  Pediatric Cardiology 04/2012; 31(5):598-606. · 1.30 Impact Factor
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  Available from: David Dunbar Ivy

  Article: Clinical perspectives with long-term pulsed inhaled nitric oxide for the treatment of pulmonary arterial hypertension.

  Robyn J Barst, Richard Channick, Dunbar Ivy, Brahm Goldstein
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  ABSTRACT: Pulmonary arterial hypertension (PAH) is a chronic, progressive disease of the pulmonary vasculature with a high morbidity and mortality. Its pathobiology involves at least three interacting pathways - prostacyclin (PGI(2)), endothelin, and nitric oxide (NO). Current treatments target these three pathways utilizing PGI(2) and its analogs, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE-5) inhibitors. Inhaled nitric oxide (iNO) is approved for the treatment of hypoxic respiratory failure associated with pulmonary hypertension in term/near-term neonates. As a selective pulmonary vasodilator, iNO can acutely decrease pulmonary artery pressure and pulmonary vascular resistance without affecting cardiac index or systemic vascular resistance. In addition to delivery via the endotracheal tube, iNO can also be administered as continuous inhalation via a facemask or a pulsed nasal delivery. Consistent with a deficiency in endogenously produced NO, long-term pulsed iNO dosing appears to favorably affect hemodynamics in PAH patients, observations that appear to correlate with benefit in uncontrolled settings. Clinical studies and case reports involving patients receiving long-term continuous pulsed iNO have shown minimal risk in terms of adverse events, changes in methemoglobin levels, and detectable exhaled or ambient NO or NO(2). Advances in gas delivery technology and strategies to optimize iNO dosing may enable broad-scale application to long-term treatment of chronic diseases such as PAH.
  Pulmonary circulation. 04/2012; 2(2):139-47.
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  Available from: David Dunbar Ivy

  Article: Clinical features of paediatric pulmonary hypertension: a registry study.

  Rolf M F Berger, Maurice Beghetti, Tilman Humpl, Gary E Raskob, D Dunbar Ivy, Zhi-Cheng Jing, Damien Bonnet, Ingram Schulze-Neick, Robyn J Barst
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  ABSTRACT: Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension. Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients' physicians according to the individual's health-care needs. 362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m(-2)). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3-12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent with preserved right-heart function. TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies. Actelion Pharmaceuticals.
  The Lancet 02/2012; 379(9815):537-46. · 38.28 Impact Factor
• Article: An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.

  Raymond L Benza, Dave P Miller, Robyn J Barst, David B Badesch, Adaani E Frost, Michael D McGoon
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  ABSTRACT: The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was established to characterize the clinical course, treatment, and predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the United States. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL Registry cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation. Newly or previously diagnosed patients (aged ≥ 3 months at diagnosis) with PAH enrolled from March 2006 to December 2009 at 55 US centers were included in the current analysis. A total of 2,635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91% ± 2%, 74% ± 2%, 65% ± 3%, and 59% ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation. Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past 2 decades since the establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts
  Chest 01/2012; 142(2):448-56. · 5.25 Impact Factor
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  Available from: David Dunbar Ivy

  Article: A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension.

  Robyn J Barst, D Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Alberto E Garcia, B K S Sastry, Tomas Pulido, Gary R Layton, Marjana Serdarevic-Pehar, David L Wessel
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  ABSTRACT: Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. http://www.clinicaltrials.gov. Unique identifier: NCT00159913.
  Circulation 11/2011; 125(2):324-34. · 14.74 Impact Factor
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  Available from: David Dunbar Ivy

  Article: Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management.

  Robyn J Barst, Michael D McGoon, C Gregory Elliott, Aimee J Foreman, Dave P Miller, D Dunbar Ivy
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  ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m(2), respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts (P=0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P=0.087) and lower brain natriuretic peptide (P=0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. URL: www.clinicaltrials.gov. Unique identifier: NCT00370214.
  Circulation 11/2011; 125(1):113-22. · 14.74 Impact Factor
• Article: PET imaging may provide a novel biomarker and understanding of right ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension.

  Sabahat Bokhari, Amresh Raina, Erika Berman Rosenweig, P Christian Schulze, Justin Bokhari, Andrew J Einstein, Robyn J Barst, Lynne L Johnson
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  ABSTRACT: The clinical course in pulmonary arterial hypertension (PAH) is variable, and there is limited information on the determinants and progression of right ventricular (RV) dysfunction. The objective is to develop PET metabolic imaging of the RV as a noninvasive tool in patients with PAH. We performed PET scanning in 16 patients with idiopathic PAH (age, 41±14 years, 82% women) using (13)N-NH(3) for perfusion imaging and (18)F-fluorodeoxyglucose for metabolic imaging. The myocardium was divided into 6 regions of interest (3 left ventricular [LV], 3 RV), and time-activity curves were generated. A 2- compartment model was used to calculate myocardial blood flow (MBF), and Patlak analysis was used to calculate the rate of myocardial glucose uptake (MGU). All patients underwent cardiac catheterization, cardiac MRI, and cardiopulmonary exercise testing with gas exchange. MBF, MGU, and the ratio of RV/LV MGU were correlated to clinical parameters. Pulmonary artery (PA) pressure was 79±19/30±8 mm Hg (mean, 48±10 mm Hg). MBF was 0.84±0.33 mL/g per minute for the LV and 0.45±0.14 mL/g per minute for the RV. Mean MGU was 136±72 nmol/g per minute for the LV and 96±69 nmol/g per minute for the RV. The ratio of RV/LV MGU correlated significantly with PA systolic (r=0.75, P=0.0085) and mean (r=0.87, P=0.001) pressure and marginally with maximum oxygen consumption (r=-0.59, P=0.05). RV free wall MGU also correlated well with mean PA pressure (r=0.66, P=0.03). PET scanning with (13)N-NH(3) and (18)F-fluorodeoxyglucose is a feasible modality for quantifying RV blood flow and metabolism in patients with idiopathic PAH.
  Circulation Cardiovascular Imaging 09/2011; 4(6):641-7. · 5.94 Impact Factor
• Article: Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom.

  Vandana Sachdev, Gregory J Kato, J Simon R Gibbs, Robyn J Barst, Roberto F Machado, Mehdi Nouraie, Kathryn L Hassell, Jane A Little, Dean E Schraufnagel, Lakshmanan Krishnamurti, [......], Claudia R Morris, Erika Berman Rosenzweig, David B Badesch, Sophie Lanzkron, Oswaldo L Castro, James G Taylor, Hwaida Hannoush, Jonathan C Goldsmith, Mark T Gladwin, Victor R Gordeuk
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  ABSTRACT: Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively. Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the U.S. and U.K. Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean±SD, 2.8±0.1) in 26% of the subjects and ≥3.0 m/s (mean±SD, 3.4±0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity ≥2.7 m/s. Increased hemolysis (P<0.0001), LV lateral E/e' ratio (P=0.0001), blood urea nitrogen (P=0.0002), and erythropoietin (P=0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P<0.0001), older age (P<0.0001), LV lateral E/e' ratio (P=0.014), and tricuspid regurgitation velocity (P=0.019) were independent predictors of a shorter 6-minute walk distance. Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00492531.
  Circulation 09/2011; 124(13):1452-60. · 14.74 Impact Factor
• Article: Portopulmonary hypertension: a report from the US-based REVEAL Registry.

  Michael J Krowka, Dave P Miller, Robyn J Barst, Darren Taichman, Raed A Dweik, David B Badesch, Michael D McGoon
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  ABSTRACT: We evaluated survival and hospitalization rates in patients with group 1 portopulmonary hypertension (PoPH) in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry). The REVEAL Registry is a multicenter, observational, US-based study evaluating demographics and management of patients with pulmonary arterial hypertension (PAH). Outcomes were examined using Kaplan-Meier time-to-event estimates and compared with patients with idiopathic PAH (IPAH) or familial PAH (FPAH). One hundred seventy-four patients with PoPH were enrolled in the REVEAL Registry (IPAH/FPAH; n = 1,478) from March 2006 to December 2009. Mean age was 53 ± 10 years, 52% were female, 32% were newly diagnosed, and 6% were New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH vs IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%, P < .001), 5-year survival from time of diagnosis (40% vs 64%, P < .001), and 2-year freedom from all-cause hospitalization (49% vs 59%, P = .019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH vs IPAH/FPAH, respectively: mean pulmonary artery pressure (49 mm Hg vs 53 mm Hg, P < .001), mean right atrial pressure (9 mm Hg vs 10 mm Hg, P = .005), pulmonary vascular resistance (8 Wood units vs 12 Wood units, P < .001), and cardiac output (5 L/min vs 4 L/min, P < .001). Compared with patients with IPAH/FPAH, patients with PoPH were less likely to be on a PAH-specific therapy at enrollment (P < .001), suggesting potential delays in therapy for patients with PoPH. Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with patients with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.
  Chest 07/2011; 141(4):906-15. · 5.25 Impact Factor
• Article: Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management.

  Shelley Shapiro, Glenna L Traiger, Michelle Turner, Michael D McGoon, Prieya Wason, Robyn J Barst
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  ABSTRACT: Pulmonary arterial hypertension (PAH) is a life-threatening disease that affects more women than men. The reasons for the female preponderance are unclear, and there are limited data available for men with PAH. Data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) were analyzed to explore sex differences among patients with PAH with regard to 2-year survival from enrollment and 5-year survival from time of diagnosis. The data set included 2,318 women and 651 men. More women had PAH associated with connective tissue disease (P < .001), and more men had portopulmonary hypertension (P < .001) and HIV-associated PAH (P < .001). More women had congenital heart disease-associated PAH (P = .017), thyroid disease (P < .001), and depression reported (P ≤ .001). At diagnosis, men had higher mean pulmonary artery pressure (53 ± 14 vs 51 ± 14.3 mm Hg; P = .013) and mean right atrial pressure (10 ± 6 vs 9 ± 6 mm Hg; P = .031). Women had better survival estimates for 2 years from enrollment and for 5 years from diagnosis. Stratifying by age showed that survival from enrollment was similar between men and women aged < 60 years at enrollment, whereas men aged ≥ 60 years have lower survival rates compared with women aged ≥ 60 years. Our findings highlight similarities and differences between men and women with PAH, raising questions for future exploration regarding the role of hormones and sex in causation and survival in PAH. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.
  Chest 07/2011; 141(2):363-73. · 5.25 Impact Factor