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Hypertension: Riociguat therapy for pulmonary hypertension. (36)

FK506 in PAH (1)

Transitioning between endothelin receptor blockers: monitoring to ensure a smooth transition. (8)

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. (16)

- And 33 other publications
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1. J Clin Invest. 2013 Aug 1;123(8):3600-13. doi: 10.1172/JCI65592. Epub 2013 Jul 15.

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.

Spiekerkoetter ETian XCai JHopper RKSudheendra DLi CGEl-Bizri NSawada HHaghighat RChan R,Haghighat Lde Jesus Perez VWang LReddy SZhao MBernstein DSolow-Cordero DEBeachy PAWandless TJTen Dijke PRabinovitch M.

Abstract

Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.
PMCID: PMC3726153 Free PMC Article
  PMID: 23867624 [PubMed - in process]
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2. Cardiol Young. 2013 Jul 18:1-3. [Epub ahead of print]

An unusual cause of refractory persistent pulmonary hypertension of the newborn: anomalous origin of one pulmonary artery.

Guzoglu NSari FNAltug N.
Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey.

Abstract

Persistent pulmonary hypertension of the newborn is a source of considerable mortality and morbidity. Anomalous origin of one pulmonary artery, an uncommon congenital cardiac malformation, is a rare cause of persistent pulmonary hypertension. Here, we report the case of a patient with an anomalous origin of one pulmonary artery from the innominate artery who presented with persistent pulmonary hypertension refractory to treatment.
  PMID: 23866972 [PubMed - as supplied by publisher]
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3. Am Heart J. 2013 Jun;165(6):1024-31. doi: 10.1016/j.ahj.2013.02.027. Epub 2013 Apr 6.

Prognostic significance of 2-dimensional, M-mode, and Doppler echo indices of right ventricular function in children with pulmonary arterial hypertension.

Kassem EHumpl TFriedberg MK.
The Labatt Family Heart Center, Division of Cardiology, Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON, Canada.

Abstract

BACKGROUND:

Echocardiographic measures of right ventricular (RV) function are associated with adverse outcomes in adults with idiopathic pulmonary arterial hypertension (iPAH) but have not been adequately studied in children. We investigated the prognostic value of 2D, M-mode and Doppler indices of RV function in relation to death or lung transplant in children with iPAH and PAH associated with congenital heart diseases (cPAH).

METHODS:

Children with iPAH and cPAH were studied. Two echocardiograms were analyzed for each patient: at diagnosis and at last follow-up. Clinical data, catheter hemodynamics and 6-minute walk distance were recorded. Echo indices of RV function were compared between the first and follow-up echo, between iPAH and cPAH patients, and between iPAH patients alive at follow-up versus those who had died or had undergone lung transplant. Survival probability stratified by RV function was analyzed.

RESULTS:

Fifty-four children were studied: 36 cPAH patients (7.5 ± 5.9 years) and 18 iPAH patients (8.9 ± 5.7 years) of whom 12 were alive and 6 had died or were transplanted. Despite similar pulmonary hemodynamics, RV function, including right atrial volume, tricuspid annular planar excursion, fractional area of change, and left ventricular eccentricity index were worse in iPAH at presentation and at follow-up. At last echo there was further worsening of RV function in iPAH patients, particularly in those who had died or were transplanted, compared with improved or unchanged indices in cPAH patients or iPAH survivors.

CONCLUSION:

Conventional echo RV functional parameters are valuable to identify risk for transplant or death in children with PAH.
Copyright © 2013 Mosby, Inc. All rights reserved.
  PMID: 23708176 [PubMed - indexed for MEDLINE]
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4. Hosp Pract (1995). 2013 Apr;41(2):62-71. doi: 10.3810/hp.2013.04.1049.

Hepatopulmonary syndrome and portopulmonary hypertension.

Restrepo RSinger EFBaram MRestrepo RSinger EFBaram M.
Department of Medicine, Division of Pulmonary Critical Care Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

Abstract

Hepatopulmonary syndrome and portopulmonary hypertension are 2 of many diseases that affect the lungs in patients with liver disease. The 2 vascular conditions are often confused. We review both hepatopulmonary syndrome and portopulmonary hypertension to better understand their pathophysiologies, clinical presentations, tools to aid in differentiating and diagnosing the disease states, treatment options, and influences on patient prognosis. We also consider patient viability for liver transplantation.
  PMID: 23680738 [PubMed - indexed for MEDLINE]
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5. Orphanet J Rare Dis. 2013 Apr 4;8:52. doi: 10.1186/1750-1172-8-52.

Effective treatment of malignant atrophic papulosis (Köhlmeier-Degos disease) with treprostinil--early experience.

Shapiro LSToledo-Garcia AEFarrell JF.
Steffens Scleroderma Center, Saratoga Springs, NY, USA. leeshapiromd@gmail.com

Abstract

BACKGROUND:

Malignant atrophic papulosis (Köhlmeier-Degos disease; MAP) is an uncommon endotheliopathy with pathological findings similar to the vascular lesions of systemic sclerosis. These two disorders can overlap. When associated with visceral lesions, MAP has been considered almost universally and rapidly fatal. A recent report described dramatic response to treatment with eculizumab, but disease progression after initial response to therapy has occurred.

METHODS:

We describe the clinical and pathologic findings in two patients, one with MAP and the other with MAP like lesions, who received treatment with subcutaneous treprostinil. One patient had an overlap syndrome with features of systemic lupus erythematosus (SLE) and scleroderma and severe pulmonary hypertension. She also had very extensive MAP like cutaneous lesions. There was no evidence of central nervous system (CNS) disease and laparoscopy revealed no visible MAP lesions on the serosa of the small bowel. The second patient had experienced life-threatening disease progression despite ongoing eculizumab therapy. During this treatment, he had developed CNS and bladder involvement with neurologic symptoms and gross hematuria.

RESULTS:

Patient one was placed on therapy with treprostinil for her pulmonary hypertension, but in the months subsequent to initiation of treatment, dramatic and complete resolution of cutaneous MAP like lesions and disabling digital pain occurred. In patient two, therapy with treprostinil was temporally associated with clearing of hematuria, resolution of CNS symptoms and improvement in MRI findings.

CONCLUSIONS:

Treprostinil may offer a second effective treatment approach to individuals with MAP or "rescue therapy" to those in whom eculizumab treatment has failed to maintain suppression of disease activity.
PMCID: PMC3636001 Free PMC Article
  PMID: 23557362 [PubMed - indexed for MEDLINE]
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6. Laryngoscope. 2013 Jun;123(6):1527-30. doi: 10.1002/lary.23865. Epub 2013 Apr 2.

Hearing loss with phosphodiesterase-5 inhibitors: a prospective and objective analysis with tadalafil.

Thakur JSThakur SSharma DRMohindroo NKThakur ANegi PC.
Department of Otolaryngology-Head and Neck Surgery, Indira Gandhi Medical College, Shimla, India.anujagdeep@yahoo.co.in

Abstract

OBJECTIVES/HYPOTHESIS:

To assess the effect of tadalafil on auditory functions.

STUDY DESIGN:

Prospective observational study in a tertiary care hospital.

METHODS:

Twenty-five tadalafil naïve patients with erectile dysfunction or pulmonary artery hypertension were subjected to pure-tone and brainstem-evoked response audiometry before drug therapy, and 3 and 30 days following drug therapy. Results were compared using analysis of variance for repeated measures with Bonferonni correction.

RESULTS:

Fifteen patients were taking tadalafil 10 mg for erectile dysfunction, and another 10 patients were on tadalafil 20 mg once daily for pulmonary artery hypertension. No statistically significant difference was found in hearing threshold at baseline and at follow-up (P > .05). However, three patients on tadalafil 20 mg showed a significant increase in hearing threshold at higher frequencies. There was no incidence of sudden sensorineural hearing loss in the study group.

CONCLUSIONS:

This is the first prospective and observational study that evaluated the effect of tadalafil on auditory functions with objective tests. Although there was no statistically significant result to confirm or refute the association between tadalafil and hearing impairment, increased threshold at higher frequencies after taking tadalafil supports the results from previous studies and hints at a possible relationship between the two. Similar large sample studies are warranted to know the exact association of phosphodiesterase-5 inhibitors on auditory functions.
Copyright © 2012 The American Laryngological, Rhinological and Otological Society, Inc.
  PMID: 23553123 [PubMed - indexed for MEDLINE]
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7. Can J Cardiol. 2013 Jun;29(6):683-90. doi: 10.1016/j.cjca.2012.09.019. Epub 2012 Dec 20.

Pulmonary artery pulse wave velocity in idiopathic pulmonary arterial hypertension.

Kopeć GMoertl DJankowski PTyrka ASobień BPodolec P.
Department of Cardiac and Vascular Diseases at John Paul II Hospital, Krakow, Poland.gkopec@szpitaljp2.krakow.pl

Abstract

BACKGROUND:

Idiopathic pulmonary artery (PA) hypertension (IPAH) is associated with severe PA remodelling. Although the resulting increase in pulse wave velocity (PWV) might be of major pathophysiological relevance, little is known about PA-PWV in IPAH. The aim of this study was to characterize PA-PWV and its predictors in patients with IPAH.

METHODS:

We studied 26 consecutive patients with incident IPAH aged 55.0 (45.0-66.0) years (62% female) and 10 control subjects without pulmonary hypertension. PA-PWV was measured invasively; PA wall thickness and diameter were assessed using intravascular and transthoracic ultrasonography.

RESULTS:

PA-PWV was higher in IPAH than in control subjects (10.0 [7.5-14.0] m/s vs 3.5 [1.9-4.0] m/s; P < 0.001) as was also PA diameter and PA wall thickness. In IPAH patients, in univariate analysis PA-PWV was greater in men than in women and in patients with body mass index (BMI) < 25 kg/m(2) than with BMI ≥ 25 kg/m(2) and correlated positively with symptomatic disease duration, mean PA pressure, pulmonary vascular resistance, creatinine level, and negatively with low-density lipoprotein (LDL) cholesterol and triglyceride level but not with PA diameter or PA wall thickness. In multiple regression analysis mean PA pressure, LDL cholesterol level and BMI < 25 kg/m(2) were the main predictors of PA-PWV in IPAH patients (R(2) = 77%; P < 0.001).

CONCLUSIONS:

PA-PWV is increased in IPAH patients. High PA pressure, low LDL cholesterol level, and BMI < 25 kg/m(2) explain most of its variability in this group.
Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
  PMID: 23260799 [PubMed - indexed for MEDLINE]
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8. Can J Cardiol. 2013 Jun;29(6):659-61. doi: 10.1016/j.cjca.2012.07.006. Epub 2012 Sep 15.

Transitioning between endothelin receptor blockers: monitoring to ensure a smooth transition.

Luo NRyan JJ.

Comment on

Hemodynamic stability after transitioning between endothelin receptor antagonists in patients with pulmonary arterial hypertension.Fox B, Langleben D, Hirsch AM, Schlesinger RD, Eisenberg MJ, Joyal D, Blenkhorn F, Lesenko L. Can J Cardiol. 2013 Jun; 29(6):672-7. Epub 2012 Jul 21.
  PMID: 22985784 [PubMed - indexed for MEDLINE]
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9. Can J Cardiol. 2013 Jun;29(6):672-7. doi: 10.1016/j.cjca.2012.05.013. Epub 2012 Jul 21.

Hemodynamic stability after transitioning between endothelin receptor antagonists in patients with pulmonary arterial hypertension.

Fox BLangleben DHirsch AMSchlesinger RDEisenberg MJJoyal DBlenkhorn FLesenko L.
Center for Pulmonary Vascular Disease, Jewish General Hospital and McGill University, Montreal, Québec, Canada.

Comment in

Transitioning between endothelin receptor blockers: monitoring to ensure a smooth transition.Luo N, Ryan JJ. Can J Cardiol. 2013 Jun; 29(6):659-61. Epub 2012 Sep 15.

Abstract

BACKGROUND:

Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.

METHODS:

We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data.

RESULTS:

Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of ≥5 mm Hg, and 4 had pulmonary artery wedge pressure increase of ≥5 mm Hg.

CONCLUSIONS:

Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures.
Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
  PMID: 22819360 [PubMed - indexed for MEDLINE]
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10. Can J Cardiol. 2013 Jun;29(6):678-82. doi: 10.1016/j.cjca.2012.04.009. Epub 2012 Jun 19.

Incidence and significance of pericardial effusion in patients with pulmonary arterial hypertension.

Shimony AFox BDLangleben DRudski LG.
Center for Pulmonary Vascular Disease and Division of Cardiology, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, Québec, Canada.

Abstract

BACKGROUND:

The incidence of pericardial effusion (PEF) during long-term follow-up among patients with pulmonary arterial hypertension (PAH) is unknown. We aimed to determine the incidence and prognostic significance of developing a new PEF among PAH patients.

METHODS:

Records of consecutive patients diagnosed with PAH between January 1990 and May 2010 were reviewed. Patients had systematically undergone right heart catheterization, transthoracic echocardiography, and coronary angiography during their initial assessment as well as routine echocardiograms during follow-up. Effusions were graded as small (echo-free space in diastole <10 mm), moderate (10-20 mm), or large (≥ 20 mm).

RESULTS:

The entire cohort consisted of 154 patients. The prevalence of identified PEF during initial assessment was 28.6%. The incidence of PEF among patients with no effusions who had additional echocardiographic studies during follow-up (n = 102) was 44.1%. Patients who developed PEF during follow-up had no differences with respect to baseline characteristics, associated aetiologies, hemodynamic parameters, and extent of coronary disease. Among these 102 patients, survival estimates were 94.9%, 75.0%, and 62.4% at 1, 3, and 5 years, respectively. Development of a PEF that was at least moderate-sized at its first appearance was a predictor of mortality in univariate (hazard ratio, 6.85; 95% confidence interval, 2.60-18.10) as well as multivariate analysis (hazard ratio, 3.95; 95% confidence interval, 1.26-12.40).

CONCLUSIONS:

PEF develops frequently in PAH patients. In patients with no PEF at baseline, the appearance of a new moderate-size or larger PEF is associated with increased mortality, whereas no significantly increased mortality was observed when a small PEF develops.
Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
  PMID: 22717247 [PubMed - indexed for MEDLINE]
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11. Chest. 2013 Jul 1;144(1):329-40. doi: 10.1378/chest.12-1752.

Perioperative risk and management in patients with pulmonary hypertension.

Minai OAYared JPKaw RSubramaniam KHill NS.

Abstract

Pulmonary hypertension (PH) is a known risk factor for perioperative complications. Unlike in the case of cardiac surgery, PH is currently not listed as an independent risk factor for postoperative complications in guidelines for the management of noncardiac surgery. Despite the paucity of data, though, patients with PH are often counseled against having elective procedures because early and sudden postoperative deaths have been reported. Patients with PH are unable to accommodate alterations in right ventricular (RV) preload or afterload induced by fluid shifts, medications, or changes in the autonomic nervous system precipitated by hypoxia or hypercapnia. These factors become magnified in situations of added stress such as surgical intervention. Systemic hypotension and arrhythmias may precipitate RV ischemia, further worsening RV function. Patient and surgical characteristics and choice of anesthetic technique are crucial factors in perioperative management. The two main principles of perioperative management are the prevention of systemic hypotension (risk of RV ischemia) and the prevention of acute elevations in pulmonary arterial pressure (risk of RV failure). Close monitoring, optimization of systemic BP, pain control, oxygenation and ventilation, avoidance of exacerbating factors, and use of vasopressors and pulmonary vasodilators as necessary are essential elements of management. Understanding the pathophysiology, cause, and severity of PH in the individual perioperative patient allows accurate risk assessment, optimization of PH and RV function prior to surgery, and appropriate intraoperative and postoperative management.
  PMID: 23880683 [PubMed - in process]
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12. Chest. 2013 Jul 1;144(1):274-83. doi: 10.1378/chest.12-1246.

Biomarkers in pulmonary hypertension: what do we know?

Foris VKovacs GTscherner MOlschewski AOlschewski H.

Abstract

Pulmonary hypertension (PH) is a hemodynamic condition that has a poor prognosis and can lead to right-sided heart failure. It may result from common diseases such as left-sided heart or lung disease or may present as the rare entity of idiopathic pulmonary arterial hypertension. Biomarkers that specifically indicate the pathologic mechanism, the severity of the disease, and the treatment response would be ideal tools for the management of PH. In this review, markers related to heart failure, inflammation, hemostasis, remodeling, and endothelial cell-smooth muscle cell interaction are discussed, and their limitations are emphasized. Anemia, hypocarbia, elevated uric acid, and C-reactive protein levels are unspecific markers of disease severity. Brain natriuretic peptide and N-terminal fragment of pro-brain natriuretic peptide have been recommended in current guidelines, whereas other prognostic markers, such as growth differentiation factor-15, osteopontin, and red cell distribution width, are emerging. Chemokines of the CC family and matrix metalloproteases have been linked to the vascular pathologic mechanisms, and new markers such as apelin have been described. Circulating endothelial and progenitor cells have received much attention as markers of disease activity, but with controversial findings. A lack of standards for cell isolation and characterization methods and differences in the pathologic mechanisms of the investigated patients may have contributed to the discrepancies. In conclusion, although several promising markers have been identified over the past few years, the development of more specific markers, standardization, and prospective validation are warranted.
  PMID: 23880678 [PubMed - in process]
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13. Curr Opin Pulm Med. 2013 Sep;19(5):562-74. doi: 10.1097/MCP.0b013e3283645a00.

Imaging techniques in chronic thromboembolic pulmonary hypertension.

Giannouli EMaycher B.
aSection of Respirology, Department of Internal Medicine bDepartment of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada.

Abstract

PURPOSE OF REVIEW:

Chronic thromboembolic pulmonary hypertension (CTEPH) can affect up to 4-5% of patients with acute pulmonary embolism. It is likely an underdiagnosed entity. Misdiagnosis is common because patients often present with nonspecific symptoms of pulmonary hypertension. Early diagnosis may help improve the outcome, as CTEPH is potentially curable with pulmonary thromboendarterectomy (PEA). Imaging is central to an accurate diagnosis, and for assessing correctly the technical feasibility of PEA. This review examines the findings of various imaging techniques in CTEPH and their contribution in the diagnostic and therapeutic evaluation of the disease.

RECENT FINDINGS:

Ventilation-perfusion scintigraphy remains a sensitive method for excluding CTEPH. Multidetector computed tomography angiography (MDCTA) depicts directly changes of CTEPH, provides a surgical 'road map', and should be used for the diagnostic assessment of all suitable patients with pulmonary arterial hypertension. In many centers, the role of conventional pulmonary angiography is gradually being replaced by cross-sectional methods. MRI has a role in preoperative and postoperative assessment of right ventricular function and can depict vascular abnormalities up to segmental level.

SUMMARY:

MDCTA in combination with MRI represent the main techniques for the diagnosis and management of CTEPH. Newer techniques such as dual spectrum computed tomography may further improve preoperative and postoperative assessment of CTEPH patients.
  PMID: 23880705 [PubMed - in process]
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14. J Thorac Cardiovasc Surg. 2013 Jul 18. pii: S0022-5223(13)00653-3. doi: 10.1016/j.jtcvs.2013.06.014. [Epub ahead of print]

Paracorporeal lung assist device: An innovative surgical strategy for bridging to lung transplant in an infant with severe pulmonary hypertension caused by alveolar capillary dysplasia.

Boston USFehr JGazit AZEghtesady P.
Division of Cardiothoracic Surgery, Department of Surgery, Saint Louis Children's Hospital, Washington University in Saint Louis, St Louis, Mo. Electronic address: bostonu@wudosis.wustl.edu.
  PMID: 23871141 [PubMed - as supplied by publisher]
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15. N Engl J Med. 2013 Jul 25;369(4):386-8. doi: 10.1056/NEJMe1306684.

Riociguat for pulmonary hypertension--a glass half full.

Archer SL.

Comment on

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, et al. N Engl J Med. 2013 Jul 25; 369(4):319-29.
Riociguat for the treatment of pulmonary arterial hypertension.Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, et al. N Engl J Med. 2013 Jul 25; 369(4):330-40.
  PMID: 23883383 [PubMed - indexed for MEDLINE]
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16. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657.

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.

Ghofrani HAD'Armini AMGrimminger FHoeper MMJansa PKim NHMayer ESimonneau GWilkins MR,Fritsch ANeuser DWeimann GWang CCHEST-1 Study Group.
Collaborators: Perna EWilliams TLang IKaehler CDelcroix MVachiery JLArakaki JWaetge DMeyer G,Granton JHirsch AHelmersen DMehta SMielniczuk LLiu ZWang CCheng ZJing ZPan LJansa P,Nielsen-Kudsk JSimonneau GFranchon IChaouat ADe Groote PBergot EBauer FDromer CMarquette CH,Ghofrani HAHoeper MNeurohr CWilkens HHoffken GRosenkranz SWirtz HEwert RGrünig EKlose H,Filusch AHeld MD'Armini AMorsolini MFukumoto YTanabe NSano MHatano MTakeda YSakuma M,Higo TSatoh TOhe MOwa MOkazaki OAjioka MIwabuchi MTakata MAkashi YBoonstra ADiaz C,Martinez UGamba MZamudio TTorbicki APodolec PCastro GLee SKim HMoiseeva OChernyavsky A,Simkova ISanchez MBarbera JSpeich RLin YHKarabiyikoglu GMogulkoc NOkumus GPepke-Zaba J,Peacock AHoward LAllen RSood NChaparro STorres FHeresi GZaiman AKerr KFarber HHansdottir SGhofrani HAGrimminger FHoeper MMKim NHMayer ESimonneau GWilkins MRKlepetko WLinder JJenkins DPMadani MMD'Armini AMBiederman AOlschewski HHaverkamp WLehmacher WHoischen SMenezes FKlein DHallman MColorado PFesske W.
University of Giessen and Marburg Lung Center, Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de

Comment in

Riociguat for pulmonary hypertension--a glass half full.Archer SL. N Engl J Med. 2013 Jul 25; 369(4):386-8.

Abstract

BACKGROUND:

Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension.

METHODS:

In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.

RESULTS:

By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).

CONCLUSIONS:

Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)
  PMID: 23883377 [PubMed - indexed for MEDLINE]
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17. Cardiorenal Med. 2013 Jul;3(2):96-103.

Pulmonary Hypertension and Right Heart Failure in Chronic Kidney Disease: New Challenge for 21st-Century Cardionephrologists.

Di Lullo LFloccari FRivera RBarbera VGranata AOtranto GMudoni AMalaguti MSantoboni ARonco C.
Department of Nephrology and Dialysis, L. Parodi Delfino Hospital, Colleferro, Italy.

Abstract

Pulmonary hypertension is defined as an increased systolic pulmonary pressure of >30 mm Hg, and it shows a 40% prevalence in hemodialysis patients due to vascular access (both central venous catheter and arteriovenous fistula). Secondary pulmonary hypertension in chronic kidney disease patients is strictly related to pulmonary circulation impairment together with chronic volume overload and increased levels of cytokines and growth factors, such as FGF, PDGF, and TGF-β, leading to fibrosis. Endothelial dysfunction, together with lower activation of NOS, increased levels of serum endothelin and fibrin storages, involves an extensive growth of endothelial cells leading to complete obliteration of pulmonary vessels. Pulmonary hypertension has no pathognomonic and distinctive symptoms and signs; standard transthoracic echocardiography allows easy assessment of compliance of the right heart chambers. The therapeutic approach is based on traditional drugs such as digitalis-derived drugs, vasodilatory agents (calcium channel blockers), and oral anticoagulants. New pharmacological agents are under investigation, such as prostaglandin analogues, endothelin receptor blockers, and phosphodiesterase-5 inhibitors.
PMCID: PMC3721135 Free PMC Article
  PMID: 23922549 [PubMed - as supplied by publisher]
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18. Eur J Clin Invest. 2013 Jul 10. doi: 10.1111/eci.12138. [Epub ahead of print]

Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension.

Chen YJYang QHLiu DLiu QQEyries MWen LWu WHJiang XYuan PZhang RSoubrier FJing ZC.
Department of Cardiology, the 4th Affiliated Hospital, Harbin Medical University, Harbin, China.

Abstract

BACKGROUND:

Mutations in activin receptor-like kinase-1 (ACVRL-1) or endoglin (ENG) are mostly identified in patients with hereditary haemorrhagic telangiectasia (HHT) associated with pulmonary hypertension (PH), but have not yet been studied in Chinese patients.

MATERIAL AND METHODS:

In this study, we investigated the clinical and molecular genetic features of Chinese patients with HHT-associated PH and analysed genotype/phenotype correlations in 14 probands and their relatives. Mutation analyses in ACVRL-1, bone morphogenetic protein receptor type 2 (BMPR2) and ENG were performed in 14 Chinese Han patients with HHT-associated PH.

RESULTS:

The overall mutation rate was 71·4%, including 8 ACVRL-1 mutations and 2 ENG mutations, 6 of which were novel. Six patients were identified with arteriovenous malformations (AVMs), including four patients with pulmonary AVMs and two patients with liver AVMs. Five of the patients with AVMs were identified with mutations. Most patients received targeted therapy for PH.

CONCLUSIONS:

Our findings have revealed the clinical phenotype and molecular genetic features of HHT-associated PH in Chinese Han patients and indicate that mutations of ACVRL-1 and ENG are genetic predisposing factors in Chinese patients. Our data further addressed clinical management and have provided limited experience in treating this group of disorders.
© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.
  PMID: 23919827 [PubMed - as supplied by publisher]
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19. Ther Adv Respir Dis. 2013 Feb;7(1):39-49. doi: 10.1177/1753465812463627. Epub 2012 Nov 5.

Tadalafil as monotherapy and in combination regimens for the treatment of pulmonary arterial hypertension.

Udeoji DUSchwarz ER.
Heart Institute of Southern California, Beverly Hills, Los Angeles, CA, USA. Ernst.schwarz@cshs.org

Abstract

The purpose of this review is to evaluate the use of tadalafil as monotherapy and in combination regimens for the treatment of pulmonary arterial hypertension (PAH). A systematic English language search of the medical literature using PubMed was conducted between January 1960 and May 2012 using the search terms 'tadalafil', 'therapy', 'pulmonary (arterial) hypertension' and 'combination therapy'. Special emphasis was given to controlled clinical trials and case studies relevant for the use of tadalafil in PAH. The search revealed 113 relevant publications, 31 of which were clinical trials, 52 were reviews and 12 were case reports. Of these, 12 were clinical studies in human patients with PAH who were treated with tadalafil alone, and seven were clinical studies in human patients with PAH who were treated with tadalafil in combination with other agents. Only clinical studies in human patients were included. Exclusion criteria were monotherapy other than using tadalafil and any combination therapy that excluded tadalafil as part of the treatment regimen. Overall, 1353 human subjects were studied; 896 were treated with tadalafil alone while 457 subjects were treated with tadalafil in coadministration. Tadalafil appears to be an effective and a safe treatment option for patients with PAH. It improves clinical status, exercise capacity, hemodynamic parameters, compliance issues and quality of life and reduces the occurrence of clinical worsening. Tadalafil in combination therapy seems to be additive and synergistic in relaxing pulmonary vascular muscle cells but more clinical trials on human subjects are warranted.
  PMID: 23129569 [PubMed - indexed for MEDLINE]
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20. Ther Adv Respir Dis. 2013 Feb;7(1):51-63. doi: 10.1177/1753465812461680. Epub 2012 Oct 11.

Pulmonary arterial hypertension in pregnant women.

Safdar Z.
Baylor Pulmonary Hypertension Center, Pulmonary-Critical Care Medicine, Baylor College of Medicine, Houston, TX 77030, USA. safdar@bcm.edu

Abstract

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling that limits the ability of the pulmonary vascular bed to withstand the physiological changes of pregnancy. Historically, pregnancy in PAH carries a high risk to the parturient. Normal pulmonary vasculature can withstand the hemodynamic and physiological changes associated with pregnancy without the development of respiratory symptomatology. However, in the presence of pulmonary vascular remodeling the capacity to handle these changes is compromised. During pregnancy, increase in cardiac output from the increased intravascular volume can lead to right heart failure. Therefore, all patients with PAH of childbearing potential should receive preconception counseling and be advised to use two methods of contraception. Patients with PAH should be advised against continuing pregnancy if they do become pregnant. According to the literature, deterioration in pregnancy mainly occurs in the second trimester and early in the third trimester; immediately postpartum is the most critical time for patients with PAH. In this review, we will discuss the recent advances in the management of parturient patients with PAH.
  PMID: 23060536 [PubMed - indexed for MEDLINE]
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21. Chest. 2013 Aug;144(2):704-7. doi: 10.1378/chest.12-2811.

A 49-year-old man with acute pulmonary hypertension post lung transplantation.

Abdulaziz SAl-Shahid MAl-Thenayan E.
  PMID: 23918117 [PubMed - in process]
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22. Chest. 2013 Aug;144(2):638-50. doi: 10.1378/chest.12-2114.

WHO's in Second?: A Practical Review of World Health Organization Group 2 Pulmonary Hypertension.

Hansdottir SGroskreutz DJGehlbach BK.

Abstract

World Health Organization (WHO) group 2 pulmonary hypertension (PH) due to left-side heart disease (ie, heart failure or left-sided valvular heart disease) is the most common form of PH in western countries. Distinguishing patients with WHO group 2 PH, particularly the subset of patients with PH due to heart failure with preserved ejection fraction (HFpEF), from those with WHO group 1 pulmonary arterial hypertension (PAH) is challenging. Separating the two conditions is of vital importance because treatment strategies differ completely. Furthermore, therapies that are indicated for WHO group 1 PAH may be harmful in patients with WHO group 2 PH. We review the somewhat confusing PH nomenclature and the WHO classification system and rationale behind it. We then focus on left-side heart disorders that cause PH. An aging population and advances in the medical management of common cardiovascular disorders have caused the prevalence of heart failure to rise significantly, with more than one-half of patients having HFpEF. We review contemporary studies that focus on clinical and echocardiographic findings that help to distinguish HFpEF from PAH in the patient with PH. We discuss the typical, and sometimes atypical, hemodynamic profiles that characterize these two groups, review challenges in the interpretation of data obtained by right-sided heart catheterization, and highlight special maneuvers that may be required for accurate diagnosis. Finally, we review the largely disappointing studies on the use of PAH-specific therapies in patients with WHO group 2 PH, including the use of prostacyclins, endothelin receptor antagonists, and the more promising phosphodiesterase-5 inhibitors.
  PMID: 23918108 [PubMed - in process]
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23. Curr Opin Pulm Med. 2013 Sep;19(5):531-7. doi: 10.1097/MCP.0b013e328363f4a3.

Sarcoidosis-associated pulmonary hypertension.

Cordova FCD'Alonzo G.
aDivision of Pulmonary and Critical Care Medicine, Medical Director, Lung Transplant Program, bDivision of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.

Abstract

PURPOSE OF REVIEW:

Pulmonary hypertension is a serious complication of sarcoidosis. This review discusses clinical characteristics of patients with sarcoid-associated pulmonary hypertension (SAPH) and pitfalls in the diagnosis, and highlights potential therapies.

RECENT FINDINGS:

SAPH is common in patients with advanced disease, but it can occur in patients with minimal disease burden. Risk factors for SAPH include restrictive lung physiology, hypoxemia, advanced Scadding chest X-ray stage, and low carbon monoxide diffusion capacity. Echocardiogram is a good initial screening tool in the diagnosis of pulmonary hypertension, but right heart catheterization is necessary to confirm the diagnosis. Treatment with pulmonary vasodilators, including endothelin antagonists, can lead to improvements in pulmonary hemodynamics in some patients but may not improve their exercise capacity. Forced vital capacity is an important predictor of exercise performance in patients with SAPH. Clinical observations and response to specific therapies for pulmonary hypertension suggest the presence of different SAPH phenotypes.

SUMMARY:

Patients who complain of persistent dyspnea should be screened for the presence of pulmonary hypertension. The prognosis of SAPH is poor and it is prudent to consider referral of these patients for lung transplantation. In some patients with SAPH, treatment with anti-inflammatory agents and pulmonary vasodilators can lower pulmonary arterial pressures, improve dyspnea and functionality, and enhance overall quality of life.
  PMID: 23912192 [PubMed - in process]
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24. Curr Opin Pulm Med. 2013 Sep;19(5):422-9. doi: 10.1097/MCP.0b013e328364379f.

Why acute pulmonary embolism becomes chronic thromboembolic pulmonary hypertension: clinical and genetic insights.

Morris TA.
Division of Pulmonary and Critical Care Medicine, San Diego School of Medicine, University of California, San Diego, California, USA.

Abstract

PURPOSE OF REVIEW:

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication that affects a small but appreciable percentage of patients after acute pulmonary embolism. The cause of CTEPH is under investigation, but no single causative mechanism has yet been identified.

RECENT FINDINGS:

CTEPH is likely a complication of residual thrombotic material in the pulmonary arteries that becomes transformed into intravascular scars. Pulmonary artery residua are relatively common after acute pulmonary embolism, and CTEPH may be an extreme manifestation of this phenomenon. Several intriguing observations have been made in patients with CTEPH that give insights into the mechanisms responsible for its formation. Two general pathways have been investigated: resistance of thromboemboli to lysis and attenuation of cellular processes involved in thrombus resolution. This review discusses the evidence supporting each pathway as a mechanism for CTEPH formation, as well as the interaction between the two.

SUMMARY:

CTEPH may be due to a complex interaction between thrombotic/thrombolytic processes and angiogenic cellular remodeling of organized thrombi. The factors involved may, in fact, vary among CTEPH patients. An understanding of the interplay between the factors that cause CTEPH may help quantify the risk of its occurrence and provide insights into how it can be prevented.
  PMID: 23907454 [PubMed - in process]
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25. J Heart Lung Transplant. 2013 Aug 2. pii: S1053-2498(13)01326-0. doi: 10.1016/j.healun.2013.06.020. [Epub ahead of print]

An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: Emerging role of CT-proET-1.

Silva Marques JMartins SRCalisto CGonçalves SAlmeida AGde Sousa JCPinto FJDiogo AN.
Department of Cardiology I, Lisbon Academic Medical Centre, Lisbon, Portugal. Electronic address:silvamarques.j@gmail.com.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH.

METHODS:

Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality.

RESULTS:

Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6).

CONCLUSIONS:

CT-proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers.
Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
  PMID: 23916896 [PubMed - as supplied by publisher]
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26. N Engl J Med. 2013 Jul 25;369(4):351-61. doi: 10.1056/NEJMoa1211097.

A novel channelopathy in pulmonary arterial hypertension.

Ma LRoman-Campos DAustin EDEyries MSampson KSSoubrier FGermain MTrégouët DABorczuk A,Rosenzweig EBGirerd BMontani DHumbert MLoyd JEKass RSChung WK.
Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.

Abstract

BACKGROUND:

Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes.

METHODS:

We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis.

RESULTS:

We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082.

CONCLUSIONS:

Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (Funded by the National Institutes of Health.)
  PMID: 23883380 [PubMed - indexed for MEDLINE]
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27. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655.

Riociguat for the treatment of pulmonary arterial hypertension.

Ghofrani HAGaliè NGrimminger FGrünig EHumbert MJing ZCKeogh AMLangleben DKilama MOFritsch A,Neuser DRubin LJPATENT-1 Study Group.
Collaborators: Bortman GKeogh AKermeen FFeenstra JWilliams TReeves GKilpatrick DLang IKahler C,Mascherbauer-Steringer RVachiery JLDelcroix MMeyer GArakaki JSantana MWaetge DGranton JLangleben D,Helmersen DHe JJing ZZhou DHuang YWang CJansa PNeilsen-Kudsk JEHachulla EDe Groote PFrachon I,Bourdin APison CBauer FDromer CMarquette CHDegano BNeurohr CWilkens HHoffken GHoeper M,Ghofrani AWirtz HRosenkranz SGrünig EEwert ROrfanos SKramer MBen Gal TScelsi LVizza CHarari S,Confalonieri MAlbera CFukumoto YSano MHatano MSaji TTanaka STakeda YTakehara KMatsubara H,Kihara YShiohira YKawai HHomma SSatoh TTokunaga TIshizaki TDiaz CZamudio TDe Los Rios M,Estupian SCacho JRGamba MBeckert LTorbicki ACastro GReis AAgapito AMartins SKim HLee SChang HSong YChazova IMoiseeva OLim SYip JBarbera JRoman APalma Jdel CReitan OSoderberg SJansson K,Speich RHsu HHLin HYCheng CCPhrommintikul AJaimchariyatam NSayin TKultursay HOngen GPepke-Zaba JCoghlan GPeacock AGibbs JWagoner LBadesch DFrost AHill NAllen RWaxman ASood NTorres F,Minai OShapiro SKlinger JEngel PGarcia HSchuller DPoch DRosenzweig EMcConnell JRischard FGhofrani HAGaliè NGrimminger FHumbert MKeogh AMLangleben DRubin LJOlschewski HHaverkamp WLehmacher WHoischen SCollamati SDehay JHallmann MMenezes F.
University of Giessen and Marburg Lung Center, Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de

Comment in

Riociguat for pulmonary hypertension--a glass half full.Archer SL. N Engl J Med. 2013 Jul 25; 369(4):386-8.

Abstract

BACKGROUND:

Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension.

METHODS:

In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety.

RESULTS:

By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively).

CONCLUSIONS:

Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).
  PMID: 23883378 [PubMed - indexed for MEDLINE]
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28. Eur J Prev Cardiol. 2013 Jul 29. [Epub ahead of print]

Effects of treatment with a combination of cardiac rehabilitation and bosentan in patients with pulmonary Langerhans cell histiocytosis associated with pulmonary hypertension.

Fukuda YMiura SIFujimi KYano MNishikawa HYanagisawa JHiratsuka MShiraishi TIwasaki ASaku K.
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.

Abstract

Pulmonary hypertension (PH), which is classified as group 5 in the clinical classification of PH, is sometimes a complication of Pulmonary langerhans cell histiocytosis (PLCH), and is associated with high mortality. A 36-year-old woman had suffered from severe dyspnea 9 years previously and was diagnosed with PLCH and was on a waiting list for a lung transplant. Right heart failure had been observed and the mean pulmonary artery pressure was over 40 mmHg. The patient was diagnosed as PLCH with PH. After combined treatment with exercise rehabilitation and bosentan for 6 months, the cardiothoracic ratio, brain natriuretic peptide, and bodyweight were significantly decreased (cardiothoracic ratio from 43 to 38%, brain natriuretic peptide from 284 to10 pg/ml and bodyweight from 63 to 58 kg). Six-minute walk test also improved from 214 to 275 meters and the SF36 score for screening of depressive and anxiety disorders was improved. This is the report demonstrating the efficacy and safety of cardiac rehabilitation in combination with bosentan in a single patient with PLCH associated with PH.
  PMID: 23897898 [PubMed - as supplied by publisher]
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29. Biol Blood Marrow Transplant. 2013 Jul 23. pii: S1083-8791(13)00319-4. doi: 10.1016/j.bbmt.2013.07.017. [Epub ahead of print]

Pulmonary Hypertension after Hematopoietic Stem Cell Transplant.

Dandoy CHirsch RChima RDavies SMJodele S.
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. Electronic address: christopher.dandoy@cchmc.org.

Abstract

Pulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Given its non-specific clinical presentation it is likely that this clinical entity is under diagnosed after HSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients is minimal. Physicians caring for HSCT recipients should be aware of this severe post-transplant complication since timely diagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinical presentation, diagnosis and management of PH in HSCT recipients.
Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
  PMID: 23891748 [PubMed - as supplied by publisher]
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30. Int J Cardiol. 2013 Jul 23. pii: S0167-5273(13)01190-X. doi: 10.1016/j.ijcard.2013.07.005. [Epub ahead of print]

Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension.

D'Alto MRomeo EArgiento PD'Andrea AVanderpool RCorrera ABossone ESarubbi BCalabrò RRusso MG,Naeije R.
Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy. Electronic address: mic.dalto@tin.it.

Abstract

BACKGROUND:

Echocardiographic studies have contributed to progress in the understanding of the pathophysiology of the pulmonary circulation and have been shown to be useful for screening for and prognostication of pulmonary hypertension, but are considered unreliable for the diagnosis of pulmonary hypertension. We explored this apparent paradox with rigorous Bland and Altman analysis of the accuracy and the precision of measurements collected in a large patient population.

METHODS:

A total of 161 patients referred for a suspicion of pulmonary hypertension were prospectively evaluated by a Doppler echocardiography performed by dedicated cardiologists within 1h of an indicated right heart catheterization.

RESULTS:

Nine of the patients (6%) were excluded due to an insufficient signal quality. Of the remaining 152 patients, 10 (7%) had no pulmonary hypertension and most others had either pulmonary arterial hypertension (36%) or pulmonary venous hypertension (40%) of variable severities. Mean pulmonary artery pressure, left atrial pressure and cardiac output were nearly identical at echocardiography and catheterization, with no bias and tight confidence intervals, respectively ±3mm Hg, ±5mm Hg and ±0.3L/min. However, the ±2SD limits of agreement were respectively of +19 and -18mm Hg for mean pulmonary artery pressure, +8 and -12mm Hg for left atrial pressure and +1.8 and -1.7L/min for cardiac output.

CONCLUSIONS:

Doppler echocardiography allows for accurate measurements of the pulmonary circulation, but with moderate precision, which explains why the procedure is valid for population studies but cannot be used for the individual diagnosis of pulmonary hypertension.
© 2013.
  PMID: 23890907 [PubMed - as supplied by publisher]
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31. Int J Cardiol. 2013 Jul 25. pii: S0167-5273(13)01283-7. doi: 10.1016/j.ijcard.2013.07.072. [Epub ahead of print]

Long-term effects of continuous prostacyclin therapy in adults with pulmonary hypertension associated with congenital heart disease.

Thomas ICGlassner-Kolmin CGomberg-Maitland M.
Department of Medicine, Section of Internal Medicine, University of Chicago, United States. Electronic address:isac.thomas@uchospitals.edu.

Abstract

BACKGROUND:

The continuous administration of prostacyclin analogs (PGI2) is a proven and effective therapy in patients with group 1 pulmonary arterial hypertension (PAH). However, few studies have addressed its use in adults with PAH associated with congenital heart disease (CHD-PAH). Concerns remain regarding the theoretical risk of worsening right-to-left intracardiac shunt. In this study, we present the hemodynamic and clinical effects of long-term, continuous PGI2 administration in eight adult patients with CHD-PAH.

METHODS:

We retrospectively reviewed the records of patients with CHD-PAH treated with continuous prostacyclin analogs epoprostenol and treprostinil. Nine patients were identified; one patient had no documentation of an intracardiac shunt and was excluded from this study. Hemodynamic, functional, laboratory, and clinical data were included.

RESULTS:

Mean duration of continuous PGI2 therapy was 1year. Compared to baseline, patients exhibited significant improvements in mean pulmonary artery (PA) pressure and PA oxygen saturation, without a significant decline in systemic blood pressure or systemic oxygen saturation. Metabolic equivalents (METs) achieved on exercise testing increased, with an improvement in oxygen desaturation. World Health Organization functional classification remained the same.

CONCLUSIONS:

Long-term continuous PGI2 therapy in CHD-PAH patients resulted in hemodynamic and clinical improvements similar to those with group 1 PAH. The increase in PA oxygen saturation suggests that the net effect of PGI2 therapy did not result in increased right-to-left shunting, but, instead, diminished shunt. Though larger studies are needed, PGI2 should be considered as a potential treatment modality in adult patients with severe CHD-PAH who fail conventional therapy.
© 2013.
  PMID: 23890862 [PubMed - as supplied by publisher]
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32. Adv NPs PAs. 2013 May;4(5):33-7.

Pulmonary arterial hypertension. Recognition is the first essential step.

Nider V.
Columbus Radiology Corporation, Grant Medical Center, Columbus, Ohio, USA.
  PMID: 23724447 [PubMed - indexed for MEDLINE]
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33. J Electrocardiol. 2013 Jan-Feb;46(1):38-42. doi: 10.1016/j.jelectrocard.2012.07.014. Epub 2012 Sep 19.

Elevated pulmonary artery systolic pressures are associated with a lower risk of atrial fibrillation following lung transplantation.

Malik AHsu JCHoopes CItinarelli GMarcus GM.
Division of Cardiology, Electrophysiology Section, San Francisco, CA, USA.

Comment in

The association between pulmonary hypertension and lower risk of postoperative atrial fibrillation after lung transplantation.Zimmermann M. J Electrocardiol. 2013 Jan-Feb; 46(1):43-4.

Abstract

BACKGROUND:

Atrial fibrillation (AF) is common after open-chest procedures, but the etiology remains poorly understood. Lung transplant procedures allow for the study of novel contributing factors.

METHODS:

Records of lung transplant procedures performed at a single center between 2002 and 2009 were reviewed.

RESULTS:

Of 174 patients, 27 (16%) had AF a median 6 days post-surgery. Post-operative AF patients less often had right ventricular hypertrophy (RVH) by either electrocardiogram (0 versus 14%, P=.042) or echocardiography (19% versus 47%, P=.006), and had lower pulmonary artery systolic pressures (PASP) (39 ± 12 versus 51 ± 22, P=.005). After multivariable adjustment, every 10-mm Hg increase in PASP was associated with a 31% reduction in the odds of post-operative AF (OR 0.69, 95% CI 0.49-0.98, P=.035). A higher pulmonary pressure was the only predictor independently associated with less post-operative AF.

CONCLUSIONS:

Higher PASP was associated with a lower risk of AF after lung transplantation.
Copyright © 2013 Elsevier Inc. All rights reserved.
PMCID: PMC3690322 [Available on 2014/1/1]
  PMID: 22999321 [PubMed - indexed for MEDLINE]
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34. Eur Respir J. 2013 Feb;41(2):462-8. doi: 10.1183/09031936.00049312. Epub 2012 Jun 14.

Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding.

Lang IMPesavento RBonderman DYuan JX.
Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18–20, Vienna, Austria.irene.lang@meduniwien.ac.at

Abstract

All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH. A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, "sticky" red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelial-mesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.
  PMID: 22700839 [PubMed - indexed for MEDLINE]
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35. PLoS One. 2013 Jul 22;8(7):e69635. doi: 10.1371/journal.pone.0069635. Print 2013.

Fibrinogen Aα Thr312Ala Polymorphism Specifically Contributes to Chronic Thromboembolic Pulmonary Hypertension by Increasing Fibrin Resistance.

Li JFLin YYang YHGan HLLiang YLiu JYang SQZhang WJCui NZhao LZhai ZGWang JWang C.
Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China ; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China ; Department of Physiology, Capital Medical University, Beijing, P.R. China ; Department of Respiratory Disease, Capital Medical University, Beijing, P.R. China.

Abstract

BACKGROUND:

Polymorphisms are associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary thromboembolism (PTE), but no polymorphism specific to CTEPH but not PTE has yet been reported. Fibrin resistance is associated with CTEPH, but the mechanism has not been elucidated.

METHODS:

Polymorphisms were analyzed in 101 CTEPH subjects, 102 PTE subjects and 108 healthy controls by Massarray or restriction fragment length polymorphism (RFLP). Plasmin-mediated cleavage of fibrin was characterized in 69 subjects (29 with CTEPH, 21 with PTE and 19 controls).

RESULTS:

Genotype frequencies and allele frequencies of fibrinogen Aα Thr312Ala were significantly higher in CTEPH subjects than in controls and PTE subjects, while there was no difference between PTE subjects and controls. The odd ratio (OR 2.037) and 95% confidence interval (95% CI, 1.262-3.289) showed that Thr312Ala polymorphism was a risk factor for CTEPH but not PTE. Fibrin from CTEPH subjects was more resistant to lysis than that from PTE subjects and controls. Fibrin resistance was significantly different between Aα Thr312Ala (A/G) genotypes within CTEPH subjects, and the fibrin with GG genotype was more resistant than that with AA and AG genotype.

CONCLUSIONS:

Fibrinogen Aα Thr312Ala (A/G) polymorphism was associated with CTEPH, but not PTE, suggesting that the fibrinogen Aα Thr312Ala polymorphism may act as a potential biomarker in identifying CTEPH from PTE. GG genotype polymorphism contributes to CTEPH through increasing fibrin resistance, implying that PTE subjects with fibrinogen Aα GG genotype may need long-term anticoagulation therapy.
PMCID: PMC3718692 Free PMC Article
  PMID: 23894515 [PubMed - in process]
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36.

Hypertension: Riociguat therapy for pulmonary hypertension.

  Lim GB.
  Nat Rev Cardiol. 2013 Aug 13. doi: 10.1038/nrcardio.2013.122. [Epub ahead of print] No abstract available.
  PMID: 23939482 [PubMed - as supplied by publisher]
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37.

Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.

  Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ; Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) Study Group.
  Circulation. 2013 Jul 30;128(5):502-11. doi: 10.1161/CIRCULATIONAHA.113.001458. Epub 2013 Jun 17.
  PMID: 23775260 [PubMed - in process]
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