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Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial.

Screening and treating pulmonary arterial hypertension in a tertiary hospital-based multidisciplinary clinic: the first 200 patients.

Pulmonary hypertension as an independent predictor of cardiovascular mortality and events in hemodialysis patients.
 
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 2013 May 7;158(9):641-9. doi: 10.7326/0003-4819-158-9-201305070-00003.

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial.

Source

Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, 1959 NE Pacific, Campus Box 356175, Seattle, WA 98195, USA.

Abstract

BACKGROUND:

Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor.

OBJECTIVE:

To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression.

DESIGN:

Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300) SETTING: Academic and private hospitals.

PARTICIPANTS:

Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans.

INTERVENTION:

Ambrisentan, 10 mg/d, or placebo.

MEASUREMENTS:

Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function.

RESULTS:

The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point.

LIMITATION:

The study was terminated early.

CONCLUSION:

Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations.

PRIMARY FUNDING SOURCE:

Gilead Sciences.

 
Intern Med J. 2013 Jan;43(1):32-7. doi: 10.1111/j.1445-5994.2011.02624.x.

Screening and treating pulmonary arterial hypertension in a tertiary hospital-based multidisciplinary clinic: the first 200 patients.

Low AJFowler DManghani MKYoung IGarsia RTorzillo PYoussef PCelermajer DS.
Sydney Medical School, Sydney, New South Wales, Australia.

Comment in

Contraception advice in women with pulmonary arterial hypertension.Morton AP. Intern Med J. 2013 May; 43(5):608.
Author reply.Low AJ, Celermajer DS. Intern Med J. 2013 May; 43(5):609.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is an increasingly recognised serious illness with insidious onset, delayed diagnosis, complex diagnostic algorithms and poor prognosis, but with recently available effective treatments.

AIMS:

To efficiently diagnose and to offer treatment for PAH, we established a multidisciplinary service in 2005, where patients attend a clinic staffed by specialists in cardiology, respiratory medicine, rheumatology and immunology in a tertiary referral hospital setting.

METHODS:

We studied the first 200 patients referred. Serology, echocardiography, lung function tests, high-resolution computed tomography, World Health Organisation Class determination and 6-min walk tests and/or right heart catheterisation were performed, as clinically indicated.

RESULTS:

Of the 200 patients seen, 66 had confirmed pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg) diagnosed on echocardiography ± right heart catheterisation. Of these patients, 58 had catheter-proven PAH (mean pulmonary artery pressure > 25 mmHg with mean wedge pressure < 15 mmHg). Underlying diagnoses for the confirmed PAH patients were idiopathic (32), scleroderma-associated (14), other connective tissue disease (4) and associated with congenital heart disease (8). Patients with confirmed PAH were commenced on PAH-specific therapy--initially bosentan in the majority but sildenafil, and iloprost were occasionally used initially for patient-specific reasons. Median time from when the patient first called the clinic to prescription of therapy was 16 days (interquartile range; 0-31 days). All surviving patients with PAH have attended for regular 6-monthly follow-up visits with a 100% retention rate up to 4 years.

CONCLUSION:

A multidisciplinary clinic can provide efficient diagnosis and rapid triage to PAH-specific therapy, if appropriate. Retention rates remain high, at follow up.
© 2011 The Authors; Internal Medicine Journal © 2011 Royal Australasian College of Physicians.
  PMID: 22032309 [PubMed - indexed for MEDLINE]
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Cardiovasc Res. 2013 Jun 25. [Epub ahead of print]

GAPDH is critical for superior efficacy of female bone marrow-derived mesenchymal stem cells on pulmonary hypertension.

Tan RLi JPeng XZhu LCai LWang TSu YIrani KHu Q.
Department of Pathophysiology.

Abstract

AIMS:

Pulmonary arterial hypertension, a chronic lung disease, remains an unacceptable prognosis despite significant advances in conventional therapies. Stem cell therapy represents a novel and effective modality. This study was aimed to add new insight in gender differences of bone marrow-derived mesenchymal stem cells on therapy against pulmonary arterial hypertension and the underlying mechanism.Methods and ResultsBy in vivo experiments, we showed for the first time female bone marrow-derived mesenchymal stem cells possessed a better therapeutic potential against monocrotaline-induced pulmonary arterial hypertension in C57BL/6J mice compared with male counterparts. In vitro experiments demonstrated superior function of female bone marrow-derived mesenchymal stem cells in cell proliferation, migration and [Ca2+]i kinetics. Moreover, we unexpectedly found that, compared to male ones, female bone marrow-derived mesenchymal stem cells had a higher expression level of glyceraldehyde-3-phosphate dehydrogenase and manipulations of its expression in female or male bone marrow-derived mesenchymal stem cells profoundly affected their cellular behaviors and therapeutic efficacies against pulmonary arterial hypertension.

CONCLUSION:

Our results suggest that glyceraldehyde-3-phosphate dehydrogenase plays a critical role in determining the superior functions of female bone marrow-derived mesenchymal stem cells in cell therapy against pulmonary arterial hypertension by regulating [Ca2+]i signal-associated cellular behaviors.
  PMID: 23801767 [PubMed - as supplied by publisher]
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  J Am Soc Echocardiogr. 2013 Jun 22. pii: S0894-7317(13)00404-5. doi: 10.1016/j.echo.2013.05.016. [Epub ahead of print]

Derivation of Mean Pulmonary Artery Pressure from Systolic Pressure: Implications for the Diagnosis of Pulmonary Hypertension.

Chemla DHerve P.
Faculté de Médecine Paris-Sud, Le Kremlin Bicêtre, France.
  PMID: 23800508 [PubMed - as supplied by publisher]
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  Indian Pediatr. 2013 Apr 5. pii: S097475591200806. [Epub ahead of print]

Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn.

Janjindamai WThatrimontrichai AManeenil GChanvitan PDissaneevate S.
Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand. Correspondence to: Dr Waricha Janjindamai, Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, 15 Kanjanavanit Road, Hat Yai, Songkhla, Thailand, 90110. jwaricha@medicine.psu.ac.th.

Abstract

OBJECTIVE:

The aims of this study were to determine the effectiveness (oxygenation), safety (hemodynamic status) and short term outcomes of intravenous iloprost (IVI) administration as a rescue therapy in severe persistent pulmonary hypertension of the newborn (PPHN).

DESIGN:

Retrospective medical records review.

SETTING:

Tertiary neonatal intensive care unit at Songklanagarind Hospital, Songkhla Province, Hat Yai, Thailand.

PARTICIPANTS:

Newborns who received IVI as an adjunctive therapy for treatment of severe PPHN, as defined by an oxygen index (OI) of >;20 and without response to conventional therapies.

MAIN OUTCOME MEASURES:

The change of OI and alveolar-arterial oxygen difference before and after commencement of IVI.

RESULTS:

33 neonates with severe PPHN at a median gestation of 39 weeks and a baseline OI of 40 (range, 21-101) received IVI. The median OI and alveolar-arterial oxygen difference had a statistically significant decrease after 2 hours of treatment and continued to decline thereafter (P<0.05). All infants received one or more inotropic medications and volume expanders to provide blood pressure support with no statistically significant difference of blood pressure and heart rate before and after IVI treatment. The mortality rate was 15.2%, all of them had initially severe hypoxemia with a median OI of 53.6.

CONCLUSIONS:

IVI may be effective in improving oxygenation and should be considered as a rescue therapy for infants with severe PPHN, especially in a limited resource environment with no inhaled nitric oxide available. Systemic hypotension may be a cause for concern.
  PMID: 23798625 [PubMed - as supplied by publisher]
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  Am J Perinatol. 2013 Jun 24. [Epub ahead of print]

Inhaled Iloprost in Preterm Infants with Severe Respiratory Distress Syndrome and Pulmonary Hypertension.

Yilmaz OKahveci HZeybek CCiftel MKilic O.
Department of Pediatric Cardiology, District Training and Research Hospital, Erzurum, Turkey.

Abstract

Objective Many vasodilator drugs, including inhaled iloprost, are used to treat insufficient pulmonary vasodilatation, which is the main issue in pulmonary hypertension in newborns.Study Design The safety and efficacy of inhaled iloprost for the treatment of pulmonary hypertension were evaluated retrospectively in 15 preterm infants diagnosed with respiratory distress syndrome and pulmonary hypertension.Results The infants were unresponsive to surfactant and conventional mechanical ventilation and thus were treated with inhaled iloprost. Oxygenation parameters and hypoxemia improved rapidly after treatment. There was no decline in systemic blood pressure, no need for increased doses of vasopressor, and no side effects during treatment. One patient died of sepsis during treatment.Conclusion In the treatment of severely sick premature babies with pulmonary hypertension, inhaled iloprost has high tolerability and a low incidence of systemic side effects. Based on the benefits of inhaled iloprost in preterm infants with pulmonary hypertension in this case series, further studies are required to evaluate its efficacy and safety in the preterm population.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
  PMID: 23797963 [PubMed - as supplied by publisher]
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  Pneumologie. 2013 Jul;67(7):376-87. doi: 10.1055/s-0033-1344316. Epub 2013 Jun 24.

[Early diagnosis and therapy in pulmonary hypertension - aspects of a vision].

[Article in German]
Ewert ROlschewski HGhofrani HAOpitz CF.
Universitätsmedizin Greifswald, Klinik für Innere Medizin B, Greifswald, Deutschland.

Abstract

In patients with pulmonary hypertension progressive vascular changes in the lung precede the clinical and hemodynamic manifestations of the disease. Therefore, early diagnosis and timely treatment of the disease are crucial. This has been the topic of an expert meeting in Greifswald, Germany in June 2012. The current definition of pulmonary hypertension requires a mean pulmonary artery pressure ≥ 25 mmHg at rest, a hemodynamic abnormality already reflecting pulmonary vascular changes beyond early disease. There is increasing evidence supporting the concept that a lower pressure threshold at rest or an abnormal pressure response with exercise better characterize early disease. While right heart catheterization at rest remains the diagnostic gold standard other methods for detecting early disease are explored with echocardiography being the most frequently used technique. Targeted therapy has been approved for patients with pulmonary arterial hypertension (PAH, WHO-group I) in functional class II-IV. Preliminary data in functional class I patients suggest therapeutic potential of theses drugs in early disease as well. Current guidelines propose therapeutic goals based on parameters with prognostic importance. However, these recommendations are based on mostly retrospective analyses of pre-treatment data obtained in patients with pulmonary hypertension in functional class II-IV. Therefore, evidence-based therapeutic goals for early interventions in functional class I patients are lacking.
© Georg Thieme Verlag KG Stuttgart · New York.
  PMID: 23797491 [PubMed - in process]
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  J Mol Med (Berl). 2013 Jun 21. [Epub ahead of print]

Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.

Piao LFang YHParikh KRyan JJToth PTArcher SL.
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA.

Abstract

The rapid growth of cancer cells is permitted by metabolic changes, notably increased aerobic glycolysis and increased glutaminolysis. Aerobic glycolysis is also evident in the hypertrophying myocytes in right ventricular hypertrophy (RVH), particularly in association with pulmonary arterial hypertension (PAH). It is unknown whether glutaminolysis occurs in the heart. We hypothesized that glutaminolysis occurs in RVH and assessed the precipitating factors, transcriptional mechanisms, and physiological consequences of this metabolic pathway. RVH was induced in two models, one with PAH (Monocrotaline-RVH) and the other without PAH (pulmonary artery banding, PAB-RVH). Despite similar RVH, ischemia as determined by reductions in RV VEGFα, coronary blood flow, and microvascular density was greater in Monocrotaline-RVH versus PAB-RVH. A sixfold increase in 14C-glutamine metabolism occurred in Monocrotaline-RVH but not in PAB-RVH. In the RV working heart model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) decreased glutaminolysis, caused a reciprocal increase in glucose oxidation, and elevated cardiac output. Consistent with the increased glutaminolysis in RVH, RV expressions of glutamine transporters (SLC1A5 and SLC7A5) and mitochondrial malic enzyme were elevated (Monocrotaline-RVH > PAB-RVH > control). Capillary rarefaction and glutamine transporter upregulation also occurred in RVH in patients with PAH. cMyc and Max, known to mediate transcriptional upregulation of glutaminolysis, were increased in Monocrotaline-RVH. In vivo, DON (0.5 mg/kg/day × 3 weeks) restored pyruvate dehydrogenase activity, reduced RVH, and increased cardiac output (89 ± 8, vs. 55 ± 13 ml/min, p < 0.05) and treadmill distance (194 ± 71, vs. 36 ±7 m, p < 0.05) in Monocrotaline-RVH. Glutaminolysis is induced in the RV in PAH by cMyc-Max, likely as a consequence of RV ischemia. Inhibition of glutaminolysis restores glucose oxidation and has a therapeutic benefit in vivo.

KEY MESSAGE:

Patients with pulmonary artery hypertension (PAH) have evidence of cardiac glutaminolysis. Cardiac glutaminolysis is associated with microvascular rarefaction/ischemia. As in cancer, cardiac glutaminolysis results from activation of cMyc-Max. The specific glutaminolysis inhibitor DON regresses right ventricular hypertrophy. DON improves cardiac function and exercise capacity in an animal model of PAH.
  PMID: 23794090 [PubMed - as supplied by publisher]
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  Int Urol Nephrol. 2013 Jun 21. [Epub ahead of print]

Pulmonary hypertension as an independent predictor of cardiovascular mortality and events in hemodialysis patients.

Li ZLiu SLiang XWang WFei HHu PChen YXu LLi RShi W.
Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106# Zhongshan Er lu, Guangzhou, 510080, Guangdong, People's Republic of China.

Abstract

BACKGROUND:

Hemodialysis patients are at an increased risk of cardiovascular (CV) morbidity and mortality. Pulmonary hypertension (PH) has been recently reported as a new entity and unrecognized threat in maintenance hemodialysis (MHD) patients, whether PH predicts CV mortality and events in this population remains unknown. The aim of the present study was to determine the value of PH in predicting CV mortality and events in a prospective cohort of MHD patients.

METHODS:

We studied 278 MHD patients (98 with and 180 without PH) in Guangdong General Hospital Blood Purification Center, Guangzhou, China. All patients had been followed up for 2 years, and in survival analysis, we considered time to death or first cardiovascular event. The endpoints were all-cause mortality, CV mortality and CV events. PH was defined as systolic pulmonary artery pressure (SPAP) ≥ 35 mmHg as determined by Doppler echocardiographic evaluation.

RESULTS:

Of the 278 MHD patients, 53 (19.1 %) died as a result of all causes, 28 (10.1 %) died from CV events (52.8 % of causes of death), and 87 (31.3 %) had new-onset CV events. The survival curve showed that all-cause and CV mortality and new-onset CV events were higher in PH group than the non-PH group. In a multivariate Cox proportional hazard model, the adjusted HR for all-cause mortality, CV mortality and CV events was 1.85 [95 % confidence interval (CI) 1.03-3.34], 2.36 (95 % CI 1.05-5.31) and 2.27 (95 % CI 1.44-3.58), respectively.

CONCLUSIONS:

Our study showed that PH was an independent predictor of all-cause mortality and CV mortality and events in MHD patients. We suggest to evaluate SPAP in MHD patients in order to stratify risk of death and CV events.
  PMID: 23793619 [PubMed - as supplied by publisher]
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  J Extra Corpor Technol. 2013 Mar;45(1):16-20.

Extracorporeal membrane oxygenation: beneficial strategy for lung transplant recipients.

Cottini SRWenger USailer SStehberger PASchuepbach RAHasenclever PWilhelm MBéchir M.
Surgical Intensive Care Medicine, University Hospital of Zurich, Zurich, Switzerland.

Abstract

The role of extracorporeal membrane oxygenation (ECMO) as a therapeutic strategy has been very well documented for over a decade now with consistently positive remarks. The aim of the present study was analyzing the outcome of ECMO application in our lung transplant program, especially the feasibility and safety of our ECMO approach. Therefore, we retrospectively analyzed the data of 15 patients recipients requiring ECMO support. We analyzed clinical data, complications, and survival of the lung-transplanted population that needed ECMO support at our institution from 2006-2009. During that period, 19 applications of ECMO were done on 15 adult patients with the following indications: primary graft dysfunction (10 patients), "bridge to transplantation" (five), pulmonary hypertension (three), and severe acute respiratory distress syndrome (one). At 28 days, the overall survival was 93% (14 of 15 patients) and 12 of these patients (80%) survived at least 6 months. Complications included acute renal insufficiency with temporary need of renal replacement therapy (53%), bleeding (33%), critical illness polyneuropathy (66%), and reversible thrombocytopenia (73%). Based on the evaluation of the patients in this analysis, ECMO seems to be a safe therapeutic approach in lung transplant recipients with severe respiratory failure directly after transplantation.
  PMID: 23691779 [PubMed - indexed for MEDLINE]
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  Curr Opin Crit Care. 2013 Feb;19(1):44-50. doi: 10.1097/MCC.0b013e32835c5137.

Management of pulmonary arterial hypertension.

Judge EPGaine SP.
National Pulmonary Hypertension Unit, Department of Respiratory Medicine, Mater Misericordiae University Hospital, Dublin, Ireland.

Abstract

PURPOSE OF REVIEW:

Pulmonary arterial hypertension (PAH) is a complex disease with a high mortality. Management of this disease is underpinned by supportive and general therapies delivered by multidisciplinary teams in specialist centres. In recent years, a number of PAH-specific therapies have improved patient outcomes. This article will discuss the management of PAH in the context of relevant recently published studies in this area.

RECENT FINDINGS:

PAH-specific therapies are targeted towards dysfunctional signalling identified within the pulmonary circulation, and include endothelin receptor antagonists, phosphodiesterase type-5 inhibitors and prostanoids. Combination of these therapies is considered in patients with more severe disease. In addition, timely referral for surgical intervention (e.g. atrial septostomy, lung transplantation) should be made in selected patients with advanced disease. New treatment modalities currently in development may further improve patient outcomes in future years. However, further development and expansion of patient registries is vital for enhanced understanding of this disease, and may guide the optimal use of existing therapies and the development of new treatment approaches.

SUMMARY:

Outcomes in PAH have improved in recent years through a management approach characterized by general and supportive measures, and PAH-specific and surgical therapies in selected patients. Continued development of patient registries is vital to improve understanding and outcomes of this disease.
  PMID: 23242212 [PubMed - indexed for MEDLINE]
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  Curr Opin Anaesthesiol. 2013 Feb;26(1):71-81. doi: 10.1097/ACO.0b013e32835b8be2.

Perioperative right ventricular dysfunction.

Denault AYHaddad FJacobsohn EDeschamps A.
Department of Anesthesiology, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.andre.denault@umontreal.ca

Abstract

PURPOSE OF REVIEW:

To evaluate new information on the importance of right ventricular function, diagnosis and management in cardiac surgical patients.

RECENT FINDINGS:

There is growing evidence that right ventricular function is a key determinant in survival in cardiac surgery, particularly in patients with pulmonary hypertension. The diagnosis of this condition is helped by the use of specific hemodynamic parameters and echocardiography. In that regard, international consensus guidelines on the echocardiographic assessment of right ventricular function have been recently published. New monitoring modalities in cardiac surgery such as regional near-infrared spectroscopy can also assist management. Management of right ventricular failure will be influenced by the presence or absence of myocardial ischemia and left ventricular dysfunction. The differential diagnosis and management will be facilitated using a systematic approach.

SUMMARY:

The use of right ventricular pressure monitoring and the publications of guidelines for the echocardiographic assessment of right ventricular anatomy and function allow the early identification of right ventricular failure. The treatment success will be associated by optimization of the hemodynamic, echocardiographic and near-infrared spectroscopy parameters.
  PMID: 23235519 [PubMed - indexed for MEDLINE]
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  Respir Med. 2013 Feb;107(2):298-304. doi: 10.1016/j.rmed.2012.10.007. Epub 2012 Nov 3.

Hypoxaemia in patients with pulmonary arterial hypertension during simulated air travel.

Burns RMPeacock AJJohnson MKChurch AC.
Scottish Pulmonary Vascular Unit, Golden Jubilee Hospital, Agamemnon Street, Clydebank, Glasgow G81 4DY, UK.

Abstract

BACKGROUND:

Recent air travel recommendations suggest patients with precapillary pulmonary hypertension (PCPH) in New York Heart Association (NYHA) functional class 3 and 4 should have in-flight oxygen without the need for pre-flight testing. However it remains unclear as to how best to determine patients fitness to fly.

METHODS:

This study (i) investigates the effect of hypoxic challenge testing (HCT) on the arterial oxygen levels in a cohort of 36 patients with PCPH and (ii) compares the relative frequency with which FC and HCT predict the requirement for in-flight oxygen.

RESULTS:

The degree of arterial hypoxaemia induced by HCT (fall in partial pressure of oxygen in arterial blood (PaO(2)) 2.36 kPa, 95% CI 2.06-2.66 kPa) was similar to the drop observed in other published studies of chronic respiratory diseases. Following current air travel recommendations based on FC, 25 patients of the cohort would require in-flight oxygen whilst 10 subjects failed the HCT. Fourteen subjects had flown post-diagnosis. Of these, nine subjects should have had in-flight oxygen based on FC but were asymptomatic without. Also one who passed the HCT had developed symptoms during the flight whilst three who failed the HCT were asymptomatic flying without in-flight oxygen.

CONCLUSIONS:

Hypoxaemia induced by simulated air travel in patients with PCPH is similar to that seen in published studies of patients with other chronic respiratory diseases. HCT failed to predict correctly who had developed symptoms during an aircraft flight in a significant minority of the study subjects. Similarly guidelines based on functional class result in a major increase in the proportion of patients being advised to use oxygen, many of whom had been asymptomatic on previous flights without it. More work is required to improve prediction of need for in-flight oxygen in patients with PCPH.
Copyright © 2012. Published by Elsevier Ltd.
  PMID: 23127571 [PubMed - indexed for MEDLINE]
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  Cardiovasc Ther. 2013 Feb;31(1):38-44. doi: 10.1111/1755-5922.12008.

Rapid transition from inhaled iloprost to inhaled treprostinil in patients with pulmonary arterial hypertension.

Bourge RCTapson VFSafdar ZBenza RLChannick RNRosenzweig EBShapiro SWhite RJMcSwain CSGotzkowsky SKNelsen ACRubin LJ.
University of Alabama at Birmingham, Birmingham, AL 35294, USA. bbourge@uab.edu

Abstract

BACKGROUND:

Inhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy.

AIMS:

In this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 μg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6-9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed.

RESULTS:

Most patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (-74 pg/mL; P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains P < 0.001).

CONCLUSIONS:

Pulmonary arterial hypertension patients can be safely transitioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.
© 2012 Blackwell Publishing Ltd.
PMCID: PMC3561685 Free PMC Article
  PMID: 22970909 [PubMed - indexed for MEDLINE]
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  Am J Physiol Heart Circ Physiol. 2013 Jun 21. [Epub ahead of print]

Strong linear relationship between heart rate and mean pulmonary artery pressure in exercising patients with severe precapillary pulmonary hypertension.

Chemla DCastelain VHoette SCreuze NProvencher SZhu KHumbert MHerve P.
1EA4533-APHP-Reanimation medicale.

Abstract

The contribution of heart rate (HR) to pulmonary artery hemodynamics has been suggested in pulmonary hypertension. Our high-fidelity pressure, retrospective study tested the hypothesis that HR explained the majority of mean pulmonary artery pressure (mPAP) and pulse pressure (PApp) variation in twelve severe precapillary pulmonary hypertension patients performing incremental-load cycling while supine. Seven idiopathic pulmonary arterial hypertension and five chronic thrombo-embolic pulmonary hypertension were studied. Four-to-five PAP-thermodilution cardiac output (CO) points (mean 4.4) were obtained. Heart period was computed at 1,000Hz. At rest, mPAP was 57±9mmHg, PApp=51±11mmHg, HR=90±12bpm, stroke volume SV=50±22mL. At peak exercise, mPAP was 76±10mmHg, PApp=67±11mmHg and HR=125±19bpm (i.e.,71±10% of maximum heart rate) (each P<0.05) while SV=51±20mL (P=NS). The input resistance did not change (mPAP/CO=14.1±4.1 vs 13.5±4.4 mmHg/L/min). The relative increase in mPAP was related to the relative increase in HR (n=12; r&sup2; = 0.74), not in CO. The mPAP was linearly related to CO in 8/12 patients (median r&sup2;=0.83) and to HR in 12/12 (median r&sup2;=0.985). The parsimony principle favored the latter fit. The PApp was linearly related to mPAP in 12/12 patients (median r&sup2;=0.985), HR in 10/12 (median r&sup2;=0.97), CO in 7/12 (median r&sup2;=0.87) and SV in 1/12. Strong linear relationship between HR and mPAP was consistently documented in severe precapillary pulmonary hypertension performing supine exercise. The limited value of thermodilution CO to predict mPAP could be explained by unavoidable precision errors in CO measurement, unchanged/decreased SV on exercise, curvilinearity of the mPAP-CO relationship at high flow, or flow-independent additional mechanisms increasing mPAP on exercise.
  PMID: 23792679 [PubMed - as supplied by publisher]
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  Circulation. 2013 Apr 16;127(15):1597-608. doi: 10.1161/CIRCULATIONAHA.112.000999. Epub 2013 Mar 13.

Right ventricular systolic function in organic mitral regurgitation: impact of biventricular impairment.

Le Tourneau TDeswarte GLamblin NFoucher-Hossein CFayad GRichardson MPolge ASVannesson C,Topilsky YJuthier FTrochu JNEnriquez-Sarano MBauters C.
Inserm, UMR 1087, Institut du thorax, Nantes, France. thletourneau@yahoo.fr

Comment in

The myocardium in mitral regurgitation: a tale of 2 ventricles.Carabello BA. Circulation. 2013 Apr 16; 127(15):1567-8.

Abstract

BACKGROUND:

To assess the prevalence, determinants, and prognosis value of right ventricular (RV) ejection fraction (EF) impairment in organic mitral regurgitation.

METHODS AND RESULTS:

Two hundred eight patients (62±12 years, 138 males) with chronic organic mitral regurgitation referred to surgery underwent an echocardiography and biventricular radionuclide angiography with regional function assessment. Mean RV EF was 40.4±10.2%, ranging from 10% to 65%. RV EF was severely impaired (≤35%) in 63 patients (30%), and biventricular impairment (left ventricular EF<60% and RV EF≤35%) was found in 34 patients (16%). Pathophysiologic correlates of RV EF were left ventricular septal function (β=0.42, P<0.0001), left ventricular end-diastolic diameter index (β=-0.22, P=0.002), and pulmonary artery systolic pressure (β=-0.14, P=0.047). Mitral effective regurgitant orifice size (n=84) influenced RV EF (β=-0.28, P=0.012). In 68 patients examined after surgery, RV EF increased strongly (27.5±4.3-37.9±7.3, P<0.0001) in patients with depressed RV EF, whereas it did not change in others (P=0.91). RV EF ≤35% impaired 10-year cardiovascular survival (71.6±8.4% versus 89.8±3.7%, P=0.037). Biventricular impairment dramatically reduced 10-year cardiovascular survival (51.9±15.3% versus 90.3±3.2%, P<0.0001; hazard ratio, 5.2; P<0.0001) even after adjustment for known predictors (hazard ratio, 4.6; P=0.004). Biventricular impairment reduced also 10-year overall survival (34.8±13.0% versus 72.6±4.5%, P=0.003; hazard ratio, 2.5; P=0.005) even after adjustment for known predictors (P=0.048).

CONCLUSIONS:

In patients with organic mitral regurgitation referred to surgery, RV function impairment is frequent (30%) and depends weakly on pulmonary artery systolic pressure but mainly on left ventricular remodeling and septal function. RV function is a predictor of postoperative cardiovascular survival, whereas biventricular impairment is a powerful predictor of both cardiovascular and overall survival.
  PMID: 23487435 [PubMed - indexed for MEDLINE]
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