Scottish Pulmonary Vascular Unit

Glasgow, United Kingdom

Scottish Pulmonary Vascular Unit

Glasgow, United Kingdom

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Shah N.P.,University of California at San Francisco | Wallis N.,Bristol Myers Squibb | Farber H.W.,Boston University | Mauro M.J.,Sloan Kettering Cancer Center | And 5 more authors.
American Journal of Hematology | Year: 2015

The prognosis of most leukemia patients treated with BCR-ABL tyrosine kinase inhibitors (TKIs) is favorable, and a more precise understanding of serious and potentially irreversible treatment-related toxicities is essential to properly inform treatment choice. Few cases of pulmonary arterial hypertension (PAH) have been reported in patients with leukemia treated with dasatinib, a second-generation BCR-ABL TKI. To better understand characteristics and outcomes of dasatinib-treated patients with PAH, all clinical cases of PAH confirmed by right-heart catheterization in the Bristol-Myers Squibb pharmacovigilance database (N=41), including 22 previously unpublished cases, were examined for previous treatments for leukemia, patient characteristics, time to PAH onset, and outcomes. Our analysis shows that compared with PAH due to other etiologies, dasatinib-related PAH is atypical, in that it is associated with partial to complete reversibility upon treatment discontinuation. The incidence of dasatinib-related PAH appears to be low. Most PAH cases were observed in patients who had received prior treatments for leukemia. No specific patient attributes appear to be associated with an increased risk of developing PAH while receiving dasatinib. Symptoms of PAH in dasatinib-treated leukemia patients should prompt a thorough workup, including consideration of confirmatory right-heart catheterization. In cases of confirmed PAH, dasatinib should be discontinued. © 2015 Wiley Periodicals, Inc.


McGoon M.D.,Mayo Medical School | Benza R.L.,Allegheny General Hospital | Jiang X.,Chinese Academy of Sciences | Miller D.P.,ICON Clinical Research | And 7 more authors.
Journal of the American College of Cardiology | Year: 2013

Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases. © 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc.


Peacock A.,Scottish Pulmonary Vascular Unit | Keogh A.,St Vincentas Hospital | Humbert M.,Hopital Antoine Beclere
Current Opinion in Pulmonary Medicine | Year: 2010

Purpose of review: Design and selection of endpoints used in clinical trials is a complex and compelling topic; the diverse needs of clinicians, patients and regulatory authorities represent a challenge in devising the most relevant, meaningful yet practical measures. In trials of therapies for pulmonary arterial hypertension (PAH), a variety of endpoints have been used, including assessments of exercise capacity (6-min walk distance [6MWD]), functional class, hemodynamics, and time to clinical worsening. Most have relied upon 6MWD as the primary endpoint. Recent findings: Accumulating experience and expertise suggests that the relevance of the 6-min walk test as a stand-alone measure of efficacy is now a topic for consideration. Furthermore, 6MWD tends to correlate poorly with other endpoints and, most importantly, there is no linear relationship between 6MWD and morbidity/mortality. Although no linear relationship has been identified with other endpoints, time to clinical worsening may be considered a better endpoint for assessing the effectiveness of PAH therapies, in particular the impact of treatment on disease progression, because it is very relevant to the clinical outcome of patients. Treatment of mildly symptomatic patients, for example, has demonstrated a clear delay in time to clinical worsening and the endpoint might be better suited than others to demonstrate the efficacy of combination therapy. Summary: As the field of PAH develops and progresses, time to clinical worsening may be the best way currently of distinguishing between the increasing number of treatment options available. A clear definition must, therefore, be established, with adjudication by an expert panel; the needs of clinicians, patients, and regulators should be balanced when selecting the most appropriate endpoints. © 2010 Wolters Kluwer Health. Lippincott Williams & Wilkins.


Gaine S.P.,National University of Ireland | Naeije R.,Erasme University Hospital | Peacock A.J.,Scottish Pulmonary Vascular Unit
The Right Heart | Year: 2014

The heart and lung are intricately linked. When the heart is affected by disease, the lungs will often show some related pathological or clinical conditions and vice versa. Pulmonary heart disease is by definition a condition when the lungs cause the heart to fail. The left ventricle in combination with the other structures in the "left heart" pumps blood throughout the body. The right ventricle (and structures of the "right heart") pumps blood to the lungs where it is oxygenated and returned to the left heart for distribution. In normal circumstances, the right heart pumps blood into the lungs without any resistance. The lungs usually have minimal pressure and the right heart easily pumps blood through. However when there is lung disease present, like emphysema, chronic obstructive lung disease (COPD) or pulmonary hypertension- the small blood vessels become very stiff and rigid. The right ventricle is no longer able to push blood into the lungs and eventually fails. This is known as pulmonary heart disease. Pulmonary heart disease is also known as right heart failure or cor pulmonale. The chief cause of right heart failure is the increase in blood pressure in the lungs (pulmonary artery). © 2014 Springer-Verlag London. All rights are reserved.


Shah A.M.,Brigham and Women's Hospital | Campbell P.,Brigham and Women's Hospital | Rocha G.Q.,Brigham and Women's Hospital | Peacock A.,Scottish Pulmonary Vascular Unit | And 2 more authors.
European Heart Journal | Year: 2015

Aims Imatinib mesylate, as add-on therapy in patients with pulmonary arterial hypertension (PAH) who remain inadequately treated despite receiving at least two PAH-specific drugs, improves exercise capacity and haemodynamics. We evaluated whether 24 weeks of add-on therapy with imatinib compared with placebo also improves right ventricular (RV) function assessed by echocardiography. Methods and results Echocardiograms were obtained at baseline, 12 weeks, and 24 weeks in 74 patients randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial. Right ventricular function was assessed by tissue Doppler tricuspid annular peak systolic velocity (TA S′), tricuspid annular plane systolic excursion (TAPSE), RV Tei index, and RV fractional area change. Between-treatment-group differences in the changes from baseline to week-24 were assessed using an ANCOVA with the last observation carried forward. At week-24 patients randomized to imatinib demonstrated greater improvements in TA S′ (1.6 ± 2.3 imatinib vs. 0.5 ± 2.4 cm/s placebo, P = 0.007) and RV Tei index (-0.11 ± 0.18 imatinib vs. 0.05 ± 0.18 placebo, P = 0.005) compared with placebo, but not in TAPSE (0.07 ± 0.44 imatinib vs. 0.03 ± 0.32 cm placebo, P = 0.08). Imatinib therapy was also associated with significant reduction in peak tricuspid regurgitation velocity, increase in LV size, and improvement in LV early diastolic relaxation velocity. Conclusions Among patients with advanced PAH who remain symptomatic on at least two PAH-specific drugs, treatment with imatinib compared with placebo is associated with significant improvements in echocardiographic measures of RV function, in addition to LV size and LV early diastolic relaxation. © 2014 Published on behalf of the European Society of Cardiology.


Bayes H.K.,University of Glasgow | Church A.C.,Scottish Pulmonary Vascular Unit | Fisher A.J.,Northumbria University
Thorax | Year: 2012

This is the second annual review of the British Thoracic Society Winter Scientific Meeting held from 7-9 December 2011, which was attended by over 2000 delegates. Although a wide spectrum of respiratory research was presented at the meeting, the content of the review focuses specifically on three key themes: cystic fibrosis, pulmonary vascular disease and thoracic oncology. Advances in clinical and translational respiratory research presented within the major symposia and spoken sessions related to these areas are summarised. Additional sessions recognising topics relevant to the forthcoming 2012 London Olympics are also highlighted.


Bayes H.K.,University of Glasgow | Church A.C.,Scottish Pulmonary Vascular Unit | Fisher A.J.,Northumbria University
Thorax | Year: 2013

This review highlights new developments in scientific and clinical research presented at the British Thoracic Society Winter Scientific Meeting held from 5 to 7 December 2012. Although a wide spectrum of respiratory research was presented at the meeting the content of the review focuses specifically on the key themes of pleural disease, interstitial lung disease and future therapies in respiratory medicine. Advances in clinical and translational respiratory research presented in the major symposia and spoken sessions related to these areas are summarised. Additional sessions covering lifestyle dilemmas in the context of respiratory disease and the early career investigator awards are also highlighted.


Carlin C.M.,Scottish Pulmonary Vascular Unit | Celnik D.F.,Scottish Pulmonary Vascular Unit | Pak O.,Scottish Pulmonary Vascular Unit | Wadsworth R.,University of Strathclyde | And 2 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2012

Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models, but the mechanism of action and applicability of these results to human treatment are not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodeling. We previously showed that acute hypoxic pulmonary adventitial fibroblast proliferation can beselectively inhibitedby statins and p38 mitogen-activated protein (MAP) kinase inhibitors. Here we used complementary chronic hypoxic and acute hypoxic coculture models to obtain necessary preclinical information regarding the utility of fluvastatin in the treatment of chronic hypoxic pulmonary hypertension. The effects of fluvastatin, cholesterol pathway intermediates, and related inhibitors on hypoxic adventitial fibroblast proliferation, p38 MAP kinase phosphorylation, and pulmonary artery smooth muscle cell proliferation were determined, using complementary chronic hypoxic rat and acute hypoxic bovine cell models. Fluvastatin reversed the proliferative phenotypic switch in adventitial fibroblasts from chronic hypoxic animals. This effect was circulation-specific, and implicated a Rac1-p38 MAP kinase signaling pathway. Coculture and conditioned media experiments also implicated this statin-sensitive signaling pathway in the release of pulmonary artery smooth muscle cell mitogens by hypoxic pulmonary adventitial fibroblasts. Treprostinil, sildenafil, and bosentan exerted no effect on the hypoxic fibroblast phenotype. Phenotypic changes (increased proliferation and mitogen release) in pulmonary artery fibroblasts during chronic hypoxia are dependent on a Rac1-p38 MAP kinase signaling pathway. The inhibition of these phenotypic changes with fluvastatin may be therapeutically relevant in high-altitude residents and in patients with hypoxic lung disease. Copyright © 2012 by the American Thoracic Society.


Welsh D.J.,Scottish Pulmonary Vascular Unit | Peacock A.J.,Scottish Pulmonary Vascular Unit
High Altitude Medicine and Biology | Year: 2013

Welsh, David J., and Andrew J. Peacock. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol 14:111-116, 2013. - Hypoxia can be defined as a reduction in available oxygen, whether in a whole organism or in a tissue or cell. It is a real life cause of pulmonary hypertension in humans both in terms of patients with chronic hypoxic lung disease and people living at high altitude. The effect of hypoxia on the pulmonary vasculature can be described in two ways; Hypoxic pulmonary vasoconstriction (HPV) (resulting from smooth muscle cell contraction) and pulmonary vascular remodelling (PVR) (resulting from pulmonary vascular cell proliferation). The pulmonary artery is made up of three resident cell types, the endothelial (intima), smooth muscle (media) and fibroblast (adventitia) cells. This review will examine the effects of hypoxia on the cells of the pulmonary vasculature and give an insight into the possible underlying mechanisms. © Mary Ann Liebert, Inc.


Peacock A.J.,Scottish Pulmonary Vascular Unit | Noordegraaf A.V.,VU University Amsterdam
European Respiratory Review | Year: 2013

Cardiac magnetic resonance imaging (CMRI) provides accurate information about right ventricular (RV) mass, RV volumes and other markers of RV function. CMRI is proving to be a particularly useful tool in pulmonary arterial hypertension (PAH), as measures of RV function have been shown to be prognostic of long-term outcomes in this disease. Changes in RV function can also provide important information about a patient's disease course and response to treatment. As CMRI is noninvasive it can be used to regularly monitor patients with PAH, which is an important advantage over invasive right heart catheterisation. This review will explore the use of CMRI in the context of existing monitoring tools for PAH and will explore the forthcoming developments that are likely to be important in the future monitoring of patients with PAH. © ERS 2013.

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