Publications
393 results found
Dimopoulos K, Condliffe R, Tulloh RMR, et al., 2018, Echocardiographic Screening for Pulmonary Hypertension in Congenital Heart Disease <i>JACC</i> Review Topic of the Week, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 72, Pages: 2778-2788, ISSN: 0735-1097
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- Citations: 31
Drakopoulou M, Nashat H, Kempny A, et al., 2018, Arrhythmias in adult patients with congenital heart disease and pulmonary arterial hypertension, Heart, Vol: 104, Pages: 1963-1969, ISSN: 1355-6037
OBJECTIVES: Approximately 5%-10% of adults with congenital heart disease (CHD) develop pulmonary arterial hypertension (PAH), which affects life expectancy and quality of life. Arrhythmias are common among these patients, but their incidence and impact on outcome remains uncertain. METHODS: All adult patients with PAH associated with CHD (PAH-CHD) seen in a tertiary centre between 2007 and 2015 were followed for new-onset atrial or ventricular arrhythmia. Clinical variables associated with arrhythmia and their relation to mortality were assessed using Cox analysis. RESULTS: A total of 310 patients (mean age 34.9±12.3 years, 36.8% male) were enrolled. The majority had Eisenmenger syndrome (58.4%), 15.2% had a prior defect repair and a third had Down syndrome. At baseline, 14.2% had a prior history of arrhythmia, mostly supraventricular arrhythmia (86.4%). During a median follow-up of 6.1 years, 64 patients developed at least one new arrhythmic episode (incidence 3.47% per year), mostly supraventricular tachycardia or atrial fibrillation (78.1% of patients). Arrhythmia was associated with symptoms in 75.0% of cases. The type of PAH-CHD, markers of disease severity and prior arrhythmia were associated with arrhythmia during follow-up. Arrhythmia was a strong predictor of death, even after adjusting for demographic and clinical variables (HR 3.41, 95% CI 2.10 to 5.53, p<0.0001). CONCLUSIONS: Arrhythmia is common in PAH-CHD and is associated with an adverse long-term outcome, even when managed in a specialist centre.
Swietlik EM, Hodgson J, Hadinnapola C, et al., 2018, PHENOTYPIC CHARACTERISATION OF GDF2 MUTATION CARRIERS IN A LARGE COHORT OF PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A24-A26, ISSN: 0040-6376
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- Citations: 1
Issitt T, Toe Q, Quinlan G, et al., 2018, HEPCIDIN TREATMENT OF HUMAN PULMONARY ARTERY SMOOTH MUSCLE CELLS AND MITOCHONDRIAL DYSFUNCTION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A23-A24, ISSN: 0040-6376
Nashat H, Barbosa J, Harries C, et al., 2018, EFFICACY OF MACITENTAN IN A LARGE, REAL LIFE POPULATION OF PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A76, ISSN: 0040-6376
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- Citations: 2
Pedersen S, Toe Q, Wort SJ, et al., 2018, Stabilised ferroportin activity affects pulmonary vascular cells responses: implications for pulmonary hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: European Respiratory Society, ISSN: 0903-1936
Bohnen MS, Ma L, Zhu N, et al., 2018, Loss-of-function ABCC8 mutations in pulmonary arterial hypertension, Circulation: Genomic and Precision Medicine, Vol: 11, Pages: 1-9, ISSN: 2574-8300
Background:In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target.Methods:Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.Results:We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.Conclusions:Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Nashat H, Harries C, Parfitt L, et al., 2018, A single-centre, placebo-controlled, double-blinded, randomized, cross-over study of Iloprost in patients with Eisenmenger syndrome, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Blanche C, Alonso-Gonzalez R, Uribarri A, et al., 2018, Use of intravenous iron in cyanotic patients with congenital heart disease and/or pulmonary hypertension, Annual Meeting of the European-Society-of-Cardiology (ESC), Publisher: ELSEVIER IRELAND LTD, Pages: 79-83, ISSN: 0167-5273
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- Citations: 15
Nashat H, Da Costa R, Barbosa J, et al., 2018, Clinical efficacy of Macitentan in patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wort SJ, Favoccia C, Kempny A, et al., 2018, emPHasis-10 score predicts mortality in patients with pulmonary hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 3
Price L, Mccabe C, Herbert S, et al., 2018, Critical care admissions in patients with pulmonary arterial hypertension., 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Price L, Kempny A, Mccabe C, et al., 2018, Sildenafil in Patients with Severe Group 3 Pulmonary Hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bax S, Jacobs J, Kouranos V, et al., 2018, 10 years' experience of referral of ILD patients with Suspected PH to a National PH Service: Demographics and Outcomes, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Vranesic II, Li W, Price L, et al., 2018, Increased right ventricular systolic: diastolic duration ratiopredicts mortality in idiopathic pulmonary arterial hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Nashat H, Montanaro C, Li W, et al., 2018, Atrial septal defects and pulmonary arterial hypertension, JOURNAL OF THORACIC DISEASE, Vol: 10, Pages: S2953-S2965, ISSN: 2072-1439
Ramakrishnan L, Pedersen SL, Toe QK, et al., 2018, The Hepcidin / Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells, Scientific Reports, Vol: 8, ISSN: 2045-2322
Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.
Constantine AH, Kempny A, Swan L, et al., 2018, Pregnancy in adults with congenital heart disease in England between 1997 and 2015: Clinical outcomes and risk factors for the peri-partum period, European-Society-of-Cardiology Congress 2018, Publisher: OXFORD UNIV PRESS, Pages: 1281-1281, ISSN: 0195-668X
Constantine AH, Dimopoulos K, Alonso-Gonzalez R, et al., 2018, Sub-aortic stenosis in England between 1997 and 2015: reoperation rates and risk factors, European Society of Cardiology Congress 2018, Publisher: OXFORD UNIV PRESS, Pages: 464-464, ISSN: 0195-668X
Favoccia C, Kempny A, Price LC, et al., 2018, The emPHasis-10 quality of life score for pulmonary hypertension is a strong predictor of mortality, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 633-633, ISSN: 0195-668X
Vranesic II, McCabe C, Kempny A, et al., 2018, Prolonged right ventricular systolic to diastolic duration ratio predicts mortality in idiopathic pulmonary arterial hypertension, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 924-924, ISSN: 0195-668X
Keir GJ, John Wort S, Kokosi M, et al., 2018, Pulmonary hypertension in interstitial lung disease: limitations of echocardiography compared to cardiac catheterization, Respirology, Vol: 23, Pages: 687-694, ISSN: 1323-7799
BACKGROUND AND OBJECTIVE: In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well-characterized ILD cohort. METHODS: Two hundred and sixty-five consecutive patients with ILD and suspected PH underwent comprehensive assessment, including RHC, between 2006 and 2012. ESC/ERS recommended tricuspid regurgitation (TR) velocity thresholds for assigning high (>3.4 m/s), intermediate (2.9-3.4 m/s) and low (<2.8 m/s) probabilities of PH were evaluated against RHC testing. RESULTS: RHC testing confirmed PH in 86% of subjects with a peak TR velocity >3.4 m/s, and excluded PH in 60% of ILD subjects with a TR velocity <2.8 m/s. Thus, the ESC/ERS guidelines misclassified 40% of subjects as 'low probability' of PH, when PH was confirmed on subsequent RHC. Evaluating alternative TR velocity thresholds for assigning a low probability of PH did not significantly improve the ability of TR velocity to exclude a diagnosis of PH. CONCLUSION: In patients with ILD and suspected PH, currently recommended ESC/ERS TR velocity screening thresholds were associated with a high positive predictive value (86%) for confirming PH, but were of limited value in excluding PH, with 40% of patients misclassified as low probability when PH was confirmed at subsequent RHC.
Bax S, Bredy C, Kempny A, et al., 2018, A stepwise composite echocardiographic score predicts severe pulmonary hypertension in patients with interstitial lung disease (vol 4, 124, 2018), ERJ Open Research, Vol: 4, Pages: 1-1, ISSN: 2312-0541
Ramakrishnan L, Pedersen S, Toe Q, et al., 2018, Pulmonary arterial hypertension: iron matters, Frontiers in Physiology, Vol: 9, ISSN: 1664-042X
The interplay between iron and oxygen is longstanding and central to all aerobic life. Tight regulation of these interactions including homeostatic regulation of iron utilization ensures safe usage of this limited resource. However, when control is lost adverse events can ensue, which are known to contribute to an array of disease processes. Recently, associations between disrupted iron homeostasis and pulmonary artery hypertension (PAH) have been described with the suggestion that there is a contributory link with disease. This review provides a background for iron regulation in humans, describes PAH classifications, and discusses emerging literature, which suggests a role for disrupted iron homeostatic control in various sub-types of PAH, including a role for decompartmentalization of hemoglobin. Finally, the potential for therapeutic options to restore iron homeostatic balance in PAH are discussed.
Bax S, Bredy C, Kempny A, et al., 2018, A stepwise composite echocardiographic score predicts severe pulmonary hypertension in patients with interstitial lung disease, ERJ Open Research, Vol: 4, ISSN: 2312-0541
European Respiratory Society (ERS) guidelines recommend the assessment of patients with interstitial lung disease (ILD) and severe pulmonary hypertension (PH), as defined by a mean pulmonary artery pressure (mPAP) ≥35 mmHg at right heart catheterisation (RHC). We developed and validated a stepwise echocardiographic score to detect severe PH using the tricuspid regurgitant velocity and right atrial pressure (right ventricular systolic pressure (RVSP)) and additional echocardiographic signs. Consecutive ILD patients with suspected PH underwent RHC between 2005 and 2015. Receiver operating curve analysis tested the ability of components of the score to predict mPAP ≥35 mmHg, and a score devised using a stepwise approach. The score was tested in a contemporaneous validation cohort. The score used "additional PH signs" where RVSP was unavailable, using a bootstrapping technique. Within the derivation cohort (n=210), a score ≥7 predicted severe PH with 89% sensitivity, 71% specificity, positive predictive value 68% and negative predictive value 90%, with similar performance in the validation cohort (n=61) (area under the curve (AUC) 84.8% versus 83.1%, p=0.8). Although RVSP could be estimated in 92% of studies, reducing this to 60% maintained a fair accuracy (AUC 74.4%). This simple stepwise echocardiographic PH score can predict severe PH in patients with ILD.
Gräf S, Haimel M, Bleda M, et al., 2018, Identification of rare sequence variation underlying heritable pulmonary arterial hypertension, Nature Communications, Vol: 9, Pages: 1-16, ISSN: 2041-1723
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
Kempny A, Wort SJ, Dimopoulos K, 2018, Balloon pulmonary angioplasty for chronic thromboembolic disease: aiming for perfection, EUROINTERVENTION, Vol: 13, Pages: 1983-1986, ISSN: 1774-024X
Piper AJ, Wort SJ, Renzoni EA, et al., 2018, Year in review 2017: interstitial lung disease, pulmonary vascular disease and sleep, Respirology, Vol: 23, Pages: 421-433, ISSN: 1323-7799
Herbert S, Harries C, Barbosa J, et al., 2018, EXERCISE CAPACITY IMPROVEMENT IN ADULT CONGENITAL HEART DISEASE PATIENTS SWITCHING FROM BOSENTAN TO MACITENTAN THERAPY, Annual Meeting of the British-Congenital-Cardiac-Association, Publisher: BMJ PUBLISHING GROUP, Pages: A8-A9, ISSN: 1355-6037
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- Citations: 1
Farmery JHR, Smith ML, Lynch AG, et al., 2018, Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data, Scientific Reports, Vol: 8, ISSN: 2045-2322
Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.
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