Publications
393 results found
Jee AS, Corte TJ, Wort SJ, et al., 2017, Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep, RESPIROLOGY, Vol: 22, Pages: 1022-1034, ISSN: 1323-7799
Price LC, Wort SJ, 2017, Pulmonary hypertension in ARDS: inflammation matters!, THORAX, Vol: 72, Pages: 396-397, ISSN: 0040-6376
Nashat H, Kempny A, McCabe C, et al., 2017, Eisenmenger syndrome: current perspectives, Research Reports in Clinical Cardiology, Vol: 8, Pages: 1-12, ISSN: 1179-8475
Abstract: Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). It results from a cardiac defect allowing significant systemic-to-pulmonary (left-to-right) shunting, which triggers the development of pulmonary vascular disease (PVD) if the defect is not repaired in a timely fashion. Once severe PVD has developed, the defect cannot be repaired. With advances in pediatric cardiology and surgery, the prevalence of ES is steadily falling in developed countries; nonetheless, there will always be patients who are unsuitable for repair at the time of diagnosis, or emigrating from countries with less advanced healthcare, who will develop ES. ES is a multisystem disorder causing chronic hypoxemia and reduced cardiac output resulting in significant morbidity and mortality. While lung (plus defect repair) or combined heart and lung transplantation is thought be the definitive treatment for ES, transplant organs are a limited resource and long-term results are still suboptimal. PAH pharmacotherapy was, until quite recently, largely directed at symptomatic relief and had no impact on morbidity and mortality. Targeted PAH therapies have recently been proven to be beneficial in various forms of PAH in terms of functional status, progression of disease, and prognosis. Data on the effect of PAH therapies in the ES cohort remain limited, but available studies demonstrate evidence of improvement in symptoms, exercise capacity, and some evidence of survival benefit. ES patients should be followed in specialized centers, by means of an interdisciplinary approach by clinicians experienced in PAH and CHD. However, local physicians working in cardiology, respiratory medicine, primary care, and emergency services are likely to encounter ES patients and need to be aware of the main issues and pitfalls in their care. The authors present an overview of the management of ES, focusing on the most common issues and co
Rhodes CJ, Ghataorhe P, Wharton J, et al., 2017, Plasma metabolomics implicate modified transfer RNAs and altered bioenergetics in the outcome of pulmonary arterial hypertension, Circulation, Vol: 135, Pages: 460-475, ISSN: 0009-7322
Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality.Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis.Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects.Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.
Bax S, Bredy C, Kempny A, et al., 2017, A Composite Echocardiography Score Predicts Pulmonary Hypertension In Patients With Interstitial Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Sithamparanathan S, Nair A, Thirugnanasothy L, et al., 2016, Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 36, Pages: 770-779, ISSN: 1053-2498
Moceri P, Bouvier P, Baudouy D, et al., 2016, Cardiac remodelling amongst adults with various aetiologies of pulmonary arterial hypertension including Eisenmenger syndrome-implications on survival and the role of right ventricular transverse strain., Eur Heart J Cardiovasc Imaging
AIMS: Survival in pulmonary arterial hypertension (PAH) and Eisenmenger syndrome (ES) relates to right ventricular (RV) function. Little is known about differences of ventricular function between ES patients and those suffering from other PAH aetiologies. In this study, we compared global ventricular function assessed by speckle-tracking in adult patients with ES, other PAH aetiologies, or healthy controls; and assessed the relationship between ventricular function and survival. METHODS AND RESULTS: We performed a prospective cohort study recruiting 83 adult PAH patients (43 ES and 40 other PAH aetiologies patients) and 37 controls between March 2011 and June 2015. Patients with complex congenital heart disease were excluded. Fifty-three patients (63.9%) were in NYHA functional class ≥III at baseline and 60 (72.3%) were on advanced therapies. Mean RV peak longitudinal strain was -16.3 ± 7% in ES, lower compared with healthy controls (P < 0.001) but similar to other PAH aetiologies (P = 0.6). Mean RV peak transverse strain was +26.1 ± 17% in ES, lower than in controls (P < 0.001) but higher than in other PAH aetiologies (P < 0.001). No difference was observed between ES and other PAH in LV circumferential and longitudinal strain. Over a median follow-up of 22.6 months (3.3-32.2), 22 (26.5%) patients died all from cardio-pulmonary causes. ES and RV peak transverse strain were independent predictors of survival. RV peak transverse strain ≤22% identified patients with a 14-fold increased risk of death. CONCLUSION: Right ventricular remodelling differs between adults with ES and other PAH aetiologies. ES and increased RV free wall transverse strain are associated with better survival.
Kempny A, Hjortshøj CS, Gu H, et al., 2016, Predictors of death in contemporary adult patients with Eisenmenger syndrome: a multicentre study, Circulation, Vol: 135, Pages: 1432-1440, ISSN: 0009-7322
BACKGROUND: -Eisenmenger syndrome (ES) is associated with substantial morbidity and mortality. There is no consensus, however, on mortality risk stratification. We aimed to investigate survival and predictors of death in a large, contemporary cohort of ES patients. METHODS: -We identified in a multicentre approach adults with ES under follow-up between 2000 and 2015. We examined survival and its association with clinical, electrocardiographic, echocardiographic and laboratory parameters. RESULTS: -We studied 1098 patients (median age 34.4years, range 16.1-84.4years, 65.1% female, 31.9% with Down syndrome). The majority had a post-tricuspid defect (n=643, 58.6%), followed by patients with a complex (n=315, 28.7%) and pre-tricuspid lesion (n=, 12.7%). Over a median follow-up of 3.1years [IQR 1.4-5.9], allowing for 4361.6 patient-years observation, 278 patients died and six and six underwent transplantation. Twelve parameters emerged as significant predictors of death on univariable analysis. On multivariable Cox regression analysis only age (HR 1.41/10years, 95%CI 1.24-1.59, P<0.001), pre-tricuspid shunt (HR 1.56, 95%CI 1.02-2.39, P=0.041), oxygen saturation at rest (HR 0.53/10%, 95%CI 0.43-0.65, P<0.001), presence of sinus rhythm (HR 0.53, 95%CI 0.32-0.88, P=0.013) and presence of pericardial effusion (HR 2.41, 95%CI 1.59-3.66, P<0.001) remained significant predictors of death. CONCLUSIONS: -There is significant premature mortality amongst contemporary adults with ES. We report, herewith a multivariable mortality risk stratification model based on five simple, non-invasive predictors of death in this population.
Hadinnapola C, Haimel M, Bleda M, et al., 2016, GENOTYPE-PHENOTYPE ASSOCIATIONS IN PULMONARY ARTERIAL HYPERTENSION CAUSED BY BMPR2 AND EIF2AK4 VARIANTS, British Thoracic Society Winter Meeting 2016, Publisher: BMJ PUBLISHING GROUP, Pages: A63-A64, ISSN: 0040-6376
Ramakrishnan L, Anwar A, Wort S, et al., 2016, Haemoglobin mediated proliferation and IL-6 release in human pulmonary artery endothelial cells: a role for CD163 and implications for pulmonary vascular remodelling., Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A220-A220, ISSN: 1468-3296
Garfield BE, Shao D, Parfitt L, et al., 2016, LOW SKELETAL MUSCLE STRENGTH AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH POOR OUTCOMES IN PULMONARY ARTERIAL HYPERTENSION, THORAX, Vol: 71, Pages: A64-A64, ISSN: 0040-6376
Graf S, Bleda M, Haddinapola C, et al., 2016, Whole Genome Sequencing in Idiopathic and Familial Pulmonary Arterial Hypertension Reveals Causal Rare Coding and Non-coding Sequence Variation, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Dimopoulos K, Muthiah K, Alonso-Gonzalez R, et al., 2016, Heart or heart and lung transplantation for patients with congenital heart disease in England: outcomes and future predictions, Quality of Care and Outcomes Research Scientific Sessions, Publisher: American Heart Association, ISSN: 0009-7322
Mumby S, Ramakrishnan L, Kempny A, et al., 2016, Dysregulation of iron homeostasis in Eisenmenger syndrome; comparison to idiopathic pulmonary arterial hypertension and healthy controls., ERS International Congress
Bax S, Dimopoulos K, Kier G, et al., 2016, Longitudinal change in non-invasive markers in interstitial lung disease associated pulmonary hypertension and correlation with invasive pulmonary haemodynamics, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Price LC, Wells AU, Wort SJ, 2016, Pulmonary tumour thrombotic microangiopathy., Current Opinion in Pulmonary Medicine, Vol: 22, Pages: 421-428, ISSN: 1531-6971
PURPOSE OF REVIEW: Pulmonary tumour thrombotic microangiopathy (PTTM) describes tumour cell microemboli with occlusive fibrointimal remodelling in small pulmonary arteries, veins and lymphatics. Progressive vessel occlusion ultimately results in pulmonary hypertension, which is often severe and rapid in onset. PTTM is associated with carcinomas, notably gastric carcinoma, with vascular endothelial growth factor and platelet-derived growth factor (PDGF) signalling implicated in driving the intimal remodelling. PTTM is a rare cause of pulmonary hypertension, but given that up to a quarter of autopsy specimens from patients dying of carcinoma show evidence for PTTM, it is probably underdiagnosed. RECENT FINDINGS: Until recently, prognosis in PTTM was universally abysmal from weeks to a few months. Diagnostic utilities include aspiration of tumour cells at wedged right heart catheterization, high-resolution computed tomography (HRCT) findings and computed tomography-positron emission tomography (CT-PET), although definitive diagnosis requires histological analysis. Reports of PTTM treated with a combination of targeted pulmonary vasodilator therapies, anticoagulation, specific chemotherapy and PDGF inhibition, for example using imatinib, suggest that these approaches can prolong survival. SUMMARY: PTTM is increasingly recognized as an important cause of pulmonary hypertension, often in patients presenting with new-onset pulmonary hypertension and as yet undiagnosed malignancy. Prospects of survival are improving with targeted combination therapy, and early recognition and diagnosis are likely to be the key factors to improve outcome.
Kokosi M, Keir G, Wort J, et al., 2016, Pulmonary hypertension in interstitial lung disease: Non-invasive assessment for detection and prognosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Tyebally S, Sturdy A, Khokhar A, et al., 2016, Intravenous prostacyclin for pulmonary hypertension: Patient's perspective on complications, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Nikolakopoulou Z, Svermova T, Chowdhury J, et al., 2016, Roundabout (Robo) receptors on pulmonary artery endothelial cells: Implications for pulmonary arterial hypertension, ERS, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Nashat H, Harries C, Parfitt L, et al., 2016, Factors prohibiting progression to prostanoid therapy in patients with pulmonary arterial hypertension and CTEPH who remain in functional class III or above despite maximal oral therapy, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 565-565, ISSN: 0195-668X
Kempny A, Boutsikou M, Dimopoulos K, et al., 2016, Long term complications and outcome in patients with repaired aortic coarctation. Analysis of 2860 community based CoA patients in England, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 1253-1253, ISSN: 0195-668X
Kempny A, Diller GP, Gatzoulis MA, et al., 2016, Mortality after surgery in patients with congenital heart disease. analysis of 57293 cardiac surgeries in England between 1997 and 2015, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 201-201, ISSN: 0195-668X
Mumby SE, Gambaryan N, Meng C, et al., 2016, Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension, Respirology, Vol: 22, Pages: 157-164, ISSN: 1440-1843
Background and objectiveNuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes.MethodsThe effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients.ResultsJQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1−. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1−-treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D ) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum-stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients.ConclusionInhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH.
Natsuki A, Wort J, Chung F, et al., 2016, TNFα stimulates an inflammatory response in human pulmonary microvascular endothelial cells (hpmecs): the role of NF-κB and Bet proteins, International Conference of the American Thoracic Society (ATS), Publisher: American Thoracic Society, ISSN: 1535-4970
Price LC, Devaraj A, Wort SJ, 2016, Central pulmonary arteries in idiopathic pulmonary fibrosis: size really matters, European Respiratory Journal, Vol: 47, Pages: 1318-1320, ISSN: 1399-3003
Despite the uncertainties of why, when it comes to PH risk in IPF, pulmonary artery size clearly matters http://ow.ly/YlKVy
Cannon JE, Su L, Kiely DG, et al., 2016, Dynamic risk stratification of patient long-term outcome after pulmonary endarterectomy: results from the UK national cohort, Circulation, Vol: 133, Pages: 1761-1771, ISSN: 0009-7322
Background—Chronic thromboembolic pulmonary hypertension results from incomplete resolution of pulmonary emboli. Pulmonary endarterectomy (PEA) is potentially curative, but residual pulmonary hypertension following surgery is common and its impact on long-term outcome is poorly understood. We wanted to identify factors correlated with poor long-term outcome after surgery and specifically define clinically relevant residual pulmonary hypertension post-PEA.Methods and Results—Eight hundred eighty consecutive patients (mean age, 57 years) underwent PEA for chronic thromboembolic pulmonary hypertension. Patients routinely underwent detailed reassessment with right heart catheterization and noninvasive testing at 3 to 6 months and annually thereafter with discharge if they were clinically stable at 3 to 5 years and did not require pulmonary vasodilator therapy. Cox regressions were used for survival (time-to-event) analyses. Overall survival was 86%, 84%, 79%, and 72% at 1, 3, 5, and 10 years for the whole cohort and 91% and 90% at 1 and 3 years for the recent half of the cohort. The majority of patient deaths after the perioperative period were not attributable to right ventricular failure (chronic thromboembolic pulmonary hypertension). At reassessment, a mean pulmonary artery pressure of ≥30 mm Hg correlated with the initiation of pulmonary vasodilator therapy post-PEA. A mean pulmonary artery pressure of ≥38 mm Hg and pulmonary vascular resistance ≥425 dynes·s−1·cm−5 at reassessment correlated with worse long-term survival.Conclusions—Our data confirm excellent long-term survival and maintenance of good functional status post-PEA. Hemodynamic assessment 3 to 6 months and 12 months post-PEA allows stratification of patients at higher risk of dying of chronic thromboembolic pulmonary hypertension and identifies a level of residual pulmonary hypertension that may guide the long-term management of patient
Jo HE, Corte TJ, Wort SJ, et al., 2016, Year in review 2015: Interstitial lung disease, pulmonary vascular disease, pulmonary function, sleep and ventilation, cystic fibrosis and paediatric lung disease, Respirology, Vol: 21, Pages: 556-566, ISSN: 1440-1843
Price LC, Wort SJ, 2016, Earlier diagnosis and international registries may improve outcomes in pulmonary tumour thrombotic microangiopathy, European Respiratory Journal, Vol: 47, Pages: 690-691, ISSN: 1399-3003
Earlier diagnosis and international registries may improve outcomes in pulmonary tumour thrombotic microangiopathy http://ow.ly/V74EI
Jutant EM, Price L, Wort SJ, et al., 2016, Pulmonary hypertension, ERS Monograph, Vol: 2016, Pages: 160-174, ISSN: 2312-508X
IPF is often associated with PH, which principally develops due to fibrotic destruction of the vasculature and pulmonary vascular remodelling. The presence of PH worsens prognosis, especially when associated with right ventricular dysfunction. The extent of PH is not closely associated with the extent of lung fibrosis, as assessed by pulmonary lung function or radiological features, suggesting that the severity of fibrosis is not the only driving factor for PH. The term “out of proportion PH” has now been abandoned and replaced with “IPF with severe PH” in the minority of patients with a mean pulmonary artery pressure >35 mmHg. Although echocardiography is a useful indicator, right heart catheterisation remains the gold standard for PH in IPF. There is no current recommendation for PH-specific therapies in IPF, and patients should be included in clinical trials. Current treatment recommendations are optimisation of treatment of the underlying IPF, oxygen supplementation when necessary and lung transplantation, despite the increase in transplantation complications when PH is associated with IPF.
Toshner M, Bleda M, Newnham M, et al., 2016, Genome Wide Association Studies In Chronic Thromboembolic Pulmonary Hypertension, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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