Imperial College London

DrLukeHoward

Faculty of MedicineNational Heart & Lung Institute

Professor of Practice (Cardiopulmonary Medicine)
 
 
 
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Contact

 

+44 (0)20 3313 3171l.howard Website

 
 
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Location

 

B3113Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

340 results found

Efstathiou C, Liew F, Fontanella S, Richardson M, Saunders R, Swieboda D, Sidhu J, Ascough S, Moore S, Mohamed N, Nunag J, King C, Leavy O, Elneima O, McAuley H, Shikotra A, Singapuri A, Sereno M, Harris V, Houchen-Wolloff L, Greening N, Lone N, Thorpe M, Thompson AAR, Rowland-Jones S, Docherty A, Chalmers J, Ho L-P, Horsley A, Ramam B, Poinasamy K, Marks M, Kon OM, Howard L, Wootton D, Quint J, de Silva T, Ho A, Chiu C, Harrision E, Greenhalf W, Baillie JK, Semple M, Turtle L, Evans R, Wain L, Brightling C, Thwaites R, Openshaw Pet al., 2024, Large scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease, Nature Immunology, ISSN: 1529-2908

Journal article

Kianzad A, Baccelli A, Braams NJ, Andersen S, van Wezenbeek J, Wessels JN, Celant LR, Vos AE, Davies R, Lo Giudice F, Haji G, Rinaldo RF, Vigo B, Gopalan D, Symersky P, Winkelman JA, Boonstra A, Nossent EJ, Tim Marcus J, Vonk Noordegraaf A, Meijboom LJ, de Man FS, Andersen A, Howard LS, Bogaard HJet al., 2024, Long-term effects of pulmonary endarterectomy on pulmonary hemodynamics, cardiac function, and exercise capacity in chronic thromboembolic pulmonary hypertension., J Heart Lung Transplant, Vol: 43, Pages: 580-593

BACKGROUND: Long-term changes in exercise capacity and cardiopulmonary hemodynamics after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been poorly described. METHODS: We analyzed the data from 2 prospective surgical CTEPH cohorts in Hammersmith Hospital, London, and Amsterdam UMC. A structured multimodal follow-up was adopted, consisting of right heart catheterization, cardiac magnetic resonance imaging, and cardiopulmonary exercise testing before and after PEA. Preoperative predictors of residual pulmonary hypertension (PH; mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥2 WU) and long-term exercise intolerance (VO2max <80%) at 18 months were analyzed. RESULTS: A total of 118 patients (61 from London and 57 from Amsterdam) were included in the analysis. Both cohorts displayed a significant improvement of pulmonary hemodynamics, right ventricular (RV) function, and exercise capacity 6 months after PEA. Between 6 and 18 months after PEA, there were no further improvements in hemodynamics and RV function, but the proportion of patients with impaired exercise capacity was high and slightly increased over time (52%-59% from 6 to 18 months). Long-term exercise intolerance was common and associated with preoperative diffusion capacity for carbon monoxide (DLCO), preoperative mixed venous oxygen saturation, and postoperative PH and right ventricular ejection fraction (RVEF). Clinically significant RV deterioration (RVEF decline >3%; 5 [9%] of 57 patients) and recurrent PH (5 [14%] of 36 patients) rarely occurred beyond 6 months after PEA. Age and preoperative DLCO were predictors of residual PH post-PEA. CONCLUSIONS: Restoration in exercise tolerance, cardiopulmonary hemodynamics, and RV function occurs within 6 months. No substantial changes occurred between 6 and 18 months after PEA in the Amsterdam cohort. Nevertheless, long-term exercise

Journal article

Ghofrani H-A, Simonneau G, D'Armini AM, Fedullo P, Howard LS, Jaïs X, Jenkins DP, Jing Z-C, Madani MM, Martin N, Mayer E, Papadakis K, Richard D, Kim NH, MERIT study investigatorset al., 2024, Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study., Lancet Respir Med, Vol: 12, Pages: e21-e30

BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd.

Journal article

Yogeswaran A, Gall H, Fünderich M, Wilkins MR, Howard L, Kiely DG, Lawrie A, Hassoun PM, Sirenklo Y, Torbas O, Sweatt AJ, Zamanian RT, Williams PG, Frauendorf M, Arvanitaki A, Giannakoulas G, Saleh K, Sabbour H, Cajigas HR, Frantz R, Al Ghouleh I, Chan SY, Brittain E, Annis JS, Pepe A, Ghio S, Orfanos S, Anthi A, Majeed RW, Wilhelm J, Ghofrani HA, Richter MJ, Grimminger F, Sahay S, Tello K, Seeger W, PVRI-GoDeep-Consortiumet al., 2024, Comparison of contemporary risk scores in all groups of pulmonary hypertension - a PVRI GoDeep meta-registry analysis, Chest, ISSN: 0012-3692

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). While various risk models were developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH group 1-4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among incident PH patients enrolled in the multicenter worldwide PVRI-GoDeep meta-registry. Analyses were performed across PH groups 1-4 and further subgroups to evaluate the predictive value of PAH-risk scores, including REVEAL Lite 2, REVEAL 2.0, ESC/ERS 2022, COMPERA 3-strata and COMPERA 4-strata. RESULTS: 8565 patients were included in the study, of whom 3537 patients were assigned to group 1 PH while 1807, 1635, and 1586 patients were diagnosed with group 2, group 3, and group 4 PH. Pulmonary hemodynamics were impaired with median mPAP of 42 [33,52]mmHg and PVR of 7 [4,11]WU. All risk scores were prognostic in the entire PH population and in each of the PH groups 1-4. The REVEAL scores, when used as continuous prediction models, possessed the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided sub-differentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, 1.4.4; 3.1, 3.2; group 2 with isolated post-capillary-PH versus combined pre-/post-capillary-PH; patients of all groups with concomitant cardiac comorbidities; severe [> 5 WU] versus non-severe PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH-centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common group

Journal article

Liley J, Newnham M, Bleda M, Bunclark K, Auger W, Barbera JA, Bogaard H, Delcroix M, Fernandes TM, Howard L, Jenkins D, Lang I, Mayer E, Rhodes C, Simpson M, Southgate L, Trembath R, Wharton J, Wilkins MR, Gräf S, Morrell N, Pepke Zaba J, Toshner Met al., 2024, Shared and distinct genomics of chronic thromboembolic pulmonary hypertension and pulmonary embolism, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Rationale: Chronic Thromboembolic Pulmonary Hypertension involves formation and non-resolution of thrombus, dysregulated inflammation, angiogenesis and the development of a small vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1907 European cases and 10363 European controls. We co-analysed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our co-analysis we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2 and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations to pulmonary embolism and to deep vein thrombosis.

Journal article

Howard LS, Price LC, 2024, Systematic pulmonary embolism follow-up: why we should all do it!, Eur Respir J, Vol: 63

Journal article

Elneima O, McAuley HJC, Leavy OC, Chalmers JD, Horsley A, Ho L-P, Marks M, Poinasamy K, Raman B, Shikotra A, Singapuri A, Sereno M, Harris VC, Houchen-Wolloff L, Saunders RM, Greening NJ, Richardson M, Quint JK, Briggs A, Docherty AB, Kerr S, Harrison EM, Lone NI, Thorpe M, Heaney LG, Lewis KE, Aul R, Beirne P, Bolton CE, Brown JS, Choudhury G, Bakerly ND, Easom N, Echevarria C, Fuld J, Hart N, Hurst JR, Jones MG, Parekh D, Pfeffer P, Rahman NM, Rowland-Jones SL, Thompson AR, Jolley C, Shah AM, Wootton DG, Chalder T, Davies MJ, De Soyza A, Geddes JR, Greenhalf W, Heller S, Howard LS, Jacob J, Jenkins RG, Lord JM, Man WD-C, McCann GP, Neubauer S, Openshaw PJ, Porter JC, Rowland MJ, Scott JT, Semple MG, Singh SJ, Thomas DC, Toshner M, Smith N, Sheikh A, Brightling CE, Wain LV, Evans RA, Brightling CE, Evans RA, Wain LV, Chalmers JD, Harris VC, Ho LP, Horsley A, Marks M, Poinasamy K, Raman B, Shikotra A, Singapuri A, Brightling CE, Evans RA, Wain LV, Dowling R, Edwardson C, Elneima O, Finney S, Greening NJ, Hargadon B, Harris VC, Houchen-Wolloff L, Leavy OC, McAuley HJC, Overton C, Plekhanova T, Saunders RM, Sereno M, Singapuri A, Shikotra A, Taylor C, Terry S, Tong C, Zhao B, Lomas D, Sapey E, Berry C, Bolton CE, Brunskill N, Chilvers ER, Djukanovic R, Ellis Y, Forton D, French N, George J, Hanley NA, Hart N, McGarvey L, Maskell N, McShane H, Parkes M, Peckham D, Pfeffer P, Sayer A, Sheikh A, Thompson AAR, Williams N, Brightling CE, Greenhalf W, Semple MG, Ashworth M, Hardwick HE, Lavelle-Langham L, Reynolds W, Sereno M, Saunders RM, Singapuri A, Shaw V, Shikotra A, Venson B, Wain LV, Docherty AB, Harrison EM, Sheikh A, Baillie JK, Brightling CE, Daines L, Free R, Evans RA, Kerr S, Leavy OC, Lone NI, McAuley HJC, Pius R, Quint JK, Richardson M, Sereno M, Thorpe M, Wain LV, Halling-Brown M, Gleeson F, Jacob J, Neubauer S, Raman B, Siddiqui S, Wild JM, Aslani S, Baxter G, Beggs M, Bloomfield C, Cassar MP, Chiribiri A, Cox E, Cuthbertson DJ, Halling-Brown M, Ferreira VMet al., 2024, Cohort profile: Post-Hospitalisation COVID-19 (PHOSP-COVID) study, International Journal of Epidemiology, Vol: 53, ISSN: 0300-5771

Journal article

Pepke-Zaba J, Howard L, Kiely DG, Sweeney S, Johnson Met al., 2024, Pulmonary Embolism (PE) to Chronic Thromboembolic Pulmonary Disease (CTEPD): findings from a Survey of UK Physicians, Advances in Respiratory Medicine, Vol: 92, Pages: 45-57, ISSN: 2543-6031

Chronic thromboembolic pulmonary disease (CTEPD) is a complication of pulmonary embolism (PE). We conducted an online survey of UK PE-treating physicians to understand practices in the follow-up of PE and awareness of CTEPD. The physicians surveyed (N = 175) included 50 each from cardiology, respiratory and internal medicine, plus 25 haematologists. Most (89%) participants had local guidelines for PE management, and 65% reported a PE follow-up clinic, of which 69% were joint clinics. Almost half (47%) had a protocol for the investigation of CTEPD. According to participants, 129 (74%) routinely consider a diagnosis of CTEPD and 97 (55%) routinely investigate for CTEPD, with 76% of those 97 participants investigating in patients who are symptomatic at 3 months and 22% investigating in all patients. This survey demonstrated variability in the follow-up of PE and the awareness of CTEPD and its investigation. The findings support the conduct of a national audit to understand the barriers to the timely detection of CTEPD.

Journal article

Ulrich A, Wu Y, Draisma H, Wharton J, Swietlik EM, Cebola I, Vasilaki E, Balkhiyarova Z, Jarvelin M, Auvinen J, Herzig K-H, Coghlan JG, Lordan J, Church C, Howard L, Pepke-Zaba J, Toshner M, Wort S, Kiely D, Condliffe R, Lawrie A, Graf S, Morrell N, Wilkins M, Prokopenko I, Rhodes C, Rhodes Cet al., 2024, Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension, Nature Communications, Vol: 15, ISSN: 2041-1723

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10−7) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10−4). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

Journal article

Varian F, Dick J, Battersby C, Roman S, Ablott J, Watson L, Binmahfooz S, Zafar H, Colgan G, Cannon J, Suntharalingam J, Lordan J, Howard L, McCabe C, Wort J, Price L, Church C, Hamilton N, Armstrong I, Hameed A, Hurdman J, Elliot C, Condliffe R, Wilkins M, Webb A, Adlam D, Benza RL, Rahimi K, Shojaei-Shahrokhabadi M, Lin NX, Wason JMS, McIntosh A, McConnachie A, Middleton JT, Thompson R, Kiely DG, Toshner M, Rothman Aet al., 2024, Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies., Pulm Circ, Vol: 14, ISSN: 2045-8932

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Journal article

Karia N, Howard L, Johnson M, Kiely DG, Lordan J, McCabe C, Pepke-Zaba J, Ong R, Preiss M, Knight D, Muthurangu V, Coghlan JGet al., 2023, Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study., Eur Heart J, Vol: 44, Pages: 4678-4691

BACKGROUND AND AIMS: Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. METHODS: A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. RESULTS: Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68

Journal article

Welch CL, Aldred MA, Balachandar S, Dooijes D, Eichstaedt CA, Gräf S, Houweling AC, Machado RD, Pandya D, Prapa M, Shaukat M, Southgate L, Tenorio-Castano J, ClinGen PH VCEP, Chung WK, International Consortium for Genetic Studies in Pulmonary Arterial Hypertension PAH-ICON at the Pulmonary Vascular Research Institute PVRIet al., 2023, Defining the clinical validity of genes reported to cause pulmonary arterial hypertension, Genetics in Medicine, Vol: 25, ISSN: 1098-3600

PURPOSE: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. METHODS: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. RESULTS: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. CONCLUSION: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

Journal article

C-MOREPHOSP-COVID Collaborative Group, 2023, Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study, The Lancet Respiratory Medicine, Vol: 11, Pages: 1003-1019, ISSN: 2213-2600

INTRODUCTION: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. METHODS: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. FINDINGS: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MR

Journal article

Afoke J, Mohal J, Kanaganayagam GS, Casula R, Bruno V, Howard L, Gibbs S, Punjabi Pet al., 2023, Cardiopulmonary exercise testing augments watchful waiting in asymptomatic severe primary mitral regurgitation, PERFUSION-UK, ISSN: 0267-6591

Journal article

Stolfo D, Barbisan D, Ameri P, Lombardi CM, Monti S, Driussi M, Zovatto IC, Gentile P, Howard L, Toma M, Pagnesi M, Collini V, Bauleo C, Guglielmi G, Adamo M, D'Angelo L, Nalli C, Sciarrone P, Moschella M, Zorzi B, Vecchiato V, Milani M, Di Poi E, Airo E, Metra M, Garascia A, Sinagra G, Lo Giudice Fet al., 2023, Performance of risk stratification scores and role of comorbidities in older vs younger patients with pulmonary arterial hypertension, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 42, Pages: 1082-1092, ISSN: 1053-2498

Journal article

Jackson C, Stewart ID, Plekhanova T, Cunningham PS, Hazel AL, Al-Sheklly B, Aul R, Bolton CE, Chalder T, Chalmers JD, Chaudhuri N, Docherty AB, Donaldson G, Edwardson CL, Elneima O, Greening NJ, Hanley NA, Harris VC, Harrison EM, Ho L-P, Houchen-Wolloff L, Howard LS, Jolley CJ, Jones MG, Leavy OC, Lewis KE, Lone NI, Marks M, McAuley HJC, McNarry MA, Patel BV, Piper-Hanley K, Poinasamy K, Raman B, Richardson M, Rivera-Ortega P, Rowland-Jones SL, Rowlands AV, Saunders RM, Scott JT, Sereno M, Shah AM, Shikotra A, Singapuri A, Stanel SC, Thorpe M, Wootton DG, Yates T, Gisli Jenkins R, Singh SJ, Man WD-C, Brightling CE, Wain LV, Porter JC, Thompson AAR, Horsley A, Molyneaux PL, Evans RA, Jones SE, Rutter MK, Blaikley JF, PHOSP-COVID Study Collaborative Groupet al., 2023, Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study, The Lancet Respiratory Medicine, Vol: 11, Pages: 673-684, ISSN: 2213-2600

BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended

Journal article

Samaranayake CB, Upham J, Tran K, Howard LS, Nguyen S, Lwin M, Anderson J, Wahi S, Price LC, Wort S, Li W, McCabe C, Keir GJet al., 2023, Right ventricular functional recovery assessment with stress echocardiography and cardiopulmonary exercise testing after pulmonary embolism: a pilot prospective multicentre study, BMJ OPEN RESPIRATORY RESEARCH, Vol: 10

Journal article

Guignabert C, Savale L, Boucly A, Thuillet R, Tu L, Ottaviani M, Rhodes CJ, De Groote P, Prevot G, Bergot E, Bourdin A, Howard LS, Fadel E, Beurnier A, Roche A, Jevnikar M, Jais X, Montani D, Wilkins MR, Sitbon O, Humbert Met al., 2023, Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension, CIRCULATION, Vol: 147, Pages: 1809-1822, ISSN: 0009-7322

Journal article

Guignabert C, Savale L, Boucly A, Thuillet R, Tu L, Ottaviani M, Rhodes CJ, De Groote P, Prevot G, Bergot E, Bourdin A, Howard L, Fadel E, Beurnier A, Roche A, Jevnikar M, Jais X, Montani D, Wilkins M, Sitbon O, Humbert MJet al., 2023, Associations Between Serum Activin A and Follistatine-Like 3 Levels and Outcomes in Pulmonary Arterial Hypertension, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Richter MJ, Fortuni F, Alenezi F, D'Alto M, Badagliacca R, Brunner NW, Dijk APV, Douschan P, Gall H, Ghio S, Lo Giudice F, Grunig E, Haddad F, Howard L, Rajagopal S, Stens N, Stolfo D, Thijssen DHJ, Vizza CD, Zamanian RT, Zhong L, Seeger W, Ghofrani HA, Tello Ket al., 2023, Imaging the right atrium in pulmonary hypertension: A systematic review and meta-analysis, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 42, ISSN: 1053-2498

Journal article

Howard L, Kiely DG, Lawrie A, Maron BA, Preston I, Rosenkranz S, Toshner M, Wilkins M, Fong Y-L, Quinn D, Stamatiadis D, Villeneuve M, Chin Ket al., 2023, PERFORMANCE OF THE ESC/ERS GUIDELINES FOR ASSESSING THE PROBABILITY OF PULMONARY HYPERTENSION (PH) BY TRANSTHORACIC ECHOCARDIOGRAM (TTE): AN ANALYSIS OF INCIDENT PATIENTS FROM THE CIPHER STUDY, 72nd Annual Scientific Session (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 1922-1922, ISSN: 0735-1097

Conference paper

Howard L, McCabe C, 2023, Follow-up assessment - Who to follow and how to investigate?, Emergent Pulmonary Embolism Management In Hospital Practice: From Hyperacute To Follow-up Care, Pages: 179-192, ISBN: 9781800612761

The follow up of acute pulmonary embolism presents a growing challenge to clinicians with decisions involving anticoagulation management, screening for complications, and investigations around persistent breathlessness key to patient recovery. Inconsistency in approach to clinical management in this setting is perhaps an inevitable consequence of a rapidly evolving evidence base for therapeutic anticoagulation options involving treatment dose and duration as well as an increased awareness of chronic thromboembolic pulmonary hypertension, a rare but severe long-term complication of pulmonary embolism. Here we review suggested clinical approaches to the investigation of patients diagnosed with pulmonary embolism focusing on the investigation of persistently symptomatic patients at risk of chronic complications. Additional discussion is provided on topical aspects of chronic thromboembolic disease less incorporated in guidelines concerning pulmonary embolism follow up.

Book chapter

Eichstaedt CA, Belge C, Chung WK, Gräf S, Grünig E, Montani D, Quarck R, Tenorio-Castano JA, Soubrier F, Trembath RC, Morrell NW, for PAH-ICON associated with the PVRIet al., 2023, Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH, European Respiratory Journal, Vol: 61, ISSN: 0903-1936

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

Journal article

Howard LS, Rosenkranz S, Frantz RP, Hemnes AR, Fister TP, Schmitz S-FH, Skara H, Humbert M, Preston IRet al., 2023, Assessing Daily Life Physical Activity by Actigraphy in Pulmonary Arterial Hypertension Insights From the Randomized Controlled Study With Selexipag (TRACE), CHEST, Vol: 163, Pages: 407-418, ISSN: 0012-3692

Journal article

Leong K, Howard L, Giudice FL, Davies R, Haji G, Gibbs S, Gopalan Det al., 2023, Utility of cardiac magnetic resonance feature tracking strain assessment in chronic thromboembolic pulmonary hypertension for prediction of REVEAL 2.0 high risk status, PULMONARY CIRCULATION, Vol: 13, ISSN: 2045-8932

Journal article

Liew F, Talwar S, Cross A, Willett B, Scott S, Logan N, Siggins M, Swieboda D, Sidhu J, Efstathiou C, Moore S, Davis C, Mohamed N, Nunag J, King C, Thompson AAR, Rowland-Jones S, Docherty A, Chalmers J, Ho L-P, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard L, Wootton D, Dunachie S, Quint J, Evans R, Wain L, Fontanella S, de Silva T, Ho A, Harrison E, Baillie JK, Semple MG, Brightling C, Thwaites R, Turtle L, Openshaw Pet al., 2023, SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination, EBioMedicine, Vol: 87, Pages: 1-14, ISSN: 2352-3964

Background:Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.Methods:In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.Findings:Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.Interpretation:The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.Funding:This

Journal article

Mulvaney EP, Renzo F, Adao R, Dupre E, Bialesova L, Salvatore V, Reid HM, Conceicao G, Grynblat J, Llucia-Valldeperas A, Michel J-B, Bras-Silva C, Laurent CE, Howard LS, Montani D, Humbert M, Noordegraaf AV, Perros F, Mendes-Ferreira P, Kinsella BTet al., 2022, The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload, Frontiers in Cardiovascular Medicine, Vol: 9, ISSN: 2297-055X

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction.Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM).Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM.Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy

Journal article

Stolfo D, Barbisan D, Ameri P, Lombardi CM, Monti S, Driussi M, Zovatto IC, Gentile P, Howard L, Toma M, Pagnesi M, Collini V, Bauleo C, Guglielmi G, Adamo M, D'angelo L, Nalli C, Sciarrone P, Moschella M, Zorzi B, Vecchiato V, Milani M, Di Poi E, Airo E, Metra M, Garascia A, Sinagra G, Giudice FLet al., 2022, PERFORMANCE OF RISK STRATIFICATION SCORES AND ROLE OF COMORBIDITIES IN OLDER VS YOUNGER PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION, Publisher: OXFORD UNIV PRESS, ISSN: 1520-765X

Conference paper

Oliveira RKF, Nyasulu PS, Iqbal AA, Gul MH, Ferreira EVM, Leclair JW, Htun ZM, Howard LS, Mocumbi AO, Bryant AJ, Tamuzi JL, Avdeev S, Petrosillo N, Hassan A, Butrous G, Perez VDJet al., 2022, Cardiopulmonary disease as sequelae of long-term COVID-19: Current perspectives and challenges, Frontiers in Medicine, Vol: 9, ISSN: 2296-858X

COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients.

Journal article

Kariotis S, Jammeh E, Swietlik EM, Pickworth JA, Rhodes CJ, Otero P, Wharton J, Iremonger J, Dunning MJ, Pandya D, Mascarenhas TS, Errington N, Thompson AAR, Romanoski CE, Rischard F, Garcia JGN, Yuan JX-J, An T-HS, Desai AA, Coghlan G, Lordan J, Corris PA, Howard LS, Condliffe R, Kiely DG, Church C, Pepke-Zaba J, Toshner M, Wort S, Graf S, Morrell NW, Wilkins MR, Lawrie A, Wang Det al., 2022, Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood, Nature Communications, Vol: 13, Pages: 1-1, ISSN: 2041-1723

Journal article

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