Imperial College London

Professor Martin Wilkins

Faculty of MedicineDepartment of Medicine

Head of the Department of Medicine
 
 
 
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Contact

 

+44 (0)20 3313 2049m.wilkins

 
 
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Location

 

NIHR / Wellcome Trust Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

183 results found

Brash L, Barnes GD, Brewis MJ, Church AC, Gibbs SJ, Howard LSGE, Jayasekera G, Johnson MK, McGlinchey N, Onorato J, Simpson J, Stirrat C, Thomson S, Watson G, Wilkins MR, Xu C, Welsh DJ, Newby DE, Peacock AJet al., 2018, Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension., JACC Basic Transl Sci, Vol: 3, Pages: 176-186

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).

JOURNAL ARTICLE

Dawes TJW, Cai J, Quinlan M, de Marvao A, Ostrowski PJ, Tokarczuk PF, Watson GMJ, Wharton J, Howard LSGE, Gibbs JSR, Cook SA, Wilkins MR, O'Regan DPet al., 2018, Fractal Analysis of Right Ventricular Trabeculae in Pulmonary Hypertension., Radiology, Vol: 288, Pages: 386-395

Purpose To measure right ventricular (RV) trabecular complexity by its fractal dimension (FD) in healthy subjects and patients with pulmonary hypertension (PH) and to assess its relationship with hemodynamic and functional parameters and future cardiovascular events. Materials and Methods This retrospective study used data acquired from May 2004 to October 2013 in 256 patients with newly diagnosed PH who underwent cardiac MRI, right-sided heart catheterization, and 6-minute walk distance testing, with median follow-up of 4.0 years. A total of 256 healthy control subjects underwent cardiac MRI only. Biventricular FD, volumes, and function were assessed on short-axis cine images. Reproducibility was assessed with the intraclass correlation coefficient, correlation between variables was assessed with the Pearson correlation test, and mortality prediction was compared by using uni- and multivariable Cox regression analyses. Results RV FD reproducibility had an intraclass correlation coefficient of 0.97 (95% confidence interval [CI]: 0.96, 0.98). RV FD was higher in patients with PH (median, 1.310; interquartile range [IQR], 1.281-1.341) than in healthy subjects (median, 1.264; IQR, 1.242-1.295; P < .001), with the greatest difference near the apex. RV FD was associated with pulmonary vascular resistance (r = 0.30, P < .001). At univariable Cox regression analysis, RV FD was a significant predictor of death (hazard ratio [HR], 1.256; 95% CI: 1.011, 1.560; P = .04); however, at multivariable analysis, RV FD did not enable prediction of survival independently of conventional parameters of RV remodeling (HR, 1.179; 95% CI: 0.871, 1.596; P = .29). Conclusion Fractal analysis of RV trabecular complexity is a highly reproducible measure of remodeling in patients with PH that is associated with afterload, although the gain in survival prediction over traditional markers is not significant. Published under a CC BY 4.0 license. Online supplemental material is available for

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Graf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, Hodgson J, Liu B, Salmon RM, Southwood M, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, Aldred M, Bogaard HJ, Church C, Coghlan G, Condliffe R, Corris PA, Danesino C, Eyries M, Gall H, Ghio S, Ghofrani H-A, Gibbs JSR, Girerd B, Houweling AC, Howard L, Humbert M, Kiely DG, Kovacs G, Ross RVM, Moledina S, Montani D, Newnham M, Olschewski A, Olschewski H, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Stein DF, Suntharalingam J, Swietlik EM, Toshner MR, van Heel DA, Noordegraaf AV, Waisfisz Q, Wharton J, Wort SJ, Ouwehand WH, Soranzo N, Lawrie A, Upton PD, Wilkins MR, Trembath RC, Morrell NWet al., 2018, Identification of rare sequence variation underlying heritable pulmonary arterial hypertension, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723

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Huertas A, Guignabert C, Barbera JA, Baertsch P, Bhattacharya J, Bhattacharya S, Bonsignore MR, Dewachter L, Anh TD-X, Dorfmuller P, Gladwin MT, Humbert M, Kotsimbos T, Vassilakopoulos T, Sanchez O, Savale L, Testa U, Wilkins MRet al., 2018, Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases, EUROPEAN RESPIRATORY JOURNAL, Vol: 51, ISSN: 0903-1936

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White RJ, Wilkins MR, 2018, New Therapeutic Approaches in Pulmonary Arterial Hypertension The Pantheon Is Getting Crowded, CIRCULATION, Vol: 137, Pages: 2390-2392, ISSN: 0009-7322

JOURNAL ARTICLE

Wilkins M, Aman J, Harbaum L, Ulrich A, Wharton J, Rhodes Cet al., 2018, Recent advances in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder with a high mortality rate. Treatment options have improved in the last 20 years, but patients still die prematurely of right heart failure. Though rare, it is heterogeneous at the genetic and molecular level, and understanding and exploiting this is key to the development of more effective treatments. BMPR2 , encoding bone morphogenetic receptor type 2, is the most commonly affected gene in both familial and non-familial PAH, but rare mutations have been identified in other genes. Transcriptomic, proteomic, and metabolomic studies looking for endophenotypes are under way. There is no shortage of candidate new drug targets for PAH, but the selection and prioritisation of these are challenges for the research community.

JOURNAL ARTICLE

Wilkins MR, Aman J, Harbaum L, Ulrich A, Wharton J, Rhodes CJet al., 2018, Recent advances in pulmonary arterial hypertension., F1000Res, Vol: 7, ISSN: 2046-1402

Pulmonary arterial hypertension (PAH) is a rare disorder with a high mortality rate. Treatment options have improved in the last 20 years, but patients still die prematurely of right heart failure. Though rare, it is heterogeneous at the genetic and molecular level, and understanding and exploiting this is key to the development of more effective treatments. BMPR2, encoding bone morphogenetic receptor type 2, is the most commonly affected gene in both familial and non-familial PAH, but rare mutations have been identified in other genes. Transcriptomic, proteomic, and metabolomic studies looking for endophenotypes are under way. There is no shortage of candidate new drug targets for PAH, but the selection and prioritisation of these are challenges for the research community.

JOURNAL ARTICLE

Dawes TJW, de Marvao A, Shi W, Fletcher T, Watson GMJ, Wharton J, Rhodes CJ, Howard LSGE, Gibbs JSR, Rueckert D, Cook SA, Wilkins MR, O'Regan DPet al., 2017, Machine Learning of Three-dimensional Right Ventricular Motion Enables Outcome Prediction in Pulmonary Hypertension: A Cardiac MR Imaging Study, RADIOLOGY, Vol: 283, Pages: 381-390, ISSN: 0033-8419

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Duluc L, Ahmetaj-Shala B, Mitchell J, Abdul-Salam VB, Mahomed AS, Aldabbous L, Oliver E, Iannone L, Dubois OD, Storck EM, Tate EW, Zhao L, Wilkins MR, Wojciak-Stothard Bet al., 2017, Tipifarnib prevents development of hypoxia-induced pulmonary hypertension, CARDIOVASCULAR RESEARCH, Vol: 113, Pages: 276-287, ISSN: 0008-6363

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Ghataorhe P, Rhodes CJ, Harbaum L, Attard M, Wharton J, Wilkins MRet al., 2017, Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development, JOURNAL OF INTERNAL MEDICINE, Vol: 282, Pages: 129-141, ISSN: 0954-6820

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Ghofrani H-A, Humbert M, Langleben D, Schermuly R, Stasch J-P, Wilkins MR, Klinger JRet al., 2017, Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension, CHEST, Vol: 151, Pages: 468-480, ISSN: 0012-3692

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Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmuller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, Ross RM, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Noordegraaf AV, Wilkins MR, Wort SJ, Wharton J, Graf S, Morrell NWet al., 2017, Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension, CIRCULATION, Vol: 136, Pages: 2022-+, ISSN: 0009-7322

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Michelakis ED, Gurtu V, Webster L, Barnes G, Watson G, Howard L, Cupitt J, Paterson I, Thompson RB, Chow K, O'Regan DP, Zhao L, Wharton J, Kiely DG, Kinnaird A, Boukouris AE, White C, Nagendran J, Freed DH, Wort SJ, Gibbs JSR, Wilkins MRet al., 2017, Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients, Science Translational Medicine, Vol: 9, ISSN: 1946-6234

Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

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Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Graf S, Morrell NW, Wilkins MRet al., 2017, Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension, CIRCULATION, Vol: 135, Pages: 460-+, ISSN: 0009-7322

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Rhodes CJ, Wharton J, Ghataorhe P, Watson G, Girerd B, Howard LS, Gibbs JSR, Condliffe R, Elliot CA, Kiely DG, Simonneau G, Montani D, Sitbon O, Gall H, Schermuly RT, Ghofrani HA, Lawrie A, Humbert M, Wilkins MRet al., 2017, Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study, LANCET RESPIRATORY MEDICINE, Vol: 5, Pages: 717-726, ISSN: 2213-2600

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Wilkins MR, 2017, Apoptosis signal-regulating kinase 1 inhibition in pulmonary hypertension: too much to ASK?, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 286-288, ISSN: 1073-449X

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Aldabbous L, Abdul-Salam V, McKinnon T, Duluc L, Pepke-Zaba J, Southwood M, Ainscough AJ, Hadinnapola C, Wilkins MR, Toshner M, Wojciak-Stothard Bet al., 2016, Neutrophil Extracellular Traps Promote Angiogenesis: Evidence From Vascular Pathology in Pulmonary Hypertension, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 36, Pages: 2078-2087, ISSN: 1079-5642

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Lythgoe MP, Rhodes CJ, Ghataorhe P, Attard M, Wharton J, Wilkins MRet al., 2016, Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future, PHARMACOLOGY & THERAPEUTICS, Vol: 164, Pages: 195-203, ISSN: 0163-7258

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Wilkins MR, Morrell NW, 2016, Prof. Almaz A. Aldashev (1953-2016) IN MEMORIAM, EUROPEAN RESPIRATORY JOURNAL, Vol: 48, Pages: 990-991, ISSN: 0903-1936

JOURNAL ARTICLE

Cotroneo E, Ashek A, Wang L, Wharton J, Dubois O, Bozorgi S, Busbridge M, Alavian KN, Wilkins MR, Zhao Let al., 2015, Iron Homeostasis and Pulmonary Hypertension Iron Deficiency Leads to Pulmonary Vascular Remodeling in the Rat, CIRCULATION RESEARCH, Vol: 116, Pages: 1680-1690, ISSN: 0009-7330

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D'Armini AM, Ghofrani H-A, Kim NH, Mayer E, Morsolini M, Pulido-Zamudio T, Simonneau G, Wilkins MR, Curram J, Davie N, Hoeper MMet al., 2015, Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 34, Pages: 348-355, ISSN: 1053-2498

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Ruiter G, Manders E, Happe CM, Schalij I, Groepenhoff H, Howard LS, Wilkins MR, Bogaard HJ, Westerhof N, van der Laarse WJ, de Man FS, Vonk-Noordegraaf Aet al., 2015, Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency, PULMONARY CIRCULATION, Vol: 5, Pages: 466-472, ISSN: 2045-8932

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Simonneau G, D'Armini AM, Ghofrani H-A, Grimminger F, Hoeper MM, Jansa P, Kim NH, Wang C, Wilkins MR, Fritsch A, Davie N, Colorado P, Mayer Eet al., 2015, Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2), EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 1293-1302, ISSN: 0903-1936

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Wilkins MR, Ghofrani H-A, Weissmann N, Aldashev A, Zhao Let al., 2015, Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease, CIRCULATION, Vol: 131, Pages: 582-590, ISSN: 0009-7322

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Zhao L, Oliver E, Maratou K, Atanur SS, Dubois OD, Cotroneo E, Chen C-N, Wang L, Arce C, Chabosseau PL, Ponsa-Cobas J, Frid MG, Moyon B, Webster Z, Aldashev A, Ferrer J, Rutter GA, Stenmark KR, Aitman TJ, Wilkins MRet al., 2015, The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia, NATURE, Vol: 524, Pages: 356-U229, ISSN: 0028-0836

JOURNAL ARTICLE

Cotroneo E, Ashek A, Wharton J, Dubois O, Bozorgi S, Busbridge M, Wilkins M, Zhao Let al., 2014, Pulmonary Vascular Remodelling In The Chronic Iron-Deficient Rat, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X

JOURNAL ARTICLE

Hoeper M, Kim NH, Mayer E, Pulido T, Wilkins MR, Simonneau G, Torbicki A, Wang C, Davie N, Fritsch A, Ghofrani H-Aet al., 2014, Effects Of Riociguat In Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension (cteph) Vs Persistent/recurrent Pulmonary Hypertension (ph) After Pulmonary Endarterectomy (pea): 1-Year Results From The Chest-2 Study, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X

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Wilkins MR, 2014, Pulmonary hypertension: the value of experimental medicine in new drug development, PULMONARY CIRCULATION, Vol: 4, Pages: 149-150, ISSN: 2045-8932

JOURNAL ARTICLE

Wilkins MR, Aldashev AA, Wharton J, Rhodes CJ, Vandrovcova J, Kasperaviciute D, Bhosle SG, Mueller M, Geschka S, Rison S, Kojonazarov B, Morrell NW, Neidhardt I, Surmeli NB, Aitman TJ, Stasch J-P, Behrends S, Marletta MAet al., 2014, alpha 1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 7, Pages: 920-U505, ISSN: 1942-325X

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Wojciak-Stothard B, Abdul-Salam VB, Lao KH, Tsang H, Irwin DC, Lisk C, Loomis Z, Stenmark KR, Edwards JC, Yuspa SH, Howard LS, Edwards RJ, Rhodes CJ, Gibbs JSR, Wharton J, Zhao L, Wilkins MRet al., 2014, Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension, CIRCULATION, Vol: 129, Pages: 1770-1780, ISSN: 0009-7322

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