Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients
Evangelos D. Michelakis,Vikram Gurtu,Linda Webster,Gareth Barnes,Geoffrey Watson,Luke Howard,John Cupitt,Ian Paterson,Richard B. Thompson,Kelvin Chow,Declan P. O'Regan,Lan Zhao,John Wharton,David G. Kiely,Adam Kinnaird,Aristeidis E. Boukouris,Christopher W. White,Jayan Nagendran,Darren H. Freed,Stephen J. Wort,J. Simon R. Gibbs,Martin R. Wilkins +21 more
TLDR
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.Abstract:
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.read more
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Journal ArticleDOI
Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.
Marc Humbert,Marc Humbert,Christophe Guignabert,Christophe Guignabert,Sébastien Bonnet,Peter Dorfmüller,Peter Dorfmüller,James R. Klinger,Mark R. Nicolls,Andrea Olschewski,Soni Savai Pullamsetti,Soni Savai Pullamsetti,Ralph T. Schermuly,Kurt R. Stenmark,Marlene Rabinovitch +14 more
TL;DR: Recent findings in pathology and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of pulmonary hypertension are reviewed and ways to improve management and to support and optimise drug development are discussed.
Journal ArticleDOI
Pulmonary arterial hypertension: pathogenesis and clinical management.
TL;DR: Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure, and targeted therapies, used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions.
Journal ArticleDOI
Characterization of the Inflammatory Response to Severe COVID-19 Illness.
Oliver J. McElvaney,Natalie L McEvoy,Oisín F. McElvaney,Tomás P. Carroll,Mark P Murphy,Danielle M Dunlea,Orna Ní Choileáin,Jennifer Clarke,Eoin O'Connor,Grace Hogan,Daniel Ryan,Imran Sulaiman,Cedric Gunaratnam,P. Branagan,Michael Emmet O'Brien,Ross K. Morgan,Richard W. Costello,Killian Hurley,Seán Walsh,Eoghan de Barra,Cora McNally,Samuel J. McConkey,Fiona Boland,Sinead Galvin,Fiona Kiernan,James O'Rourke,R. Dwyer,Michael Power,Pierce Geoghegan,Caroline Larkin,Ruth Aoibheann O’Leary,James Freeman,Alan Gaffney,Brian Marsh,Gerard F. Curley,Noel G. McElvaney +35 more
TL;DR: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need, and Cytokine ratios may predict outcomes in this population.
Journal ArticleDOI
Genetics and genomics of pulmonary arterial hypertension.
Nicholas W. Morrell,Micheala A. Aldred,Wendy K. Chung,C. Gregory Elliott,William C. Nichols,Florent Soubrier,Richard C. Trembath,James E. Loyd +7 more
TL;DR: The known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches are summarised.
Journal ArticleDOI
Clinical trial design and new therapies for pulmonary arterial hypertension
Olivier Sitbon,Mardi Gomberg-Maitland,John Granton,Michael I. Lewis,Stephen C. Mathai,Maurizio Rainisio,Norman Stockbridge,Martin R. Wilkins,Roham T. Zamanian,Lewis J. Rubin +9 more
TL;DR: The current state of the art of pulmonary arterial hypertension is summarized, and insight is provided into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.
References
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Journal ArticleDOI
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
Nazzareno Galiè,Marc Humbert,Jean-Luc Vachiery,Simon Gibbs,Irene Lang,Adam Torbicki,Gérald Simonneau,Andrew Peacock,Anton Vonk Noordegraaf,Maurice Beghetti,Ardeschir Ghofrani,Miguel Angel Gomez Sanchez,Georg Hansmann,Walter Klepetko,Patrizio Lancellotti,Marco Matucci,Theresa McDonagh,Luc Pierard,Pedro T. Trindade,Maurizio Zompatori,Marius M. Hoeper +20 more
TL;DR: In this paper, the authors defined the following terms: ALAT, alanine aminotransferase, ASAT, aspartate AMINOTE, and APAH, associated pulmonary arterial hypertension.
Journal ArticleDOI
K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
Christos S. Karapetis,Shirin Khambata-Ford,Derek J. Jonker,Christopher J. O'Callaghan,Dongsheng Tu,Niall C. Tebbutt,R. John Simes,Haji Chalchal,Jeremy Shapiro,Sonia Robitaille,Timothy J. Price,Lois E. Shepherd,Heather-Jane Au,Christiane Langer,Malcolm J. Moore,John Zalcberg +15 more
TL;DR: Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ra did benefit fromcetuxIMab.
Journal ArticleDOI
HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia
TL;DR: A hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production is revealed.
Journal ArticleDOI
A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension
Robyn J. Barst,Lewis J. Rubin,Walker Long,Michael D. McGoon,Stuart Rich,David B. Badesch,Bertron M. Groves,Victor F. Tapson,Robert C. Bourge,Bruce H. Brundage,Spencer K. Koerner,David Langleben,Cesar A. Keller,Srinivas Murali,Barry F. Uretsky,Linda M. Clayton,Maria M. Jöbsis,Shelmer D. Blackburn,Denise Shortino,James W. Crow +19 more
TL;DR: As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.
Journal ArticleDOI
[2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension].
Nazzareno Galiè,Marc Humbert,Jean-Luc Vachiery,Simon Gibbs,Irene Lang,Adam Torbicki,Gérald Simonneau,Andrew J. Peacock,Anton Vonk Noordegraaf,Maurice Beghetti,Ardeschir Ghofrani,Miguel Angel Gomez Sanchez,Georg Hansmann,Walter Klepetko,Patrizio Lancellotti,Marco Matucci,Theresa McDonagh,Luc Pierard,Pedro T. Trindade,Maurizio Zompatori,Marius M. Hoeper +20 more
TL;DR: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) is constituted.
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2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
Nazzareno Galiè,Marc Humbert,Jean-Luc Vachiery,Simon Gibbs,Irene Lang,Adam Torbicki,Gérald Simonneau,Andrew Peacock,Anton Vonk Noordegraaf,Maurice Beghetti,Ardeschir Ghofrani,Miguel Angel Gomez Sanchez,Georg Hansmann,Walter Klepetko,Patrizio Lancellotti,Marco Matucci,Theresa McDonagh,Luc Pierard,Pedro T. Trindade,Maurizio Zompatori,Marius M. Hoeper +20 more