Publications
242 results found
Wilkins MR, 2016, Developing treatments for pulmonary arterial hypertension, Pulmonary Circulation, Vol: 3, Pages: 156-159, ISSN: 2045-8940
Developing new treatments for pulmonary arterial hypertension (PAH) is a challenge. We have enjoyed success with regulatory approvals for three drug classes—prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. But we have also seen some disappointing results, for example, from studies with vasoactive intestinal polypeptide, statins and tergolide. Animal models are an unreliable predictor of efficacy in humans. The best model for the disease is the patient. This review discusses three major issues facing the evaluation of drugs in PAH patients—target validation, choosing the right dose, and early trial design.
Wilkins MR, Morrell NW, 2016, Prof. Almaz A. Aldashev (1953-2016), European Respiratory Journal, Vol: 48, Pages: 990-991, ISSN: 0903-1936
Aldabbous L, Abdul-Salam V, McKinnon T, et 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
OBJECTIVE: Inflammation and dysregulated angiogenesis are features of endothelial dysfunction in pulmonary hypertension. Neutrophil extracellular traps (NETs), produced by dying neutrophils, contribute to pathogenesis of numerous vascular disorders but their role in pulmonary hypertension has not been studied. We sought evidence of (NETs) formation in pulmonary hypertension and investigated the effect of NETs on endothelial function. APPROACH AND RESULTS: Plasma and lung tissues of patients with pulmonary hypertension were analyzed for NET markers. The effects of NETs on endothelial function were studied in vitro and in vivo. Patients with chronic thromboembolic pulmonary hypertension and idiopathic pulmonary hypertension showed elevated plasma levels of DNA, neutrophil elastase, and myeloperoxidase. NET-forming neutrophils and extensive areas of NETosis were found in the occlusive plexiform lesions and vascularized intrapulmonary thrombi. NETs induced nuclear factor κB-dependent endothelial angiogenesis in vitro and increased vascularization of matrigel plugs in vivo. Angiogenic responses were associated with increased release of matrix metalloproteinase-9, heparin-binding EGF-like growth factor, latency-associated peptide of the transforming growth factor β1, and urokinase-type plasminogen activator, accompanied by increased endothelial permeability and cell motility. NETs-induced responses depended on myeloperoxidase/H2O2-dependent activation of Toll-like receptor 4/nuclear factor κB signaling. NETs stimulated the release of endothelin-1 in HPAECs and stimulated pulmonary smooth muscle cell proliferation in vitro. CONCLUSIONS: We are the first to implicate NETs in angiogenesis and provide a functional link between NETs and inflammatory angiogenesis in vitro and in vivo. We demonstrate the potential pathological relevance of this in 2 diseases of disordered vascular homeostasis, pulmonary arterial hypertension and chronic thromboembolic pulmonary
Ghofrani HA, Humbert M, Langleben D, et al., 2016, Riociguat: Mode of action and clinical development in pulmonary hypertension, Chest, Vol: 151, Pages: 468-480, ISSN: 0012-3692
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure and increased pulmonary vascular resistance. If untreated, they can result in death due to right heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. Here we describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH, and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and the pivotal Phase III randomized clinical trials in PAH and CTEPH.
Lythgoe MP, Rhodes CJ, Ghataorhe P, et 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
The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.
Zhao L, Oliver E, Maratou K, et al., 2015, The zinc transporter, ZIP12, regulates the pulmonary vascular response to chronic hypoxia, Nature, Vol: 524, Pages: 356-360, ISSN: 0028-0836
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1, 2, 3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
Ruiter G, Manders E, Happé CM, et al., 2015, Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency., Pulmonary Circulation, Vol: 5, Pages: 466-472, ISSN: 2045-8940
In patients with idiopathic pulmonary arterial hypertension (iPAH), iron deficiency is common and has been associated with reduced exercise capacity and worse survival. Previous studies have shown beneficial effects of intravenous iron administration. In this study, we investigated the use of intravenous iron therapy in iron-deficient iPAH patients in terms of safety and effects on exercise capacity, and we studied whether altered exercise capacity resulted from changes in right ventricular (RV) function and skeletal muscle oxygen handling. Fifteen patients with iPAH and iron deficiency were included. Patients underwent a 6-minute walk test, cardiopulmonary exercise tests, cardiac magnetic resonance imaging, and a quadriceps muscle biopsy and completed a quality-of-life questionnaire before and 12 weeks after receiving a high dose of intravenous iron. The primary end point, 6-minute walk distance, was not significantly changed after 12 weeks (409 ± 110 m before vs. 428 ± 94 m after; P = 0.07). Secondary end points showed that intravenous iron administration was well tolerated and increased body iron stores in all patients. In addition, exercise endurance time (P < 0.001) and aerobic capacity (P < 0.001) increased significantly after iron therapy. This coincided with improved oxygen handling in quadriceps muscle cells, although cardiac function at rest and maximal [Formula: see text] were unchanged. Furthermore, iron treatment was associated with improved quality of life (P < 0.05). In conclusion, intravenous iron therapy in iron-deficient iPAH patients improves exercise endurance capacity. This could not be explained by improved RV function; however, increased quadriceps muscle oxygen handling may play a role. ( TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01288651).
Simonneau G, D'Armini AM, Ghofrani H-A, et 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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- Citations: 197
Zhao L, 2015, Iron homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular remodelling in the rat, Circulation Research, Vol: 116, Pages: 1680-1690, ISSN: 1524-4571
Rationale: Iron deficiency without anemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival.Objectives: We hypothesized that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy.Methods and Results: Rats were fed an iron-deficient diet (IDD, 7 mg/kg) and investigated for 4 weeks. Iron deficiency was evident from depleted iron stores (decreased liver, serum iron, and ferritin), reduced erythropoiesis, and significantly decreased transferrin saturation and lung iron stores after 2 weeks IDD. IDD rats exhibited profound pulmonary vascular remodeling with prominent muscularization, medial hypertrophy, and perivascular inflammatory cell infiltration, associated with raised pulmonary artery pressure and right ventricular hypertrophy. IDD rat lungs demonstrated increased expression of hypoxia-induced factor-1α and hypoxia-induced factor-2α, nuclear factor of activated T cells and survivin, and signal transducers and activators of transcription-3 activation, which promote vascular cell proliferation and resistance to apoptosis. Biochemical examination showed reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarization in mitochondria from IDD rat pulmonary arteries. Along with upregulation of the glucose transporter, glucose transporter 1, and glycolytic genes, hk1 and pdk1, lung fluorine-18–labeled 2-fluoro-2-deoxyglucose ligand uptake was significantly increased in IDD rats. The hemodynamic and pulmonary vascular remodeling were reversed by iron replacement (ferric carboxymaltose, 75 mg/kg) and attenuated in the presence of iron deficiency by dichloroacetate and imatinib, 2 putative treatments explored for pulmonary arterial hypertension that target aerobic glycolysis and proliferation, respectively.Conclusions: These data suggest a major role for iron in pulmonary vascular
D'Armini AM, Ghofrani H-A, Kim NH, et 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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- Citations: 11
Wilkins MR, Ghofrani H-A, Weissmann N, et al., 2015, Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease, CIRCULATION, Vol: 131, Pages: 582-590, ISSN: 0009-7322
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- Citations: 85
Wilkins MR, Aldashev AA, Wharton J, et al., 2014, α1-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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- Citations: 20
Simonneau G, D'Armini AM, Ghofrani H-A, et al., 2014, Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH): 2-year results from the CHEST-2 long-term extension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 5
Wilkins MR, 2014, Pulmonary hypertension: the value of experimental medicine in new drug development, PULMONARY CIRCULATION, Vol: 4, Pages: 149-150, ISSN: 2045-8932
Wojciak-Stothard B, Abdul-Salam VB, Lao KH, et 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
Background—Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodeled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension. CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of pulmonary arterial hypertension.Methods and Results—CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, whereas CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension attenuated the abnormal angiogenic behavior that characterizes these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilization of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1.Conclusion—Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.
Wang C, D'Armini AM, Ghofrani H-A, et al., 2014, Long-term Riociguat Treatment in Inoperable and Persistent/Recurrent CTEPH Patients in WHO Functional Class (FC) I/II Versus FC III/IV at Baseline: Results From the 16-Week Phase III CHEST-1 Study and CHEST-2 Open-Label Extension, CHEST, Vol: 145, ISSN: 0012-3692
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- Citations: 4
Hoeper M, Kim NH, Mayer E, et 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
Hoeper MM, Bogaard HJ, Condliffe R, et al., 2013, Definitions and Diagnosis of Pulmonary Hypertension, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 62, Pages: D42-D50, ISSN: 0735-1097
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- Citations: 1206
Watson G, Oliver E, Zhao L, et al., 2013, Pulmonary hypertension: Old targets revisited (Statins, PPARs, Beta-Blockers), Handbook of Experimental Pharmacology, Vol: 218, Pages: 531-548, ISSN: 0171-2004
Pulmonary arterial hypertension is a therapeutic challenge. Despite progress in recent years with three drug classes-prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors-long-term patient survival remains poor. Importantly, the introduction and commercial success of these new treatments has been accompanied by growing interest in the pathology of pulmonary hypertension. This, in turn, has stimulated a re-evaluation of the molecular factors driving the structural remodelling of pulmonary arterioles and the opportunities to preserve right ventricular function in pulmonary hypertension. Academics with restricted access to new chemicals have turned to existing drugs to investigate new ideas. It is in this context that the role of statins, peroxisome proliferator-activated receptors (PPARs) and beta-blockers are of interest as potential treatments for pulmonary hypertension. © Springer-Verlag Berlin Heidelberg 2013.
Rhodes CJ, Wharton J, Wilkins MR, 2013, Pulmonary hypertension: Biomarkers, Pages: 77-103, ISBN: 9783642386633
Physicians look to biomarkers to inform the management of pulmonary hypertension (PH) at all stages, from assessing susceptibility through screening, diagnosis, and risk stratification to drug selection and monitoring. PH is a heterogeneous disorder and currently there are no accepted blood biomarkers specific to any manifestation of the condition. Brain natriuretic peptide and its N-terminal peptide have been most widely studied. Other candidate prognostic biomarkers in patients with pulmonary arterial hypertension (PAH) include growth and differentiation factor-15, red cell distribution width, uric acid, creatinine, inflammatory markers such as interleukin-6, angiopoietins, and microRNAs. Combining the measurement of biomarkers reflecting different components of the pathology with other modalities may enable better molecular characterisation of PH subtypes and permit improved targeting of therapeutic strategies and disease monitoring. © Springer-Verlag Berlin Heidelberg 2013.
Simonneau G, D'Armini A, Ghofrani H, et al., 2013, Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH): 1-Year Results from the CHEST-2 Long-term Extension Study, Publisher: AMER COLL CHEST PHYSICIANS, ISSN: 0012-3692
Ghofrani HA, D'Armini AM, Grimminger F, et al., 2013, Riociguat for the treatment of chronic thromboembolic pulmonary hypertension., New England Journal of Medicine
Zhao L, Ashek A, Wang L, et al., 2013, Heterogeneity in lung 18FDG uptake in PAH: potential of dynamic 18FDG-PET with kinetic analysis as a bridging biomarker for pulmonary remodeling targeted treatments, Circulation
Wilkins MR, Wharton J, Gladwin MT, 2013, Update in Pulmonary Vascular Diseases 2012, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 188, Pages: 23-28, ISSN: 1073-449X
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- Citations: 4
Zhao L, Chen C-N, Hajji N, et al., 2013, Response to Letter Regarding Article, "Histone Deacetylation Inhibition in Pulmonary Hypertension: Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid", CIRCULATION, Vol: 127, Pages: E540-E540, ISSN: 0009-7322
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- Citations: 4
Rhodes CJ, Wharton J, Boon RA, et al., 2013, Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension., American Journal of Respiratory and Critical Care Medicine, Vol: 187, Pages: 294-302
MicroRNAs (miRNAs or miRs) are implicated in the pathogenesis of various cardiovascular diseases, including pulmonary arterial hypertension (PAH).
Howard LSGE, Watson GMJ, Wharton J, et al., 2013, Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension, Pulmonary Circulation, Vol: 3, Pages: 100-107, ISSN: 2045-8940
Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.
Grieve AP, Chow S-C, Curram J, et al., 2013, Advancing clinical trial design in pulmonary hypertension, Pulmonary Circulation, Vol: 3, Pages: 217-225, ISSN: 2045-8940
In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.
Zhao L, Chen C-N, Hajji N, et al., 2012, Histone Deacetylation Inhibition in Pulmonary Hypertension Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid, CIRCULATION, Vol: 126, Pages: 455-+, ISSN: 0009-7322
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- Citations: 186
Zeng W-J, Xiong C-M, Zhao L, et al., 2012, Atorvastatin in Pulmonary Arterial Hypertension (APATH) study, EUROPEAN RESPIRATORY JOURNAL, Vol: 40, Pages: 67-74, ISSN: 0903-1936
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- Citations: 47
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