Imperial College London

DrJohnWharton

Faculty of MedicineNational Heart & Lung Institute

Honorary Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 6819j.wharton

 
 
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Location

 

530ICTEM buildingHammersmith Campus

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Summary

 

Summary

Pulmonary hypertension is a relatively frequent occurrence as it is associated with common diseases such as chronic obstructive pulmonary disease, sickle cell disease, schistomiasis, sleep-disordered breathing, neonatal lung disease, chronic thromboembolic disease, heart disease and chronic exposure to high altitude. Pulmonary arterial hypertension (PAH) is one category of pulmonary hypertension that may occur as an isolated disease, known as idiopathic PAH (IPAH), or where there is evidence of inheritance, familial PAH or in association with conditions such as connective tissue disease, congenital heart disease, viral infection and exposure to drugs or toxins. The main research interest of the Group is in understanding the pathogenesis of PAH and developing new therapeutic strategies to treat this progressive disease. The increase in pulmonary artery pressure puts an excess load on the relatively thin-walled right ventricle, leading to right ventricular hypertrophy and right heart failure. The disease is generally characterized by increased pulmonary vascular resistance due to vasoconstriction and obliterative remodelling of the pulmonary circulation, involving occlusion of the lumen due to cellular proliferation in the wall of distal arteries and in situ thrombosis, as well as the loss of microvessels. Current therapies were developed on the basis of an imbalance in vasoactive factors, targeting down regulation of prostacyclin and nitric oxide (NO)-cGMP signalling and upregulation of endothelin production.

Within the Cardiovascular Group, we have adopted an integrated approach to study the mechanisms of pulmonary vascular disease and identify therapeutic targets, taking studies with human vascular cell cultures through to whole animal models and proof-of-concept studies in patients. For example, recent studies have demonstrated a beneficial role for phosphodiesterase type 5 inhibition by sildenafil in pulmonary hypertension and thereby contributed to the development of a much-needed orally-active treatment for this condition. Novel therapies are being sought that target other aspects of the pathophysiology of PAH, such as the proliferative, anti-apoptotic, oxidative and inflammatory environment in the pulmonary artery wall. We have found that agents such as simvastatin and tetrahydrobiopterin have therapeutic potential in cultured cells and experiment models and these are now at the clinical stage of investigation.

In addition to pharmacological agents, we are investigating the role of circulating bone marrow-derived progenitor and mononuclear cells in pulmonary vascular disease and their potential as a cell-based therapy for the treatment of IPAH. Indeed, we were the first to show that the treatment of IPAH patients with sildenafil increases the number of circulating progenitor cells and thereby may influence the course of the disease.

We are also utilizing blood and tissue samples from patients to identify proteins as biomarkers of pulmonary vascular disease and potential therapeutic targets. Circulating levels of specific proteins and occurrence of polymorphisms may help in distinguishing PAH due to different causes and assess response to therapy. They can also assist in identifying patient cohorts with a poor prognosis.

Publications

Journals

Liu B, Azfar M, Legchenko E, et al., 2024, ATP13A3 variants promote pulmonary arterial hypertension by disrupting polyamine transport., Cardiovasc Res

Liley J, Newnham M, Bleda M, et 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

Ulrich A, Wu Y, Draisma H, et al., 2024, Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension, Nature Communications, Vol:15, ISSN:2041-1723

Chen C-N, Hajji N, Yeh F-C, et al., 2023, Restoration of Foxp31 regulatory T cells by HDAC-dependent epigenetic modulation plays a pivotal role in resolving pulmonary arterial hypertension pathology, American Journal of Respiratory and Critical Care Medicine, Vol:208, ISSN:1073-449X, Pages:879-895

Prapa M, Lago-Docampo M, Swietlik EM, et al., 2022, First Genotype-Phenotype Study in TBX4 Syndrome Gain-of-Function Mutations Causative for Lung Disease, American Journal of Respiratory and Critical Care Medicine, Vol:206, ISSN:1073-449X, Pages:1522-1533

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