Research Summary
Our research is focused on pulmonary hypertension and is patient orientated, based on a cohort of patients with clinical data and an associated tissue bank for biomarker studies. We have used this in national and international studies to identify genetic risk factors for pulmonary hypertension and accessible biomarkers that inform prognosis and response to treatment. Among our recent successes, we have: Identified both rare (Graf et al Nat Comms 2018) and common genetic variants (Rhodes et al Lancet Resp Medicine 2019) associated with pulmonary arterial hypertension (PAH); unmasked the heterogeneity of PAH from blood transcriptomes profiles (Kariotis et al Nat Comms 2021); identified a panel of circulating proteins that predict survival in PAH (Rhodes et al Lancet Resp Med 2017; Rhodes et al AJRCCM 2022) and may be useful in treatment selection (Boucly et al AJRCCM 2025); elaborated on the plasma metabolome linked to PAH (Rhodes et al Circulation 2017); used Mendelian randomisation to reveal molecular drivers of PAH (Harbaum et AJRCCM 2022; Harbour et al AJRCCM 2025); and identified genetic determinants of response to dichloroacetate (Michelakis et al Science Translational Med 2017).

Through an active interest in hypoxia-induced pulmonary hypertension, including the study inhabitants of high altitude environments in the Kyrgyz Republic and Tibet, to better understand genetic factors that confer adaptation, we have identified a key role for the zinc transporter, ZIP12 (Zhao et al Nature 2015). This transporter is upregulated in the remodelled pulmonary vessels in PAH. We have exploited the observation that over activity of ZIP12 contributes to pulmonary vascular remodelling pharmacologically through the generation of a monoclonal antibody that inhibits ZIP12. This has now entered clinical trials in collaboration with Apollo Therapeutics.

Past studies from our lab identified phosphodiesterase type 5 as a therapeutic target for PAH using cell and animal models and investigated this in clinical trials (Zhao et al Circulation 2001; Sebkhi et al Circulation 2003; Wilkins et al AJRCCM 2005; Francis et al ERJ 2010). The phosphodiesterase type 5 inhibitor, sildenafil, was approved for the treatment of PAH by the FDA in May 2005.

Our studies have demonstrated that iron deficiency in PAH is associated with poor survival (Rhodes et al JACC 2011). Through BHF funding we have evaluated the effect of iron replacement as a therapeutic strategy for PAH (Howard et al Ann Am Thorac Soc. 2021).