Project ID BE-MI2024_16


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Vascular themeWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Cardiac themeWebsite

Photoacoustic Ultrasound Imaging of Tissue Hypoxia in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare but destructive disease of pulmonary arteries, characterised by a progressive increase in pathological remodelling, vascular resistance and ensuing right heart failure that leads to severe impairment of life quality and death. There is no cure, and available therapeutic options only slow disease progression. Hypoxia potentiates PAH by driving vascular remodelling, underpinning right heart hypertrophy and cardiac failure, causing a gradual loss of systemic oxygenation. Because of the lack of non-invasive diagnostic technologies, the relative impact of crosstalk between the PAH, peripheral organ oxygenation and (micro)vasculature is poorly understood. Photoacoustic molecular imaging enables high-resolution/high-contrast assessment of blood oxygen saturation, making detecting hypoxic tissues/regions possible. This could allow earlier and more robust diagnosis, facilitate patient stratification, provide new mechanistic insights into disease pathology and help develop novel therapies.

Employing first in the UK, multi-modal Vevo F2 LAZR-X, this project will establish a photoacoustic imaging protocol for detecting blood oxygen saturation in PAH models. Murine PAH will be characterised longitudinally, using standard non-invasive cardio-pulmonary ultrasound (i.e., 4D-echocardiography) and photoacoustic imaging in the heart, liver, kidney, brain and muscle. By employing animal interventions, metabolomics, molecular biology, biochemistry and histology techniques, it will determine how systemic hypoxia, detected by photoacoustic imaging, correlates with the disease’s hemodynamic, molecular, and metabolic markers at different stages and estimate whether it can serve as a new diagnostic and/or preclinical platform for drug development.

Year 1-2 Objectives: Assay development and training; validation and characterising mouse and/or rat PAH model using 4D-echocardiography, photoacoustic ultrasound imaging and metabolic, molecular and biochemical profiling. Year 2-3 Objectives: Assessment of PAH amelioration with 4D-echocardiography and photoacoustic imaging using clinically approved therapies (e.g., PDE5 inhibitors, Ca2+-channel blockers) – as a future platform for drug development and personalised medicine. Development of molecular imaging of myoglobin using photoacoustic imaging in a phantom, biological tissues and/or mice.

Representative Publications

1. ‘o Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension. Rudyk O*, Rowan A, Prysyazhna O, Krasemann S, Hartmann K, Zhang M, Shah A, Weiss A, Schermuly R, Zhao L, Eaton P* (2019). PNAS DOI: 10.1073/pnas.1904064116

2. (* Corr Author) o Redox Regulation, Oxidative Stress and Inflammation in Group 3 Pulmonary Hypertension. Rudyk O*, Aaronson P. (2021). Adv Exp Med Biol DOI: 10.1007/978-3-030-63046-1_13

1. o p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin. Loonat A, Martin E, Sarafraz-Shekary N, Tilgner K, Hertz NT, Levin R, Shokat KM., Burlingame AL., Arabacilar P, Uddin S, Thomas M, Marber MS & Clark JE* (2019). FASEB Journal DOI: 10.1096/fj.201701545R.

2. (* Corr Author) o Tissue acidosis does not mediate the hypoxia selectivity of [64Cu][Cu(ATSM)] in the isolated perfused rat heart. Baark F, Shaughnessy F, Pell VR, Clark JE, Eykyn TR, Blower P & Southworth R (2019). Scientific Reports DOI: 10.1038/s41598-018-36145-1

3. o Detection of anthracycline-induced cardiotoxicity using perfusion-corrected 99mTc sestamibi SPECT. Safee ZM, Baark F, Waters ECT, Veronese M, Pell VR, Clark JE, Mota F, Livieratos L, Eykyn TR, Blower P & Southworth R (2019). Scientific Reports DOI: 10.1038/s41598-018-36721-5