Novel drug to prevent cardiac reperfusion injury

Professor Levon Khachigian, University of New South Wales

Vanguard Grant - 2 Year

Years funded: 2025 - 2026

Ischaemic heart disease is the leading cause of death in Australia and the world. Percutaneous coronary intervention (PCI) abruptly restores blood flow, but paradoxically, reperfusion after ischaemia causes myocardial ischaemia/reperfusion (M/IR) injury, triggering myocardial cell death (an infarct, IF), left ventricular (LV) remodelling, reduced heart function and cardiac fibrosis which can lead to heart failure. Unfortunately, there is no approved drug indicated for reducing IF size after M/IR injury. To address this problem, we recently identified BT2, a novel anti-inflammatory agent that in rats, reduces myocardial IF size, LV remodelling, cardiac fibrosis and preserves heart function after intraperitoneal delivery. This project now tests whether BT2 is cardioprotective after perfusion in a rat model of M/IR injury when it is delivered orally. It also tests whether BT2’s effects are impacted by time of delivery. Briefly, the left anterior descending artery of Sprague-Dawley rats (of both genders) will be ligated (simulating a heart attack). After 30 min the ligature will be untied causing reperfusion (simulating PCI). BT2 (3, 30, 100 mg/kg), or vehicle alone, will be given during the ischaemia or during reperfusion (after revascularisation) then the rats will be euthanised after 24 h or 2 weeks. Heart function (EF, FS) and LV diameter (LVIDd, LVIDs) will be determined by ultrasound. Serum biomarkers will be measured by ELISA. IF size in the area-at-risk (AAR) will be determined by Evans blue/TTC staining. Cardiac fibrosis at 2 weeks will be determined by Sirius Red/methyl green staining. Transcriptional changes in the AAR will be identified by RNA-seq. This project provides a rational basis to progress BT2 to large animal models and underpins BT2’s future use in an emergency setting with heart attack patients (to be led by CIB). Project IP will be protected and commercialised through industry partnerships or licence deals. Outputs will be disseminated to the cardiovascular research community via conferences and publications in leading journals, patient and consumer groups (e.g., CIA/CIB are Board Directors of Heart Research Australia) and the general public.