Pharmacological inhibition of 11ßhydroxysteroid dehydrogenase type 1 after myocardial infarction targets extracellular matrix processing and preserves cardiac function in a translational mini-pig model

Abstract

Background and Purpose: Plasma glucocorticoids (GCs) increase acutely after myocardial infarction (MI), thereafter tissue levels are amplified selectively within cells expressing 11βHydroxysteroid Dehydrogenase type 1 (11βHSD1) that regenerates active GCs from circulating metabolites. GCs initially protect cardiomyocytes and prevent excessive inflammation after MI but can also suppress subsequent wound repair leading to functional decline. The present study aimed to investigate the potential of pharmacological 11βHSD1 inhibition after MI to prevent deterioration of cardiac function and its impact on wound repair. Experimental Approach: Adult female Gottingen mini-pigs underwent percutaneous balloon MI/reperfusion and were randomised to receive either oral 11βHSD1 inhibitor AZD8329 (n=11), or vehicle (n=9), from 2 until 27 days later, with concurrent administration of clinically relevant therapeutic intervention (anti-platelet, statin and ACE inhibitor). Key Results: AZD8329 treatment increased plasma accumulation of cortisone substrate consistent with successful 11βHSD1 inhibition. Gadolinium-enhanced MRI showed equivalent infarct size in both groups prior to commencing treatment. 28 days after MI cardiac function and LV area were preserved in the AZD8329 treated group relative to vehicle. There was no impact of 11βHSD1 inhibitor on neovascularisation or infarct area. Mass spectrometry imaging revealed AZD8329 binding to the healing infarct and altered regulation of extracellular matrix (ECM) processing was highlighted by birefringence microscopy and proteomic analysis. Conclusions and Implications: Pharmacological inhibition of 11βHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11βHSD1 inhibitors have safely reached phase 2 clinical trials in diabetes and dementia and could be repurposed as an addition to standard care after MI to prevent the development of heart failure.