Pharmacological inhibition of 11ßhydroxysteroid dehydrogenase type 1 after myocardial infarction targets extracellular matrix processing and preserves cardiac function in a translational mini-pig model
Authors: Al Disi S , Ascione R , Khan S , Johnson T , Sammut E , Bruno VD , Lopez DB , James CA , Simpson J , Homer N , Millar M , Singh T , von Kreigsheim A , Mills NL , Walker BR , Andrew R , Webster SP , Whittaker A , Freeman A , Gray GA 
Published: December 2024

Background and Purpose

Plasma glucocorticoids (GCs) increase acutely after myocardial infarction (MI), thereafter tissue levels are amplified selectively within cells expressing 11ßHydroxysteroid Dehydrogenase type 1 (11ßHSD1) 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 11ßHSD1 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 11ßHSD1 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 11ßHSD1 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 11ßHSD1 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 11ßHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11ßHSD1 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.

Bullet Point Summary

What is already known?

GCs are released from the adrenal gland after MI, but also regenerated within the heart from circulating precursors by the enzyme 11ßHSD1 in cardiomyocytes, fibroblasts and macrophages.

Genetic suppression ofHsd11b1expression in the mouse promotes neovascularisation, prevents infarct expansion during infarct repair after MI and the development of heart failure.

What does this study add?

Oral pharmacological inhibition of 11ßHSD1 after MI/reperfusion in a translational mini-pig model of MI receiving concurrent clinically relevant therapy prevents cardiac functional deterioration and adverse ventricular remodelling over the following 4 weeks.

Mass spectrometry imaging reveals target engagement of the 11ßHSD1i in the repairing infarct.

The mechanism is independent of neovascularisation but does involve modification of extracellular matrix remodelling during repair and scar formation.

What is the clinical significance?

Tissue 11ßHSD1 expression is increased in aging when the risk of MI is higher.

Pharmacological inhibitors of 11ßHSD1 have safely reached phase 2 clinical trials for dementia and metabolic disease and could be repurposed for use post-MI to prevent the development of heart failure.