Abstract Mo040: Enhanced Neovascularisation Does Not Account for Preservation of Cardiac Function by 11βhsd1 Inhibition in a Pig Model of Myocardial Infarction

While acute post-myocardial infarction (MI) survival has improved thanks to early intervention, the myocardium still sustains damage that increases the risk of heart failure. Adrenal glucocorticoids (GCs) protect cardiomyocytes immediately after MI, but inhibition of GC regeneration within the heart by 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) during infarct repair prevents subsequent deterioration of ventricular structure and function. In the 11βHSD1-knockout mouse this outcome is associated with enhancement of peri-infarct neovascularisation and prevention of infarct expansion. Here, we tested the hypothesis that pharmacological 11βHSD1 inhibition after MI can preserve function in a translational pig model and investigated the role of neovascularisation. MI was induced in female minipigs via temporary coronary occlusion. A standard clinical therapy (SCT, n =9) group received statin, anti-platelet, βadrenoreceptor antagonist and ACE inhibitor immediatley after MI, and a 11βHSD1i group (n=11) received SCT +11βHSD1 inhibitor (50mg/kg) from 48h after MI until the end of the study. Prior to 11βHSD1i treatment, short-axis cine and late gadolinium-enhanced MRI showed no difference in either infarct mass (4.2±0.4g SCT vs 4.0±0.6g 11βHSD1i) or ejection fraction (EF; 60.6±2.9% SCT vs 56.6±1.8% 11βHSD1i). However, by 28 days after MI, while EF was reduced in SCT pigs to 48±4%, it was maintained in pigs given additional 11βHSD1i treatment (57.9±1.8%, p <0.05 vs SCT). Infarct mass did not differ between the two treatments, suggesting that inhibition of infarct expansion did not account for the improvement in function, this was confirmed by a similar area of infarct collagen in histological analysis. Angiogenesis, represented by an increase in CD31 +ve capillaries, was not enhanced in the infarct or the border zone (BZ) after 11βHSD1i treatment, relative to SCT. While vessel maturation (αSMA +ve vessels) was improved in the infarct compared to the remote myocardium, there was no difference between the two groups. Proteomic pathway analysis of the BZ indicated extracellular matrix organisation as the main pathway regulated by 11βHSD1i compared to SCT. In conclusion, 11βHSD1i after MI successfully preserves cardiac function and structure but the mechanism is independent of scar size reduction or enhanced neovascularisation. Instead, the beneficial effects of 11βHSD1i are likely to result from favourable regulation of collagen processing during scar formation.