Targeting RUNX to attenuate adverse cardiac remodelling and progression to heart failure

Myocardial infarction (MI) is a leading cause of heart failure (HF) and death worldwide.

Preservation of contractile function and protection against adverse cardiac remodelling are key to limiting advancement of MI to HF.

We have published that expression of the Runt-related transcription factor (RUNX1) in adult cardiomyocytes is increased post-MI.

Cardiomyocyte-specific Runx1-deficient mice have preserved myocardial contractility and protection against adverse cardiac remodelling.

Our new data demonstrate key findings of translational importance: (1) preclinical mouse studies show that targeting RUNX1 in cardiomyocytes using adenoviral vectors preserves myocardial contractility following MI; (2) increased RUNX1 expression in the myocardium occurs in multiple HF aetiologies.

RUNX1 therefore has far-reaching therapeutic potential beyond MI; (3) RUNX3 (a distinct isoform) shows increased expression in hearts post-MI with unknown therapeutic potential; and (4) RUNX1 is found in patient serum post-MI and negatively correlates with pump function.

This programme will: (a) determine the drivers and impact on cardiac remodelling of increased RUNX1 and RUNX3 in mouse models of MI and HF with reduced/preserved ejection fraction; (b) establish the importance of serum RUNX1 for cardiomyocyte function; and (c) validate that key RUNX-related molecular targets found in our mouse MI model are present in human and pig myocardium, paving the way for future large animal translational studies.