Heart failure with preserved ejection fraction in pigs causes shifts in post transcriptional regulation of matrix associated pathways

Background: Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF), whereby increased LV chamber stiffness (LV Kc) is a hallmark. However, how post-transcriptional pathways, specifically microRNAs (miRs) may contribute to increased LV Kc and HFpEF progression remains unclear. This project tested the central hypothesis that the development of HFpEF secondary to a prolonged LVPO stimulus, will result in a shift in miRs that will be related to LV Kc. Methods: LVPO was induced in pigs (n=9) by sequential occlusion of an ascending aortic cuff and studies performed at 5 weeks of LVPO. Age and weight matched pigs (n=6) served as referent controls. LV function and left atrial area (LA) were measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84 miR array (rt-PCR). Results: LA area, LV mass, and Kc- increased with LVPO consistent with the HFpEF phenotype. A total of 36 (43%) miRs shifted of which 18 miRs correlated to LV Kc. An additional 29 miRs correlated to LA dilation. These miRs mapped to functional domains relevant to Kc such as fibrosis and calcium handling. Conclusion: These unique findings identified a specific set of miRs that change with the development of HFpEF and related to LV stiffness properties and thus may hold relevance in terms of prognosis and therapeutic targets. Overall design: LVPO was induced in pigs (n=9) by sequential occlusion of an ascending aortic cuff and studies performed at 5 weeks of LVPO. Age and weight matched pigs (n=6) served as referent controls