Heart failure with preserved ejection fraction in pigs causes shifts in posttranscriptional checkpoints

Am J Physiol Heart Circ Physiol. 2024 Nov 1;327(5):H1272-H1285. doi: 10.1152/ajpheart.00551.2023. Epub 2024 Sep 6.

Abstract

Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (n = 6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n = 10, n = 9, respectively). LV samples from LVPO and controls (n = 6, respectively) were subjected to RNA sequencing. LV mass and Kc increased by over 40% with LVPO (P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (P < 0.05) that mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.

Keywords: LA dilation; LV diastolic dysfunction; microRNA.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Heart Failure* / genetics
  • Heart Failure* / metabolism
  • Heart Failure* / physiopathology
  • Male
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • RNA Processing, Post-Transcriptional
  • Stroke Volume*
  • Sus scrofa
  • Swine
  • Ventricular Function, Left*
  • Ventricular Pressure

Substances

  • MicroRNAs