Long-lasting metabolic impairment in the failing heart: epigenetic memories at play

TL;DR

This study explores how the failing heart retains long-term metabolic changes even after stress is reduced, potentially explaining why it may not recover fully.

Contribution

The study identifies epigenetic factors that may cause persistent metabolic dysfunction in the heart after unloading.

Findings

Cardiac unloading is linked to lasting disruptions in mitochondrial and fatty acid metabolism.

Chromatin remodellers like Hdac4, Smarca2, and Brd4 are implicated in these transcriptional changes.

The findings suggest an 'epigenetic scar' hinders heart recovery after unloading.

Abstract

Understanding the factors involved in myocardial recovery after unloading is of utmost importance to unveil new therapies in patients with heart failure (HF). Lack of myocardial recovery might be explained by long-lasting molecular alterations which persist despite normalization of cardiac stress. In this issue of Epigenetics, Roth et al. present an elegant translational study addressing this important aspect at the molecular level. By leveraging a mouse model of reversible transverse aortic constriction (rTAC) and human LV samples from HF patients undergoing LVAD therapy, the authors show that cardiac unloading is associated with a persistent deregulation of transcriptional programmes implicated in mitochondrial respiration, fatty acid and acyl-CoA metabolism, suggesting a long-lasting metabolic deterioration of the failing heart. Of interest, the authors identified several chromatin remodellers (Hdac4, Smarca2, and Brd4) potentially explaining the observed transcriptional alterations. Taken together, these novel findings suggest that ‘DNA forgives but does not forget,’ thus leaving an epigenetic scar which hampers the recovery of the failing heart after unloading. Disentangling the epigenetic factors involved in such ‘transcriptional memory’ may set the stage for new interventions resetting the cardiomyocyte transcriptome and myocardial energetics thus fostering a true myocardial recovery in HF.