Reverse remodelling and myocardial recovery in heart failure

Key Points

  • Reverse remodelling is the process by which failing myocardium demonstrates normative changes in chamber geometry and function, and might also include correction of molecular and transcriptional abnormalities

  • Advances in sequencing technologies have allowed for detailed analysis of transcriptome changes in the setting of reverse remodelling, including non-coding RNAs such as microRNAs and long non-coding RNAs

  • Despite evidence of reverse remodelling, numerous abnormalities in myocardial transcriptome, metabolism, and extracellular matrix persist, supporting the concept that myocardial remission is distinct from myocardial recovery

  • The newly proposed phenotype of 'heart failure with improved ejection fraction' highlights the clinical course of 'remission' with relapses in heart failure symptoms despite improvement in ventricular structure and function

Abstract

Advances in medical and device therapies have demonstrated the capacity of the heart to reverse the failing phenotype. The development of normative changes to ventricular size and function led to the concept of reverse remodelling. Among heart failure therapies, durable mechanical circulatory support is most consistently associated with the largest degree of reverse remodelling. Accordingly, research to analyse human tissue after a period of mechanical circulatory support continues to yield a wealth of information. In this Review, we summarize the latest findings on reverse remodelling and myocardial recovery. Accumulating evidence shows that the molecular changes associated with heart failure, in particular in the transcriptome, metabalome, and extracellular matrix, persist in the reverse-remodelled myocardium despite apparent normalization of macrolevel properties. Therefore, reverse remodelling should be distinguished from true myocardial recovery, in which a failing heart regains both normal function and molecular makeup. These findings have implications for future research to develop therapies to repair fully the failing myocardium. Meanwhile, recognition by society guidelines of this new clinical phenotype, which is coming to be known as a state of heart failure remission, underscores the need to accurately define and identify reverse modelled myocardium for the establishment of appropriate therapies.

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Figure 1: Ventricular end-diastolic pressure–volume relationship curves.
Figure 2: Metabolic shift in heart failure.
Figure 3: Altered extracellular matrix.
Figure 4: Metrics for echocardiographic assessment of myocardial recovery.

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Author information

All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article, and undertook review and/or editing of the manuscript before submission.

Correspondence to Daniel Burkhoff.

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Competing interests

N.U. has received grant support from HeartWare and Thoratec; and has served as a consultant for Abiomed, HeartWare (Medtronic), and Medtronic. D.B. is a consultant for BackBeat Medical, Cardiac Implants, HeartWare (Medtronic), Impulse Dynamics, and Sensible Medical. The Cardiovascular Research Foundation is the recipient of an unrestricted educational grant from Abiomed. G.H.K. declares no competing interests.

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Glossary

Transcriptome

The part of the genetic code that is transcribed into mRNA molecules; reflects the genes that are being actively expressed at any given time.

Mechanical unloading

The reduction of ventricular end-diastolic volume and pressure (preload), peak systolic pressure generation (afterload pressure), and overall myocardial oxygen demand; unloading is provided by ventricular assist devices that pump blood from the left ventricle to the arterial system, or by other forms of mechanical circulatory support.

Epigenetic

The study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.

Next-generation sequencing

High-throughput DNA-sequencing technologies in which millions of DNA strands can be sequenced in parallel, yielding substantially more throughput and minimizing the need for the fragment-cloning methods compared with previous methods.

Metabolome

Metabolites within cells, fluids, and tissues, and their interactions within a biological system, which directly reflect the underlying biochemical activity and state of cells and tissues.

Fatty acid β-oxidation

Process by which fatty acid molecules are broken down in the mitochondria to generate acetyl-CoA, which enters the Krebs cycle, and NADH and FADH2, co-enzymes used in the electron transport chain.

Ketone bodies

Water-soluble molecules produced by the liver from fatty acids during gluconeogenesis, including acetoacetate, β-hydroxybutyrate, and acetone.

Matrix metalloproteinases

Enzymes that can break down proteins of the extracellular matrix, such as collagen, and other proteins residing on the cell surface or within the matrix.

LV sphericity indices

The ratio of left ventricular (LV) long-axis length divided by LV short-axis length, during both systole and diastole.

Functional mitral regurgitation

Mitral regurgitation occurring as a result of ventricular remodelling when apical and lateral papillary muscle displacement pulls the leaflets downward and apart in a manner that prohibits proper coaptation; the valve leaflets are generally normal.

Mitral valve repair

A surgical or percutaneous procedure in which the mitral leaflets, annulus, and/or choardae tendinae are modified to improve leaflet coaptation and reduce the degree of mitral regurgitation.

Mitral valve replacement

A surgical procedure involving the replacement of the natural mitral valve with a mechanical or bioprosthetic mitral valve; percutaneous procedures are currently under development.

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Kim, G., Uriel, N. & Burkhoff, D. Reverse remodelling and myocardial recovery in heart failure. Nat Rev Cardiol 15, 83–96 (2018). https://doi.org/10.1038/nrcardio.2017.139

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