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  • Review Article
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Reverse remodeling in heart failure—mechanisms and therapeutic opportunities

Abstract

Heart failure (HF) involves changes in cardiac structure, myocardial composition, myocyte deformation, and multiple biochemical and molecular alterations that impact heart function and reserve capacity. Collectively, these changes have been referred to as 'cardiac remodeling'. Understanding the components of this process with the goal of stopping or reversing its progression has become a major objective. This concept is often termed 'reverse remodeling', and is successfully achieved by inhibitors of the renin–angiotensin–aldosterone system, β-blockers, and device therapies such as cardiac resynchronization or ventricular assist devices. Not every method of reverse remodeling has long-lasting clinical efficacy. However, thus far, every successful clinical treatment with long-term benefits on the morbidity and mortality of patients with HF reverses remodeling. Reverse remodeling is defined by lower chamber volumes (particularly end-systolic volume) and is often accompanied by improved β-adrenergic and heart-rate responsiveness. At the cellular level, reverse remodeling impacts on myocyte size, function, excitation–contraction coupling, bioenergetics, and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and other features. Here, we review the current evidence for reverse remodeling by existing therapies, and discuss novel approaches that are rapidly moving from preclinical to clinical trials.

Key Points

  • Cardiac remodeling in the failing heart involves structural changes, such as hypertrophy, fibrosis, and dilatation, and multiple abnormalities of cellular and molecular function

  • Stopping the progression of and, ultimately, reversing maladaptive remodeling is a useful target for treatment, and could provide benefit even if the underlying cause is not removed

  • Most therapies with long-term benefit for patients with heart failure result in reverse remodeling, as demonstrated by a sustained reduction of chamber volumes not caused by acute loading effects

  • New therapies that are being tested clinically involve inhibition of GMP-specific 3′,5′-cyclic phosphodiesterase 5, or upregulation of endoplasmic/sarcoplasmic calcium ATPase 2, calcium-sensor protein S100-A1, or thymosin β4

  • Other novel approaches might include blockade of calcium/calmodulin-dependent kinase II, protein kinase C isoform α, transient receptor potential channels, or transforming growth factor β

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Figure 1: Molecular signaling pathways targeted by novel approaches to reverse-remodel the failing heart.

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Both authors contributed equally to researching data for the article, made substantial contributions to the discussion of content, wrote, and reviewed and edited the manuscript before submission.

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Correspondence to David A. Kass.

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D. A. Kass declares that he is a consultant for Glaxo Smith Kline and St Jude Medical, and has received grant/research support from Glaxo Smith Kline. N. Koitabashi declares no competing interests.

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Koitabashi, N., Kass, D. Reverse remodeling in heart failure—mechanisms and therapeutic opportunities. Nat Rev Cardiol 9, 147–157 (2012). https://doi.org/10.1038/nrcardio.2011.172

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