Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

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Abstract

Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies). ¹ In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy.

This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

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Most cited references 73

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The Randle cycle revisited: a new head for an old hat.

Louis Hue, Heinrich Taegtmeyer (2009)

In 1963, Lancet published a paper by Randle et al. that proposed a "glucose-fatty acid cycle" to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

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Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

Sheri Hartman, John Finer, David Morgans … (2011)

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

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Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy.

Allison Cirino, Petr Jarolim, Begoña López … (2010)

Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy and a proposed substrate for arrhythmias and heart failure. In animal models, profibrotic genetic pathways are activated early, before hypertrophic remodeling. Data showing early profibrotic responses to sarcomere-gene mutations in patients with hypertrophic cardiomyopathy are lacking. We used echocardiography, cardiac magnetic resonance imaging (MRI), and serum biomarkers of collagen metabolism, hemodynamic stress, and myocardial injury to evaluate subjects with hypertrophic cardiomyopathy and a confirmed genotype. The study involved 38 subjects with pathogenic sarcomere mutations and overt hypertrophic cardiomyopathy, 39 subjects with mutations but no left ventricular hypertrophy, and 30 controls who did not have mutations. Levels of serum C-terminal propeptide of type I procollagen (PICP) were significantly higher in mutation carriers without left ventricular hypertrophy and in subjects with overt hypertrophic cardiomyopathy than in controls (31% and 69% higher, respectively; P<0.001). The ratio of PICP to C-terminal telopeptide of type I collagen was increased only in subjects with overt hypertrophic cardiomyopathy, suggesting that collagen synthesis exceeds degradation. Cardiac MRI studies showed late gadolinium enhancement, indicating myocardial fibrosis, in 71% of subjects with overt hypertrophic cardiomyopathy but in none of the mutation carriers without left ventricular hypertrophy. Elevated levels of serum PICP indicated increased myocardial collagen synthesis in sarcomere-mutation carriers without overt disease. This profibrotic state preceded the development of left ventricular hypertrophy or fibrosis visible on MRI. (Funded by the National Institutes of Health and others.)

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Author and article information

Journal

Journal ID (nlm-ta): Cardiovasc Res

Journal ID (iso-abbrev): Cardiovasc. Res

Journal ID (publisher-id): cardiovascres

Title: Cardiovascular Research

Publisher: Oxford University Press

ISSN (Print): 0008-6363

ISSN (Electronic): 1755-3245

Publication date (Print): 01 August 2018

Publication date (Electronic): 15 June 2018

Publication date PMC-release: 15 June 2018

Volume: 114

Issue: 10

Pages: 1273-1280

Affiliations

[1 ]Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

[2 ]Netherlands Heart Institute, Utrecht, The Netherlands

[3 ]Department of Translational Medical Sciences, Federico II University, Naples, NA, Italy

[4 ]Department of Cardiology, Maastricht University Medical Center & CARIM, Maastricht University, Maastricht, The Netherlands

[5 ]Molecular Cardiology, Department of Cardiology and Angiology, Medical School Hannover, Germany

[6 ]Department of Systems Physiology, Ruhr University Bochum, Bochum, Germany

[7 ]Department of Surgery and Physiology, Faculty of Medicine, Cardiovascular Research Centre, University of Porto, Porto, Portugal

[8 ]The James Black Centre & King's British Heart Foundation Centre, King's College, University of London, London, UK

[9 ]Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany

[10 ]National Heart and Lung Institute, Imperial College London, London, UK

[11 ]REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany

[12 ]School of Medicine & Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, UK

[13 ]Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique (IREC), and Clinique Universitaire Saint-Luc, Université catholique de Louvain, Brussels, Belgium

[14 ]Department of Cardiovascular Sciences, Leuven University, Leuven, Belgium

Author notes

Corresponding author. Tel: +31 627339910; E-mail: j.vandervelden@ 123456vumc.nl

Article

Publisher ID: cvy147

DOI: 10.1093/cvr/cvy147

PMC ID: 6054261

PubMed ID: 29912308

SO-VID: 9a0f29f1-b434-444d-ae70-255dc8906c57

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 18 February 2018

Date revision received : 13 April 2018

Date accepted : 13 June 2018

Page count

Pages: 8

Funding

Funded by: Netherlands Cardiovascular Research Initiative

Funded by: Dutch Heart Foundation 10.13039/501100002996

Award ID: CVON2014-40

Funded by: European Union Commission’s Seventh Framework

Award ID: N° 305507

Funded by: HOMAGE

Award ID: N° 602904

Funded by: FIBROTARGETS

Funded by: FP7-Health-2013-Innovations-1

Award ID: N° 602156

Funded by: Netherlands Cardiovascular Research Initiative

Funded by: Dutch Heart Foundation 10.13039/501100002996

Funded by: CVON2011-ARENA

Funded by: CVON2016-Early HFPEF

Award ID: 2015-10

Funded by: CVON ShePREDICTS

Award ID: 2017-21

Funded by: Research and Innovation

Funded by: Ministry of Economic Affairs 10.13039/501100003195

Funded by: Top Sector Life sciences & Health

Funded by: Leuven University

Funded by: European Research Area Network on Cardiovascular Diseases

Funded by: Fonds National de la Recherche Scientifique

Funded by: FNRS 10.13039/501100002661

Award ID: PDR T.0144.13

Funded by: European Union

Award ID: UE LSHM-CT-05-018833

Funded by: Federation Wallonie-Bruxelles

Funded by: Action de Recherche Concertée

Award ID: ARC11-16/035

Funded by: Norte Portugal Regional Operational Programme

Award ID: NORTE 2020

Funded by: PORTUGAL 2020 Partnership Agreement

Funded by: European Regional Development Fund 10.13039/501100008530

Funded by: ERDF 10.13039/501100008530

Funded by: NETDIAMOND

Award ID: POCI-01-0145-FEDER-016385

Funded by: European Structural and Investment Funds

Funded by: Lisbon’s Regional Operational Program 2020

Funded by: Portuguese Foundation for Science and Technology

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Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

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Cancer Metabolism

Most cited references 73

The Randle cycle revisited: a new head for an old hat.

Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy.

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Cited by 37

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