Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology.

Authors:
Guido Tarone
Guido Tarone
University of Torino
Italy
Prof. Dr. Johann Bauersachs, MD
Prof. Dr. Johann Bauersachs, MD
Hannover Medical School
Cardiology, Intensive Care
Hannover | Germany
Angela Clerk
Angela Clerk
Imperial College London
United Kingdom
Stephane Heymans
Stephane Heymans
Center for Heart Failure Research
Houston | United States
Dr. Emilio Hirsch, PhD
Dr. Emilio Hirsch, PhD
University of Torino
Professor
Torino | Italy

Eur J Heart Fail 2014 May 17;16(5):494-508. Epub 2014 Mar 17.

Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino, Torino, Italy.

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

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http://doi.wiley.com/10.1002/ejhf.62
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May 2014
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18 Citations
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References

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GRK2 at the control shaft of cellular metabolism
Ciccarelli et al.
Curr Pharm Des 2012

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