title: 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.
abstract: 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.
authors.affiliation: Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino, Torino, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Angela
authors.initials: A
authors.lastname: Clerk
authors.forename: Leon
authors.initials: L
authors.lastname: De Windt
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.forename: André P
authors.initials: AP
authors.lastname: Lourenço
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D015507:Drugs, Investigational / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000494:pharmacology*; D057170:Translational Research, Biomedical; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D015507:Drugs, Investigational; C547293:omecamtiv mecarbil; D016572:Cyclosporine; D014508:Urea; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Adaptive hypertrophy; Cardiac remodelling; Cardiomyocyte survival; Contractility; Heart failure