title: Ranolazine in the prevention of anthracycline cardiotoxicity.
abstract: Ranolazine is a selective inhibitor of the cardiomyocyte late inward sodium current, INaL, and features anti-ischemic, antiarrhythmic and ATP-sparing actions. Extensive laboratory data show that anthracyclines can induce the production of reactive oxygen species (ROS). Other laboratory data show that ROS can hyperactivate the cardiac isoform of calmodulin-dependent protein kinase II (CaMKII δ), in turn inducing a hyperactivation of the cardiac late sodium current (INaL) and a resulting cytosolic calcium overload. This, as a consequence of the related sodium overload, can induce a mitochondrial calcium depletion that, in turn, triggers a chronic vicious cycle characterized by mitochondrial H2O2 production (increased oxidative stress), and NAD(P)H and ATP depletion (energetic stress), both sustaining ROS production. We hypothesize that anthracyclines may induce both INaL hyperactivation and an oxidative/energetic vicious cycle in cardiomyocytes. These sustained oxidative and energetic stresses may induce low-level cardiomyocyte and cardiac stem cell death by various mechanisms, leading to heart failure in the presence of genetic factors, age, ischemic and arrhythmic events, harmful dietary behaviors, and concomitant diseases. By reducing INaL in a myocardium particularly vulnerable to apoptotic stress and ischemia ranolazine might thus exert cardioprotection interfering with the vicious cycle of anthracycline cardiotoxicity.
authors.affiliation: Institute of Cardiology and Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Corradi
authors.affiliation: Institute of Cardiology and Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Paolini
authors.affiliation: Institute of Cardiology and Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, Italy; G. Monasterio Foundation, Pisa, Italy. Electronic address: rdecater@unich.it.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use*; D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D010879:Piperazines / Q000627:therapeutic use*; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000627:therapeutic use*
chemical_list: D000083:Acetanilides; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine
keywords: Anthracyclines; Cardiotoxicity; Heart failure; Oxidative stress; Reactive oxygen species