title: Subcellular mechanisms underlying digitalis-induced arrhythmias: role of calcium/calmodulin-dependent kinase II (CaMKII) in the transition from an inotropic to an arrhythmogenic effect.
abstract: Cardiotonic glycosides or digitalis are positive inotropes used in clinical practice for the treatment of heart failure, which also exist as endogenous ligands of the Na(+)/K(+) ATPase. An increase in the intracellular Ca2+ content mediates their positive inotropic effect, but has also been proposed as a trigger of life-threatening arrhythmias. Although the mechanisms involved in the positive inotropic effect of these compounds have been extensively studied, those underlying their arrhythmogenic action remain ill defined. Recent evidence has placed posttranslational modifications of the ryanodine receptor (RyR2), leading to arrhythmogenic Ca2+ release, in the centre of the storm. In this review we will examine, in depth, the mechanisms that generate the arrhythmogenic substrate, focussing on the role played by the RyR2 and how its CaMKII-dependent regulation may shift the balance from an inotropic to an arrhythmogenic Ca2+ release. Finally, we will provide evidence suggesting that stabilising RyR2 function could result in a potential new strategy to prevent cardiotonic glycoside-induced arrhythmias that could lead to a safer and more extensive use of these compounds.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
authors.forename: Luis Alberto
authors.initials: LA
authors.lastname: Gonano
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina. Electronic address: mvila@med.unlp.edu.ar.
authors.forename: Martín Vila
authors.initials: MV
authors.lastname: Petroff
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004071:Digitalis Glycosides / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D004071:Digitalis Glycosides; D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Arrhythmia; CaMKII; Calcium handling; Cardiotonic glycosides; RyR2