CaMKII Inhibition in Heart Failure Makes Jump to Human

Abstract

See related article, pages 1150–1161 In this issue of Circulation Research , Sossalla et al1 show that acute inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II in failing human myocardium causes functional improvement in contractility by restoring a positive force–frequency relationship (FFR) in cardiac trabeculae. The loss of this normal positive FFR (and often an induction of a negative FFR) is a functional hallmark of failing human myocardium2 and has been seen as an intrinsic limitation of the failing heart to enhance contractility appropriately at higher heart rates. This failure of positive FFR also constitutes a reduction in functional cardiac reserve. So, why might CaMKII inhibition be beneficial in heart failure (HF)? For several years, evidence has been accumulating that CaMKII is increased in both expression level and activity in both animal models of HF and in failing human hearts.3,–,9 It has also come to light that CaMKII has many different functional effects in cardiac myocytes, including alterations in ion channels, Ca2+ handling proteins, myofilaments, and transcriptional regulation.10,–,12 Moreover, many of these CaMKII effects on myocyte properties have been implicated in hypertrophy, HF, and arrhythmias in animal models. Indeed, CaMKII inhibition (or knockout of the dominant cardiac isoform CaMKIIδ) can improve cardiac function and delay the onset of maladaptive aspects of the hypertrophic/HF phenotype in animal models, resulting in beneficial functional effects.13,–,15 Sossalla et al1 provide important novel data that acute CaMKII inhibition in human HF myocardium causes functional improvement. This is an important validation step with respect to consideration of cardiac CaMKII inhibition as therapeutic strategy in human HF. So, what are some key acute functional effects of CaMKII that can alter cardiac Ca2+ handling and excitability? CaMKII phosphorylates …