CaMKII Confirms its Promise in Ischaemic Heart Disease

The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. This article refers to ‘Ca2+/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca2+ leak in human ischaemic and dilated cardiomyopathy’ by T.H. Fischer et al., on page 1292 The multitudes of therapies available for heart failure (HF) management have only partially been able to reduce the burden of this disease. Novel therapies are therefore urgently needed. Over the years, sophisticated experimental studies have identified numerous pathways underlying HF development and also identified several attractive nodal points for intervention. The translation of these mechanistic insights into clinical practice has, however, been disappointing at best. In fact, all the drugs that are currently at our disposal target the same pathway, neurohumoral activation. Fortunately, promising candidates have emerged at the brink of clinical translation, one of which is the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII).1 The serine/threonine protein kinase CaMKII phosphorylates several proteins that are critically involved in cardiac calcium handling and gene transcription, thereby regulating both acute and chronic adaptations to cardiac stress. CaMKII activity is markedly increased in failing hearts, and this excessive CaMKII activation has been linked to progressive cardiac remodelling and arrhythmias. This pathophysiological duality is exemplified by CaMKII-mediated activation of the ryanodine receptor (RyR2), which promotes diastolic calcium release from the sarcoplasmic reticulum (SR). These diastolic calcium release events trigger arrhythmias through multiple mechanisms and impair myocardial contractility at least in part by depleting SR calcium stores. CaMKII could therefore provide a promising nodal point for intervention, which could allow us simultaneously to modulate HF progression and arrhythmias. While the majority of clinical HF is ischaemic in nature, most of evidence supporting the concept of therapeutic CaMKII inhibition has paradoxically been derived from non-ischaemic models. Indeed, other investigations have even challenged the concept that CaMKII inhibition is relevant for cardiac remodelling after myocardial infarction (MI).2, 3 The paucity of data supporting the pathophysiological effects of CaMKII in the majority of HF patients may significantly limit the potential impact of CaMKII inhibitors on HF management and could therefore dampen the enthusiasm to develop specific drugs. In an elegant study in this issue of the journal, Fischer et al. present compelling evidence for the potential therapeutic benefit of CaMKII inhibition in ischaemic as well as non-ischaemic HF.4 By western blotting experiments on a large set of human myocardial tissue samples, they demonstrate that CaMKII expression levels are equally increased in human ischaemic (ICM) and dilated cardiomyopathy (DCM). Importantly, the extent of CaMKII autophosphorylation, which is indicative of CaMKII activity, was similar in cardiac samples of both disease aetiologies. Supporting this finding, the authors identified an equal degree of phosphorylation of the CaMKII targets phospholamban and RyR2 in ICM and DCM samples. Furthermore, in a set of very sophisticated Ca2+ imaging experiments using freshly isolated human cardiomyocytes, it was shown that the severity of SR Ca2+ leak and occurrence of associated arrhythmic events did not differ in cells from ICM and DCM patients. Finally, the authors provide evidence that CaMKII inhibition with autocamide-2-related inhibitory peptide is equally effective at reducing diastolic Ca2+ leak and lowering the frequency of arrhythmic events in ICM- and DCM-derived cardiomyocytes. The fact that CaMKII inhibiton attenuates arrhythmogenesis in ICM and DCM harbours the translationally important implication that CaMKII inhibition may be beneficial for all types of HF patients. Studies in mouse models have already implicated a role for CaMKII activation in cardiac remodelling and loss of contractility after MI.5, 6 Nevertheless, the downstream CaMKII phosphorylation events causing these adverse changes have not been revealed. Although definite proof would require more detailed experiments that include other parameters of SR calcium handling such as diastolic Ca2+ levels and SR Ca2+ load, the study by Fisher et al. points to a possible role for CaMKII-dependent phosphorylation of RyR2 at S2814 in inducing SR Ca2+ leak after MI. Studies using knock-in mice with a genetically inactivated CaMKII phosphorylation site on RyR2 (S2814A) have previously demonstrated that phosphorylation of this single serine in RyR2 is important for the development of arrhythmias and loss of cardiac contractility after pressure overload-induced HF.2, 7 While it has been demonstrated by two different groups that these RyR2 S2814A knock-in mice are not protected from HF development after MI,2, 3 this could reflect the fact that other CaMKII targets contribute to cardiac remodelling after MI. The implication that increased phosphorylation of RyR2 by CaMKII does not induce SR calcium leak and associated cardiac remodelling in ischaemic forms of HF is challenged by the current study of Fisher et al. In considering how to interpret the failure of reduced RyR2 phosphorylation to protect in an experimental MI model vs. the findings presented here, one should also consider that the location and extent of damage following acute MI in mice can be tightly controlled, whereas the pathology of human ischaemic heart disease is more heterogeneous and complex. For example, the detrimental effects on cardiac function after an MI in humans might in part be explained by reperfusion injury, which can occur after restoring the blood flow to the ischaemic myocardium.8 In this regard, recent evidence indicates that increases in CaMKII activity and in CaMKII-dependent phosphorylation of RyR2 contribute to the myocardial damage that occurs after experimental cardiac ischaemia/reperfusion injury in mice.9, 10 Thus there appears to be a pathological role for CaMKII-induced Ca2+ leak during cardiac ischaemia/reperfusion, and the present study by Fischer et al. further suggests that CaMKII inhibition might be helpful in improving clinical outcome after MI. While the study by Fisher et al. reassures us that CaMKII is a relevant potential therapeutic target for patients with HF of varying aetiologies, there are significant challenges that limit the clinical translation of CaMKII inhibitors in the near future (reviewed in Westenbrink et al.1 and Pellicena et al.11). First and foremost is the paucity of molecular CaMKII inhibitors that are specific enough to reliably study the mechanism of CaMKII activation, and that have the properties required for drug disposition and efficacy as a HF drug. Moreover, recent studies suggest that the different splice variants of CaMKII may play distinct and opposing roles in cardiomyocyte survival and thus in HF development.12, 13 Accordingly, the efficacy of generic CaMKII inhibitors could be limited by their simultaneous effects on non-pathological splice variants. CaMKII is activated downstream of multiple neurohumoral agonists for which effective antagonists are already available and have proven their efficacy in randomized controlled clinical trials. Thus, while CaMKII is a convergence point for a number of critical signals, there are as yet no data supporting the efficacy of CaMKII inhibition when added on top of contemporary evidence-based therapy. Despite the challenges ahead, the study by Fischer et al. provides us with important data supporting the concept that CaMKII inhibitors, when available, could become the next evidence-based therapeutics for HF. R.J.vO. is supported by a VENI grant (916.11.150) from the Netherlands Organization for Scientific Research (NWO) and a Dr Dekker Senior Postdoc grant (2012 T094) from the Dutch Heart Foundation (NHS). B.D.W. is supported by the NHS, (grant 2012 T066). J.H.B. is supported by the National Institute of Health (NIH HL080101). Conflict of interest: none declared