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Invited Commentary
April 14, 2021

To Be or Not to Be a CaMKII Inhibitor?

Author Affiliations
  • 1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Cardiol. 2021;6(7):769-770. doi:10.1001/jamacardio.2021.0701

It is exciting to read the first clinical study, to my knowledge, designed to test the potential benefits of a calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor in patients with an anterior ST-segment elevation myocardial infarction (STEMI).1 CaMKII is one of the most extensively preclinically validated targets for treating arrhythmias and heart failure still lacking support (or refutation) by clinical trial. In full disclosure, I have spent much of my adult life, as a physician-scientist and cardiologist, researching the molecular physiology of CaMKII, including investigation of the response of disease models to CaMKII inhibition. CaMKII is a serine/threonine kinase that is expressed in most cells, but is relatively enriched in muscle (including myocardium), immune cells, and neurons. CaMKII is expressed as 4 isoforms (α, β, γ, and δ) encoded by 4 distinct genes. These isoforms are similar in terms of their structure (including the critical adenosine 5′-triphosphate [ATP]-binding pocket), regulation, and substrate specificity. However, they are differentially expressed; the α and β isoforms predominate in neurons, while δ and γ isoforms have greater expression outside of the nervous system. The δ isoform is the major isoform in heart muscle. CaMKII functions in physiology as a turbo-charging signal, catalyzing the transfer of the γ phosphate from ATP to a diverse range of protein targets to enhance their function. In heart, CaMKII-mediated phosphorylation of ion channels and other proteins contributes to heart rate acceleration, increased contractile performance, enhanced oxidative phosphorylation, and gene transcription. All these changes, except gene transcription, can occur on a moment-to-moment timescale, making them ideal for the rapid responses demanded by evolutionarily engrained fight-or-flight physiology. However, the rub comes from sustained excessive CaMKII activity that overactivates various protein targets, including ion channels and transcription factors. In cardiomyocytes, these actions contribute to increased intracellular calcium leak from ryanodine receptors that reduces availability of the myofilament activator calcium needed to drive contraction and perturbs normal intracellular calcium homeostasis, triggering arrhythmias and pathological calcium-linked gene transcription. Because CaMKII itself is activated by calcium and oxidative stress, signals that are heightened and dysregulated in failing heart muscle, it has the attributes of a feed-forward pathological force. Again and again, numerous investigators using highly selective genetic inhibition strategies, tool inhibitors, and bona fide highly selective and potent oral agents2 have shown success in treating heart failure and arrhythmias in large (pigs, dogs) and small (mice, rats) animal models and in failing and arrhythmogenic human heart tissues.3

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