CaMKII: A link between metabolic disorders and cardiac arrhythmias

The prevalence of metabolic diseases -such as obesity, prediabetes, metabolic syndrome or diabetes-has increased globally over the years. These diseases, mainly diabetes mellitus (DM), are among the leading causes of mortality and morbidity worldwide, with increased risk of diabetic cardiomyopathy (DC), cardiac arrhythmias, and heart failure (HF).

In metabolic diseases several steps and proteins involved in excitation-contraction coupling (ECC) are compromised, precluding an efficient and rhythmic cardiac contraction; moreover, calcium/calmodulin-dependent protein kinase II (CaMKII) a kinase involved in ECC, is upregulated in several metabolic maladies and significantly contributes to cardiac remodeling and arrhythmias, among which are calcium (Ca²⁺)-triggered arrhythmias. CaMKII activation is canonically produced by an increase and binding of Ca²⁺-calmodulin followed by auto-phosphorylation; furthermore, it may occur as a result of several post-translational modifications, including oxidation and O-GlcNAcylation that are usually present in metabolic illnesses and support chronic CaMKII upregulation and ECC impairment.

The aim of the present review is to summarize what is known about the different pathways modifying CaMKII activity and Ca²⁺ handling in metabolic disorders and may promote Ca²⁺-triggered arrhythmias even at the early stages of metabolic alterations. Future challenges in this field may encompass unraveling the precise mechanisms by which metabolic disturbances modulate CaMKII activity and its downstream effects on cardiac electrophysiology among different species. This would allow the development of robust and valid preclinical human models that can accurately recapitulate the pathophysiology of the human heart. Additionally, investigating the impact of targeted interventions, such as pharmacological inhibitors or gene therapies, could provide valuable insights into the feasibility and efficacy of manipulating CaMKII signaling to prevent or treat arrhythmias in metabolic disorders.