Introduction: Cytosolic kinases in cardiomyocytes, particularly Ca2+/calmodulin-dependent kinase II (CaMKII), have been implicated in the regulation of cellular ionic currents, specifically Na+ and Ca2+ currents, and thus may play a crucial role in promoting cardiac arrhythmias. Importantly, CaMKII levels have been shown to increase in conditions of compromised cardiac function such as heart failure. CaMKII effects on cellular currents have been assumed to be restricted to post-translational modification. However, CaMKII possesses a nuclear localisation signal which allows it to influence gene transcription via effects on transcription factors and epigenetic chromatin accessibility. The Scn5a gene encodes the cardiac sodium channel NaV1.5 responsible for action potential activation and propagation and hence plays a crucial role in regulating cardiac electrophysiological function. As such, disrupted NaV1.5 expression and function have been implicated in a variety of inherited arrhythmic syndromes such as Brugada syndrome (BrS) and Long QT syndrome 3 (LQT3), as well as following cardiac structural or energetic dysfunction. CaMKII phosphorylation of NaV1.5 at multiple sites has been shown to increase arrhythmic tendency and promote BrS and LQT3 phenotypes. NaV1.5 also appears to be inhibited by intracellular Ca2+. CaMKII can control the activity of the sarcolemmal L-type Ca2+ channel CaV1.2 regulating cellular Ca2+ homeostasis which is known to be important in arrhythmogenesis. However, the mechanisms underlying CaMKII-Nav1.5 and CaMKII-Ca2+ relationships are poorly understood. Specifically, we hypothesise modification by CaMKII at the transcriptional level. Aim: To explore the effects of CaMKII inhibition on (1) Scn5a gene transcription and NaV1.5 protein expression, (2) Cacn1ac gene transcription, and CaV1.2 protein expression, and (3) cellular Ca2+ flux. Methods: This utilised induced pluripotent stem cells (iPSC) derived cardiomyocyte populations (N = 5, with 50000 cells per sample). CaMKII inhibition was achieved via incubation with KN93 inhibitory peptide for 24 hours at a concentration of 10µM. KN92 peptide was used in controls for the same concentration and time period. Scn5a and Cacn1ac gene expression was investigated using SYBRgreen qPCR, whereas NaV1.5 and CaV1.2 protein expression was investigated using both western blotting and immunofluorescence. Fluo 4-AM Ca2+ dye and Clariostar microplate reader were used to investigate Ca2+ flux. Results: Interestingly, CaMKII inhibition significantly increased Scn5a transcription by 160% (± 10%) (P = 0.001) and significantly increased Cacn1ac transcription by 140% (± 10%) (P = 0.007). Western blots and immunofluorescence did not reveal significant differences. Finally, CaMKII inhibition completely abolished cellular Ca2+ flux. Conclusions: Thus, the findings elucidate molecular mechanisms underlying arrhythmogenesis by providing insight into the CaMKII-Nav1.5 and CaMKII- CaV1.2 relationships. This demonstrated an important regulatory role of CaMKII in the transcription of Scn5a and Cacn1ac genes. Additionally, the results show the importance of CaMKII in mediating cellular Ca2+ flux. Hence, pathological conditions elevating CaMKII could result in significant reductions of sarcolemmal Na+ and Ca2+ currents as well as dramatic increases in cellular Ca2+ flux. Together these promote arrhythmic triggers and substrates e.g. alternans and afterdepolarisations from increased Ca2+ flux and slowed conduction velocity from reduced Na+ current. This highlights CaMKII as a novel potential antiarrhythmic pharmacological target.