https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland
Background Mutations in the cardiac sodium channel and calcium channel genes may cause Brugada syndrome (BrS), an arrhythmic disorder that can cause of sudden death. Optimal pharmacotherapy for BrS is still lacking. Milrinone and cilostazol, oral phosphodiesterase type III (PDE3) inhibitors, have been shown to increase ICa by elevating the level of intracellular cAMP in animal model, and listed as Class 2b and Class 3 recommendation on Brugada therapy due to the paucity of information available. This study aimed to explore effects and underlying mechanisms of milrinone and cilostazol on BrS phenotypic features.
Methods Human induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts from BrS patients carrying mutations in sodium channel SCN5A, SCN10A and calcium channel CACNB2 genes. IPSCs were differentiated into cardiomyocytes (iPSC-CMs) using monolayer-based differentiation protocol. Calcium and sodium currents and arrhythmic events were analyzed in cells with and without drug treatment.
Results In BrS-hiPSC-CMs with SCN5A mutation but SCN10A or CACNB2 mutations, both milrinone and cilostazol (PDE3 inhibitors) increased the peak sodium channel current (INa). In Brs-hiPSC-CMs with CACNB2 mutation, both drugs enhanced calcium channel current (ICa-L). Both PDE3 inhibitors decreased the burden of arrhythmias in all three BrS cell lines, but milrinone is more potent that cilostazol to attenuate the abnormality in BrS-iPSC-CMs. Notably, an cAMP (Cyclic adenosine monophosphate) blocker (H89) attenuated both PDE3 inhibitors effects.
Conclusons Our findings suggest that PDE3 inhibitor can exert an antiarrhythmic effect on BrS by activating CAMP pathway.
Keywords iPSC-CMs, Brugada syndrome, Nav1.5, PDE3 inhibitor