Key result
Screening of 727 compounds identified ezetimibe and disulfiram as novel mitochondrial Ca2+ uptake enhancers that suppress arrhythmogenesis at nanomolar concentrations in preclinical models.
Why the study?
Treatment of cardiac arrhythmia remains challenging due to severe anti-arrhythmic drug side effects, and druggable agonists of mitochondrial Ca2+ uptake suitable for studies are missing.
Do ezetimibe and disulfiram suppress cardiac arrhythmogenesis in preclinical models?
Do ezetimibe and disulfiram suppress cardiac arrhythmogenesis in preclinical models?
Ezetimibe and disulfiram were identified as novel mitochondrial Ca2+ uptake enhancers that suppress arrhythmogenesis in preclinical models, suggesting potential for future anti-arrhythmic drug development.
Should not alter arrhythmia management; leaves open clinical utility of mitochondrial Ca2+ enhancers pending human trials.
Background and Purpose Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti‐arrhythmic drugs. We previously demonstrated that mitochondrial Ca2+ uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists of mitochondrial Ca2+ uptake suitable for preclinical and clinical studies are still missing. Experimental Approach Herewe screened 727 compounds with a history of use in human clinical trials in a three‐step screening approach. As a primary screening platform we used a permeabilized HeLa cell‐based mitochondrial Ca2+ uptake assay. Hits were validated in cultured HL‐1 cardiomyocytes and finally tested for anti‐arrhythmic efficacy in three translational models: a Ca2+ overload zebrafish model and cardiomyocytes of both a mouse model for catecholaminergic polymorphic ventricular tachycardia (CPVT) and induced pluripotent stem cell derived cardiomyocytes from a CPVT patient. Key Results We identifiedtwo candidate compounds, the clinically approved drugs ezetimibe and disulfiram, which stimulate SR‐mitochondria Ca2+ transfer at nanomolar concentrations. This is significantly lower compared to the previously described mitochondrial Ca2+ uptake enhancers (MiCUps) efsevin, a gating modifier of the voltage‐dependent anion channel 2, and kaempferol, an agonist of the mitochondrial Ca2+ uniporter. Both substances restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model and significantly suppressed arrhythmogenesis in freshly isolated ventricular cardiomyocytes from a CPVT mouse model as well as induced pluripotent stem cell derived cardiomyocytes from a CPVT patient. Conclusion and Implications Taken together we identified ezetimibe and disulfiram as novel MiCUps and efficient suppressors of arrhythmogenesis and as such as, promising candidates for future preclinical and clinical studies.
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Sander et al. (2021) studied Cardiac arrhythmia. Ezetimibe and disulfiram was evaluated on Mitochondrial Ca2+ uptake and arrhythmogenesis. Screening of 727 compounds identified ezetimibe and disulfiram as novel mitochondrial Ca2+ uptake enhancers that suppress arrhythmogenesis at nanomolar concentrations in preclinical models.
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