Key result
In vitro and ex vivo inhibition of the Ca2+/CaM-CaMKII pathway reversed the arrhythmic profile of isolated hearts and cardiomyocytes in experimental Chagas disease.
Why the study?
No medication is available to prevent or reverse cardiac symptoms in Chagasic cardiomyopathy, where disrupted calcium dynamics and oxidative stress may hyperactivate the Ca2+/CaM-CaMKII pathway.
Does inhibition of the Ca2+/CaM-CaMKII pathway reduce arrhythmias and improve electro-mechanical function in experimental Chagasic cardiomyopathy?
Does inhibition of the Ca2+/CaM-CaMKII pathway reduce arrhythmias and improve electro-mechanical function in experimental Chagasic cardiomyopathy?
Inhibition of the Ca2+/CaM-CaMKII pathway reverses arrhythmic profiles and restores calcium dynamics in experimental models of Chagasic cardiomyopathy, highlighting a potential novel therapeutic target.
Hypothesis-generating for CaMKII inhibition in Chagasic cardiomyopathy; prospective trials needed before clinical adoption.
Chagasic cardiomyopathy (CCC) is one of the main causes of heart failure and sudden death in Latin America. To date, there is no available medication to prevent or reverse the onset of cardiac symptoms. CCC occurs in a scenario of disrupted calcium dynamics and enhanced oxidative stress, which combined, may favor the hyper activation of calcium/calmodulin (Ca 2+ /CaM)‐calcium/calmodulin‐dependent protein kinase II (CaMKII) (Ca 2+ /CaM‐CaMKII) pathway, which is fundamental for heart physiology and it is implicated in other cardiac diseases. Here, we evaluated the association between Ca 2+ /CaM‐CaMKII in the electro‐mechanical (dys)function of the heart in the early stage of chronic experimental Trypanosoma cruzi infection. We observed that in vitro and ex vivo inhibition of Ca 2+ /CaM‐CaMKII reversed the arrhythmic profile of isolated hearts and isolated left‐ventricles cardiomyocytes. The benefits of the limited Ca 2+ /CaM‐CaMKII activation to cardiomyocytes' electrical properties are partially related to the restoration of Ca 2+ dynamics in a damaged cellular environment created after T. cruzi infection. Moreover, Ca 2+ /CaM‐CaMKII inhibition prevented the onset of arrhythmic contractions on isolated heart preparations of chagasic mice and restored the responsiveness to the increase in the left‐ventricle pre‐load. Taken together, our data provide the first experimental evidence for the potential of targeting Ca 2+ /CaM‐CaMKII pathway as a novel therapeutic target to treat CCC.
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Santos‐Miranda et al. (2021) studied Chagasic cardiomyopathy (experimental Trypanosoma cruzi infection). Ca2+/CaM-CaMKII inhibition was evaluated on Arrhythmic profile and electro-mechanical function. In vitro and ex vivo inhibition of the Ca2+/CaM-CaMKII pathway reversed the arrhythmic profile of isolated hearts and cardiomyocytes in experimental Chagas disease.
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