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 (Ca²⁺/CaM)-calcium/calmodulin-dependent protein kinase II (CaMKII) (Ca²⁺/CaM-CaMKII) pathway, which is fundamental for heart physiology and it is implicated in other cardiac diseases. Here, we evaluated the association between Ca²⁺/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 Ca²⁺/CaM-CaMKII reversed the arrhythmic profile of isolated hearts and isolated left-ventricles cardiomyocytes. The benefits of the limited Ca²⁺/CaM-CaMKII activation to cardiomyocytes' electrical properties are partially related to the restoration of Ca²⁺ dynamics in a damaged cellular environment created after T. cruzi infection. Moreover, Ca²⁺/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 Ca²⁺/CaM-CaMKII pathway as a novel therapeutic target to treat CCC.

中文翻译：

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抑制钙/钙调蛋白 (Ca2+/CaM)——钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 轴减少实验性恰加斯病的体外和体外心律失常

恰加斯心肌病 (CCC) 是拉丁美洲心力衰竭和猝死的主要原因之一。迄今为止，没有可用的药物来预防或逆转心脏症状的发作。CCC 发生在钙动力学紊乱和氧化应激增强的情况下，两者结合可能有利于钙/钙调蛋白 (Ca ²⁺ /CaM)-钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) (Ca ²⁺ / CaM-CaMKII) 通路，这是心脏生理学的基础，它与其他心脏疾病有关。在这里，我们评估了慢性实验性克氏锥虫早期阶段Ca ²⁺ /CaM-CaMKII 与心脏机电（功能障碍）功能之间的关联感染。我们观察到 Ca ²⁺ /CaM-CaMKII 的体外和离体抑制逆转了离体心脏和离体左心室心肌细胞的心律失常特征。有限的 Ca ²⁺ /CaM-CaMKII 激活对心肌细胞电特性的好处部分与在克氏锥虫感染后产生的受损细胞环境中恢复 Ca ²⁺动力学有关。此外，Ca ²⁺ /CaM-CaMKII 抑制可防止 chagasic 小鼠离体心脏制备物发生心律失常收缩，并恢复对左心室前负荷增加的反应。总之，我们的数据为靶向 Ca 的潜力提供了第一个实验证据²⁺ /CaM-CaMKII 通路作为治疗 CCC 的新治疗靶点。