Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Chagas cardiomyopathy is the most severe manifestation of human Chagas disease and represents the major cause of morbidity and mortality in Latin America. We previously demonstrated diastolic Ca²⁺ alterations in cardiomyocytes isolated from Chagas’ patients with different degrees of cardiac dysfunction. Exposure of cardiomyocytes to agents that enhance inositol 1,4,5 triphosphate (IP3) generation or concentration like endothelin (ET-1) or bradykinin (BK), or membrane-permeant myoinositol 1,4,5-trisphosphate hexakis(butyryloxy-methyl) esters (IP3BM) caused an elevation in diastolic [Ca²⁺] ([Ca²⁺]_d) that was always greater in cardiomyocytes from Chagas’ than non- Chagas’ subjects, and the magnitude of the [Ca²⁺]_delevation was related with the degree of cardiac dysfunction. Incubation with xestospongin-C (Xest-C) a membrane-permeable selective blocker of the IP3 receptors (IP3Rs) significantly reduced [Ca²⁺]_d in Chagas’ cardiomyocytes but did not have a significant effect in non- Chagas’ cells. Furthermore, cardiomyocytes from Chagas’ patients had a higher intracellular IP3 concentration ([IP3]_i) and markedly depressed contractile properties compared to control subjects. These results provide additional and convincing support about implications of IP3 in the pathogenesis of Chagas cardiomyopathy in patients at different stages of chronic infection. Additionally, these findings open the door for novel therapeutic strategies oriented to improve cardiac function and quality of life of individuals suffering from Chagas cardiomyopathy.