Cardiotrophin-1 induces sarcoplasmic reticulum Ca2+ leak and arrhythmogenesis in adult rat ventricular myocytes

Abstract

Aims Plasma levels of cardiotrophin-1 (CT-1) are elevated in several cardiovascular diseases and are correlated with the severity of the pathology. However, the mechanisms by which this inflammatory cytokine participates in the pathology of the heart are not completely understood. It is well established that alterations in intracellular calcium ([Ca2+]i) handling are involved in cardiac dysfunction during heart failure, but it is unknown whether CT-1 modulates [Ca2+]i handling in adult cardiomyocytes. Here we have analyzed for the first time the effects of CT-1 on [Ca2+]i homeostasis in adult rat cardiomyocytes.

Methods and results L-type calcium current (ICaL) was recorded using patch-clamp techniques, and [Ca2+]i transients and Ca2+ sparks were viewed by confocal microscopy. Treatment of cardiomyocytes with 1 nM CT-1 for 20–60 min induced a significant increase in ICaL density, [Ca2+]i transients, and cell shortening compared with control cells. Our study reveals that CT-1 increases ICaL by a protein kinase A-dependent mechanism, and Ca2+ sparks by a Ca2+/calmodulin kinase II-dependent and protein kinase A-independent mechanism. Cardiomyocytes treated with CT-1 exhibited a higher occurrence of arrhythmogenic behaviour, manifested as spontaneous Ca2+ waves and aftercontractions. Conclusion Our findings provide evidence that cardiomyocytes treated with CT-1 present high spontaneous Ca2+ release during diastole, a mechanism linked to arrhythmogenicity in the pathologic heart.