부산대학교 도서관

Objective : Dilated cardiomyopathy (DCM) is a disease that often leads to heart failure (HF) and lethal arrhythmia. Recently a mouse model of DCM was created by a mutation of cardiac troponin T that closely mimics human DCM. These mice appeared to die suddenly with a t1 2 of 70 days. In the present study, to explore arrhythmogenic mechanism of the DCM mice, we examined effects of isoproterenol (Iso) and acetylcholine (Ach) on DCM myocardium because sensitivity of DCM hearts to autonomic effects seems to change in vivo. Materials and Methods : A knock-in mouse lacking Lys-210 in its endogenous cardiac troponin T gene (Tnnt2 ΔK210) was used as the DCM model at 8 to 10 weeks of age. Left ventricular (LV) muscles were isolated from wild type (WT) and DCM model mice. Membrane potentials were optically determined with di-4-ANEPPS using a laser scanning confocal microscope during field stimulation. The gene expression levels of receptors for autonomic nervous system and related downstream proteins were evaluated using a real-time PCR assay. Results : In normal Krebs solution, WT LV developed action potentials only by electrical stimulation, whereas DCM LV showed spontaneous action potential in addition to stimulation-induced activity. When the β-agonist isoproterenol was applied to LV, both WT and DCM LV developed spontaneous activity, and their frequency was much more prominent in DCM LV. The spontaneous activity was suppressed by β1-blocker (atenolol) and Ach, and their suppressive effects were much weaker in DCM LV. Gene expression analysis revealed down-regulation of KAch channel and up-regulation of some cAMP related proteins, whereas no significant change was detected in adrenaline β1-receptor. Conclusions : In DCM model mice, the change in balance between adrenergic and cholinergic effects of autonomic nerves on myocardium may relate to the development of lethal arrhythmias.