Background-Cardiac memory refers to an altered T-wave morphology induced by ventricular pacing or arrhythmias that persist for variable intervals after resumption of sinus rhythm. Methods and Results-We induced long-term cardiac memory (LTM) in conscious dogs by pacing the ventricles at 120 bpm for 3 weeks. ECGs were recorded daily for 1 hour, during which time pacing was discontinued. At terminal study, the heart was removed and the electrophysiology of left ventricular epicardial myocytes was investigated. Control (C) and LTM ECG did not differ, except for T-wave amplitude, which decreased from 0.12Ϯ0.18 to Ϫ0.34Ϯ0.21 mV (ϮSEM, PϽ0.05), and T-wave vector, which shifted from Ϫ37Ϯ12°to Ϫ143Ϯ4°(PϽ0.05). Epicardial action potentials revealed loss of the notch and lengthening of duration at 20 days (both PϽ0.05). Calcium-insensitive transient outward current (I to ) was investigated by whole-cell patch clamp. No difference in capacitance was seen in C and LTM myocytes. I to activated on membrane depolarization to Ϫ25Ϯ1 mV in C and Ϫ7Ϯ1 mV (PϽ0.05) in LTM myocytes, indicating a positive voltage shift of activation. I to density was reduced in LTM myocytes, and a decreased mRNA level for Kv4.3 was observed. Recovery of I to from inactivation was significantly prolonged: it was 531Ϯ80 ms (nϭ10) in LTM and 27Ϯ6 ms (nϭ9) in C (PϽ0.05) at Ϫ65 mV. Conclusions-I to changes are associated with and can provide at least a partial explanation for action-potential and T-wave changes occurring with LTM. (Circulation. 1999;99:1898-1905.)

CM is a dynamic process for which the final T vector is predicted by the paced QRS vector and which is associated with significant changes in epicardial and endocardial but not midmyocardial cell action potential duration, such that the transmural gradient of repolarization is altered. It is unaccompanied by evidence of altered hemodynamics or flow, requires a change in pathway of activation, and appears to require new protein synthesis.

Granulocyte colony-stimulating factor and its receptor are needed for skeletal muscle development and injury-induced regeneration in mice.

During a screen for humoral factors that promote cardiomyocyte differentiation from embryonic stem cells (ESCs), we found marked elevation of granulocyte colony-stimulating factor receptor (G-CSFR) mRNA in developing cardiomyocytes. We confirmed that both G-CSFR and G-CSF were specifically expressed in embryonic mouse heart at the midgestational stage, and expression levels were maintained throughout embryogenesis. Intrauterine G-CSF administration induced embryonic cardiomyocyte proliferation and caused hyperplasia. In contrast, approximately 50% of csf3r(-/-) mice died during late embryogenesis because of the thinning of atrioventricular walls. ESC-derived developing cardiomyocytes also strongly expressed G-CSFR. When extrinsic G-CSF was administered to the ESC- and human iPSC-derived cardiomyocytes, it markedly augmented their proliferation. Moreover, G-CSF-neutralizing antibody inhibited their proliferation. These findings indicated that G-CSF is critically involved in cardiomyocyte proliferation during development, and may be used to boost the yield of cardiomyocytes from ESCs for their potential application to regenerative medicine.