Transient Outward Current, I _to1 , Is Altered in Cardiac Memory

Abstract

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.)

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

“…11,26 A less prominent notch of the AP as observed in experiments 41,72 would occur if not only I Ca,L kinetics were adapted, but also I to conductance was reduced. In addition to I Ca,L and I to , transmural heterogeneity was found in I Ks 43 and in I NaCa .…”

“…69 Experimental results indicate that both the transient outward potassium (K + ) current (I to ) 57 and the L-type calcium (Ca 2+ ) current (I Ca,L ) 7,49 are involved in electrical remodeling after changing the activation sequence in the ventricles. Yu et al 72 observed a reduction in I to current size, which explains disappearance of the notch in the AP after remodeling. Plotnikov et al 49 reversed the activation sequence in the canine heart from epicardium to endocardium by pacing the left ventricle.…”

“…41,42,72 Since reducing g to has no significant influence on the Ca 2+ transient and on F norm in our model, scaling g to is not further considered in the present study. With increasing g Ca,L , the Ca 2+ transient and F norm increase, but APD is not affected.…”

“…2). After changing the activation sequence for 20 days, Yu et al 72 observed disappearance of the notch and APD prolongation. Jeyaraj et al 26 observed APD prolongation without disappearance of the notch, indicating that I to may not be the only ionic current that changes when the activation sequence is changed.…”

Mechanisms linking short- and long-term electrical remodeling in the heart .....is it a stretch?

“…18 Yu and colleagues, 19 for example, reported a positive shift in activation and slowed recovery from inactivation in epicardial I to after induction of cardiac memory in the canine heart. In addition, K V 4.3 (KCND3) mRNA levels were reduced, which would be expected to further reduce I to .…”