T wave changes persisting after ventricular pacing in canine heart are altered by 4-aminopyridine but not by lidocaine. Implications with respect to phenomenon of cardiac 'memory'.

Abstract

BACKGROUND Cardiac "memory" refers to changes in T wave polarity induced by ventricular pacing that persist long after resumption of normal atrioventricular conduction. METHODS AND RESULTS We studied the occurrence and mechanism of T wave changes in the open-chest anesthetized dog subjected to three discontinuous 20-minute periods of right ventricular pacing. ECG changes were recorded in the standard limb leads during normal conduction (prepacing) and three trains (T1, T2, and T3) of right ventricular pacing at a rate 50% higher than normal (pacing), each followed by a period of normal conduction (postpacing) lasting as long as necessary for T wave changes to return to control values. During each of these phases, heart rate, QRS, corrected QT (QTc) duration, and T wave amplitude were measured. In the first group (control), T wave inversions occurred during normal atrioventricular conduction after a period of right ventricular pacing. These T wave anomalies appeared in the absence of any change in heart rate, QRS, or QTc duration. The magnitude of the T wave amplitude change was significantly greater after each successive pacing period. Furthermore, the changes in T wave morphology persisted for a longer period after each successive pacing train. In a second experimental group, lidocaine, which depresses the sodium window current, was administered to six dogs that were subjected to the same pacing protocol. Lidocaine decreased the QTc interval and prolonged QRS duration but did not alter the magnitude of changes in T wave amplitude and time to recovery described in control animals during the three postpacing intervals. In contrast, in the third group, 4-aminopyridine, a drug that blocks the transient outward current (ito), abolished the changes in T wave morphology that occurred during any postpacing interval. CONCLUSIONS These results demonstrate that the manifestation of cardiac memory in the in situ dog heart is not altered by lidocaine but is abolished by 4-aminopyridine. Thus, cardiac memory may be based on a physiological property of the myocardium that is related to specific K+ channels.

Transient Outward Current, I to1 , Is Altered in Cardiac Memory

“…6 It was also hypothesized that if this voltage gradient were minimized by pharmacological interventions, memory might be prevented. This hypothesis gained support when 4-AP (an I to blocker) prevented development of memory in the intact canine heart 5 and an isolated tissue model. 6 The above-described work was performed in models of short-term cardiac memory, lasting minutes.…”

“…[1][2][3][4] Canine studies have shown that short-term T-wave memory is prevented by intravenous 4-aminopyridine (4-AP), suggesting that the memory might depend on pacing-induced changes in the transient outward current, I to . 5 Studies of an isolated tissue model of cardiac memory supported this view, demonstrating that an altered epicardial-endocardial voltage gradient contributes to memory and that 4-AP abolishes it. 6 The expression of 4-AP-sensitive I to is heterogeneous through the canine ventricular wall, with current density higher in epicardial than endocardial myocytes.…”

Role of L-Type Calcium Channels in Pacing-Induced Short-Term and Long-Term Cardiac Memory in Canine Heart

“…Each rapid pacing period with changed activation was interrupted by pacing from the basal end of the preparation at a CL of 650 ms for 30 minutes. This protocol was identical to those in our original in vivo and in vitro studies, 13,15 which consistently evoked CM.…”

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

“…Intriguingly, accumulation occurs even in the absence of overt T wave changes. Both Rosenbaum and colleagues and del Balzo and colleagues 6,9 demonstrated that multiple trains of pacing stimuli resulted in progressively more cardiac memory, even when enough time was left between trains for apparently complete resolution of the alterations in T wave morphology. This observation suggests that the changes observed in the T wave in cardiac memory do not provide an accurate reflection of the underlying pacing-induced electrical changes that have transpired in the ventricular myocardium.…”

“…In studies on the intact canine heart, it has been shown that the K + channel blocker 4-aminopyridine (4-AP) inhibits the formation of cardiac memory, whereas the Na V channel blocker lidocaine has no effect. 9 In canine tissue, the Ca V channel blocker nifedipine also inhibits memory formation, but the beta adrenergic blocker propanolol has no effect on cardiac memory. 13 In a study of human short-term memory, Lee and colleagues 14 reported that both lidocaine (Na V channel blocker) and verapamil (another Ca V channel blocker) inhibited the induction of short-term memory.…”