Author + information
- Pablo A. Chiale, MD†∗ (, )
- Daniel Etcheverry, MD†,
- Julio D. Pastori, MD†,
- Hugo A. Garro, MD†,
- Pablo A. Fernández, MD†,
- Mario D. González, MD‡ and
- Marcelo V. Elizari, MD†
- †Centro de Arritmias Cardíacas de la Ciudad Autónoma de Buenos Aires, División Cardiología, Hospital J.M. Ramos Mejía, Buenos Aires, Argentina
- ‡Clinical Electrophysiology, Heart & Vascular Institute, Penn State University, Hershey, Pennsylvania
- ↵∗Division Cardiología, Hospital J. M. Ramos Mejía, General Urquiza 609, 1221 Buenos Aires, Argentina
To the Editor:
It is known that a transient change in the sequence of ventricular depolarization may be followed by inverted T waves that become apparent once ventricular activation normalizes. In 1982, Rosenbaum et al. (1) coined this cumulative phenomenon “cardiac memory,” as it occurs earlier if the ventricular myocardium has been previously exposed to the same conditioning stimulus. The most characteristic feature of “memory-induced” T waves, better known as T-wave memory (TWM), is that their spatial polarity tracks the direction of the conditioning QRS complexes.
TWMs have been experimentally prevented by blockade of either angiotensin I angiotensin receptors (ATIAR) or L-type calcium channels (LCaCh) (2–4), suggesting that specific ion channels and receptors are involved in the mechanism of TWM. No information regarding the effect of these drugs on clinical TWM is available.
We assessed the effects of losartan (ATIAR blocker) and diltiazem (LCaCh blocker) on induction of TWM in patients with implanted pacemakers (PM).
Patients with sinus node dysfunction, normal atrioventricular conduction, QRS, and T waves receiving a dual-chamber PM were studied. Pacing was performed from the right ventricular apex. After implantation, the devices were programmed to pace only the atria (AAI) at 70/min. An electrocardiogram (ECG) was recorded (C1) and repeated 1 week later (C2). Thereafter, the PM was programmed DDD at 70/min with a short atrio-ventricular (A-V) interval resulting in a fully paced QRS (C3). ECGs were repeated 1 (C4) and 2 (C5) weeks later during DDD and transient AAI stimulation. Figure 1A shows an example of TWM. Then, the PM was programmed to AAI and ECGs repeated at weekly intervals until the T waves normalized. Patients were then randomized to diltiazem (240 mg/day slow released) or losartan (50 mg twice a day) during 3 weeks and the pacing protocol repeated (D2 to D5) after 1 week of treatment.
An inverted protocol was performed in 8 patients treated for a week with losartan (n = 4) or diltiazem (n = 4) and proceeding from steps D2 to D5 during treatment. The protocol for TWM induction was repeated to obtain baseline data.
The study protocol conformed to the principles outlined in the Declaration of Helsinki and was approved by the Ethical Board of Ramos Mejía Hospital.
Continuous variables between groups were compared with the Mann-Whitney U test. The chi-square or Fisher exact tests were used for categorical variables. Before and after diltiazem or losartan administration, the T-wave axis on the frontal plane, the T-wave amplitude (in lead III and in a precordial lead with most conspicuous TWM changes), and the QTc interval were compared with the Wilcoxon signed rank test for nonparametric paired data. A p value <0.05 was statistically significant.
Thirty of 42 patients in the study completed the protocol. The mean age was 64.1 ± 7.4 years (40% males). Before drug administration, the electrical axis of TWM shifted from +30° to –60° (p < 0.001) (Fig. 1B). No statistical differences were observed with losartan (from –60° to –60°; p < 0.715) or diltiazem (from –55° to –60°; p < 0.334). TWM polarity and amplitude were not modified by losartan or diltiazem (Fig. 1C).
Induction of TWM caused a small prolongation of QTc interval at baseline, from 0.42 to 0.43 s (p = 0.002), and also during both losartan, from 0.42 to 0.43 s (p = 0.008), and diltiazem, from 0.42 to 0.43 s (p = 0.022). Similar TWM changes were obtained in 8 patients already receiving losartan or diltiazem before initiating right ventricular apical pacing (RVAP).
The present study demonstrates that losartan and diltiazem do not modify the TWM induced by RVAP, in contrast to experimental observations. The reasons for these dissimilar results are not readily apparent.
TWM appears as a benign electrical remodeling, although it shares transduction pathways with factors that may be pathological, such as angiotensin II and reactive oxygen species. TWM in patients denotes that pacing evokes regional changes in the repolarization process depending on electrotonic influence of surrounding tissues and activation time of ventricular myocardium. During RVAP, activation departs from the right ventricular apex and ends in the basal left ventricle causing depolarizing forces oriented posteriorly and leftward. Repolarization lengthens in the apex but shortens at the base. Once normal activation resumes, negative T waves appear in the ECG leads in which the paced QRS complexes had been negative, signaling an important change in the repolarization gradient (5). TWM may be due to regional stretching of cardiomyocytes (4,6), leading to increased synthesis and liberation of angiotensin II causing augmented trafficking and internalization of a complex composed by the ATIAR and the potassium-channel protein KV4,3/KChIP2CH and an increment in the calcium current ICaL. The cAMP response element binding is reduced in ventricular myocardium of dogs undergoing 2 h ventricular pacing and saralasin (ATIAR blocker) and nifedipine (LCaCh blocker) prevented this effect (7). This could impede changes in the density of Ito, IKr, and ICaL currents thought to play a major role in TWM. Ventricular pacing also leads to myocardial angiotensin II production and to proteosomal degradation of cAMP response element binding (8) and the downstream ion channel changes involved in the onset of long-term TWM.
Based on experimental data we hypothesized that in our clinical model, TWM could be prevented by losartan and/or diltiazem administration. This assumption was not confirmed by our results although the small sample size is a limitation. Further studies are necessary to determine whether faster or longer periods of RVAP may modify the results.
The results of our study suggest that the mechanisms involved in clinical TWM may be more complex than previously recognized under experimental conditions.
Please note: This work was supported by FICE (Fundación de Investigaciones Cardiológicas Einthoven) and a grant from FONCYT (PICT Bicentenario 2010 #2591). All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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- Plotnikov A.N.,
- Yu H.,
- Geller J.C.,
- et al.
- Janse M.J.,
- Sosunov E.A.,
- Coronel R.,
- et al.
- Patberg K.W.,
- Plotnikov A.N.,
- Quamina A.,
- et al.