Repercussions of cardiac resynchronization therapy on the ventricular repolarization of heart failure patients as assessed by body surface potential mapping.

ABSTRACT

Objective: Cardiac resynchronization therapy (CRT) is an adjunct treatment for heart failure (HF) which associates with left bundle-branch block (LBBB) and is refractory to medical therapy. However, nearly 1/3 of the patients still do not respond, the reasons for which have yet to be determined. Additionally, experimental studies proved that epicardial left ventricle (LV) pacing yields reversed electrical activation sequence, increasing QT interval duration and dispersion of the ventricular repolarization, and leaving patients at greater risk for ventricular arrhythmias.

Methods: In this study, a series of 60 patients (61.7% male, mean age 59.2 [+ or -] 11.54 years) in NYHA-functional class III-IV heartfailure and LBBB, who received CRT through implantation of atria 1-biventricular pacemakers, were assessed by 87-lead body surface potential mapping (BSPM). The BSPM, noninvasive technique with semi-automatic readings, allowed analysis of variables associated with the cardiac ventricular repolarization QT intervals, maximal, minimum and mean Tpeak-end, and QT dispersion (QTmax - min), in addition to transmural dispersion of repolarization (Tpeak-end max - Tpeak-end min), in two different moments: baseline rhythm and during atrial-biventricular pacing.

Results: QT dispersion showed a significant 19.6% reduction (p=0.0009) under CRT, as compared with baseline measurements (85.58 [+ or -] 26.63 msec vs. 68.83 [+ or -] 25.16 msec). The transmural dispersion of repolarization (Tpeak-end max - Tpeak-end] min) showed smaller statistical significance (p=0.0343); however, its values were similarly decreased (55.50 [+ or -] 15.45 msec vs 49.41 [+ or -] 14.11 msec) during CRT.

Conclusion: These results may corroborate findings from major randomized clinical trials. We consider that the electrocardiographic variables obtained with the use of the BSPM, namely, the QT and Tpeak-end intervals, are appropriate for analysis and study of the effects of cardiac resynchronization therapy on the improved electrical dispersion as characterizing the improvement of homogeneity of cardiac ventricular repolarization.

Keywords: heart failure, dilated cardiomyopathy, cardiac resynchronization therapy, ventricular repolarization Introduction

**********

Heartfailure (HF) is increasingly prevalent among the population (1), with high morbidity/mortality from arrhythmogenic events and sudden cardiac death (SCD) among diseased patients; this mainly occurs when the condition associates with left bundle branch block, which occurs in nearly one third of the patients (2-4). There has been a surge of research to develop optimal drug therapy and, more recently, a growing use of electrical cardiac pacing devices, in an attempt to achieve greater homogeneity of electrical activation in the myocardium with such marked dyssynchrony, and to enhance the electrical dispersion of ventricular repolarization as well (5).

Named as cardiac resynchronization therapy (CRT), the procedure had its beneficial effects clearly evidenced in large randomized clinical trials, with improvements in cardiac synchronism and systolic function, enhanced tolerance to stress and improved quality of life (6-9). However, little is known about the ventricular repolarization process during CRT pacing. Since this may be involved in the clinical improvement or worsening of patients undergoing CRT, as well as for the greater (or lesser) risk of patients for cardiac arrhythmic events, which findings have also been detected by those trials (10-13), a growing interest in understanding this process has developed.

The aim of this study was to assess electrocardiographic variables related to the ventricular repolarization process in patients during atrial-biventricular pacing (from cardiac resynchronization therapy received as an adjunct management strategy for severe congestive heart failure associated with left bundle-branch block), by using the non-invasive method of body surface potential mapping.

Methods

From 2001 to 2006, 93 patients with heart failure in NYHA functional class III or IV of any etiology, associated to a left bundle-branch block with QRS [greater than or equal to] 120 ms, clinically treated with optimal medical therapy at the Pacing and Arrhythmia Unit of InCor-HCFMUSP, were retrospectively investigated. All the patients had atrio-biventricular pacemakers implanted as adjunct clinical management strategy for advanced congestive heart failure. After preliminary clinical evaluation, 33 patients were excluded, 2 for having right bundle-branch block and 31 because of their total dependence on the pacemaker (therefore, baseline rhythm was not assessed).

The final study group included 60 patients, 37 (61.7%) male, mean age 59.2 [+ or -] 11.54 years, whose electrocardiographic variables were assessed with body surface potential mapping (BSPM). The BSPM study was performed with a model 7100 Fukuda-Denshi equipment (Fukuda-Denshi, Tokyo, Japan), with 87 electrodes, 58 placed on the anterior chest and 29 on the back. Each patient was assessed in two moments, (1) with CRT device turned on, and 30 minutes after, (2) with CRT device turned off, i.e., with the patients baseline cardiac rhythm. In the two study situations, each electrode had semi-automatic measurements read by the same operator directly from the monitor, through two cursors placed at the onset and at the end of the interval of interest Two measurements were processed, the QT-interval and the Interval Tpeak-end (interval from the peak of the T wave to its end).

The cardiac ventricular repolarization process was analyzed in the two moments of study through the following variables: maximum QT (QTmax), minimum QT (QTmin), and mean QT (QTmean) intervals; QT dispersion (QTmax]-QTmin); maximum Tpeak-end (Tpeak-end max); minimum Tpeak-end (Tpeak-end min); Tpeak-end mean; and the transmural dispersion of repolarization (Tpeak-end max - Tpeak-end min) (14-17).

Statistical analysis: The comparison of continuous variables (QTmax, QTmin, QTmean], Tpeak-end max, Tpeak-end min, Tpeak-end mean) assessed during CRT therapy on and off was performed using pairwise t test analysis. For QT dispersion analysis (QTmax-QTmin]) and transmural dispersion analysis (Tpeak-end max - Tpeak-end min) the nonparametric Mann-Whitney's test was used. Statistical significance was established at p [less than or equal to] 0.05.

Results

By comparing the QTmax], QTmin] and QTmean] intervals in CRT, with respective values obtained in baseline rhythm, the significant reduction of all variables were noticed during CRT (p<0.0001, p=0.0088 and p=0.0003, respectively) (Table 1).

QT dispersion also showed a significant 19.6% reduction (p=0.0009) under CRT, as compared with baseline measurements (85.58 [+ or -] 26.63 msec vs. 68.83 [+ or -] 25.16 msec).

The same occurred with the intervals Tpeak-end max, Tpeak-end min and Tpeak-end mean, which showed significant differences between CRT and baseline states (p<0.0001, p=0.0009 and p<0.0001, respectively) (Table 2).

The transmural dispersion of repolarization (Tpeak-end max - Tpeak-end min) showed smaller statistical significance (p=0.0343); however, its values were similarly decreased (55.50 [+ or -] 15.45 msec vs 49.41 [+ or -] 14.11 msec) during CRT.

Discussion

Cardiac pacing devices, among which the multi-site (atrial-biventricular) pacemakers, have already been used with the purpose of promoting better homogeneity of electrical activation of the myocardium, and therefore, of the segmentary contractility as well, in the hearts of patients suffering from left bundle-branch block or other intraventricular conduction disorders. However, and for reasons which are not yet well established, their use sometimes does not promote the expected improvement. The causes for this failure may be diverse, such as the different anatomical pacing sites, the degree of interventricular dyssynchrony, or the extent of damage to the ventricles and etiology of the cardiomyopathy, among others (7, 8).

Experimental studies suggest that epicardial activation of the left ventricle may increase the risk of severe arrhythmia arising because of increased heterogeneity of ventricular repolarization and, consequently, of the dispersion of repolarization (11, 12). Some other studies recently issued showed similar results, suggesting that there may be a protective effect from events generated by the arrhythmogenic substrate of dilated cardiomyopathies (18-20).

On the other hand, some other studies suggest that the parameters for evaluating the ventricular repolarization may not have been the most appropriate in terms of their applicability to obtain reliable results (18). The use of the standard 12-lead electrocardiogram carries many limitations, especially because it is restricted to a small number of electrodes, besides its difficulty in setting limits for deflections, which define the ventricular repolarization phenomena (QRS onset, end of T wave, T wave peak and J point). Thus, certain parameters, such as the QT interval, are influenced by depolarization, so that other parameters, which depend less upon the depolarization, like the JT and Tpeak-end intervals, and especially the Tpeak-end integral, may be more appropriate for use. Nevertheless, there are other studies pointing out to the JT interval as being very little influenced by the diverse forms of artificial stimulation in relation to baseline, which was remarkably clear when using the Tpeak-end interval or its integral (18).

Concerning the high number of variables which may somehow interfere with the analysis of the repolarization phenomenon, the BSPM is capable of noninvasively capturing a greater number of data on the study variables. Through its 87 leads, distributed 59 over the anterior thorax and 28 on the back, this sophisticated system explores the whole myocardium. Additionally, by magnifying the recordings and in a semi-automatic way, it allows the reading of parameters through two cursors placed between the chosen intervals, which makes their measurements easier to be made.

The findings of this study show overall consistence for demonstrating that times of ventricular repolarization (maximum, minimum and mean QT intervals) are shortened, turning it more homogeneous and promoting a smaller electrical dispersion when it occurs under the effect of atrial-biventricular pacing. In that same direction, the data show that maximum, minimum and mean Tpeak-end intervals, in addition to the transmural dispersion of repolarization, decreased under the effect of cardiac resynchronization therapy. This proves that, in such case, there was no influence of the ventricular activation (QRS) over the QT interval values obtained, although left bundle-branch block was present in all the patients.

Conclusion

In agreement with the results obtained in this study, we consider that the electrocardiographic variables obtained with the use of the body surface potential mapping, namely, the QT and Tpeak-end intervals, are appropriate for analysis and study of the effects of cardiac resynchronization therapy on the improved electrical dispersion as characterizing the improvement of homogeneity of cardiac ventricular repolarization.

Limitations

This study sought to evaluate only the electrocardiographic aspects of the cardiac ventricular repolarization in this specific group of patients. Notwithstanding the results obtained, it is mandatory to associate the present findings with the patient's clinical conditions of evolution, functional class, ejection fraction, arrhythmic events and mortality.

References

(1.) Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: The Framingham Study. J Am Coll Cardiol 1993; 22 (4 Suppl A): 6A-13A.

(2.) Shamim W, Francis DP, Yousufuddin M, Varney S, Pieopli MF, Anker SO, et al. Intraventricular conduction delay: A prognostic marker in chronic heart failure. IntJ Cardiol 1999; 70:171-8.

(3.) Baldasseroni S, Opasich C, Gorini M, Lucci D, Marchionni N, Marini M, et al; Italian Network on Congestive Heart Failure Investigators. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143: 398-405.

(4.) luliano S, Fisher SG, Karasik PE, Fletcher RD, Sing SN. Department of Veterans' Affairs Survival Trial of antiarrhythmic therapy in congestive heartfailure. (IRS duration and mortality in patients with congestive heart failure. Am Heart J 2002;146: 1085-91.

(5.) Leclercq C, Kass DA. Retiming the failing heart: Principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002; 39:194-201.

(6.) Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 2140-50.

(7.) Cleland JGF, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heartfailure. N Engl J Med 2005;352:1539-49.

(8.) Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al. Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators: Effect of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001; 344: 873-80.

(9.) Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. MIRACLE Study Group: Multicenter InSync Randomized Clinical Evaluation: Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346:1845-53.

(10.) Medina-Ravell VA, Lankipalli RS, Yan GX, Antzelevitch C, Medina-Malpica NA, Medina-Malpica OA, et al. Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization. Does resynchronization therapy pose a risk for patients predisposed to long QT or torsade de pointes? Circulation 2003;107: 740-6.

(11.) Fish JM, DiDiego JM, Nesterenko VV, Antzelevitch C. Epicardial activation of leftventricularwall prolongs QT interval and transmural dispersion of repolarization: implications for biventricular pacing. Circulation 2004;109: 2136-42.

(12.) Fish JM, Brugada J, Antzelevitch C. Potential proarrhythmic effects of biventricular pacing. J Am Coll Cardiol 2005; 46: 2340-7.

(13.) Walker S, Levy T, Rex S. Does biventricular pacing decrease ventricular arrhythmogenesis? Eur Heart J 2000; 21: 1124.

(14.) Antzelevitch C, Fish J. Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 2001; 96: 517-27.

(15.) Fuller MS, Sandor G, Punske B, Taccardi B, MacLeod RS, Ershler PR, et al. Estimates of repolarization dispersion from electrocardiographic measurements. Circulation 2000;102: 685-91.

(16.) Murray A, MacLaughlin NB, Campbell RWF. Measuring QT dispersion: man versus machine. Heart 1997; 77: 539-42.

(17.) Mirvis DM. Current status of body surface mapping. Circulation 1987; 75: 684-8.

(18.) Berger T, Hanser F, Hintringer F, Poelzi G, Fischer G, Modre R, et al. Effect of cardiac resynchronization therapy on ventricular repolarization inpatients with congestive heart failure. J Cardiovasc Electrophysiol 2005;16: 611-7.

(19.) Huysduynen BH, Swenne CA, Bax JJ, Bleeker GB, Draisma HH, Erven L, et al. Dispersion of repolarization in cardiac resynchroniza tion therapy. Heart Rhythm 2005; 2: 1286-93.

(20.) Santangelo L, Ammendola E, Russo V, Cavallaro C, Vecchione F, Garofalo S, et al. Influence of biventricular pacing on myocardial dispersion of repolarization in dilated cardiomyopathy patients. Europace 2006; 8: 502-5.

Carlos Alberto Pastore, Roberto A. Douglas, Nelson Samesima, Martino Martinelli Filho *, Silvana D. Nishioka *, Elisabeth Kaiser, Jose Antonio F. Ramires

Electrocardiology Service and Arrhythmia and Pacing Unit *, Heart Institute (InCor) of the University of Sao Paulo Medical School, Sao Paulo, Brazil

Address for Correspondence: Prof. Carlos Alberto Pastore, Operational Director--Executive Board of Directors; Director of the Electrocardiology Service, Heart Institute (InCor) of the University of Sao Paulo Medical School, Sao Paulo, Brazil Phone: [phone] Fax: [phone] E-mail: [e-mail]

Table 1. QT interval measurements at baseline and during CRT

Variables                    Baseline                   CRT

QTmax, msec            495.58 [+ or -] 50.22   456.75 [+ or -] 46.03
QTmin, msec            409.92 [+ or -] 41.67   387.05 [+ or -] 37.51
QTmean, msec           455.03 [+ or -] 47.94   422.48 [+ or -] 38.63

Variables                        p

QTmax, msec                   <0.0001
QTmin, msec                   0.0088
QTmean, msec                  0.0003

CRT--cardiac resynchronization therapy

Table 2. T wave measurements at baseline and during CRT

Variables                    Baseline                   CRT

Tpeak-end max, msec    138.92 [+ or -] 20.91   123.58 [+ or -] 19.06
Tpeak-end min, msec    83.58 [+ or -] 14.98    74.25 [+ or -] 16.41
Tpeak-end mean, msec   111.97 [+ or -] 17.51   99.58 [+ or -] 15.96

Variables                        p

Tpeak-end max, msec           <0.0001
Tpeak-end min, msec           0.0009
Tpeak-end mean, msec          <0.0001

CRT--cardiac resynchronization therapy