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J Am Coll Cardiol, 2003; 41:1218-1226, doi:10.1016/S0735-1097(03)00091-3 © 2003 by the American College of Cardiology Foundation |
* Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Medtronic, Bakken Research Center, Maastricht, the Netherlands
Manuscript received May 29, 2002; revised manuscript received October 8, 2002, accepted November 27, 2002.
* Reprint requests and correspondence: Dr. Frits W. Prinzen, Department of Physiology, Cardiovascular Research Institute Maastricht, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
frits.prinzen{at}fys.unimaas.nl
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Abstract |
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BACKGROUND: Pacing at the conventional site, the right ventricular (RV) apex, adversely affects hemodynamics. During normal sinus rhythm (SR), electrical activation of the working myocardium starts at the LV septal endocardium and spreads from apex to base.
METHODS: Experiments were conducted in anesthetized open-chest dogs with normal ventricular conduction to investigate hemodynamic effects of pacing at various epicardial LV sites, the RV apex, and combinations of these sites (n = 11) and of RV and LV septal pacing (n = 8). The LV septal endocardium was reached via the RV by puncturing through the septum with a barbed electrode. Left ventricular systolic (LVdP/dtpos and stroke work) and diastolic (LVdP/dtneg and Tau) function were assessed using pressure-volume relations (conductance catheter technique).
RESULTS: Left ventricular systolic and diastolic function were highly dependent on the site of pacing, but not on QRS duration. Left ventricular function was maintained at SR level during LV septal, LV apex, and multisite pacing, was moderately depressed during pacing at epicardial LV free wall sites, and was most severely depressed during RV apex pacing. On average, RV septal pacing did not improve LV function, compared with RV apex pacing, but in each experiment one (variable) RV pacing site was found, which only moderately reduced LV function.
CONCLUSIONS: During ventricular pacing, LV pump function is maintained best (i.e., at SR level) when pacing at the LV septum or LV apex, potentially because pacing from these sites creates a physiological propagation of electrical conduction.
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There is considerable evidence that the severity of impairment of ventricular function depends on the site of pacing. The conventional pacing site, the right ventricular (RV) apex, is one of the worst sites. Single-site left ventricular (LV) and multisite pacing improve cardiac function as compared with RV apex pacing (4,8–13). In several studies LV function was found to be better during RV septal than during RV apex pacing (4,7,14–17), but others were unable to demonstrate such a difference (18–22).
Results from a previous study, comparing values of the maximal rate of rise of LV pressure (LVdP/dtpos) during pacing from the LV apex, LV lateral wall, and RV apex, alone or in combination with each other, suggested that the sequence of activation is more important than its synchrony (12). It seems likely that the activation sequence leading to the best LV pump function would be that occurring during sinus rhythm (SR). Under these conditions the electrical impulse exits the Purkinje system at sites located at the LV endocardial surface of the septum (23,24), especially the lower third part (25).
The aim of the present study was to test the hypothesis that pacing near LV exit sites of the Purkinje system (LV apex, LV septum) results in optimal LV systolic and diastolic function. To this purpose, LV pressure-volume analysis was performed in two series of experiments. Series 1 was designed to compare single-site pacing at the RV apex and at various epicardial LV sites (various activation sequences) with multisite pacing (optimal synchrony). In series 2 the hemodynamic effects of pacing at the RV and LV endocardial surface of the septum were compared with pacing at the best epicardial LV site (the LV apex).
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Preparation. Dogs were premedicated with acepromazine 0.2 mg/kg, atropine 0.1 mg/kg, and oxycodone 2 mg/kg intramuscularly. Anesthesia was induced with thiopental 15 mg/kg intravenously and maintained by ventilation with halothane (0.8% to 1.0%) in a 1:2 mixture of O2 and N2O. An electrocardiogram (ECG) was recorded from the limb leads. A 7F combined catheter tip manometer and conductance catheter (CD-Leycom, Zoetermeer, the Netherlands) was introduced through a carotid artery into the LV cavity. A 7F catheter tip manometer (CD-Leycom) was introduced into a femoral artery to measure ascending aortic pressure. After opening the chest, an aortic flowprobe (Transonic, Ithaca, New York) was positioned around the ascending aorta to measure stroke volume (SV), except in two animals in series 2, where cardiac output was measured by means of thermodilution (Baxter thermodilution catheter and computer, Deerfield, Illinois).
Temporary myocardial pacing leads (Medtronic, type 6500, Minneapolis, Minnesota) were attached to the upper surface of the right atrium (1 to 2 cm from the sinus node) and to the epicardium of the LV apex and of the LV anterior wall (along the left anterior descending coronary artery, immediately below the first diagonal branch) and the lateral and posterior walls (both approximately 2 cm below the base) (Fig. 1). A Medtronic 5076 screw-in lead was introduced through the jugular vein and advanced until the endocardium of the RV apex. Pacing at the RV septum was performed using a Medtronic MarinR steerable ablation catheter or a Medtronic 5076 screw-in lead. Exact location was facilitated by fluoroscopic visualization of various opaque markers attached to the outer surface of the heart and of the Swan-Ganz catheter, depicting the trajectory from the RV inflow to the RV outflow tract.
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The leads were connected to an external pacemaker (Medtronic AV pacing System Analyzer Model 5311B). In series 1 the four LV electrodes were connected to a four-channel external pulse stimulator (Medtronic model 2883), allowing setting of thresholds for each electrode separately and pacing of each of the electrodes separately or in combination with one or more other electrodes. By connecting the RV apex electrode to a splitter in between the external pacemaker and the external stimulator, it was possible to pace up to four LV sites and the RV apex simultaneously. Pacing was unipolar with an indifferent electrode positioned in between intercostal muscles.
Measurements. Left ventricular pressure, aortic flow, and ECG signals were digitized at 200 Hz and stored on disk for off-line analysis. Duration of the QRS complex of the surface ECG was used as measure of the synchrony of electrical activation of the ventricles.
Left ventricular cavity volume was measured using a 12-electrode dual-field conductance catheter (7F, Sentron), connected to a Leycom Sigma 5DF signal conditioner processor (CD-Leycom). Parallel conductance was estimated by injecting 7.5 ml of hypertonic saline (6.5%) into the pulmonary artery (26). Calibration of absolute LV volume was performed by calibrating SV, as determined with the conductance catheter, with SV measured with the aortic flow probe.
Protocol. After completion of the preparation, the measurements started after a stabilization period of minimally 15 min. In series 1 the heart was paced from the four epicardial LV ventricular sites, and from the RV apex alone, and, subsequently, from the LV apex simultaneous with the RV apex ("biventricular"), with two to three other LV sites ("multi-LV") and with all LV sites in combination with the RV apex ("multi-LV + RV"). In series 2 the heart was paced from the LV apex, the RV apex, the LV septum (transseptal electrode), and from various RV septal sites. In order to pace several RV septal sites, the (steerable) pacing lead was repositioned after each measurement, aiming at the lower, middle, mid-high, and the high septum.
Pacing was performed in the VDD mode, so that atrial sensing was used to govern ventricular pacing. A short (25- to 40-ms) AV interval was used, to assure that the entire ventricle was activated from the ectopic site(s). Measurements were performed on 5 to 10 heartbeats after 1 to 2 min of pacing at a particular site. The various sites were paced in random order. After studying two or three different pacing sites and after pacing each RV septal site, measurements were repeated during SR, serving as baseline.
Data analysis. The dedicated data analysis software package CIRCLAB (developed by Dr. P. Steendijk, Leiden University Medical Center, the Netherlands) was used for analysis of all data from the conductance catheter, including calculation of the maximal first positive (LVdP/dtpos) and negative derivative of LV pressure (LVdP/dtneg) and the time constant of relaxation Tau.
In order to improve comparison of the data obtained throughout the experiment, absolute values were normalized to those obtained during the SR measurement most adjacent to the measurement during pacing at each site.
Statistical analysis. For comparison of the effect of pacing from the various sites, each animal was used as its own control. One-way analysis of variance for repeated measurements was used to evaluate the significance of the effect of pacing site on a hemodynamic variable. If significant differences were found, significant points were isolated using Fisher protected LSD test as post-hoc test followed by Bonferroni correction. The level of significance was set at p < 0.05. Data are presented as mean values ± SD.
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Discussion |
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The optimal pacing site. The favorable hemodynamic effect of LV apex pacing has been recognized before (8,9,12,13), but the finding of the equally good performance of LV septal pacing is novel. The finding that pacing at these two sites did not reduce LV systolic function as compared with SR, even though activation was more asynchronous (wide QRS) and the AV delay of pacing was relatively short, is interesting. This suggests that a good sequence of electrical activation is sufficient to allow for normal LV function. During normal SR the electrical impulse travels from the His-bundle towards the apex, but this first part of ventricular activation concerns the rapid conduction system, not the working myocardium. In the LV the working myocardium is activated first at the LV endocardium in low septal and anterior free-wall regions, which are very close to the LV apex and LV septal endocardium (23,24). From these exits of the Purkinje system, the LV activation wavefront travels from apex to base (23,24). Pacing at the LV apex and the lower LV septal endocardium would thus provide a fairly physiological sequence of activation.
The importance of a proper sequence of activation is further supported by the finding that, in normal hearts, biventricular and multisite pacing does not improve LV function as compared with LV apex pacing alone (9,13, present study), even though QRS duration is shorter in the former pacing modes. The situation might be different in a pathological situation, because in dogs (13) and patients with heart failure but still normal conduction (27), biventricular pacing improved LV function beyond that during LV pacing alone. This might be explained by an increased heart size and, therefore, longer total conduction times in the failing hearts as compared with normal hearts.
RV septal pacing. The present study does not confirm earlier findings in dogs, showing that high septal pacing is associated with narrow QRS complexes, resynchronized LV contraction, and improved LV function (4,28,29). There are two possible explanations for this controversy. The three previous studies indicate pacing at the very basal part of the septum in the vicinity of, or even within, the His-bundle. They also have used screw-in electrodes rather than an endocardial approach, as in the present study. The use of the long screw may have enabled delivery of the impulses close to the Purkinje system, a prerequisite for quick spread of activation within the ventricular myocardium during ectopic stimulation (25). Use of a long screw-in electrode to pace the His-bundle in patients also improved hemodynamics and clinical status significantly (30).
In the present study we used pacing leads attaching to the RV endocardium, similar to the ones used in most clinical studies on the effect of high septal pacing. The variable results during RV septal pacing in the present study may explain the inconsistent findings in patients. Schwaab et al. (31) found a positive correlation between QRS duration and LV function during RV septal and RV apex pacing, but in the majority of their patients QRS duration was longer and LV function was lower during RV septal than during RV apex pacing. Other studies are less clear in describing the lead implant procedure and report either no difference between RV apex and RV septal pacing (18–22) or a significant improvement in at least one hemodynamic variable during RV septal pacing (14–17). In some of these studies, the alternative pacing site was referred to as the "RV outflow tract." This nomenclature has lead to confusion because some investigators considered this to be part of the high RV septum, whereas others meant the upper RV free wall, and, again, other investigators did not specify the site. The upper RV free wall was not studied in the present study because previous studies already showed that this "RV outflow tract" site deteriorated LV function significantly (32).
The present study shows that some RV septal sites provide a sequence of activation, which maintains LV function fairly well. These sites are, however, not consistently located at a certain level in the septum nor correlated with the narrowest paced QRS complexes. Therefore, hemodynamic monitoring would be required to find the best RV pacing site.
Preference for LV sites. The present study extends the finding in other studies that, in general, LV pacing maintains LV function better than RV pacing (33). The explanation for this phenomenon is not entirely clear. In the present study, QRS duration tends to be shorter during pacing at the endocardial RV sites than at the epicardial LV sites. Also, in other studies, the best LV function did not occur at the shortest QRS duration (12,19,34). Magnetic resonance tagging studies of contraction patterns showed similar degrees of mechanical asynchrony within the LV wall during RV apex and LV lateral wall pacing, but a larger number of hypocontractile regions during RV apex pacing (1). The latter might be due to a larger region of early-activated myocardium during RV apex pacing. Alternatively, an abnormal sequence of septal activation (from the RV to the LV side) could lead to abnormal septal motion and abnormal interventricular coupling, evidenced by paradoxical septal motion (10,35).
Potential clinical relevance. The better LV than RV performance has been found in closed-chest conscious dogs (9) and in dogs (13) and patients with heart failure and an opened thorax (27) and, thus, appears to be a universal property. The short AV delay (25 ms), which was used to acquire complete ventricular capture, is not normal but well-tolerated in healthy canine hearts, because LV function was similar during LV apex, LV septal pacing, and during SR. Also, end-diastolic pressure is not significantly different between SR and ventricular pacing, indicating sufficient filling despite lack of the "atrial kick." The finding that the optimal (combination of) pacing site(s) was different in normal than in failing dog hearts (13) and different in the absence and presence of coronary artery disease (36) indicates that extrapolation of the data from the present study in nonfailing dog hearts to patients should be done with care. Nevertheless, it appears worthwhile to investigate whether LV apex and LV septal pacing have the same beneficial hemodynamic effects in patients with normal ventricular conduction systems. Improved hemodynamic function during pacing in bradycardia-pacing patients is desirable in light of the increasing evidence that chronic ventricular pacing leads to acute and chronic deterioration of cardiac structure and function (3,5–7), increased risk for development of heart failure in sick sinus syndrome patients (37), and increased risk of cardiac death in heart failure patients (38) and in patients over 70 years of age (39). Because the present study indicates the importance of a good sequence of activation for proper ventricular function, its data do not permit prediction of a possible beneficial effect of LV apex and LV septum pacing in patients with intrinsic conduction system disease.
With the currently available pacing leads, the LV apex could be reached using the transcoronary venous approach, if the lead can be advanced far enough. Alternatively, a minimally invasive thoracotomy can be used to place the lead at the LV apex. The LV septal endocardium may become an attractive site because it can be reached when using a conventional transvenous route towards the RV cavity followed by a transventricular-septal approach. Such approach would require the development of a dedicated delivery system, facilitating penetration of the interventricular septum. If only the tip of this lead is in contact with the blood in the LV cavity, thromboembolic complications are unlikely.
Conclusions. In canine hearts with normal ventricular conduction, LV apex and LV septal pacing result in significantly better LV function than conventional RV apex pacing. Pacing at some RV septal sites also results in fairly well-maintained LV function, but these sites can only be found using hemodynamic monitoring.
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