Author + information
- Received May 29, 2002
- Revision received October 8, 2002
- Accepted November 27, 2002
- Published online April 2, 2003.
- Maaike Peschar, PhD*,
- Hans de Swart, MD†,
- Koen J Michels, MSc, Ing‡,
- Robert S Reneman, MD, PhD* and
- Frits W Prinzen, PhD*,* ()
- ↵*Reprint requests and correspondence:
Dr. Frits W. Prinzen, Department of Physiology, Cardiovascular Research Institute Maastricht, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
Objectives The goal of this study was to test the hypothesis that left ventricular (LV) pump function is optimal when pacing is performed at the LV near the sites where the impulses exit the Purkinje system.
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.
Ventricular pacing is becoming a generally accepted way to resynchronize ventricular activation in hearts with conduction abnormalities. However, there are indications that the original application of ventricular pacing, restoring physiological heart rate in patients with bradycardia, could still be improved. Ventricular pacing induces abnormal, asynchronous electrical activation and contraction (1), leading to impaired cardiac pump function, even when atrioventricular (AV) synchronization is optimized by using a dual-chamber pacemaker (2–4). Long-term ventricular pacing is associated with hemodynamic deterioration (3,5,6)and pathological changes in myocardial structure (5,7).
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).
Animal handling was performed according to the Dutch Law on Animal Experimentation (WOD) and the European Directive for the Protection of Vertebrate Animals used for experimental and other purposes (86/609/EU). The protocol was approved by the Experimental Animal Committee of the Maastricht University. Two series of experiments were conducted: series 1 (n = 11) for comparison of hemodynamic effects of RV apex, single LV, multiple LV, biventricular (RV + LV), and multiple (up to four) LV + RV pacing and series 2 (n = 8) for comparison of RV and LV septal pacing.
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 O2and 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.
In order to pace the LV endocardium of the septum (series 2), leads were constructed by attaching an insulated silver wire to a curved needle-tip. This curved tip served as a barb for active fixation and as stimulation electrode. The lead was introduced in an 8-cm long approximately 18-gauge needle, with the hook just outside the needle. The needle was introduced into the RV cavity through the lower RV free wall and pushed through the interventricular septum until the LV cavity was reached. Subsequently, the needle was withdrawn, allowing the barbed electrode of the pacing lead to fix position at the LV septal endocardium (Fig. 1). Left ventricular endocardial position was verified postmortem, and proved to be in the lower one-half to one-third of the septum.
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.
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.
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.
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.
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.
Single site RV apex and LV pacing
During ventricular pacing QRS duration was almost twice as wide as during SR, QRS duration being longest during LV apex and LV lateral pacing (Table 1). Right ventricular apex pacing significantly deteriorated all measures of systolic (SV, stroke work [SW], LVdP/dtpos, end-systolic LV pressure) and diastolic function (LVdP/dtneg, Tau, end-diastolic LV pressure) (Table 1). Pacing at the LV wall induced less pronounced reductions in LV systolic and diastolic function. Stroke volume and SW were not significantly depressed during LV anterior and lateral wall pacing and tended to be even higher during LV apex pacing than during SR (0.05 < p < 0.10) (Table 1, Fig. 2). Left ventricular apex and LV anterior wall pacing did not change LVdP/dtpos as compared with SR, but LVdP/dtpos was reduced significantly during LV lateral and LV posterior wall pacing (Table 1). Pacing at LV sites slowed down relaxation, as evidenced by significantly lower LVdP/dtneg and higher Tau values during LV pacing than during SR. These changes were least pronounced during LV apex pacing. Moreover, LV apex and LV anterior wall pacing reduced LVdP/dtneg less than RV apex pacing. The increase in Tau was greater during LV lateral and anterior wall pacing than during LV apex pacing. End-diastolic and end-systolic LV pressures were hardly influenced by pacing from any LV site (Table 1).
Pacing at multiple sites
Pacing the LV apex in combination with the RV apex, with the three other LV sites or with all sites together, reduced QRS duration by approximately 25% as compared with single-site LV apex pacing, but QRS duration remained significantly (approximately 70%) higher than during SR. The pressure-volume diagrams in Figure 3illustrate that pressure development, SV, and SW were not improved by pacing from more sites than from the LV apex alone. The bar graphs in Figure 3show that this was also the case for the group as a whole. Also, for the other hemodynamic variables, no significant differences were found between single-site LV apex pacing and pacing at multiple sites.
Pacing at the RV and LV septum
In series 2 it was investigated how pacing from the various septal sites affected LV function. The size and shape of the LV pressure-volume diagrams varied considerably with the site of pacing at the RV septum (Fig. 4); LVdP/dtpos and SW were not significantly different between RV septum and RV apex pacing but significantly lower than during SR (bar graphs in Fig. 4).
For each experiment LVdP/dtpos and SW varied with the site of RV septal pacing (Fig. 5). The figure also depicts that in each experiment a site at the RV apex or septum was found, which resulted in only moderate reduction of LV function, and that the position of that site varied between the experiments. When pacing from this “best RV site,” SW was still significantly lower than during SR, but LVdP/dtpos was not (Table 2).
Per experiment, only one or two LV septal sites were paced. In each case, SW (Fig. 6) and LVdP/dtpos were close to the value during SR. For the entire group, the values of LVdP/dtpos, SW, and the other hemodynamic variables were similar during LV septal pacing, LV apex pacing, and SR (Table 2). QRS duration was prolonged during pacing at any ventricular site, but significantly longer during pacing at the epicardium of the LV apex than during pacing of the RV or LV septal endocardium (Table 2).
The present study, performed in canine hearts with normal ventricular conduction, demonstrates that LV function is maintained at SR level when pacing the LV apex or the LV endocardial surface of the interventricular septum. Pacing at the RV apex and RV septum reduces LV function significantly. The RV pacing site, which leads to the best LV function, is not predicted by anatomical position or by QRS duration. The hemodynamic superiority of LV apex and LV septum pacing may be explained by a relatively physiological sequence of electrical activation when pacing from these sites.
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.
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.
The authors are indebted to Theo van der Nagel and Arne van Hunnik for their excellent biotechnical assistance and to Dr. Paul Steendijk (Leiden University Medical Center) for supplying the CIRCLAB program.
☆ Supported by the Netherlands Heart Foundation (grant 95.043) and by Medtronic Inc. (Minneapolis, Minnesota).
- left ventricle/ventricular
- maximal rate of fall of left ventricular pressure
- maximal rate of rise of left ventricular pressure
- right ventricle/ventricular
- sinus rhythm
- stroke volume
- stroke work
- Received May 29, 2002.
- Revision received October 8, 2002.
- Accepted November 27, 2002.
- American College of Cardiology Foundation
- Wyman B.T.,
- Hunter W.C.,
- Prinzen F.W.,
- McVeigh E.R.
- Nielsen J.C.,
- Boetcher M.,
- Toftegaard Nielsen T.,
- Pedersen A.K.,
- Andersen H.R.
- Van Oosterhout M.F.M.,
- Prinzen F.W.,
- Arts T.,
- et al.
- Tantengco M.V.,
- Thomas R.L.,
- Karpawich P.P.
- Little W.C.,
- Reeves R.C.,
- Arciniegas J.,
- Katholi R.E.,
- Rogers E.W.
- Gold M.R.,
- Shorofsky S.R.,
- Metcalf M.D.,
- Feliciano Z.,
- Fisher M.L.,
- Gottlieb S.S.
- Blanc J.J.,
- Etienne Y.,
- Gilard M.,
- et al.
- Victor F.,
- Leclercq C.,
- Mabo P.,
- et al.
- Durrer D.,
- Dam R.T.,
- Freud G.E.,
- Janse M.J.,
- Meyler F.L.,
- Arzbaecher R.C.
- Spach M.S.,
- Barr R.C.
- Myerburg R.J.,
- Nilsson K.,
- Gelband H.
- Steendijk P.,
- Baan J.
- Saxon L.A.,
- Kerwin W.F.,
- Cahalan M.K.,
- et al.
- Deshmukh P.,
- Casavant D.A.,
- Romanyshyn M.,
- Anderson K.
- Schwaab B.,
- Frohlig G.,
- Alexander C.,
- et al.
- Prinzen F.W.,
- Augustijn C.H.,
- Arts T.,
- Allessie M.A.,
- Reneman R.S.
- Park R.C.,
- Little W.C.,
- O’Rourke R.A.
- Kingma I.,
- Tyberg J.V.,
- Smith E.R.
- Sweeney M.O.,
- Hellkamp A.S.,
- Greenspon A.J.,
- et al.