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J Am Coll Cardiol, 2006; 47:1938-1945, doi:10.1016/j.jacc.2006.01.056
(Published online 20 April 2006). © 2006 by the American College of Cardiology Foundation |
Divisione Clinicizzata di Cardiologia, Facoltà di Medicina e Chirurgia di Novara, Università degli Studi del Piemonte Orientale, Novara, Italy.
Manuscript received November 8, 2005; revised manuscript received December 12, 2005, accepted January 2, 2006.
* Reprint requests and correspondence: Dr. Eraldo Occhetta, Divisione Clinicizzata di Cardiologia, Azienda Ospedaliera Maggiore della Carità Corso Mazzini 18, 28100 Novara, Italy. (Email: occhetta{at}r-j.it).
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Abstract |
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BACKGROUND: Right ventricular apical pacing, inducing asynchronous ventricular contraction, may impair cardiac function; permanent para-Hisian pacing could preserve interventricular synchrony and improve left ventricular function.
METHODS: After AV node ablation, 16 patients were implanted with a dual-chamber pacemaker connected to a screw-in lead positioned in close proximity to the His bundle and to a right ventricular apical lead. Clinical and echocardiographic data were collected at baseline and after two randomized six-month periods (with para-Hisian and conventional pacing).
RESULTS: During para-Hisian pacing, the interventricular electromechanical delay improved as well (34 ± 18 ms) as during right apical pacing (47 ± 19 ms), p < 0.05. Para-Hisian pacing allowed an improvement in New York Heart Association functional class (1.75 ± 0.4 vs. 2.33 ± 0.6 at baseline and 2.5 ± 0.4 during apical pacing, p < 0.05 for both), in quality-of-life score (16.2 ± 8.7 vs. 32.5 ± 15.0 at baseline, p < 0.05), and in the 6-min walk test (431 ± 73 m vs. 378 ± 60 m at baseline and 360 ± 71 m during apical pacing, p < 0.5 for both). Mitral and tricuspid regurgitation improved during para-Hisian pacing (1.22 ± 0.8 and 1.46 ± 0.5 index, respectively, vs. 1.68 ± 0.6 [p < 0.05] and 1.62 ± 0.7 [p = NS] index at baseline, respectively), with a slight worsening during apical pacing (1.93 ± 1 and 1.93 ± 0.7 index, respectively, p < 0.05 for both).
CONCLUSIONS: Permanent para-Hisian pacing is feasible and safe. Compared with conventional right apical pacing, it allows an improvement in functional and hemodynamic parameters over long-term follow-up.
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Recently, the use of cardiac resynchronization has been proposed for "primary prevention" in patients with congestive heart failure that requires a high percentage of ventricular pacing (10). In subjects with preserved intraventricular conduction and AV block, physiologic cardiac stimulation could be achieved with biventricular pacing (11) as well as with permanent direct His-bundle or para-Hisian pacing (12,13).
The aims of our crossover, patient blind, randomized study, in a patient population with chronic AF undergoing AV node ablation, were: 1) to evaluate the feasibility and long-term safety of permanent para-Hisian pacing; and 2) to compare the effects of permanent para-Hisian pacing with those of conventional right apical stimulation on functional and hemodynamic parameters.
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Patient population |
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Eighteen patients were excluded from the study: nine because they had already been implanted with a pacemaker (PM) or an implantable cardioverter-defibrillator (ICD); three due to the absence of escape rhythm after RF ablation; six because they were in poor clinical condition and not suitable for adequate clinical follow-up. In the end, 18 subjects (50%) (9 men, age 71 ± 5 years) were enrolled in the study; their clinical characteristics are outlined in Table 1.
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Methods |
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Echocardiographic recordings were made using a phased-array echo-Doppler system (Sonos 5500, Philips, Andover, Massachusetts) equipped with a 3-MHz transducer. Complete standard echocardiography, including measurements of left ventricular ejection fraction (EF), internal left ventricular diastolic dimensions, end-systolic and end-diastolic volumes computed according to a biplane Simpson’s method, was performed at baseline and was repeated at the 6- and 12-month follow-up examinations. The severity of mitral and tricuspid regurgitation was graded semiquantitatively from color-flow Doppler in the conventional parasternal long-axis and apical four-chamber images, according to the American Society of Echocardiography recommendations (semiquantitative analysis: 1 = mild, 2 = moderate, 3 = severe) (16). Systolic pulmonary pressure was estimated from the continuous-wave Doppler tricuspid regurgitation velocity. Pulsed-wave Doppler velocity signals were recorded from the right and left ventricular outflow tracts to measure the right and left electromechanical delay (time from the beginning of QRS to the start of pulmonary or aortic flow). The difference between pre-ejection times (interventricular mechanical delay) was used as an indicator of synchronicity between right and left ventricular contraction.
AV nodal RF ablation.
Atrioventricular junction ablation was performed positioning a standard electrode in the right ventricular apex for backup pacing, and an ablation 4-mm catheter at the AV junction where the His-bundle potential was barely visible and the atrial-to-ventricular electrogram amplitude ratio was 
2:1. Radiofrequency was then delivered (70° for 60 s) in order to achieve a stable AV block with an escape rhythm of >30 beats/min and narrow QRS, preceded by a Hisian potential. The ablation catheter was left to guide the following lead positioning for para-Hisian pacing.
Pacemaker implant with para-Hisian and apical right ventricular pacing. After RF ablation, a conventional bipolar (passive or active fixation) lead was positioned in the right ventricular apex, via the right cephalic or subclavian vein; the correct position was confirmed using standard parameters (pacing threshold, lead impedance, and R-wave sensing).
Through the same approach, another bipolar screw-in lead (1.5-mm retractable helix) was advanced and positioned, using a steerable stylet (Locator 4036, St. Jude, Sylmar, California) high in the interventricular septum, with distal pole of the screw-in lead located as close as possible to the mapping lead dipole (in right and left anterior oblique projections).
Phrenic nerve stimulation was excluded in all the patients for both the implanted leads with a transient high-energy stimulation (8 V).
Successful criteria for direct His-bundle pacing were defined as (13):
The high interventricular septum lead was then connected to the "atrial" port, while the conventional right ventricular apical lead was connected to the "ventricular" port of a dual-chamber rate-responsive PM, which was programmed in DDDR mode with a short AV delay (90 ms). In this way, if para-Hisian stimulation was effective, the following apical stimulus fell in the ventricular refractory period, whereas if para-Hisian stimulation failed due to lead dislodgement and/or pacing threshold increase, cardiac stimulation was guaranteed by the conventional apical lead. Pacemaker output was adjusted with a 100% voltage safety margin above the pacing threshold for both the leads.
Clinical evaluation and follow-up. All the pacing parameters were re-evaluated before hospital discharge; chest X-rays with anterior-posterior, right and left anterior oblique, and lateral projections were also taken. After one month, the proper functioning of the system (both for para-Hisian and apical pacing) and the lead position stability were checked using fluoroscopic images.
The enrolled patients were randomly assigned to a six-month period of "DDDR" pacing mode (para-Hisian stimulation with backup apical pacing), or to six months of apical ventricular ("VVIR") pacing mode. Periodic 24-h Holter monitoring tests were planned in order to confirm the efficacy of the previous AV node ablation and to assess constant ventricular capture with the programmed pacing mode. After completion of the first six-month period, patients crossed over for a six-month period of the alternative pacing modality.
Rate-responsive algorithm programming (with activity sensor activated) was the same in all patients and unchanged in both randomized study periods; the lower rate was 80 beats/min during the run-in period to minimize the risk of bradycardia-dependent ventricular arrhythmias, and 70 beats/min during the two randomized study periods; the upper rate was between 120 and 130 beats/min. Patients were blinded to the pacing mode assigned.
The run-in period and the subsequent balanced randomization of the sequence of pacing sites avoided the influence of heart rate stabilization on the evaluated clinical effects concerning the different pacing sites. At the end of each period, a complete assessment of QoL, functional class, and echocardiographic parameters was performed; the medical investigators who conducted the clinical and echocardiographic evaluation were also blinded to the pacing mode. Para-Hisian pacing effectiveness was determined by comparing the data obtained after six months with this pacing modality with the results achieved after six months of apical pacing.
At the end of the one-year follow-up study period, the PM was permanently programmed in the para-Hisian pacing mode. The drug therapy administered after the run-in period was the same during the two crossover study periods in all patients (digoxin in 56% of patients, angiotensin-converting enzyme inhibitors–angiotensin receptor blockers in 75%, diuretics in 68%, beta-blockers in 31%, diltiazem in 19%, vasodilators in 37%, dicumarolics in 87%, acetylsalicylic acid in 12%).
Statistical analysis. All the data are expressed as mean ± SD. The results were analyzed using paired two-tailed t tests.
Repeated-measures analysis of variance was used to assess the site-pacing-related changes in left ventricular volumes, with the value of the EF (median of baseline value 52%) as a between-patient factor.
A p value <0.05 was considered statistically significant.
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Results |
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In one patient (#7), it was not possible to perform para-Hisian pacing because of lead instability, probably due to AV junction anatomical changes subsequent to previous mitral and aortic valve replacement. In another patient (#10), five days after the implant, the patient experienced an in-hospital cardiac arrest due to primary ventricular fibrillation; the system was then explanted, and a rate-responsive single-chamber cardioverter-defibrillator was implanted.
Implant and complete follow-up data were collected in 16 patients with permanent para-Hisian pacing and backup right ventricular apical stimulation. In 4 of 16 patients (25%), true direct His-bundle stimulation was achieved (Fig. 2), with a correct latency between spike and paced QRS onset, similar to the native H-V interval. In 12 of 16 patients (75%), all the criteria for para-Hisian pacing were met. Mean QRS duration was 88.3 ± 7.1 ms at baseline, 121.1 ± 9.9 ms during para-Hisian pacing, 179.4 ± 17.8 ms during apical pacing (p < 0.001 QRS width during para-Hisian vs. apical stimulation). Data collected in each patient (baseline QRS duration, QRS width during para-Hisian and apical pacing) are reported in Table 2.
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At follow-up examinations after 1, 6, and 12 months, the QRS duration remained the same as that recorded at implantation. Pacing thresholds remained within acceptable safety margins (1.0 ± 0.8 V; 0.5 ms vs. 0.68 ± 0.2 V during apical stimulation; p = 0.13) after 12 months of follow-up; both for apical and para-Hisian pacing, <5 V (0.5 ms) were used, with conventional impact on the battery life.
Hemodynamic and functional evaluation. Data on hemodynamic and functional performances collected at the enrollment, after six months of para-Hisian pacing, and after six months of right ventricular apical pacing are reported in Table 3.
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The left ventricular EF did not show significant differences, with a slight increase during para-Hisian pacing (53.4 ± 7.9%) compared with apical pacing (50.0 ± 7.9%). However, when patients were stratified according to the EF (median of baseline values 
52% or >52%), the site-pacing related changes in volumes differed between the two groups. In patients with EF 52% (n = 9), baseline left ventricular volumes (diastolic 118 ± 30 ml; systolic 66 ± 27 ml) were larger than those of patients with EF >52% (n = 7) (diastolic 82 ± 14 ml, p < 0.04; systolic 31 ± 5 ml, p = 0.06). Furthermore, there was a site-specific interaction between the two groups, which was of borderline significance (p = 0.076), with a 13 ± 20% (para-Hisian pacing) and 5 ± 21% (apical pacing) cavity volume reduction in the group with low EF, and a 26 ± 66% (para-Hisian pacing) and 35 ± 58% (apical pacing) volume dilation in patients with good EF.
The degree of mitral and tricuspid regurgitation was significantly greater during apical pacing (1.93 ± 1 and 1.93 ± 0.7 index at semiquantitative analysis, respectively) than during para-Hisian pacing (1.22 ± 0.8 and 1.46 ± 0.5; p < 0.05 for both). A significant relation between pacing site and the degree of mechanical dyssynchrony was observed as well: conventional pacing resulted in significant prolongation of interventricular mechanical delay (47 ± 19 ms), which was significantly higher than during para-Hisian pacing (34 ± 18 ms, p < 0.05) (Fig. 3).
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Discussion |
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Electrical stimulation of the His bundle has been used for diagnostic purposes since the 1970s, and recently too, by various researchers (24–27). In the 1990s, other researchers (28–30) introduced this approach for therapeutic purposes, as an experimental non-conventional pacing site. In 2000, Deshmukh et al. (12) presented, for the first time, a study population in which direct His-bundle pacing was achieved; they confirmed the reliability and the effectiveness of this modality of pacing in 12 of 18 patients (65%) with chronic AF, dilated cardiomyopathy (EF <40%), NYHA functional class III to IV, and spontaneous narrow QRS complexes. During a mean follow-up of 23 months, they observed a significant improvement in functional class and hemodynamic parameters; it was not clear if the documented benefit could be related, at least in part, to ventricular rate control rather than to pacing modality. Similarly encouraging results were also reported by Padeletti et al. (31) in 5 patients, and by Vazquez et al. (32) in 12 patients.
Recently, Deshmukh and Romanyshyn (13) confirmed the previously obtained results in a larger patient cohort, well defining the possible problems related to this pacing modality. In particular, he emphasized that the criteria for true direct His-bundle pacing are very rigorous and not easily met: they were fulfilled in 70% of patients. In our experience, direct His-bundle stimulation was achieved in 25% of patients. In the majority (75%) of the population, para-Hisian pacing was obtained: the muscular portion of the high interventricular septum was activated together with the His-bundle conduction system. This is proved by the relatively narrow paced QRS (always shorter than 130 ms) and, overall, the electrical axis that was always concordant with that of native QRS. The latter observation could mean that, despite a partial "pre-excitation" of the superior portion of the interventricular septum, the conduction in the His-Purkinje system allows the stimulus to be conducted to the ventricular myocardium simultaneously, activating both ventricles in a synchronous fashion. The hypothetical possibility of damaging the His bundle using the helix of the screw-in lead must be considered, however, even if it has not been reported in preliminary studies (28,30).
Patients with chronic AF in whom the "ablate and pace" procedure is performed are particularly suitable for comparing "non-physiological" right ventricular apical pacing with "physiological" para-Hisian stimulation. In these subjects, in fact, the absence of atrial contraction allows researchers to ascribe possible hemodynamic improvements only to ventricular resynchronization. In preliminary results reported by Deshmuck et al. (12), the benefits induced by Hisian pacing were determined by the comparison between the basal pre-ablation situation and this new mode of pacing; these positive results, however, could also have been related to the reversal of tachycardiomyopathy, which was achieved with AV node ablation. The clinical experience of our group, reported in previous preliminary abstracts (33,34) and in the present study, seems to confirm that, apart from the benefits induced by the regression of tachycardiomyopathy, which might have been achieved by ablation of the AV node, physiological para-Hisian stimulation also induces significant functional and hemodynamic improvements. They seem, to some extent, to be modulated by basal EF. Although there were no overall changes in ventricular volumes, when patients were stratified according to pump function (EF >52% vs. 52%), site-pacing related changes in volumes of borderline significance could be detected between the two pacing sites in favor of the para-Hisian mode. Despite the limited number of depressed ventricles in our population, it is conceivable that differences in favor of para-Hisian pacing, according to our analysis, would be further amplified by recruiting patients with very low EF.
Furthermore, the amount of mitral and tricuspid regurgitation significantly decreased (Table 3) only with para-Hisian pacing, suggesting that the clinical and functional improvements with stimulation at this site are probably mediated by improvement of interventricular dyssynchrony, as evidenced by the decrease in the interventricular mechanical delay associated with QRS shortening.
In conclusion, the efficacy on functional and hemodynamic parameters and the long-term safety of para-Hisian pacing may allow a more widespread use of this technique, justifying this approach as the first choice in patients with left ventricular dysfunction and preserved intraventricular conduction who require permanent ventricular stimulation.
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