Summary
Experimental and clinical studies have shown that right ventricular apical pacing may result in long-term deleterious effects on account of its negative impact on left ventricular remodeling through desynchronization. This risk appears more pronounced in patients with even moderate left ventricular dysfunction and generally occurs after at least 1 year of pacing. As right ventricular apical pacing may be associated with the development of organic mitral insufficiency, other sites that allow for more physiological stimulation, such as right ventricular outflow tract septal pacing, have been developed, with good feasibility and reproducibility. However, the prospective randomized studies and meta-analyses to date have only demonstrated a modest effect on ejection fraction in the medium term, without any significant effect on quality of life and morbimortality. However, the absence of a favorable effect for right ventricular outflow tract septal pacing compared with right ventricular apical pacing in terms of clinical manifestations and patient prognosis appears to be more associated with the designs of these studies, which were not homogeneous with regard to methodology used, judgment criteria, follow-up and, especially, statistical power. Two randomized prospective multicentre studies are currently ongoing in order to evaluate the favorable effect of infundibular septal pacing, when considering the indirect negative effects of right ventricular apical pacing as reported in the literature.
Résumé
Les études expérimentales et cliniques ont montré que la stimulation ventriculaire droite apicale peut avoir des effets délétères sur le long terme du fait de son impact négatif sur le remodelage ventriculaire par le biais de la désynchronisation. Ce risque semble plus marqué chez les patients avec dysfonction ventriculaire gauche même modérée et s’exprime généralement après au moins un an de stimulation. Il peut être associé au développement d’une insuffisance mitrale organique. Par conséquent, d’autres sites de stimulation plus physiologique comme la stimulation septale infundibulaire ont été développés avec une excellente faisabilité et reproductibilité. Malheureusement, les études prospectives randomisées et les méta-analyses n’ont jusqu’alors démontré qu’un effet modeste à moyen terme sur la fraction d’éjection sans effet significatif sur la qualité de vie et la morbidité. L’absence d’effet favorable de la stimulation septale infundibulaire par rapport à la stimulation ventriculaire droite apicale sur les manifestations cliniques et le pronostic des patients semble plus liée à la méthodologie des études qui ne sont pas homogènes entre elles en termes de méthodologie, de critère de jugement, de suivi, et surtout de puissance. Deux études prospectives randomisées multicentriques sont en cours qui devraient aboutir très certainement sur un effet favorable de la stimulation septale infundibulaire si l’on se base sur tous les effets indirects négatifs démontrés dans la littérature avec la stimulation ventriculaire droite apicale.
Why is an alternative to right ventricular apical pacing needed?
Physiopathological consequences of right ventricular apical pacing
The concept of preventing ventricular desynchronization while avoiding stimulation of the RV apex dates back to the middle of the 1990s . Several experimental studies reported that the degree of ventricular dyssynchrony during RV pacing was dependent on several physiological properties of the myocardium: electrical conduction at least four times slower in the myocardium compared with that in the Purkinje system; conduction along muscle fibres twice as fast compared with perpendicular activation, such as during RVAP, when the activation front becomes ellipsoidal, resulting in slowed conduction, particularly in the intermediate and epicardial layers ; inability of the electrical impulses in the myocardium to reactivate the Purkinje system, as shown experimentally by Myerburg et al. ; a different conduction between the endocardial and epicardial layers on account of the smaller endocardial circumference . All these tissue properties consequently affect the movement of the electrical impulse from the RV to the LV. Several studies have shown that the LV is generally activated at least 50 to 70 ms after the initial RV activation, at 100 ms on average, with a gradual movement from the septum towards the posterior-inferior wall, which is the last area of the LV to be activated . It is thus not surprising that electrical asynchrony is responsible for both inter- and intradyssynchrony in LV myocardial contraction. This asynchrony not only depends on the beginning of the contraction but, more importantly, on the contraction mode, load conditions and fibre orientation in relation to the underlying myocardial state. If the septum is activated first during RVAP, the different phases of contraction will likely depend on interactions with other tissue areas, which are in either the contraction or the relaxation phase . When analysing contraction asynchrony using ultrasound imaging, ‘paradoxical’ septal motion is found, which actually results from various forces exerted in relation to the movement between the RV and LV, thus producing pressure differences across the septum. Several studies have demonstrated that asynchrony has an impact on both systolic and diastolic functions as well as on other phases, particularly isovolumetric relaxation and contraction . Numerous phenomena secondary to inter- and intraLV asynchrony develop over time, such as perfusion abnormalities, oxygen demand, histological modifications, localized hypertrophic areas, dilatation of ventricular cavities, occurrence of mitral insufficiency, filling problems and decreased cardiac output secondary to reduced filling and ejection. Furthermore, the long-term structural consequences are currently known, involving decreased EF and frequent mitral insufficiency .
Mechanical consequences of RVAP versus septal pacing
The short-term as well as long-term mechanical consequences of permanent apical pacing were evaluated in two recent studies . Delgado et al. demonstrated a detrimental acute effect of RVAP on global LV function in 25 healthy patients . A more dyssynchronous LV contraction was observed in the patient group together with an impairment in LV longitudinal shortening and twist, using two-dimensional speckle-tracking strain imaging . The long-term effect was also evaluated in 58 patients with normal LVEF who were prospectively randomized to pacing either from the right ventricular apex or the RVOT septum. After 29 ± 10 months, there was a significant deterioration in LVEF, LV end-systolic volume and left atrial volume, favouring the RVOT septal-paced group . Moreover, the RVAP mode was associated with greater inter- and intraventricular dyssynchrony than RVOT septal pacing .
Potential clinical consequences of RVAP
The combination of acute haemodynamic effects and ventricular remodelling explains why electrical and mechanical asynchrony may exhibit adverse clinical consequences in the long-term . Several studies showed that RV pacing exerted a negative impact on long-term morbimortality rates compared with atrial pacing, for example, which was preferable in certain indications, such as sinus-node dysfunction . Despite the fact that these studies did not compare septal pacing and apical pacing, the detrimental long-term effects of ventricular pacing argue for seeking alternative more physiological pacing sites.
In the main randomized studies involving patients with sinus-node dysfunction but normal LV function, the risk of heart failure and AF was significantly higher during RVAP, showing a deleterious long-term effect compared with preferential atrial pacing, the latter being more physiological . Several studies demonstrated a negative correlation between increased percentage of RVAP and long-term cardiovascular events . A subanalysis from the MOST study highlighted the strong risk of AF and hospitalization for heart failure in the two patient groups treated using the DDD ( n = 707) and VVI ( n = 632) pacing modes . The risk occurred at a cut-off value of more than 40% for RVAP in the DDD group (HR 2.6; P < 0.05) and more than 80% in the VVI group . In the DAVID study, patients with an indication for implantable automatic defibrillator but not for cardiac pacing were randomized into two groups: DDD (heart rate < 70 beats/minute) and VVI (heart rate < 40 beats/minute) . After a median follow-up period of 8.4 months, the percentage of pacing was significantly higher in the DDD group and, moreover, there were more events in relation to the combined endpoint of death and heart failure in this group (HR 1.6; P = 0.03). These data imply not only the role of RVAP but also that of elevated heart rate in the occurrence of cardiovascular events . However, the percentage of RVAP cases exhibiting deleterious effects has not been clearly established and the populations most at risk of developing such effects have not been identified, although there appears to be a trend pointing towards patients with underlying conduction problems or coronaropathy . Nonetheless, in daily practice, not all patients benefiting from RVAP will develop LV dysfunction. The risk was estimated at 9% in a retrospective study on 286 patients benefiting from atrioventricular node ablation and at 26% in another retrospective study on 304 patients undergoing definitive cardiac pacing for high-degree atrioventricular block after a follow-up period of 6.5 years . These figures, however, differ from the percentage of ventricular asynchronism reported in numerous studies, estimated at 50% in the acute phase . The potential deleterious effect of RVAP is also shown by interpreting the benefit of CRT in patients with LV dysfunction and cardiac pacemaker . All of the studies demonstrating the benefits of CRT in patients with heart failure and RVAP were reported in a literature review by Tops et al. .
However, all these studies concern the deleterious effect of long-term ventricular pacing rather than the consequences of right apical pacing. The studies presented point out that one should not pace the ventricle if it is not necessary but there is no clinical evidence yet that these studies will be different with septal pacing. To our knowledge, no clinical studies have been published so far demonstrating a more deleterious clinical long-term effect of RVAP compared with septal pacing.
What are the different pacing modes available as alternatives to RVAP?
The alternatives to RVAP are numerous but not well defined : they include His-bundle pacing and para-His pacing, medial septum, lower septum, RVOT in the septal region and, finally, pulmonary infundibulum . The most studied area of pacing is RVOT in the septal region (septal RVOT), given the ease of catheter implantation and catheter stability in this region, as well as reproducibility of the method . To better comprehend the areas to stimulate at the location termed RVOT, a full understanding of anatomy is necessary . This area was fully described in the recent work of Hillock and Mond . The area of the RVOT includes several parts, with the septum behind, RV free wall in front and a part of the anterior wall ( Fig. 1 ); this area is surrounded by the pulmonary valve above and the tricuspid valve below. Of most interest to us is the septal area: being situated in the lower part of this area is more favourable to physiological pacing, which would not be the case if pacing were done in the upper part of the infundibulum, which is closer to the aorta than the LV. The infundibular region (conus arteriosus) is too high and thin to be an area suitable for pacing. In addition, pacing thresholds are generally increased in this region . Consequently, only the low septal RVOT may be considered a suitable area for pacing; it is situated just below the region known as ‘crista supraventricularis’ and contains trabeculations, which facilitate the implantation of a stimulation catheter ( Fig. 1 ).
In practice, the region being stimulated requires three radioscopic views ( Figs. 2–4 ): the anteroposterior view in order to put the catheter between the RVOT and the middle part of the septum; the left anterior oblique view to differentiate the septal region from the RV free wall, the septal position being characterized by the posterior orientation of the catheter in a column direction in this instance; and the right anterior oblique view, serving to avoid positioning of the catheter at the level of the coronary sinus ostium.
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