A. CURNIS1, G. SGARITO2, G. MASCIOLI1, L. BONTEMPI1, T. BORD ONALI1, G. CIARAMITARO2, E. DEMARIA1, S. NOVO2, L. DEICAS1
Introduction
The era of the pacemaker began with the work of the Swedish surgeon Senning in 1958. Subsequently, endocardial right ventricular apex (RVA) became the most extensively used site for cardiac pacing because it was easi- ly accessible, even by infrequent implanters, and, with its short fluoroscopy time and few peri/post-operative complications, provided stable and reliable chronic pacing parameters.
However, animal data and recent findings in humans have led to ques- tions regarding the safety of pacing the heart from the RVA. In fact, even though this kind of stimulation was effective, it was suboptimal from a phys- iologic point of view. Many studies now support the conclusion that RVA pacing contributes to left ventricular dysfunction in patients with normal cardiac function and in those whose cardiac function is impaired.. Moreover, impairment of the normal heart in patients undergoing RVA pacing seems to be only a matter of time.
Although RVA pacing maintains heart rate and atrioventricular syn- chrony (providing that a dual-chamber device is implanted), it is associated with increased morbidity and mortality when compared with patients with normal atrioventricular conduction. The result is an increase in end-systolic volume and wall stress, energetic inefficiency, and reduced systolic and dias- tolic function and cardiac output; this may also lead to asymmetric septal hypertrophy, myofibrillar disarray, increased myocardial catecholamine con- centration, and perfusion and metabolic abnormalities.
1 Divisione e Cattedra di Cardiologia, Facoltà di Medicina e Spedali Civili di Brescia;
2Divisione e Cattedra di Cardiologia, Facoltà di Medicina, Policlinico ‘Paolo Giaccone’, Palermo, Italy
Effects of Right Ventricular Apical Pacing
About 80 years ago, Wiggers pointed out that RVA pacing in animals caused a prolonged initial rise of intraventricular pressure and an increase of the isometric contraction phase, resulting in a prolonged ventricular systole.
Other studies in animal models observed that RVA stimulation is responsible for anomalous contraction patterns, leading to a negative inotropic effect because of a detrimental consequence on maximal oxygen consumption.
The potential deleterious effects of RVA pacing in humans have been late- ly highlighted in several reports in which an increased incidence of sympto- matic congestive heart failure was found in patients paced at the RVA.
Recently, Nielsen et al. published the first randomised trial that compared the echocardiographic changes in left atrium (LA) size and left ventricular (LV) size and function (primary end-point) during rate-adaptive AAI and DDD in patients with sick sinus syndrome (SSS) and relatively normal atri- oventricular (AV) conduction [1]. In their study, 177 consecutive patients were randomised to treatment with one of three rate-adaptive pacemakers:
AAIR, DDDR with a short atrioventricular delay (110–150 ms) (DDDR-s), or DDDR with a fixed long atrioventricular delay (≥ 250 ms) (DDDR-l).
During a mean follow-up of 3 R pacing caused increased LA diameter, and DDDR-s also caused decreased LVFS. These results clearly demonstrate how a high proportion of RV pacing (90% in DDDR-s arm vs 17% in DDDR-l arm) may provoke a decrease in LV function. Atrial fibrillation was also more common in the DDDR group, indicating that ventricular desynchroni- sation promotes atrial fibrillation, probably through LA dilation. These data underline, as demonstrated elsewhere, that what is achieved via improved rate-responsive and atrioventricular synchrony is countered by the more fre- quent delivery of single-site ventricular stimulation [2, 3].
Harmful consequences of RVA pacing were also evident in the DAVID trial that provided important insight into negative effect of RVA pacing on LV performance behind some of the current thinking [4].
In this randomised clinical trial, the efficacy of dual-chamber rate- responsive pacing at 70/min (DDDR-70) was compared with back-up ven- tricular pacing at 40/min (VVI-40) in patients with standard indication for ICD implantation but without indication for antibrady pacing. All enrolled patients (506) had an ejection fraction ≤ 40% and were on optimal medical therapy for LV dysfunction. At the end of the study, there was a strong trend toward higher mortality and hospitalisation for new or worsened congestive heart failure in the DDDR-70 arm. In this group, the AV delay was not opti- mised in order to preserve intrinsic AV contraction, so nearly 60% of all ven- tricular beats were paced compared with 1% in the VVI-40 group.
The results of the DAVID trial were consistent with those of the recent
MOST study, which demonstrated an association between the percentage of RVA pacing (while maintaining AV synchrony) and heart failure and atrial fibrillation in patients affected with sick sinus syndrome and non-enlarged QRS [5, 6].
In the Multicenter Automatic Defibrillator Implantation II trial (MADIT II), the incidence of new or worsened heart failure was 14.9% in the control group vs 19.9% in those implanted with a device (P = 0.09) [7].
In retrospective, post-hoc analysis of the MADIT-II database, approxi- mately 40% of the ICD-treated patients had dual-chamber devices (mostly set at DDD 60–70 beats/min) and 60% had single-chamber ones (mostly set at VVI 60 beats/min). Patients with dual-chamber ICD paced the ventricle about 85% of the time, whereas those with single-chamber units paced the ventricle only 15% of the time. The slightly increased occurrence of heart failure was clearly associated with dual-chamber ICD units having a higher frequency of ventricular pacing.
Pathophysiology of Right Ventricular Pacing
After RV pacing, in the early stimulated territory, there is initial shortening at low chamber stress (small pressure load) because this motion is principal- ly converted to pre-stretch of the opposite region, i.e. the still-inactive mus- cle. As systole progresses, the late-activated region must develop higher load, re-lengthening the early-activated muscle. The net result of this mechanism is a decline in ejection and depression of systolic chamber function.
Furthermore, higher end-systolic volumes cause a right shift of the pres- sure–volume loop, with reduced width (stroke volume) and area, and of the end-systolic pressure/volume relation [8]. This phenomenon was first demonstrated in animals in 1985 by Park et al. [9] and, subsequently, by Pak et al. [10] in a study on humans.
There are also important regional and global metabolic/energetic conse- quences that arise from dyssynchrony; in fact, the prematurely activated myocardium develops less overall work, consuming less energy, while the late-activated free wall operates under a higher load, with larger metabolic demand, with the net consequence of a compromise of systolic function and reduced energetic efficiency.
Recently, Prinzen et al. [11] used magnetic resonance tagging methods to asses circumferential strain, regional external work, and regional total work in normal canine hearts under sinus rhythm and RV apex vs LV basal pre- excitation. Reciprocal increases and decreases in strain and work were observed, with reduced values in the early-activated myocardium and higher values in the late-activated regions.
Moreover, van Oosterhout et al. demonstrated that dyssynchronous con- traction due to RVA pacing generated myocardial hypertrophy in the territo- ry remote to the pacing site. Regional dyssynchrony also rapidly generated regional blood-flow gradients, with higher flow in the late-activated higher- stress region; later, however, the flow became more homogeneous, with the development of hypertrophy and adaptive changes [12]. Inhomogeneous contraction is also a mechanism for delaying muscle relaxation and likely contributes to diastolic dysfunction. Furthermore, papillary muscle discoor- dination following the altered ventricular activation sequence leads to mitral valve dysfunction with mitral regurgitation [13–15].
These functional abnormalities of ventricular pacing appear to have potentially deleterious effects over time, leading to ventricular remodelling.
Experimental studies have demonstrated that long-term RV apical pacing induces anomalous histologic changes (myofibrillar disarray) and molecular abnormalities not observed in ‘normal’ heart failure, such as marked reduc- tion in protein expression for gap junction connexin, excitation–contraction coupling proteins, and increased stress kinase expression/activation in the late-activated lateral endocardium [16–18].
Selective Site Pacing
Current data indicating that even patients with underlying ventricular dys- function but minimal symptoms can be adversely affected by discoordinated ventricular activity due to RVA pacing have led electrophysiologists to focus on an alternative pacing site, especially in sites close to the native conduc- tion system (such as the RV outflow tract and His bundle).
There is a great deal of interest in RV septal pacing despite some very confusing results. In 16 patients with chronic atrial tachyarrythmia and complete AV-block, Victor et al. evaluated the long-term functional and haemodynamic effects of right ventricular outflow tract (RVOT) vs RVA pac- ing. After 3 months of RVOT pacing, no symptomatic improvement or haemodynamic benefit was observed, also in those patients with an ejection fraction < 40% [19].
Similar results were obtained in the Right Ventricular Outflow Versus Apical Pacing (ROVA) trial, which enrolled patients with chronic AF, heart failure, and LV systolic dysfunction. There was no consistent incremental benefit associated with long-term RV outflow tract or dual-site RV pacing either in patients following AV nodal ablation or in those receiving pharma- cologic heart rate control [20].
Opposite results were obtained by others authors. De Cock et al. com- pared nine studies (217 patients) with regarding the haemodynamic effect of
RVOT pacing. The data from this meta-analysis suggested that RVOT pacing may offer a modest but significant benefit over RVA [21].
As for His bundle pacing, only studies with a small number of patients have been published. Desmuckh demonstrated the feasibility and safety of this approach in a group of 14 patients with chronic heart failure and chron- ic AF who were candidates for the ablate-and-pace strategy. Direct His bun- dle pacing led to a decrease in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-sistolic diameter (LVESD) and in New York Heart Association (NYHA) class and to an increase in LV ejection fraction [22]. Perhaps the major problem, accounting for the inconsistent findings, is that these trials have not used the same pacing site.
Conclusions
As discussed above, the more frequently the RV apex is paced, the more like- ly cardiac performance will be compromised. This explains why, although maintenance of AV synchrony afforded by conventional DDDR is intuitively superior to VVIR, this has been surprisingly difficult to prove. Large ran- domised clinical trials have reached a consensus that there is no survival benefit in patients conventionally DDDR paced; furthermore, DDDR pacing may be associated with an increased risk of death among ICD patients.
These trials have highlighted the importance of developing sophisticated pacemakers and ICDs capable of minimising, in patients without AV block, RV pacing, thus preserving normal ventricular activation while providing physiologic pacing support.
A reliable alternative to RV pacing may well be biventricular pacing, which seems to be a valid option to preserve LV function in patients who present with LV dysfunction and heart failure symptoms. In addition, there is the option to use CRT for ‘primary prevention’ in selected patients who require ventricular pacing for electrical reasons.
References
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tricular pacing on the risk of stroke and death due to cardiovascular causes.
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4. Wilkoff BL, Cook JR, Epstein AE et al (2002) Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 288(24):3115–3123
5. Sweeney MO (2002) Effect of pacing mode and cumulative percent time ventricu- lar paced on heart failure in patients with sick sinus syndrome and baseline QRS duration ≤120 milliseconds in MOST. Pacing Clin Electrophysiol 25:561 (abs) 6. Sweeney MO, Hellkamp AS, Ellenbogen KA for MOde Selection Trial Investigators
et al (2003) Adverse effect of ventricular pacing on heart failure and atrial fibrilla- tion among patients with normal baseline QRS duration in a clinical trial of pace- maker therapy for sinus node dysfunction. Circulation 107(23):2932–2927
7. Moss AJ, Zareba W, Hall WJ et al (2002) Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 346(12):877–883
8. Nelson GS, Berger RD, Fetcs BJ et al (2000) Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated car- diomyopathy and left bundle branck block. Circulation 102:3053–3059
9. Park RC, Little WC, O’Rourke RA (1985) Effect of alteration of left ventricular acti- vation sequence on the left ventricular end-systolic pressure-volume relation in closed-chest dogs. Circ Res 57(5):706–717
10. Pak PH, Maughan WL, Baughman KL et al (1998) Mechanism of acute mechanical benefit from VDD pacing in hypertrophied heart: similarity of responses in hyper- trophic cardiomyopathy and hypertensive heart disease. Circulation 98(3):242–248 11. Prinzen FW, Hunter WC, Wyman BT et al (1999) Mapping of regional myocardial
strain and work during ventricular pacing: experimental study using magnetic res- onance imaging tagging. J Am Coll Cardiol 33(6):1735–1742
12. van Oosterhout MF, Arts T, Bassingthwaighte JB et al (2002) Relation between local myocardial growth and blood flow during chronic ventricular pacing. Cardiovasc Res 53(4):831–840
13. Mark JB, Chetham PM (1991) Ventricular pacing can induce hemodynamically sig- nificant mitral valve regurgitation. Anesthesiology 74:375–377
14. Sassone B, De Simone N, Parlangeli R et al (2001) Pacemaker-induced mitral regur- gitation: prominent role of abnormal ventricular activation sequence versus altered atrioventricular synchrony. Ital Heart J 2(6):441–448
15. Tse HF, Yu C, Wong KK et al (2002) Functional abnormalities in patients with per- manent right ventricular pacing: the effect of sites of electrical stimulation. J Am Coll Cardiol 40:1451–1458
16. Vernooy K, Verbeek XA, Peschar M et al (2003) Relation between abnormal ven- tricular impulse conduction and heart failure. J Interv Cardiol 16(6):557–562 17. Karpawich PP, Justice CD, Cavitt DL et al (1990) Developmental sequelae of fixed-
rate ventricular pacing in the immature canine heart: an electrophysiologic, hemo- dynamic, and histopathologic evaluation. Am Heart J 119(5):1077–1083
18. Adomian GE, Beazell J (1986) Myofibrillar disarray produced in normal hearts by chronic electrical pacing. Am Heart J 112(1):79–83
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Patients with Sick Sinus Syndrome: Why and How?
A.B. CURTIS, S.S. BAROLD, B. HERWEG
Introduction
It is now generally accepted that the avoidance of left ventricular (LV) dyssyn- chrony explains the remarkable long-term haemodynamic benefit of AAI com- pared with VVI pacing in patients with sick sinus syndrome. This finding was documented in two Danish studies carried out in 1997 and 1998 [1, 2].
Compared to the AAI group (with normal LV depolarisation), the VVI group (with LV dyssynchrony) exhibited a higher incidence of congestive heart fail- ure (CHF), a significant reduction in LV fractional shortening, a larger left atri- al (LA) diameter, and a higher cardiovascular mortality. A number of more recent studies (reviewed in this chapter) have now firmly established that long- term right ventricular (RV) pacing (mostly apical) can cause LV dysfunction and CHF on the basis of mechanical LV dyssynchrony [3–13]. Consequently, minimising potentially harmful RV pacing has become an important goal in treating patients with sick sinus syndrome, since they generally have less cumulative need for pacing over time than patients with AV block.
The Dual-Chamber and VVI Implantable Defibrillator (DAVID) Trial
The DAVID trial compared the clinical effectiveness of dual-chamber implantable cardioverter defibrillators (ICDs) programmed to the DDDR pacing mode at 70 ppm vs the VVI mode at 40 ppm in patients with LV ejec- tion fraction (LVEF) ≤ 40% [4, 5]. The atrioventricular (AV) delay was pro- grammed according to the clinical judgment of the investigators and was
University of South Florida College of Medicine and Tampa General Hospital, Tampa, FL, USA
commonly set at 180 ms, thereby favouring ventricular pacing in the majori- ty of patients. The patients had no indication for antibradycardia pacing and no persistent atrial arrhythmias. Twelve percent of the patients were in NYHA classes III and IV. One-year survival free of the primary combined endpoint of hospitalisation for CHF or death was lower in patients paced in the dual-chamber mode (73.3%) than in patients randomised to ventricular backup pacing (83.9%) (hazard ratio 1.61, 95% confidence inter vals 1.06–2.44). Ventricular backup pacing produced up to 3.5% ventricular and no atrial pacing, while dual-chamber pacing (DDDR-70) produced approxi- mately 60% atrial- and ventricular-paced heart beats. The poor outcome in the dual-chamber paced group correlated with the percentage of ventricular pacing and suggested that RV pacing caused LV dyssynchrony. The DAVID study concluded that unnecessary RV apical pacing delivered as part of the DDDR arm produced LV ventricular desynchronisation with impaired LV haemodynamic performance that was ultimately harmful. The depression of LV function by RV apical pacing (mean LVEF = 27% in the DAVID trial) may be more important in ICD patients that start with poor LV function and a common prior history of CHF.
The Mode Selection Trial (MOST)
MOST was a randomised trial of DDDR vs VVIR pacing in 2010 patients with sick sinus syndrome who were followed for 6 years. The study demon- strated an association between the percentage of RV pacing in the DDDR mode (with maintenance of AV synchrony) and CHF in patients with sick sinus syndrome and QRS < 120 ms [6]. The harmful consequences of RV pacing in MOST appeared related to nonphysiologic LV contraction. A cumulative percent of ventricular pacing index (Cum%VP) < 10% was asso- ciated with lower rates of CHF-related hospitalisations, while an index >
90% was associated with higher rates.
For DDDR pacing, the risk of CHF hospitalisation increased linearly until the Cum%VP reached 40% and then it was level from 40 to 100%. A related analysis showed that ventricular pacing > 40% in the DDDR mode was asso- ciated with a 2.6-fold increased risk of hospitalisation due to heart failure compared with pacing < 40% of the time. For VVIR pacing, the risk of CHF hospitalisation was level from 0 to 80% and increased with increased Cum%VP from 80 to 100%. In a related analysis, ventricular pacing > 80% of the time in the VVIR mode was associated with a 2.5-fold increased risk of CHF-related hospitalisation compared with pacing < 80% of the time.
The MOST study also found a correlation between the Cum%VP index and the development of atrial fibrillation presumably induced by LV dys-
function. The incidence of atrial fibrillation increased linearly in the DDDR and VVIR modes up to a Cum%VP of 80–85%. The risk of atrial fibrillation in the DDDR group was increased by 1% for each 1% increase in Cum%VP up to 85%. In the VVIR group the risk was increased by 0.7% for each 1%
increase in Cum%VP up to 80%.
Multicenter Automatic Defibrillator Trial II (MADIT II)
A subanalysis by Steinberg et al. [7, 8] of the MADIT II data involving 567 ICD patients (54% with a single-chamber device and 46% with a dual-cham- ber device programmed with an AV delay of 190 ± 43 ms) indicated that the harmful effects of RV pacing were correlated with the percentage of ven- tricular pacing, confirming the findings of MOST [4]. Steinberg et al. divided the MADIT II ICD patients into two groups since the vast majority of them had Cum%VP under 10% or over 90% (bimodal distribution): (1) Cum%VP
≤ 50% group 1 (N = 369) consisted of patients with very little pacing (medi- an Cum%VP = 0.2%), and (2) Cum%VP > 50% group 2 (N = 198) consisted of patients being paced most of the time (Cum%VP = 95.6%). Group 2 patients (30%) had a significantly higher probability of new or worsened CHF (CHF hospitalisation) at 2 years vs only 17% in group 1 (P < 0.001). A similar pattern emerged with the combined endpoint of CHF hospitalisation or death (P < 0.001). Group 2 patients were also more likely to undergo ICD therapy for ventricular tachycardia/fibrillation (P < 0.005), raising the pos- sibility that RV pacing is proarrhythmic. It is highly unlikely that the results can be explained solely in terms of sicker patients requiring more pacing.
The Danish AAIR vs DDDR Trial
Andersen et al. [3] reported the results of the first randomised trial compar- ing the AAIR and DDDR modes of pacing in 117 consecutive patients who received a first pacemaker for sick sinus syndrome [1]. The patients were fol- lowed for 2.9 ± 1.1 years and had normal AV conduction (according to pre- viously used arbitrary criteria by these investigators), and no bundle-branch block. The primary endpoints were changes from baseline to last follow-up in LA size and LV function, as determined by M-mode echocardiography.
The patients were randomised to three arms: AAIR, DDDR-s (short rate- adaptive AV delay, 110–150 ms), and DDDR-l (fixed long AV delay, ≥ 250 ms) modes. The AV delay was not optimised because the study was designed to evaluate the effect of cumulative RV pacing. The AAIR group exhibited no significant change in LA and LV diameters and LV fractional shortening.
