HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (42) Citing Articles via Google Scholar Google Scholar Articles by Bax, J. J. Articles by Yu, C.-M. Search for Related Content PubMed PubMed Citation Articles by Bax, J. J. Articles by Yu, C.-M.

STATE-OF-THE-ART PAPER

Cardiac Resynchronization Therapy

Part 2—Issues During and After Device Implantation and Unresolved Questions

Jeroen J. Bax, MD^_*,_*, Theodore Abraham, MD, FACC, S. Serge Barold, MD, FACC, Ole A. Breithardt, MD, Jeffrey W.H. Fung, MD^||, Stephane Garrigue, MD, PhD^¶, John Gorcsan, III, MD, FACC^#, David L. Hayes, MD, FACC^_**, David A. Kass, MD, Juhani Knuuti, MD, PhD, Christophe Leclercq, MD, PhD, Cecilia Linde, MD, PhD, Daniel B. Mark, MD, PhD, FACC^||||, Mark J. Monaghan, PhD^¶¶, Petros Nihoyannopoulos, MD, FRCP, FACC, FESC^_***, Martin J. Schalij, MD^_*, Christophe Stellbrink, MD and Cheuk-Man Yu, MD^||

^_* Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
Johns Hopkins University, Baltimore, Maryland
University of South Florida, Tampa, Florida
University Klinikum Mannheim, Mannheim, Germany
^|| The Chinese University of Hong Kong, Hong Kong, China
^¶ Hopital cardiologique du Haut-Leveque, Pessac, France
^# University of Pittsburgh, Pittsburgh, Pennsylvania
^_** Mayo Clinic, Rochester, Minnesota
Turku PET Center, University of Turku, Turku, Finland
Hopital Pontchaillou, Rennes, France
Karolinska University Hospital, Stockholm, Sweden
^|||| Duke Clinical Research Institute, Durham, North Carolina
^¶¶ King’s College Hospital, London, United Kingdom
^_*** Hammersmith Hospital, London, United Kingdom
Stadtische Kliniken Bielefeld, Bielefeld, Germany

Manuscript received May 2, 2005; revised manuscript received September 19, 2005, accepted September 19, 2005.

^_* Reprint requests and correspondence: Dr. Jeroen J. Bax, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. (Email: jbax{at}knoware.nl).

	Abstract

Top Abstract Issues during CRT implantation Issues after CRT implantation Unresolved issues in CRT References

 
Encouraged by the clinical success of cardiac resynchronization therapy (CRT), the implantation rate has increased exponentially, although several limitations and unresolved issues of CRT have been identified. This review concerns issues that are encountered during implantation of CRT devices, including the role of electroanatomical mapping, whether CRT implantation should be accompanied by simultaneous atrioventricular nodal ablation in patients with atrial fibrillation, procedural complications, and when to consider surgical left ventricular lead positioning. Furthermore, (echocardiographic) CRT optimization and assessment of CRT benefits after implantation are highlighted. Also, controversial issues such as the potential value of CRT in patients with mild heart failure or narrow QRS complex are addressed. Finally, open questions concerning when to combine CRT with implantable cardioverter-defibrillator therapy and the cost-effectiveness of CRT are discussed.

Abbreviations and Acronyms   AF = atrial fibrillation   AV = atrioventricular   COMPANION = Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure   CRT = cardiac resynchronization therapy   ICD = implantable cardioverter-defibrillator   LBBB = left bundle branch block   LV = left ventricle/ventricular   LVEF = left ventricular ejection fraction   MR = mitral regurgitation   MUSTIC = Multisite Simulation in Cardiomyopathies trial   NYHA = New York Heart Association   PET = positron emission tomography   QALY = quality adjusted life year   RV = right ventricle/ventricular   TDI = tissue Doppler imaging   VV = interventricular

	Issues during CRT implantation

Top Abstract Issues during CRT implantation Issues after CRT implantation Unresolved issues in CRT References

 
Role of electroanatomical mapping in CRT.   In normal individuals, electrical activation of both ventricles is preceded by depolarization of the His-Purkinje system resulting in rapid activation of both ventricles with only a short delay in activation between the earliest and the latest activated segments (2). In patients with left bundle branch block (LBBB), the total activation of the LV is prolonged with delayed activation and contraction of the lateral wall. However, even in the presence of LBBB, endocardial activation may be prolonged only minimally (2). In these patients, LBBB morphology could primarily be caused by delayed intramural activation (3). Consequently, it was demonstrated that although QRS duration showed a continuous distribution, there was binary distribution of trans-septal activation times supporting the concept of two different forms of LV activation in the presence of LBBB on the electrocardiogram (ECG). The first entity is characterized by a relatively short trans-septal time (<20 ms) indicating intact His-Purkinje activation, whereas the second entity is characterized by a longer trans-septal activation time (>40 ms) indicating "cell-to-cell" activation from right ventricle (RV) to LV (3). Both mechanisms of delayed LV activation may result in an intraventricular mechanical delay of the LV, which can be analyzed in detail with tissue Doppler imaging (TDI) and electroanatomical mapping. The use of electromechanical mapping to assess intraventricular and intramural dyssynchrony has been reported (3). Of interest, three-dimensional mapping studies revealed the presence of long lines of block or slow conduction in heart failure with LBBB (Fig. 1) (2–4). The location and length of these lines of conduction block were highly variable, with delayed activation of different parts of the lateral wall of the LV. Moreover, the location of these lines of block was not fixed and could change, suggesting that they were (at least in part) functionally determined rather than related to areas of scar tissue. By comparing uni- and bipolar recordings, the conduction delay within these lines of block could be located in the subendocardium or could be intramural in origin (3). The exact nature of the intramural conduction delay is not entirely clear. As a consequence of the presence of long lines of conduction block, a "U" shaped activation pattern was often observed in patients with LBBB. The activation wave front turns around the LV apex and inferior wall in order to activate the lateral wall. Furthermore, as the activation sequence behind the line of block developed from the apical to the basal part of the lateral wall, the basal part is activated last. It has been hypothesized (3) that absence of these lines of block may preclude CRT benefit (Fig. 2). One of the proposed mechanisms underlying response to CRT in patients with heart failure and LBBB is pre-excitation of the most delayed LV segment, thereby reducing LV dyssynchrony and restoring coordinated contraction. It is reasonable to postulate that, in order to correct electrical dyssynchrony, LV pacing sites should be located lateral to the lines of conduction block (Fig. 1). Positioning of the pacing lead on the "wrong" site of the line of block may even result in an increase of dyssynchrony (the activation wave front has to complete a full U-turn in that case). Furthermore, because the basal part of the LV is activated last, it is tempting to speculate that the LV pacing lead should be positioned near the most basal segments. Currently, however, no studies are available to substantiate this hypothesis.

View larger version (98K): [in this window] [in a new window]   Figure 1 (Top) Ventricular activation sequence using three-dimensional noncontact mapping (EnSite 3000, Endocardial Solutions, Minneapolis, Minnesota) in a patient with dilated (non-ischemic) cardiomyopathy (left ventricular [LV] ejection fraction [EF] 30%, New York Heart Association [NYHA] functional class III) with a QRS duration of 154 ms who responded to cardiac resynchronization therapy (CRT). The propagation wavefront splits when encountering a conduction block located at the LV anterior wall, resulting in delayed activation of the lateral wall. (Bottom) The virtual electrograms over the line of block are displayed. Note the fragmented or double potential electrograms. The LV lead was positioned at the basal lateral region of LV (white arrow, top). One year after CRT, the LVEF was 42%, and the patient was in NYHA functional class I. LAT = lateral.

View larger version (122K): [in this window] [in a new window]   Figure 2 (Top) Ventricular activation sequence (right anterior oblique view [Ant]) using three-dimensional noncontact mapping (EnSite 3000, Endocardial Solutions) in a patient with ischemic cardiomyopathy (left ventricular [LV] ejection fraction [EF] 35%, New York Heart Association functional class III) with a QRS duration of 148 ms who did not respond to cardiac resynchronization therapy (CRT). (Bottom) Ventricular activation sequence (posterior view [POST]). There was no line of block or acute change in propagation direction of the depolarization wavefront detected by the mapping system. Of note, there were differences in the electrocardiogram (ECG) pattern between this patient and the patient displayed in Figure 1, indicating that the surface ECG fails to predict the activation sequences in these patients. The prolonged LV activation time in this patient may be due to the relatively slow conduction velocity in the myocardium. The LV lead was positioned in the posterolateral vein. One year after CRT, the LVEF was 34% and the clinical status of the patient unchanged.

The main procedural complications include lead dislodgement, coronary sinus dissection, and phrenic nerve stimulation. Lead dislodgement occurred in 6% of the patients in the Cardiac Resynchronization-Heart Failure (CARE-HF) trial, in 4% in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, and in 12% in the Multisite Simulation in Cardiomyopathies (MUSTIC) trial (7–9). Coronary sinus dissection has been reported in about 0.4% to 4% of patients (10); healing is usually uncomplicated, and vessel perforation is uncommon. In most instances, LV lead implantation can safely be performed several weeks after a dissection.

Phrenic nerve stimulation has been noted chronically in 1.6% to 12% of patients (11) and should therefore be assessed during the implant procedure. Still, phrenic nerve stimulation may occur de novo during follow-up due to changes in body position. Adjustment of pacing output or using other pacing configurations can often resolve this situation, but occasionally lead repositioning is required.

Although lead positioning is limited by anatomical and technical factors, the aim is to resynchronize the LV. With current echocardiographic techniques, including TDI and tissue synchronization imaging, it is possible to precisely locate (before device implantation) the site of latest activation. In general, the site of latest activation is located in the posterolateral region. In a relatively early study, investigators demonstrated that benefit from CRT was significantly greater when the lateral wall was paced as compared to the anterior wall (12); TDI was not used to assess the site of latest activation in this study. A later study confirmed with TDI that the site of latest activation was located in the inferior or posterolateral regions in 75% of patients undergoing CRT (13).

Integration of TDI to assess the site of latest activation and visualization of venous anatomy will allow determination of the feasibility of a transvenous approach. When the site of latest activation is not in the region of suitable veins, surgical LV lead positioning may be considered, using limited left-lateral thoracotomy with direct epicardial lead placement (14). There is no data from large trials on surgical LV lead placement. Mair et al. (15) compared 16 patients undergoing surgical lead placement with 63 patients undergoing transvenous lead placement; the authors reported a lower incidence of procedural-related events with the surgical approach. Koos et al. (14) evaluated 81 patients undergoing CRT, with 25 having a surgical approach for LV lead positioning. A lower incidence of re-interventions was observed after surgical LV lead positioning; however, hospitalization was longer, and clinical benefit was smaller (lesser LV reverse remodeling, less increase in LV ejection fraction [EF] and peak O₂) as compared to transvenous lead positioning. With surgery, the LV leads were more often positioned anteriorly (44% vs. 4.5% with the transvenous approach), and this position may not be ideal for LV resynchronization. More data on surgical LV lead implantation are needed.

CRT in chronic AF.   Chronic AF occurs frequently in patients with end-stage heart failure. The prevalence of AF has been reported to increase in parallel to the severity of heart failure, with 10% to 15% of patients in New York Heart Association (NYHA) functional class II to III and up to 50% of patients in NYHA class IV having AF (16). Considering the high prevalence of AF in patients with severe heart failure, it is noteworthy that all major trials reported on patients with sinus rhythm, which may not be an adequate reflection of the heart failure population. If CRT is considered in patients with chronic AF, it is essential that rapid intrinsic AV nodal conduction does not inhibit resynchronization therapy. This is at times accomplished by performing an AV nodal ablation. At present, no controlled, randomized studies are available to support this hypothesis.

The limited available evidence suggests a beneficial effect of CRT in patients with chronic AF. Initial studies have focused on the acute effect of CRT on hemodynamic parameters in patients with AF. Several single-center studies with relatively small numbers of patients have been reported (17,18) and demonstrated acute hemodynamic improvement in patients with chronic AF receiving CRT. The available evidence on the long-term effects of CRT in patients with heart failure and chronic AF is also scarce. As illustrated in Table 1, the effects of CRT (with follow-up between 3 and 14 months) were evaluated in a total of 124 patients with AF, ranging from 15 to 59 patients per study. In the majority of these four studies, however, an improvement in NYHA functional class, 6-min walking distance, and quality-of-life score was shown, associated with improvement in LVEF. In single-center studies, improvement in additional echocardiographic parameters has been shown (19).

View larger version (10K): [in this window] [in a new window]   Figure 3 The incidence of responders to cardiac resynchronization therapy in patients with sinus rhythm (left) is higher than in patients with atrial fibrillation (right) (data based on reference 21). Black = non-responders; white = responders.

From the limited data (Table 1), it appears that CRT is effective in patients with chronic AF, although larger studies are needed to confirm the findings. An important issue remains whether CRT in chronic AF patients should be accompanied with AV nodal ablation, and, although anecdotal data support this concept, more substantial data are needed. A theoretical argument against AV nodal ablation is the hypothesis that CRT results in reverse LV remodeling, with reduction of mitral regurgitation (MR), and that sinus rhythm may be restored spontaneously over time during CRT. However, no solid data exist on the incidence of spontaneous restoration of sinus rhythm in AF patients undergoing CRT.

	Issues after CRT implantation

Top Abstract Issues during CRT implantation Issues after CRT implantation Unresolved issues in CRT References

 
Optimization of AV and interventricular (VV) delays in CRT.   Optimization of pacemaker settings may further enhance benefit from CRT. Both AV and VV delay can be optimized with contemporary CRT devices. The aim of AV delay optimization is to avoid LV systolic contraction taking place after suboptimal LV filling. In an early study (24) in 15 patients with heart failure and severely depressed LV function who underwent dual-chamber (atrial synchronized RV) pacing, AV delay optimization substantially increased cardiac output. The AV delay was optimized using Doppler echocardiography, and benefit was validated by invasive measurements including cardiac output. An optimal AV delay was programmed when the end of the "Doppler A-wave" (corresponding to left atrial contraction) occurred just before the onset of aortic systolic Doppler flow. This echocardiography-guided AV optimization appeared crucial in some heart failure patients who exhibited an increase in cardiac output by 50%. Unfortunately, the LV systolic activation sequence remained delayed and heterogeneous because pacing was performed via the RV apex, not using the highly differentiated Purkinje tissue. Cardiac resynchronization therapy now allows stimulation of both ventricles simultaneously, which reduces the aortic pre-ejection time interval (25,26) making re-optimization of the timing between the end of the "Doppler A-wave" and the onset of the aortic systolic flow necessary (Fig. 4). Auricchio et al. (27) have shown that quality of LV filling determined optimal LV ejection. The authors studied 27 patients and evaluated the acute effect of different AV delays on maximum LV pressure derivative and aortic pulse pressure, and demonstrated individual AV optimization yielded optimal improvements in hemodynamic measurements. These observations indicate that the AV delay needs to be evaluated on a patient basis instead using generalized settings. Still, evidence is needed on the beneficial effect of AV delay optimization during long-term follow-up.

View larger version (28K): [in this window] [in a new window]   Figure 4 Consequences of optimization of atrioventricular (AV) delay during biventricular pacing at stable heart rate. The QRS complex resulting from P1 is wide due to apical right ventricular pacing (165 ms). The aortic pre-ejection time interval (Pre-Ao1) is long; the aortic systolic phase is also long due to the wide QRS complex. The second QRS complex resulting from P2 is narrowed due to biventricular pacing leading to a shorter aortic pre-ejection time interval (Pre-Ao2) compared with Pre-Ao1. Consequently, time duration of the aortic systolic phase is reduced, and the E-wave corresponding to P3 occurs earlier (compared to P1 and P2) with a greater amplitude, indicating a better LV filling phase. Pre-Ao3 is even shorter than Pre-Ao2 due to the addition of an AV delay optimization during P3, resulting in a greater cardiac output (CO) during P3 compared with the one obtained during P2, in which biventricular pacing was delivered without AV delay optimization.

View larger version (43K): [in this window] [in a new window]   Figure 5 Changes in mitral regurgitation according to different pacing modes. (A) Spontaneous sinus rhythm showing severe mitral regurgitation. (B) Simultaneous biventricular pacing, showing significant reduction in mitral regurgitation. (C) Further reduction of mitral regurgitation after biventricular pacing with optimized interventricular delay (left ventricular pre-activation of 20 ms).

What benefit can be measured acutely and chronically after CRT?.   The effects of CRT can be divided into acute and chronic effects (Table 2). Studies in the acute setting have demonstrated that CRT abruptly enhances LV systolic function. In both experimental and clinical studies, this is manifest by a modest (6 mm Hg) rise in systolic pressure (27,32), increase in stroke volume (10% to 30%) (32), reduction in the LV end-systolic volume and, thus, LV end-systolic stress, and a more rapid rise of LV pressure (dP/dt_max, between 15% to 35%) (27,32,33). There is also improved cardiac work at similar or lower oxygen consumption (34) so that chamber energetic efficiency is improved. Many of these changes can be observed within a single beat upon activating CRT, and are sustained in the short-term studies until CRT is abruptly terminated where they are rapidly reversed. The impact of CRT on diastolic function remains somewhat less clear. Acute studies have rarely shown significant effects on relaxation time constant, and there is no demonstrable effect on chamber stiffness (32).

Effect of CRT on MR.   A significant reduction in MR has also been reported after CRT. Some patients exhibit immediate reduction in MR, whereas other patients show improvement only late after CRT. This is related to the underlying pathophysiology of MR in end-stage heart failure. The LV dilation results in systolic retraction of the papillary muscles towards the apex, which inhibits complete leaflet coaptation in particular in the presence of a simultaneous decrease in the systolic closing force (38). In addition, wall motion abnormalities in the inferior/posterior regions can result in papillary muscle dysfunction with subsequent MR (39); LV dyssynchrony does also contribute to MR (40). A prolonged AV interval delays the onset of LV contraction and predisposes to incomplete mitral valve closure with the occurrence of pre-systolic (diastolic) MR (41). The resulting LV volume overload contributes further to the progressive deterioration in LV function, which in turn again increases MR (42). The pre-systolic component of MR can be effectively eliminated by pacing with a short (optimized) AV delay, while the CRT-related immediate reduction in the degree of systolic MR is associated with an acute hemodynamic improvement. Breithardt et al. (43) studied patients during brief re-programming of a CRT device and quantified the changes in the extent of MR with echocardiography by the proximal isovelocity surface area method. The changes in MR severity were compared to the changes in LV systolic function (LV peak positive rate of pressure rise, LV +dP/dt_max), measured noninvasively by Doppler echocardiography. A linear correlation between the effective regurgitant orifice area and LV +dP/dt_max was observed, and it was concluded that an improved transmitral pressure gradient (the closing force on the mitral leaflet) reduces MR severity by earlier and more effective mitral leaflet closure. An example of an acute reduction in MR after onset of CRT is demonstrated in Figure 6. Kanzaki et al. (44) confirmed these findings and added data on the role of papillary muscle resynchronization during CRT. The authors studied the deformation sequence of the papillary muscles by strain rate imaging and reported a direct relationship between the interpapillary muscle activation time delay and the improvement in the degree of MR by CRT. Thus, the immediate reduction in MR severity can be attributed to an improved coordination of ventricular contraction, including resynchronized papillary muscle activation, which results in improved systolic function and reduced mitral leaflet tethering forces. This effect can be observed in patients with ischemic and non-ischemic cardiomyopathy (36). Effective CRT immediately reduced the transmitral regurgitant volume at rest by about 30% to 40% on average (35,43,44). A further 10% to 20% improvement can be observed after some months of CRT and is probably related to the LV reverse remodeling (35).

View larger version (109K): [in this window] [in a new window]   Figure 6 Immediate effect of cardiac resynchronization therapy (CRT) on the severity of mitral regurgitation. Color-coded Doppler echocardiography shows moderate mitral regurgitation during no pacing (CRT OFF, A) and the estimated left ventricular (LV)peak +dP/dt is 361 mm Hg/s (CRT OFF, B). During CRT, the mitral regurgitant jet is smaller, corresponding to mild mitral regurgitation (CRT ON, C). The simultaneously acquired LVpeak +dP/dt by continuous-wave Doppler echocardiography has improved significantly to 823 mm Hg/s (CRT ON, D).

View larger version (18K): [in this window] [in a new window]   Figure 7 Cardiac resynchronization therapy (CRT) appears to have no effect on basal (resting) blood flow (measured quantitatively by positron emission tomography using O15-labeled water) (left) or blood flow reserve (measured after adenosine vasodilation, right). (Data based on reference 50).

In addition, three studies evaluated LV oxidative metabolism using PET and C11 acetate before and after CRT (48,50,51). These studies uniformly demonstrated no change in global LV oxidative metabolism, although an improvement in systolic LV function was demonstrated. The studies were also consistent in demonstrating increased myocardial efficiency, indicating improved oxygen cost of forward work by CRT (Table 3, Fig. 8). These studies confirm the earlier work by Nelson et al. (34) who demonstrated in an invasive setting that CRT improved systolic function with a reduction in energy cost. The PET studies also showed that oxidative metabolism became more homogenous throughout the LV. Similar to glucose utilization, CRT appears to enhance oxidative metabolism in the VV septum with a simultaneous reduction in the lateral wall. This observation suggests a more balanced wall stress and energy requirements during CRT.

View larger version (18K): [in this window] [in a new window]   Figure 8 Cardiac resynchronization therapy (CRT) significantly increased basal myocardial efficiency (based on assessment by positron emission tomography using C11 acetate) (left), and a similar trend was observed during dobutamine stress (although not significant, right). (Data based on reference 50). Open bars = CRT on; solid bars = CRT off.

	Unresolved issues in CRT

Top Abstract Issues during CRT implantation Issues after CRT implantation Unresolved issues in CRT References

CRT in narrow QRS complex.   The value of CRT in heart failure patients with narrow QRS complex has not been resolved. Assuming that LV dyssynchrony is the main determinant of response to CRT, these patients need to be screened with advanced echocardiographic techniques (58). Two studies evaluated the incidence of LV dyssynchrony in patients with narrow QRS complex (59,60). Yu et al. (59) evaluated 67 patients with narrow QRS complex (120 ms, average 99 ± 11 ms) and heart failure with TDI and demonstrated LV dyssynchrony in 43% of patients. An example of a patient with LV dyssynchrony is presented in Figure 9. Bleeker et al. (60) showed a somewhat lower incidence (27%) of LV dyssynchrony (Fig. 10), which may have been related to patient characteristics or to a slightly different analysis of data and definition of LV dyssynchrony. Thus far, two small studies have shown actual benefit from CRT in patients with severe heart failure, depressed LVEF, and narrow QRS complex with LV dyssynchrony on echocardiography (61,62). In a study of 14 patients with QRS duration 120 ms, an improvement in NYHA functional class, 6-min walking distance and LVEF, with reverse LV remodeling were noted after six months of CRT (61). Moreover, it was demonstrated that the magnitude of improvement in clinical parameters after CRT was similar in a comparable group of patients with wide QRS complex.

View larger version (94K): [in this window] [in a new window]   Figure 9 Tissue Doppler imaging in a patient with heart failure and narrow QRS complex, showing left ventricular (LV) dyssynchrony in multiple segments (top, middle, and bottom panels) as illustrated by the temporal difference in peak systolic velocity during the ejection phase (arrows). (Top) Tissue Doppler imaging velocity tracings obtained in the interventricular septum (yellow and light blue curves) and lateral wall (red and green curves). Earliest activation (peak systolic velocities, first arrow) is in the septum, and latest activation in the lateral wall (peak systolic velocities, second arrow). Thus, significant LV dyssynchrony is present between the septum and the lateral wall. (Middle) Tissue Doppler imaging velocity tracings obtained in the anterior wall (red and green curves) and inferior wall (yellow and light blue curves). Earliest activation (peak systolic velocities, first arrow) is in the anterior wall, and latest activation in the inferior wall (peak systolic velocities, second arrow). Thus, significant LV dyssynchrony exists between the anterior and inferior wall. (Bottom) Tissue Doppler imaging velocity tracings obtained in the anteroseptal wall (red and green curves) and posterior (yellow and light blue curves). Earliest activation (peak systolic velocities, first arrow) is in the anteroseptal wall, and latest activation in the posterior wall (peak systolic velocities, second arrow). Thus, significant LV dyssynchrony is present between the anteroseptal and posterior wall. AVC = aortic valve closure; AVO = aortic valve opening.

View larger version (18K): [in this window] [in a new window]   Figure 10 The incidence of left ventricular (LV) dyssynchrony in patients with narrow QRS complex (<120 ms) or wide QRS complex (>150 ms). The LV dyssynchrony is expressed as the extent of dyssynchrony between the septum and lateral wall. Considering LV dyssynchrony >60 ms as significant, the incidence of LV dyssynchrony was 27% in patients with narrow QRS complex as compared to 70% in the patients with wide QRS complex. (Data based on Bleeker et al. [60]).

Implantable cardioverter defibrillator therapy is the optimal therapy to prevent sudden death; efficacy of ICD therapy is well established in both secondary and primary prevention trials (64–66). Currently, the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial is the only randomized study evaluating whether CRT with or without ICD back-up would reduce all-cause mortality and hospitalization compared to optimized medical therapy (10). Patients were randomly assigned to optimized medical therapy (20%), CRT therapy (40%), and CRT + ICD back-up (40%). This trial was terminated after inclusion of 1,600 patients (originally projected 2,200 patients with a minimum follow-up of one year). The combined end point of all-cause mortality and hospitalization was 20% lower in both device groups compared to optimized medical therapy. No difference was noted with respect to the combined primary end point between the two device arms, and it was suggested that adding an ICD had no additional positive effects. However, a significant reduction (36%) in the risk of death was found in the CRT + ICD group (from 19% to 11%) compared to standard therapy whereas CRT resulted only in a non-significant risk of death reduction of 20%. Still, the trial was not designed to evaluate the individual benefits from CRT and CRT + ICD, and currently no data are available on this topic.

Considering that patients with mild-to-moderate heart failure die more often from sudden cardiac death, the improvement in NYHA functional class after CRT may be associated with a higher incidence of ventricular arrhythmias, and CRT should always be combined with ICD back-up. On the other hand, preliminary data suggest that the reverse LV remodeling was associated with a reduction in ventricular arrhythmias (that could be secondary to a reduction in wall stress) (67). Also, the inducibility of ventricular arrhythmias was less after CRT (68). Still, these results were obtained in a small number of patients, and studies are needed to provide more insight whether CRT should be combined with ICD back-up.

Economic considerations on CRT.   There are two general questions that can be addressed by medical economic analyses: 1) what is the value of a new therapy or technology, and 2) can we afford it?

To facilitate comparisons among alternative medical therapies, one can express incremental health benefits either as additional life years (if the therapy in question increases life expectancy) or as additional quality adjusted life years (QALYs) (if quality of life is an important aspect of either the therapeutic benefit or the underlying disease state being treated). By general consensus, any therapy that can generate an additional life year for $50,000 or less is judged to be economically attractive, while therapies that generate additional life years for over $100,000 are judged economically unattractive. As can be easily seen, an expensive therapy such as CRT-ICD can be economically attractive as it produces a proportionally large improvement in health benefits. In most cases, the magnitude of health benefits produced rather than the price of the therapy is the primary determinant of whether the therapy is economically attractive. Thus, economic value analysis should focus much attention on careful definition of what are the incremental health benefits of a particular therapy, along with determining the long-term net cost.

The second economic question, that of affordability, stands apart from the value question. A new therapy may be very economically attractive (that is, a very efficient way to increase health benefits with extra health care dollars), but still be out of reach for a country or health care system because there are not the extra health care dollars to spend.

Relatively little data exist on the economics of CRT. It is generally appreciated that the devices are expensive, with a typical U.S. cost for a CRT-ICD device around $30,000. As previously noted, the economic questions that need to be answered about these devices are: what extra health benefits (expressed in terms of QALYs) does CRT produce, and what are its long-term incremental costs, taking into consideration such downstream issues as device replacements, lead and other complications, as well as heart failure hospitalizations and emergency department visits prevented.

On the health benefits side, CRT has been reported to improve functional capacity (quality of life) and survival (7). On the cost side, there are reasonable data that CRT reduces heart failure hospitalizations. In the COMPANION study (10), CRT + ICD and CRT therapy were both associated with a 20% reduction in follow-up hospitalization (representing about $7,700) relative to medical therapy alone. In the COMPANION trial, CRT + ICD therapy added 0.5 life years during the course of follow-up relative to medical therapy alone. The cost effectiveness ratio for CRT-ICD therapy was $37,000 per life year saved, which is an economically attractive result.

As discussed in Part 1 of this review (1), better identification of responders to CRT should further improve cost-effectiveness of the therapy.

Conclusions.   Cardiac resynchronization therapy has significantly contributed to the treatment of patients with severe heart failure. To further optimize individual benefit from CRT, identification of potential responders is needed. Echocardiography is the technique of choice to identify responders before implantation (1). During implantation, electroanatomical mapping can be used to identify the site of latest activation in order to optimize LV lead positioning. Most patients will have suitable venous anatomy for LV lead positioning; however, in the in the absence of suitable veins in the target region, minimally invasive surgical implantation should be considered. In patients with AF, AV nodal ablation during pacemaker implantation should be considered, to further optimize response to CRT. Optimization of pacemaker settings after CRT using echocardiography is important; optimization of AV and VV delays has been demonstrated to further improve benefit from CRT.

The response to CRT extends from immediate benefit (improvement of hemodynamic parameters, MR) to long-term benefit (improvement in clinical parameters, systolic LV function, reverse LV remodelling, and further reduction in MR). In addition, PET studies have shown that cardiac efficiency is improved after CRT; blood flow does not improve after CRT.

Several issues in CRT need further study. These include: the benefit from CRT in mild-to-moderate heart failure, the benefit from CRT in patients with narrow QRS complex, and whether ICD back-up is always needed. More research in these fields is needed. Finally, economic considerations are important, and cost-effectiveness of CRT needs further study.

	Footnotes

 
Dr. Abraham receives honoraria from GE, Guidant, Medtronic, and St. Jude and receives research support from Guidant; Dr. Barold received lecture fees from Medtronic; Dr. Breithardt has been a consultant for Medtronic and Guidant and has research affiliations with Medtronic, Guidant, and GE Vingmed; Dr. Hayes is on the advisory board of Guidant Inc. and has been a speaker for Guidant Inc., Medtronic Inc., St. Jude Medical, and ELA Medical, and has received royalties from Blackwell Futura; Dr. Gorcsan received research grant support from GE, Toshiba, Siemens, Medtronic, and St. Jude; Dr. Kass has been a consultant for Guidant Inc.; Dr. Mark has been a consultant and received grants from Medtronic, Inc. Dr. Monaghan has received support from Philips, GE, Siemens, Guidant, Medtronic, and Accusphere; Dr. Schalij is on the advisory board of Guidant and has received research grants from Medtronic, Guidant, and St. Jude; Dr. Stellbrink is a sponsored investigator for Guidant, Medtronic, St. Jude, and Biotronik and is also an advisor to Guidant and Biotronik; Dr. Nihoyannopoulos received research grants and consultant fees from Medtronic.

	References

Top Abstract Issues during CRT implantation Issues after CRT implantation Unresolved issues in CRT References

 

1. Bax JJ, Abraham T, Barold SS, et al. Cardiac resynchronization therapypart 1—issues before device implantation. J Am Coll Cardiol 2005;46:2153-2167.[Abstract/Free Full Text]
2. Fung JW, Yu CM, Yip G, et al. Variable left ventricular activation pattern in patients with heart failure and left bundle branch block Heart 2004;90:17-19.[Abstract/Free Full Text]
3. Auricchio A, Fantoni C, Regoli F, et al. Characterization of left ventricular activation in patients with heart failure and left bundle-branch block Circulation 2004;109:1133-1139.[Abstract/Free Full Text]
4. Lambiase PD, Rinaldi A, Hauck J, et al. Non-contact left ventricular endocardial mapping in cardiac resynchronisation therapy Heart 2004;90:44-51.[Abstract/Free Full Text]
5. Jongbloed MR, Lamb HJ, Bax JJ, et al. Noninvasive evaluation of the cardiac venous system using multislice computed tomography J Am Coll Cardiol 2005;45:749-753.[Abstract/Free Full Text]
6. Meisel E, Pfeiffer D, Engelmann L, et al. Investigation of coronary 256 venous anatomy by retrograde venography in patients with malignant ventricular tachycardia Circulation 2001;104:442-447.[Abstract/Free Full Text]
7. Cleland J, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure N Engl J Med 2005;352:1539-1549.[Abstract/Free Full Text]
8. Cazeau S, Leclercq C, Lavergne T, et al. Multisite Simulation in Cardiomyopathies (MUSTIC) Study Investigators Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay N Engl J Med 2001;344:873-880.[Abstract/Free Full Text]
9. Abraham WT, Fisher WG, Smith AL, et al. MIRACLE Study Group Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure N Engl J Med 2002;346:1845-1853.[Abstract/Free Full Text]
10. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure N Engl J Med 2004;350:2140-2150.[Abstract/Free Full Text]
11. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias J Am Coll Cardiol 2003;42:1454-1459.[Abstract/Free Full Text]
12. Butter C, Auricchio A, Stellbrink C, et al. Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients Circulation 2001;104:3026-3029.[Abstract/Free Full Text]
13. Ansalone G, Giannantoni R, Ricci R, Trambaiolo P, Fedele F, Santini M. Doppler myocardial imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing J Am Coll Cardiol 2002;39:489-499.[Abstract/Free Full Text]
14. Koos R, Sinha AM, Markus K, et al. Comparison of left ventricular lead placement via the coronary venous approach versus lateral thoracotomy in patients receiving cardiac resynchronization therapy Am J Cardiol 2004;94:59-63.[CrossRef][ISI][Medline]
15. Mair H, Sachweh J, Meursi B, et al. Surgical left ventricular versus coronary sinus lead placement in biventricular pacing Eur J Cardiothorac Surg 2005;27:235-242.[Abstract/Free Full Text]
16. Maisel W, Stevenson L. Atrial fibrillation in heart failureepidemiology, pathophysiology and rationale for therapy. Am J Cardiol 2003;91:2D-8D.[ISI][Medline]
17. Etienne Y, Mansourati J, Gilard M, et al. Evaluation of left ventricular based pacing in patients with congestive heart failure and atrial fibrillation Am J Cardiol 2000;83:1138-1140.
18. Hay I, Melenosky V, Fetics B, et al. Short-term effects of right-left heart sequential cardiac resynchronization in patients with heart failure, chronic atrial fibrillation and atrioventricular nodal block Circulation 2004;110:3404-3410.[Abstract/Free Full Text]
19. Leon A, Greenberg J, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation J Am Coll Cardiol 2002;39:1258-1263.[Free Full Text]
20. Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation Am J Cardiol 2000;85:1154-1156.[CrossRef][ISI][Medline]
21. Molhoek SG, Bax JJ, Bleeker GB, et al. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic atrial fibrillation Am J Cardiol 2004;94:1506-1509.[CrossRef][ISI][Medline]
22. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation Eur Heart J 2002;23:1780-1787.[Abstract/Free Full Text]
23. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failureresults from the MUSTIC study. J Am Coll Cardiol 2002;40:111-118.[Abstract/Free Full Text]
24. Nishimura RA, Hayes DL, Holmes DR, et al. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunctionan acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995;25:281-288.[Abstract]
25. Cazeau S, Gras D, Lazarus A, et al. Multisite stimulation for correction of cardiac asynchrony Heart 2000;84:579-581.[Free Full Text]
26. Bordachar P, Lafitte S, Reuter S, et al. Biventricular pacing and left ventricular pacing in heart failuresimilar hemodynamic improvement despite marked electromechanical differences. J Cardiovasc Electrophysiol 2004;15:1342-1347.[CrossRef][ISI][Medline]
27. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure Circulation 1999;99:2993-3001.[Abstract/Free Full Text]
28. Van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ, Pijls NH. Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy Am J Cardiol 2004;93:1500-1503.[CrossRef][ISI][Medline]
29. Sogaard P, Eglebad H, Pedersen AK, et al. Sequential versus simultaneous biventricular resynchronization for severe heart failureevaluation by tissue Doppler imaging. Circulation 2002;106:2078-2084.[Abstract/Free Full Text]
30. Bordachar P, Lafitte S, Reuter S, et al. Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing J Am Coll Cardiol 2004;44:2154-2165.
31. Porciani MC, Dondina C, Macioce R, et al. Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy Am J Cardiol 2005;95:1108-1110.[CrossRef][ISI][Medline]
32. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay Circulation 1999;99:1567-1573.[Abstract/Free Full Text]
33. Nelson GS, Curry CW, Wyman BT, et al. Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay Circulation 2000;101:2703-2709.[Abstract/Free Full Text]
34. Nelson GS, Berger RD, Fetics BJ, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block Circulation 2000;102:3053-3059.[Abstract/Free Full Text]
35. Yu CM, Chau E, Sanderson JE, et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure Circulation 2002;105:438-445.[Abstract/Free Full Text]
36. St John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure Circulation 2003;107:1985-1990.[Abstract/Free Full Text]
37. Saxon LA, De Marco T, Schafer J, et al. Effects of long-term biventricular stimulation for resynchronization on echocardiographic measures of remodeling Circulation 2002;105:1304-1310.[Abstract/Free Full Text]
38. Otsuji Y, Kumanohoso T, Yoshifuku S, et al. Isolated annular dilation does not usually cause important functional mitral regurgitationcomparison between patients with lone atrial fibrillation and those with idiopathic or ischemic cardiomyopathy. J Am Coll Cardiol 2002;39:1651-1656.[Abstract/Free Full Text]
39. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunctiona quantitative clinical study. Circulation 2000;102:1400-1406.[Abstract/Free Full Text]
40. Erlebacher JA, Barbarash S. Intraventricular conduction delay and functional mitral regurgitation Am J Cardiol 2001;88:83-86.[ISI]
41. Brecker SJ, Xiao HB, Sparrow J, Gibson DG. Effects of dual-chamber pacing with short atrioventricular delay in dilated cardiomyopathy Lancet 1992;340:1308-1312.[CrossRef][ISI][Medline]
42. Carabello BA. Ischemic mitral regurgitation and ventricular remodeling J Am Coll Cardiol 2004;43:384-385.[Free Full Text]
43. Breithardt OA, Sinha AM, Schwammenthal E, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure J Am Coll Cardiol 2003;41:765-770.[Abstract/Free Full Text]
44. Kanzaki H, Bazaz R, Schwartzman D, Dohi K, Sade LE, Gorcsan III J. A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapyinsights from mechanical activation strain mapping. J Am Coll Cardiol 2004;44:1619-1625.[Abstract/Free Full Text]
45. Stolen KQ, Kemppainen J, Ukkonen H, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy J Am Coll Cardiol 2003;41:460-467.[Abstract/Free Full Text]
46. Bengel FM, Permanetter B, Ungerer M, Nekolla SG, Schwaiger M. Alterations of the sympathetic nervous system and metabolic performance of the cardiomyopathic heart Eur J Nucl Med Mol Imaging 2002;29:198-202.[CrossRef][ISI][Medline]
47. Neri G, Zanco P, Zanon F, Buchberger R. Effect of biventricular pacing on metabolism and perfusion in patients affected by dilated cardiomyopathy and left bundle branch blockevaluation by positron emission tomography. Europace 2003;5:111-115.[Abstract/Free Full Text]
48. Ukkonen H, Beanlands RS, Burwash IG, et al. Effect of cardiac resynchronization on myocardial efficiency and regional oxidative metabolism Circulation 2003;107:28-31.[Abstract/Free Full Text]
49. Nielsen JC, Bottcher M, Jensen HK, Nielsen TT, Pedersen AK, Mortensen PT. Regional myocardial perfusion during chronic biventricular pacing and after acute change of the pacing mode in patients with congestive heart failure and bundle branch block treated with an atrioventricular sequential biventricular pacemaker Eur J Heart Fail 2003;5:179-186.[CrossRef][ISI][Medline]
50. Sundell J, Engblom E, Koistinen J, et al. The effects of cardiac resynchronization therapy on left ventricular function, myocardial energetics and metabolic reserve in patients with dilated cardiomyopathy and heart failure J Am Coll Cardiol 2004;43:1027-1033.[Abstract/Free Full Text]
51. Braunschweig F, Sorensen J, von Bibra H, et al. Effects of biventricular pacing on myocardial blood flow and oxygen consumption using carbon-11 acetate positron emission tomography in patients with heart failure Am J Cardiol 2003;92:95-99.[CrossRef][ISI][Medline]
52. Nowak B, Stellbrink C, Sinha AM, et al. Effects of cardiac resynchronization therapy on myocardial blood flow measured by oxygen-15 water positron emission tomography in idiopathic-dilated cardiomyopathy and left bundle branch block Am J Cardiol 2004;93:496-499.[CrossRef][ISI][Medline]
53. Nowak B, Sinha AM, Schaefer WM, et al. Cardiac resynchronization therapy homogenizes myocardial glucose metabolism and perfusion in dilated cardiomyopathy and left bundle branch block J Am Coll Cardiol 2003;41:1523-1528.[Abstract/Free Full Text]
54. Knaapen P, van Campen LM, de Cock CC, et al. Effects of cardiac resynchronization therapy on myocardial perfusion reserve Circulation 2004;110:646-651.[Abstract/Free Full Text]
55. Knuuti J, Sundell J, Naum A, et al. Right ventricular oxidative metabolism assessed by PET in patients with idiopathic dilated cardiomyopathy undergoing cardiac resynchronization therapy Eur J Nucl Med Mol Imaging 2004;31:1592-1598.[CrossRef][ISI][Medline]
56. Abraham WT, Young JB, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failurethe MIRACLE-ICD trial. Circulation 2004;110:2864-2868.[Abstract/Free Full Text]
57. Braunschweig F, Lawo T, Linde C, Kramm B, Bruns HJ, Mortenson P. Monitoring of heart rate variability and daily physical activity in patients with chronic heart failure using sensors incorporated in a cardiac resynchronization device Am J Cardiol 2005;95:1104-1107.[CrossRef][ISI][Medline]
58. Bax JJ, Ansalone G, Breithardt OA, et al. Echocardiographic evaluation of cardiac resynchronization therapyready for routine clinical use? A critical appraisal. J Am Coll Cardiol 2004;44:1-9.[Abstract/Free Full Text]
59. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration Heart 2003;89:54-60.[Abstract/Free Full Text]
60. Bleeker GB, Schalij MJ, Molhoek SG, et al. Relationship between QRS duration a