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Optimizing Cardiac Resynchronization Therapy for Congestive Heart Failure
Optimizing Cardiac Resynchronization Therapy for Congestive Heart Failure Srikant Duggirala, MD, and Byron K Lee, MD Abstract: In patients with advanced systolic heart failure and mechanical dyssynchrony, cardiac resynchronization therapy (CRT) is an effective means of improving symptoms and reducing mortality. There are now several recognized approaches to optimize CRT. Imaging modalities can assist with identifying the myocardium with the latest mechanical activation for targeted left ventricular lead implantation. Device programming can be tailored to maximize biventricular pacing, and thereby is its benefit. Cardiac imaging has shown that atrioventricular and interventricular intervals can be adjusted to further reduce dyssynchrony. We review these various approaches that maximize the benefit derived from CRT. (Curr Probl Cardiol 2013; 38:215-237.) ver the past quarter century, there have been groundbreaking advances in the treatment of congestive heart failure. Despite effective pharmacologic therapies, there continues to be a considerable patient population with refractory end-stage heart failure, which is associated with overall poor prognosis and considerable economic burden.1,2 Cardiac resynchronization therapy (CRT), also known as biventricular pacing, has become an effective form of therapy for symptomatic heart failure. Currently, CRT devices can be implanted with or without a defibrillator, which, for our purposes, will be regarded as CRT-P and CRT-D, respectively. It has been well documented that CRT improves clinical symptoms and left ventricular (LV) systolic function, reduces hospitalizations, and, most importantly, reduces overall mortality.3-5 Recently, several
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Dr Duggirala has no relevant conflicts of interest to disclose. Dr Lee has received honorarium from Boston Scientific, Biotronik, and St. Jude. Curr Probl Cardiol 2013;38:215-237. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2013.03.003
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retrospective and prospective studies have also suggested similar benefits with New York Heart Association (NYHA) functional class I and II.6-8 As heart failure progresses, it is not uncommon for patients to develop electrical conduction abnormalities: first-degree heart block and intraventricular conduction delay that is often manifested as a left bundle branch block (LBBB). It has been estimated that nearly 25% of patients with systolic dysfunction have QRS duration that exceeds 120 ms.9 Progressive LV dysfunction appears to also correspond with worsening conduction disease. Additionally, atrioventricular (AV) delay associated with first-degree heart block may also lead to suboptimal ventricular filling from the atria and worsened mitral regurgitation.10 Intraventricular conduction delay, particularly with an LBBB, leads to LV mechanical dyssynchrony. With LBBB, the lateral wall of the LV is depolarized late and, as a result, has a delayed wall contraction. On transthoracic echocardiogram, the septum is seen moving paradoxically away from the lateral wall, as the septum is in early diastole, whereas the lateral wall is in systole. This discordant form of contraction is commonly regarded as LV dyssynchrony. The presence of LV dyssynchrony has been associated with increased mortality in patients with congestive heart failure.11-13 Response to CRT has been evaluated using various clinical parameters, such as NYHA classification, quality-of-life score, and the 6-Minute Walk Test, whereas other studies have used more objective measurements taken from a variety of imaging modalities.3,14-16 Clinical response to CRT is variable, but has typically been reported in the range of 70%-80%.3,14,17 Notably, ischemic cardiomyopathy was more predictive of nonresponse to CRT when compared with nonischemic or idiopathic cardiomyopathy.3,17,18 There has been great interest in trying to improve this response rate and, additionally, to increase the improvement seen in responders. Most of the approaches center on further reducing mechanical dyssynchrony. In this review, we discuss various strategies to optimize CRT response.
Jeroen J. Bax: It is important to note that a uniform definition of CRT response is lacking, which has contributed to the discussion on the precise response/nonresponse rates. Ideally, long-term survival should be used as a uniform end point in all studies. However, in most studies, 6-month response rates are reported and are generally divided into 2 major categories, including clinical response (improvement in symptoms, NYHA class, quality-of-life score, 6-minute walk distance) and echocardiographic response (improvement in LV function, reduction in LV volumes). In general, clinical response is more frequently observed than echocardiographic response. However, echocardiographic response (a reduction in LV end-systolic function) may be more 216
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closely related to long-term survival and may therefore be the preferred (surrogate) end point.
Lead Location for CRT Optimization CRT implantation is feasible from either side of the chest, but typically the left side of the chest is preferred for 2 reasons. The anatomy of the left subclavian vein allows a more continuous route to access the coronary sinus, whereas a right-sided approach can be technically more challenging due to the angulation of the superior vena cava to the coronary sinus. The left-sided approach is also favored because defibrillation vectors suggest a higher defibrillation threshold from the right side compared with the left side.19 CRT pacing leads are placed in the right atrium, right ventricle (RV), and the lateral wall of the LV through the coronary sinus. It is recommended that the RV lead be placed first, as most patients will have a baseline LBBB and are at risk for complete heart block during coronary sinus cannulation. Accidental tapping of the right bundle may temporarily halt conduction of the remaining conducting bundle. The LV lead or the atrial lead is implanted next. Because the LV lead is technically more challenging, some recommend implantation of the right atrial lead next to avoid dislodgement of the LV lead near the end of the case.20 Notably, atrial lead placement should still be considered if the patient is in atrial fibrillation (AF). It is not uncommon for patients with congestive heart failure to have AF, but it is suggested that approximately 10% of patients who undergo defibrillation testing will convert to sinus rhythm in the long-term.21 There appears to be no clear optimal location for the RV lead in CRT patients. In the REVERSE study, Thebault et al.22 analyzed apical RV lead position or nonapical lead position including RV free wall, RV outflow tract, and the septum and found no difference in response to CRT based on clinical and echocardiographic parameters. This was further corroborated by a recent study by Khan et al.,23 in which they compared the RV lead in either the apex or septal position and found no difference in degree of LV reverse remodeling between the 2 groups. Additionally, in patients who require defibrillator therapy, no significant difference was found in the defibrillation threshold between an RV outflow tract and an apical RV lead position.24 The optimal LV lead placement is technically challenging owing to anatomic variants in the cardiac venous anatomy. However, proper LV lead positioning has significant clinical implication in the efficacy of CRT. The LV lead is typically placed on the lateral or posterior-lateral Curr Probl Cardiol, June 2013
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wall of the LV through the coronary sinus or epicardially with the goal of pacing from the most mechanically delayed portion on the LV.25,26 The indications of pacing from the LV are based on the common electrocardiogram finding of an LBBB, indicating delayed depolarization of the LV; however, there are a considerable number of patients who either do not have a typical LBBB or have no electrocardiographic evidence of intraventricular conduction delay. For these patients, standard lead placement on the lateral or posterior-lateral wall of the LV may not be the most effective site for restoring synchrony with the RV. Although current guidelines suggest the use of a wide QRS complex (⬎120 ms) on surface electrocardiogram as part of the criteria for CRT, evidence suggests that there are individuals who have no evidence of dyssynchrony despite having a wide QRS complex. Conversely, individuals who have a narrow QRS complex may display mechanical dyssynchrony, suggesting that electrical dyssynchrony does not necessarily correspond with mechanical dyssynchrony. However, the presence of LV mechanical dyssynchrony is a major predictor in the response to CRT.27-30 As a result, there is considerable interest in finding better imaging modalities to assess dyssynchrony and to identify the optimal LV lead location before implantation. These imaging modalities might also be used to determine optimal timing intervals of the leads to minimize mechanical dyssynchrony. Jeroen J. Bax: The position of the LV lead has been related to CRT response. There has been considerable discussion on whether the positioning of the LV lead should be guided by the site of latest mechanical activation; preliminary data have suggested that positioning the LV lead outside the site of latest mechanical activation may be associated with suboptimal response to CRT and worse long-term outcome.
Echo Assessment of Dyssynchrony and CRT Response Transthoracic echocardiography has been the conventional imaging modality used in assessing mechanical dyssynchrony, including identifying regions of the LV with delayed contraction (intraventricular delay), and to program the CRT device to optimize the AV timing, and interventricular (VV) timing. Furthermore, echo is used in the assessment of the long-term effects of CRT through evaluation of ejection fraction, LV end-systolic and diastolic volumes, and mitral regurgitation.3,31 By using the septal–posterior wall motion delay (SPWMD) to evaluate intraventricular conduction delay derived from M-mode echocardiography, Pitzalis et al.32,33 identified this to be a predictive marker of response 218
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using a cutoff value ⱖ130 ms for the SPWMD. Using this parameter and also a cutoff values for QRS duration (ⱖ150 ms) and PQ interval (ⱖ180 ms), reverse remodeling could be predicted accurately. However, in the CONTAK-CD registry, the use of the SPWMD did not correlate with clinical improvement, and measurement reproducibility was noted to be difficult in this retrospective study.34 Additionally, it should be noted that accurate SPWMD can be difficult to obtain due to ill-defined posterior motion or an akinetic septum from previous infarction.15 Kawaguchi et al.35 used contrast-enhanced echocardiography in the evaluation of patients who immediately received CRT, and noted a 40% reduction in LV dyssynchrony. Tissue Doppler imaging has also been used for pathophysiologic information for the localization and severity of LV dyssynchrony and has been suggested to help in better selection for responders of CRT.36 Additionally, tissue Doppler longitudinal velocity may be a better predictor of LV reverse remodeling after CRT compared with longitudinal strain.37 Despite several trials highlighting efficacy of using echo to effectively identify dyssynchrony, the recent PROSPECT trial challenges the role of echo in evaluating for dyssynchrony. The PROSPECT trial represented the first large-scale, multicenter clinical trial evaluating the performance of echocardiographic measures of mechanical ventricular dyssynchrony to predict responsiveness to CRT. The results of the study suggested that various echocardiographic measures of ventricular dyssynchrony were unable to distinguish potential responders from nonresponders of CRT. Thus, this study indicates that electrocardiograms and other clinical criteria should remain as the standard for patient selection.38 Jeroen J. Bax: The value of dyssynchrony in prediction of response to CRT has attracted a lot of discussion over the recent years. Various single-center studies have demonstrated that LV dyssynchrony can predict CRT response, but the multicenter PROSPECT study failed to show the predictive value of dyssynchrony. However, a subanalysis of the PROSPECT study showed that more extensive dyssynchrony was associated with CRT response at the 6-month follow-up (Van Bommel et al. Eur Heart J 2009). Importantly, recent data demonstrated that LV dyssynchrony as assessed on echocardiographic 2-dimensional (2D) strain imaging was predictive of long-term survival after CRT (Gorcsan et al. Circulation 2010).
LV Pacing The REVERSE study showed that an apically placed LV lead was associated with an increase in the LV end-systolic index compared with Curr Probl Cardiol, June 2013
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nonapically placed LV lead.22 Similarly, the MADIT-CRT trial revealed that LV lead placed at the apex compared with leads placed in the nonapical position was associated with worse clinical outcomes, including increased death and heart failure. It is suggested that the apex is activated early during the activation sequence, with the base activated generally later. Thus, pacing the apex would be activating a region of the myocardium that has typically less delayed electrical and mechanical activation. Additionally, LV apical pacing with its proximity to the RV apex may have electromechanical effects and a clinical impact similar to worsening heart failure symptoms.39 CRT involves synchronizing the ventricles through electric stimulation from RV and LV pacing sites that should ideally be positioned as far away from each other as possible.40
Echo-Guided Lead Placement Using more advanced imaging techniques in echocardiography to identify the region of latest mechanical activation, it is feasible to guide LV lead implantation. By assessing endocardial motion using 3-dimensional echocardiography, Becker et al.42 were able to evaluate temporal changes in the segmental LV contraction. Using the volume/time curves to identify the LV segment with the latest systolic contraction, this could then be used to define the segment with maximal dyssynchrony before CRT implant. LV lead placement at these segments resulted in clinical and echocardiographic improvements, particularly in those with the largest differences between and pre- and post-CRT measurements.41 Furthermore, LV lead placement near the optimally predicted site using 2D echo with circumferential strain image analysis resulted in greater improvement of LV function and improved LV reverse remodeling compared to nonoptimal LV lead position.43 In the recent TARGET trial, using speckle-tracking 2D radial strain imaging, LV leads were positioned at the latest site of contraction and compared with standard unguided CRT LV lead placement. The results of this study revealed significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization with targeted LV lead placement.44
Magnetic Resonance Imaging for Assessing Dyssynchrony and Guiding Lead Placement Cardiac magnetic resonance imaging (MRI) has been used to provide a comprehensive assessment of cardiac morphology and function and can be used to predict improvement in functional class after CRT.45 MRI has been used in the selection of patients appropriate for CRT by assessing for 220
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dyssynchrony and evaluation of myocardial scar in a single session with excellent correlation to echocardiography.46,47 Using a novel technique for assessing dyssynchrony called cardiovascular magnetic resonancetissue synchronization index (CMR-TSI), Chalil and colleagues48 have shown that CMR-TSI in heart failure patients is synonymous with intraventricular dyssynchrony. Notably, a CMR-TSI score of ⱖ110 ms was an independent predictor of increased morbidity, cardiovascular mortality, and all-cause mortality in patients who underwent CRT despite clinical improvements in 6-minute walk test and NYHA functional class. The use of late gadolinium enhancement in cardiac MRI can be used to guide LV lead placement away from regions of myocardial scar, and this approach has been shown to yield a better clinical outcome after CRT. It should be noted that although imaging may help identify the latest contracting segment, there is considerable variation in the venous anatomy, which may limit proper LV lead localization. It is not always possible to place the lead tip at the latest contracting segment suggested by echo or other imaging modalities.49 Jeroen J. Bax: Various MRI approaches have been proposed to assess cardiac dyssynchrony before CRT. However, MRI cannot be routinely applied after CRT implantation, and therefore, follow-up studies are often not feasible.
Multiple LV Leads Alternatively, the role of using multiple LV leads has also gained some interest. In the TRIP-HF multicenter study with 40 patients, LeClerq et al.50 used 2 LV leads in comparison with the standard 1 lead and found no difference in quality of life or 6-minute walk distance; however, there was a significant difference in the LV remodeling and ejection fraction. The hemodynamic improvement of triple-site pacing appears to be most beneficial to individuals with large LV end-diastolic volumes.51 Triplesite pacing is not standard care, but it is an innovative approach that deserves more research.
Multipolar Leads and Phrenic Nerve Stimulation Phrenic nerve stimulation from the LV lead is a significant problem that can lead to dislodgement, discontinuation of LV pacing, and need for surgical repositioning. Phrenic nerve stimulation can sometimes be avoided with a lower pacing output or using multipolar or dual cathode Curr Probl Cardiol, June 2013
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leads, as they can offer multiple vector configurations.52 The recent ELECTION study was a prospective trial that evaluated the utility of multiple LV pacing configurations with bipolar leads. The study revealed that electronic repositioning improved suboptimal pacing thresholds that would result in phrenic nerve stimulation and also reduced lead dislodgment or need for surgical repositioning.53 In another recent prospective trial, Forleo et al.54 demonstrated that quadripolar leads could be safely implanted with low rates of lead dislocation and phrenic nerve stimulation. Recent experimental models suggest that multipolar LV leads can be used to adjust the LV pacing site to further reduce dyssynchrony. Although promising, this approach has not yet been proven to improve outcomes in extensive human studies.
Lead Placement and LV Scar In patients with an ischemic cardiomyopathy who meet criteria for CRT, scarring mediated by previous myocardial infarctions provides a unique challenge for LV lead placement. It is suggested that in approximately one-third of nonresponders to CRT, the nonresponse may be due to previous scar.3,18 Using MRI to identify scar, Bleeker et al.55 found a lower response rate to CRT in patients with transmural, posterolateral scar, and found no improvement in echocardiographic parameters. In another study that used myocardial perfusion imaging to identify scar, higher scar burden and scar density near the LV lead tip indicated an unfavorable response to CRT in patients with an ischemic cardiomyopathy.56 Additionally, it has also been shown that higher scar burden quantified by using single-photon emission computed tomography (SPECT)-myocardial perfusion imaging had unfavorable clinical and LV functional outcomes regardless of baseline dyssynchrony, and those with lower scar burden had outcomes similar to individuals with nonischemic cardiomyopathy.57 Despite these studies, it is still unclear whether we should avoid placement of the LV lead electrodes in areas of scar, or if scar in the posterior lateral region is simply a marker of poor response. Further prospective studies are needed. Jeroen J. Bax: MRI with contrast-enhanced assessment of myocardial scar tissue may be important in prediction of nonresponse to CRT. It has been shown that transmural scar tissue in the region where the LV lead is positioned will result in nonresponse; it is currently not clear whether CRT may still be effective in regions of nontransmural scar tissue. Independent of where the LV lead is positioned, it was shown that the extent of scar tissue in the LV is also important for CRT response. The more 222
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scar tissue is present in the LV, the lower the likelihood of response to CRT. Finally, the integrated assessment of scar tissue and cardiac dyssynchrony with MRI may be particularly useful to predict response to CRT. In addition to MRI, SPECT/positron emission tomography imaging using perfusion tracers or F18-fluorodeoxyglucose has also been used for assessment of scar tissue.
Device Programming to Maximize Biventricular Pacing Although lead placement strategies described previously may improve response rates, currently, approximately 20%-30% patients will derive no benefit or have a suboptimal response to CRT and are labeled “nonresponders”.3,17,58 Challenges remain in attempts to convert patients from “non-responders” to “responders.” Device programming features that can be attempted to optimize response to CRT include promoting CRT pacing and optimizing the AV and VV timing. Unlike conventional pacing, the goal of CRT is to encourage pacing close to 100% of the time. During interrogation, the frequency of the ventricular pacing should be confirmed. Adjustments to various parameters may be necessary to maintain maximum ventricular pacing.
Maximum Tracking Rate The maximum tracking rate (MTR) sets the highest rate at which the ventricles will be paced in response to intrinsic atrial activity. However, if the patient has high intrinsic atrial rates that exceed the MTR with normal AV conduction, the patient may not likely be paced all the time, particularly during exercise. Thus, clinical judgment should be used to ensure that the MTR is high enough to maximize pacing without getting to such high pacing rates that may not be well tolerated by the patient.
Mode Switching Mode switching turns off atrial tracking during high-rate atrial episodes. This prevents rapid ventricular pacing when patients go into atrial arrhythmias such as AF and atrial flutter. However, ventricular pacing is lost if the intrinsic rate is higher than the programmed mode switch ventricular pacing rate. Therefore, if the intrinsic rate during the atrial arrhythmia is not high (ie, under 80 bpm), the mode switch ventricular pacing rate can be programmed higher to maintain pacing and maximize the benefits of CRT.
AV Delay The programmed AV delay represents the time between the atrial beat and the corresponding paced ventricular event. There are 2 types of programmed Curr Probl Cardiol, June 2013
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AV delay: (1) sensed AV delay is the time interval from a sensed atrial event to the next paced ventricular event, and (2) paced AV delay is the time interval from a paced atrial event to the next paced ventricular event. Paced AV delay is typically programmed slightly longer than the sensed AV delay owing to interatrial conduction delay from atrial pacing. Atrial sensing or atrial pacing therefore results in different AV delays that should be evaluated during AV delay optimization. For CRT, both types of AV delay should be programmed short enough to ensure that the ventricle is paced on every or nearly every beat. Jeroen J. Bax: Various automated programs have been introduced to optimize CRT settings. It remains difficult, however, to demonstrate whether these optimization programs contribute to improved long-term survival.
Dynamic AV Delay As conduction through the AV node shortens with increased sympathetic tone, there may be intrinsic conduction to the ventricle during emotional stress or exercise, which overrides biventricular pacing. To avoid this reduction of biventricular pacing at a time when maintaining cardiac output may be most critical, the dynamic AV delay or rateresponsive AV delay feature should be turned ON. This feature automatically shortens the AV delay of the device at times of high intrinsic or paced atrial rates. This reduces the chance that intrinsic conduction will be rapid enough to depolarize the ventricles before the CRT device.
Negative Hysteresis In contrast to conventional AV hysteresis, which encourages intrinsic activity and thus is not compatible with CRT, there is also a negative AV hysteresis, which is a feature that encourages pacing. Negative AV hysteresis prevents intrinsic conduction to the ventricle by automatically shortening the AV delay whenever a nonpaced ventricular event is sensed (Fig 1). This feature causes the device to automatically adjust the AV delay to ensure biventricular pacing when intrinsic AV delay shortens unexpectedly.
Rate Responsive Mode in CRT In patients with advanced heart failure and severe chronotropic incompetence, defined as a failure to achieve at least 70% of age-predicted heart rate, the use of the rate-responsive mode in CRT demonstrated an incremental benefit in exercise capacity.59 However, the recent PE224
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Fig 1. Negative atrioventricular (AV) hysteresis. Negative AV hysteresis prevents intrinsic conduction to the ventricle by automatically shortening the AV delay whenever a nonpaced ventricular event is sensed. This feature causes the device to automatically abbreviate the AV delay to ensure biventricular pacing when intrinsic AV delay shortens unexpectedly. In this example, the ventricular sensed event leads to abrupt shortening of the paced AV delay to 135 ms (Courtesy of St. Jude Medical, Inc).
GASUS-CRT multicenter trial was designed to evaluate the effect of atrial support pacing among heart failure patients receiving a CRT defibrillator. This study randomized patients to DDD mode at a lower rate of 40 bpm (DDD-40; control arm), or one of the following 2 treatment arms: (1) DDD-70 or (2) DDDR-40. The latter 2 modes led to significantly more atrial support pacing, yet the investigators found no difference in patient outcomes when compared with control.60 The lack of improvement may be partly attributed to a low prevalence of chronotropic incompetence or sinus node dysfunction in this study population, as the inclusion criteria required patients to tolerate a lower rate of 40 bpm.
Device Programming to Optimize Timing Most studies point to a benefit in adjusting the AV and VV timing in CRT. However, there is much variability on the best approach to make these adjustments and how often it should be done.
AV Optimization As described previously, it is standard practice in CRT to shorten the programmed AV delay to ensure nearly complete ventricular pacing. However, how short to program the AV delay to optimize cardiac output has been a focus of much research. Multiple studies have shown hemodynamic improvements in patients with CRT who have a Curr Probl Cardiol, June 2013
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programmed optimal AV delay. This is typically achieved by changing the AV delay to the timing that maximizes cardiac output based on imaging. The 2008 guidelines from the American Society of Echocardiography recommend doing AV optimization after CRT device implant, particularly if the post-CRT implant Doppler echo of the mitral inflow suggests suboptimal diastolic filling patterns. In patients with an excessively long A-V interval, Doppler echo will display fused E and A waves with evidence of mitral regurgitation during diastole. Additionally, a prolonged AV delay allows the ventricle to initiate its own beat before receiving a pacing impulse. By contrast, those with an excessively short AV interval have a truncated A wave resulting in a loss of the atrial kick, resulting in reduced contribution from the atria and reduced ventricular filling time. Optimal AV timing can be identified with aortic systole that begins at the end of A wave.10,58 The optimal AV delay should allow for adequate time for passive filling of the ventricles (atrial diastole) and allow adequate time to complete atrial contraction (atrial systole). Diastolic filling patterns suggestive of either a pseudonormal (stage II) or restrictive (stage III) pattern as demonstrated by pulse Doppler echo should have adjustments made to the AV delay. Those who demonstrate milder diastolic filling patterns with mitral E-A reversal (stage I) can maintain the baseline AV delay setting.61 (Fig 2). Additionally, the aortic velocity time integral (VTI), which is a surrogate for cardiac output, can be used for AV optimization. The optimal AV delay is determined by adjusting the AV delay until the largest aortic VTI is achieved (Fig 3). Although echo AV optimization is the current standard, some have questioned its necessity. In a recent prospective trial of 28 patients, Gold et al.62 determined that there is wide range of optimal AV delay among patients and using an electrogram-based optimization method accurately predicts the optimal hemodynamic AV delay in both atrial sensed and atrial paced modes. Additionally, programming empiric AV delays or optimization with echo-based methods were inferior to the electrogram method. This study suggests that a more simplified technique using electrograms may obviate the need for echo optimization. Furthermore, in evaluating the best strategy to optimize AV delay, the SMART-AV trial compared 3 different strategies, including fixed AV delay (120 ms), device algorithm-based, and echo-guided, and found no differences in the primary end point of LV end-systolic volume.63 226
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Fig 2. AV delay screening. Simplified AV delay screening using mitral inflow Doppler velocities. Sample volume is placed within mitral valve to see closure click. AV optimization may not be necessary if E and A waves are separated, and termination of A wave is before QRS onset or mitral closure click aligned with end of A and QRS complex (usually type I diastolic dysfunction with E lower than A) (top). AV optimization is indicated if A wave is truncated, E and A waves are merged, or A wave is absent (bottom) (Courtesy of Gorcsan III J, Abraham T, Agler DA, et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group. Journal of the American Society of Echocardiography 2008).
Jeroen J. Bax: Various AV optimization protocols have been introduced; echocardiography may be particularly useful in AV optimization. The iterative approach is often used with stepwise increments (usually 10 ms) in AV delay, ranging from a short AV interval (eg, 80 ms) to a relatively long AV interval (eg, 140 ms). With pulsed-wave Doppler echocardiography, the mitral inflow is assessed (E and A waves). The balance is sought between avoiding fusion of the E and A wave (too long AV interval) and truncation of the A wave (AV interval too short). Usually the optimal AV interval is detected at around 120 ms. Again, it is currently unclear whether AV optimization will improve long-term outcome.
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Fig 3. Interventricular optimization using aortic velocity time integral (VTI). Interventricular interval delay optimization using left ventricular outflow tract (LVOT measurements of blood flow velocities for estimation of stroke volume (SV). Stroke volume is exponentially related to the left ventricular outflow tract diameter and directly to the VTI of the left ventricular outflow tract. Variation of the interventricular interval (VV) interval affects the stroke volume, as evidenced by varying volume–time integral measurements. The optimal interventricular interval in this example is obtained when pacing the right ventricle (RV) 40 ms before the left ventricle (LV) (Modified with permission from Waggoner AD, de las Fuentes L, Davila-Roman VG. Doppler echocardiographic methods for optimization of the atrioventricular delay during cardiac resynchronization therapy. Echocardiography 2008;25:1047-55).
VV Optimization VV timing refers to the synchronization of the RV and LV contractions. The goal of VV optimization is to have the ventricles contract in unison. Pulsed-wave Doppler echo has been typically used for evaluation of baseline VV dyssynchrony. Pulsed-wave Doppler uses the difference in time between the LV and RV pre-ejection intervals. The measurement is taken from the onset of the QRS complex from the electrocardiogram, which correlates with the end-diastolic filling period, to the onset of aortic and pulmonary ejection. A delayed interval of ⬎40-50 ms has been accepted as being indicative of VV dyssynchrony.15,64,65 In the MIRACLE trial, the measurement of VV mechanical delay was reduced by approximately 19% after CRT.66 Similarly, Yu et al.30 reported normalization in dyssynchrony in patients who previously had significant mechanical delay in the lateral wall of the LV and RV. Programmable features of CRT allow for simultaneous pacing (RV and LV together) or for offset pacing (one ventricle before the other). For example, the presence of scar from an ischemic cardiomyopathy may require longer VV intervals.67 228
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In a small study of 21 CRT patients, Sogaard et al.36 used 3-dimensional echo with tissue tracking Doppler and found that offset RV and LV pacing significantly improved LV systolic and diastolic performance and tissue tracking was effective to select optimum VV delay during CRT. Additionally, using other echo parameters such as LV dP/pt max and aortic VTI can also be used to optimize VV timing. Programming the optimal VV interval can be accomplished by the similar technique used to optimize AV delay optimization. The VTI as measured from the LV outflow tract can be used to estimate the stroke volume. By adjusting the VV delay on the CRT device and measuring the LV outflow tract VTI on echo, the VV time corresponding to the highest stroke volume can be identified.68,69 The value of VV timing optimization has been hotly debated. In a systematic review on ventricular optimization, Lim et al.70 highlight that various nonrandomized trials demonstrated incremental improvements with VV optimization and the 2 randomized control trials failed to demonstrate any significant improvement in functional status, LV dimensions, and quality of life.71,72 Alternatively, the use of optimization during exercise may yield hemodynamic benefits in patients with exacerbation of dyssynchrony during exercise73 (Fig 4). Jeroen J. Bax: Similarly to AV optimization, VV optimization has been proposed to improve CRT response. Echocardiography has been shown particularly useful in VV optimization; most often, VV intervals are stepwise changed from RV stimulation first, followed by simultaneous RV and LV, and ended by LV stimulation first. The intervals are usually 10- or 20-ms intervals, increasing from 0 ms (LV and RV pacing simultaneous) to 60 or 80 ms (RV or LV first). Some studies have demonstrated benefit from VV optimization, but larger randomized controlled studies failed to demonstrate improved longterm outcome.
Automated Programmer-Based Optimization Some device manufacturers have automated programmer-based IEGM method that provides a much simpler and efficient alternative to standard techniques for the optimization of AV and VV delay settings in patients with CRT. The software takes the intrinsic AV delay and the timing of RV and LV depolarization as measured from the CRT device leads. These data are then fed into a formula, which estimates the optimal AV and VV settings. This method has been shown to have high correlation with echo parameters of optimization techniques,74,75 but not yet shown to improve outcomes. Curr Probl Cardiol, June 2013
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Fig 4. Optimizing AV delay using VTI. Measurements of the continuous-wave Doppler-derived VTI to program AV delay. Before CRT (top left panel), the aortic VTI was 31 cm. The subsequent panels demonstrate the effect of various programmed AV delays and the maximal increase (ie, 36 cm) was determined at an AV delay of 140 ms (Modified with permission from Gassis S, León AR. Cardiac resynchronization therapy: strategies for device programming, troubleshooting and follow-up. Journal of Interventional Cardiac Electrophysiology 2005;13:209-22).
How Often to Optimize CRT Devices The optimal follow-up and long-term programming for CRT devices is uncertain. In a 2005 study by O’Donnell, timing cycles began to change as early as 24 hours and then as often as every 2-3 weeks. Less than 5% of patients did not need any significant changes. In contrast, 18 of the 63 patients required adjustment at every follow-up76 (Fig 5). In another study with 22 patients, the myocardial perfusion index was evaluated during follow-up of 6 and 12 months. Reoptimization of the AV and VV delays was required in 21 of 22 patients at 6 months; however, there was no difference in clinical symptoms or reverse LV remodeling at 6 and 12 months.77 These studies suggest that frequent monitoring and adjustment is needed to maintain optimal AV and VV timings. The ongoing FREEDOM trial will determine whether frequent optimization of CRT, using a new device-based algorithm, is associated with better clinical outcomes than current standard of care.78 230
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Fig 5. Changes in AV and VV delay over time. Temporal variation in optimal V-V and AV delays over the 8 postimplant visits over a period of 9 months in the overall patient cohort. There is a significant reduction in LV predominance of the V-V delay and a significant increase in optimal AV delay (Courtesy of O’Donnell D, Nadurata V, Hamer A, et al. Long-term variations in optimal programming of cardiac resynchronization therapy devices. Pacing and Clinical Electrophysiology 2005).
Jeroen J. Bax: Another important issue in AV and VV optimization remains when to perform these optimizations; should these be performed immediately after CRT implantation? Or some weeks-months later? Another question is whether optimizations should be repeated (and when)? At present, these questions remain largely unanswered.
Conclusions CRT in heart failure patients with mechanical dyssynchrony is an effective means of improving symptoms and reducing mortality. There are now several recognized approaches to optimize CRT. Imaging modalities can assist with identifying the myocardium with latest mechanical activation for targeted LV lead implantation. Device programming can be tailored to maximize biventricular pacing and thereby its benefit. Cardiac imaging has shown that AV and VV intervals can be adjusted to further reduce dyssynchrony. Optimization of CRT devices continues to be an area of active research. Therefore, we expect many more advances in this field over the next several years. Jeroen J. Bax: Over the recent years, the clinical value of CRT in patients with severe heart failure has been demonstrated, initially in small singlecenter studies, followed by large multicenter trials. For example, the CARE-HF study demonstrated a clear survival benefit with CRT as compared with optimized medical therapy alone (Cleland et al. N Engl J Med 2005). In Curr Probl Cardiol, June 2013
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the early studies, only patients with severe heart failure (NYHA class III-IV) were included, but more recently, the benefit of CRT was also demonstrated in patients with mild heart failure (Linde et al. J Am Coll Cardiol 2008). In the current issue of the Journal, Drs Duggirala and Lee have provided an excellent review on the selection of CRT patients and optimization of device settings. At present, patients are selected based on the symptoms, the QRS duration, and the LV ejection fraction (McMurray et al. Eur Heart J 2012). Most patients respond well to CRT, but a substantial percentage of patients may not benefit from CRT. The response to CRT is defined according to different criteria; often the improvement in symptoms or 6-minute walk distance is used, but echocardiographic criteria (improvement in LV ejection fraction, reduction in LV volumes) are also frequently used. As discussed previously, the improvement in echocardiographic criteria is observed less often as compared with improvement in symptoms. The optimal end point would be long-term survival. As pointed out in the current article, an important challenge remains the prediction of response to CRT. In addition to symptoms, QRS duration, and LVEF, other factors are also important, such as age, gender, comorbidity (diabetes, renal failure), and AF. Specific criteria that may be of value for enriching the population that may benefit from CRT include cardiac dyssynchrony and the presence/absence of scar tissue, as carefully outline in this article. Various imaging modalities can provide this information, including echocardiography, MRI, and gated SPECT. It has also been suggested that the LV lead position is important, particularly in relation to the area of latest mechanical activation and the location of scar tissue. Integration (or fusion) of the different imaging modalities may eventually be of use in the combined assessment of dyssynchrony, site of latest mechanical activation, and extent and location of scar tissue. Finally, Drs Duggirala and Lee have carefully discussed the value and available technology for AV and VV optimization. They have provided a good summary on the different programs for AV and VV optimization, with careful explanations on the use of echocardiography in this field. Although often applied in clinical practice, the precise value of these optimization techniques remains unclear.
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Dr Duggirala has no relevant conflicts of interest to disclose. Dr Lee has received honorarium from Boston Scientific, Biotronik, and St. Jude. Curr Probl Cardiol 2013;38:215-237. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2013.03.003
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retrospective and prospective studies have also suggested similar benefits with New York Heart Association (NYHA) functional class I and II.6-8 As heart failure progresses, it is not uncommon for patients to develop electrical conduction abnormalities: first-degree heart block and intraventricular conduction delay that is often manifested as a left bundle branch block (LBBB). It has been estimated that nearly 25% of patients with systolic dysfunction have QRS duration that exceeds 120 ms.9 Progressive LV dysfunction appears to also correspond with worsening conduction disease. Additionally, atrioventricular (AV) delay associated with first-degree heart block may also lead to suboptimal ventricular filling from the atria and worsened mitral regurgitation.10 Intraventricular conduction delay, particularly with an LBBB, leads to LV mechanical dyssynchrony. With LBBB, the lateral wall of the LV is depolarized late and, as a result, has a delayed wall contraction. On transthoracic echocardiogram, the septum is seen moving paradoxically away from the lateral wall, as the septum is in early diastole, whereas the lateral wall is in systole. This discordant form of contraction is commonly regarded as LV dyssynchrony. The presence of LV dyssynchrony has been associated with increased mortality in patients with congestive heart failure.11-13 Response to CRT has been evaluated using various clinical parameters, such as NYHA classification, quality-of-life score, and the 6-Minute Walk Test, whereas other studies have used more objective measurements taken from a variety of imaging modalities.3,14-16 Clinical response to CRT is variable, but has typically been reported in the range of 70%-80%.3,14,17 Notably, ischemic cardiomyopathy was more predictive of nonresponse to CRT when compared with nonischemic or idiopathic cardiomyopathy.3,17,18 There has been great interest in trying to improve this response rate and, additionally, to increase the improvement seen in responders. Most of the approaches center on further reducing mechanical dyssynchrony. In this review, we discuss various strategies to optimize CRT response.
Jeroen J. Bax: It is important to note that a uniform definition of CRT response is lacking, which has contributed to the discussion on the precise response/nonresponse rates. Ideally, long-term survival should be used as a uniform end point in all studies. However, in most studies, 6-month response rates are reported and are generally divided into 2 major categories, including clinical response (improvement in symptoms, NYHA class, quality-of-life score, 6-minute walk distance) and echocardiographic response (improvement in LV function, reduction in LV volumes). In general, clinical response is more frequently observed than echocardiographic response. However, echocardiographic response (a reduction in LV end-systolic function) may be more 216
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closely related to long-term survival and may therefore be the preferred (surrogate) end point.
Lead Location for CRT Optimization CRT implantation is feasible from either side of the chest, but typically the left side of the chest is preferred for 2 reasons. The anatomy of the left subclavian vein allows a more continuous route to access the coronary sinus, whereas a right-sided approach can be technically more challenging due to the angulation of the superior vena cava to the coronary sinus. The left-sided approach is also favored because defibrillation vectors suggest a higher defibrillation threshold from the right side compared with the left side.19 CRT pacing leads are placed in the right atrium, right ventricle (RV), and the lateral wall of the LV through the coronary sinus. It is recommended that the RV lead be placed first, as most patients will have a baseline LBBB and are at risk for complete heart block during coronary sinus cannulation. Accidental tapping of the right bundle may temporarily halt conduction of the remaining conducting bundle. The LV lead or the atrial lead is implanted next. Because the LV lead is technically more challenging, some recommend implantation of the right atrial lead next to avoid dislodgement of the LV lead near the end of the case.20 Notably, atrial lead placement should still be considered if the patient is in atrial fibrillation (AF). It is not uncommon for patients with congestive heart failure to have AF, but it is suggested that approximately 10% of patients who undergo defibrillation testing will convert to sinus rhythm in the long-term.21 There appears to be no clear optimal location for the RV lead in CRT patients. In the REVERSE study, Thebault et al.22 analyzed apical RV lead position or nonapical lead position including RV free wall, RV outflow tract, and the septum and found no difference in response to CRT based on clinical and echocardiographic parameters. This was further corroborated by a recent study by Khan et al.,23 in which they compared the RV lead in either the apex or septal position and found no difference in degree of LV reverse remodeling between the 2 groups. Additionally, in patients who require defibrillator therapy, no significant difference was found in the defibrillation threshold between an RV outflow tract and an apical RV lead position.24 The optimal LV lead placement is technically challenging owing to anatomic variants in the cardiac venous anatomy. However, proper LV lead positioning has significant clinical implication in the efficacy of CRT. The LV lead is typically placed on the lateral or posterior-lateral Curr Probl Cardiol, June 2013
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wall of the LV through the coronary sinus or epicardially with the goal of pacing from the most mechanically delayed portion on the LV.25,26 The indications of pacing from the LV are based on the common electrocardiogram finding of an LBBB, indicating delayed depolarization of the LV; however, there are a considerable number of patients who either do not have a typical LBBB or have no electrocardiographic evidence of intraventricular conduction delay. For these patients, standard lead placement on the lateral or posterior-lateral wall of the LV may not be the most effective site for restoring synchrony with the RV. Although current guidelines suggest the use of a wide QRS complex (⬎120 ms) on surface electrocardiogram as part of the criteria for CRT, evidence suggests that there are individuals who have no evidence of dyssynchrony despite having a wide QRS complex. Conversely, individuals who have a narrow QRS complex may display mechanical dyssynchrony, suggesting that electrical dyssynchrony does not necessarily correspond with mechanical dyssynchrony. However, the presence of LV mechanical dyssynchrony is a major predictor in the response to CRT.27-30 As a result, there is considerable interest in finding better imaging modalities to assess dyssynchrony and to identify the optimal LV lead location before implantation. These imaging modalities might also be used to determine optimal timing intervals of the leads to minimize mechanical dyssynchrony. Jeroen J. Bax: The position of the LV lead has been related to CRT response. There has been considerable discussion on whether the positioning of the LV lead should be guided by the site of latest mechanical activation; preliminary data have suggested that positioning the LV lead outside the site of latest mechanical activation may be associated with suboptimal response to CRT and worse long-term outcome.
Echo Assessment of Dyssynchrony and CRT Response Transthoracic echocardiography has been the conventional imaging modality used in assessing mechanical dyssynchrony, including identifying regions of the LV with delayed contraction (intraventricular delay), and to program the CRT device to optimize the AV timing, and interventricular (VV) timing. Furthermore, echo is used in the assessment of the long-term effects of CRT through evaluation of ejection fraction, LV end-systolic and diastolic volumes, and mitral regurgitation.3,31 By using the septal–posterior wall motion delay (SPWMD) to evaluate intraventricular conduction delay derived from M-mode echocardiography, Pitzalis et al.32,33 identified this to be a predictive marker of response 218
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using a cutoff value ⱖ130 ms for the SPWMD. Using this parameter and also a cutoff values for QRS duration (ⱖ150 ms) and PQ interval (ⱖ180 ms), reverse remodeling could be predicted accurately. However, in the CONTAK-CD registry, the use of the SPWMD did not correlate with clinical improvement, and measurement reproducibility was noted to be difficult in this retrospective study.34 Additionally, it should be noted that accurate SPWMD can be difficult to obtain due to ill-defined posterior motion or an akinetic septum from previous infarction.15 Kawaguchi et al.35 used contrast-enhanced echocardiography in the evaluation of patients who immediately received CRT, and noted a 40% reduction in LV dyssynchrony. Tissue Doppler imaging has also been used for pathophysiologic information for the localization and severity of LV dyssynchrony and has been suggested to help in better selection for responders of CRT.36 Additionally, tissue Doppler longitudinal velocity may be a better predictor of LV reverse remodeling after CRT compared with longitudinal strain.37 Despite several trials highlighting efficacy of using echo to effectively identify dyssynchrony, the recent PROSPECT trial challenges the role of echo in evaluating for dyssynchrony. The PROSPECT trial represented the first large-scale, multicenter clinical trial evaluating the performance of echocardiographic measures of mechanical ventricular dyssynchrony to predict responsiveness to CRT. The results of the study suggested that various echocardiographic measures of ventricular dyssynchrony were unable to distinguish potential responders from nonresponders of CRT. Thus, this study indicates that electrocardiograms and other clinical criteria should remain as the standard for patient selection.38 Jeroen J. Bax: The value of dyssynchrony in prediction of response to CRT has attracted a lot of discussion over the recent years. Various single-center studies have demonstrated that LV dyssynchrony can predict CRT response, but the multicenter PROSPECT study failed to show the predictive value of dyssynchrony. However, a subanalysis of the PROSPECT study showed that more extensive dyssynchrony was associated with CRT response at the 6-month follow-up (Van Bommel et al. Eur Heart J 2009). Importantly, recent data demonstrated that LV dyssynchrony as assessed on echocardiographic 2-dimensional (2D) strain imaging was predictive of long-term survival after CRT (Gorcsan et al. Circulation 2010).
LV Pacing The REVERSE study showed that an apically placed LV lead was associated with an increase in the LV end-systolic index compared with Curr Probl Cardiol, June 2013
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nonapically placed LV lead.22 Similarly, the MADIT-CRT trial revealed that LV lead placed at the apex compared with leads placed in the nonapical position was associated with worse clinical outcomes, including increased death and heart failure. It is suggested that the apex is activated early during the activation sequence, with the base activated generally later. Thus, pacing the apex would be activating a region of the myocardium that has typically less delayed electrical and mechanical activation. Additionally, LV apical pacing with its proximity to the RV apex may have electromechanical effects and a clinical impact similar to worsening heart failure symptoms.39 CRT involves synchronizing the ventricles through electric stimulation from RV and LV pacing sites that should ideally be positioned as far away from each other as possible.40
Echo-Guided Lead Placement Using more advanced imaging techniques in echocardiography to identify the region of latest mechanical activation, it is feasible to guide LV lead implantation. By assessing endocardial motion using 3-dimensional echocardiography, Becker et al.42 were able to evaluate temporal changes in the segmental LV contraction. Using the volume/time curves to identify the LV segment with the latest systolic contraction, this could then be used to define the segment with maximal dyssynchrony before CRT implant. LV lead placement at these segments resulted in clinical and echocardiographic improvements, particularly in those with the largest differences between and pre- and post-CRT measurements.41 Furthermore, LV lead placement near the optimally predicted site using 2D echo with circumferential strain image analysis resulted in greater improvement of LV function and improved LV reverse remodeling compared to nonoptimal LV lead position.43 In the recent TARGET trial, using speckle-tracking 2D radial strain imaging, LV leads were positioned at the latest site of contraction and compared with standard unguided CRT LV lead placement. The results of this study revealed significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization with targeted LV lead placement.44
Magnetic Resonance Imaging for Assessing Dyssynchrony and Guiding Lead Placement Cardiac magnetic resonance imaging (MRI) has been used to provide a comprehensive assessment of cardiac morphology and function and can be used to predict improvement in functional class after CRT.45 MRI has been used in the selection of patients appropriate for CRT by assessing for 220
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dyssynchrony and evaluation of myocardial scar in a single session with excellent correlation to echocardiography.46,47 Using a novel technique for assessing dyssynchrony called cardiovascular magnetic resonancetissue synchronization index (CMR-TSI), Chalil and colleagues48 have shown that CMR-TSI in heart failure patients is synonymous with intraventricular dyssynchrony. Notably, a CMR-TSI score of ⱖ110 ms was an independent predictor of increased morbidity, cardiovascular mortality, and all-cause mortality in patients who underwent CRT despite clinical improvements in 6-minute walk test and NYHA functional class. The use of late gadolinium enhancement in cardiac MRI can be used to guide LV lead placement away from regions of myocardial scar, and this approach has been shown to yield a better clinical outcome after CRT. It should be noted that although imaging may help identify the latest contracting segment, there is considerable variation in the venous anatomy, which may limit proper LV lead localization. It is not always possible to place the lead tip at the latest contracting segment suggested by echo or other imaging modalities.49 Jeroen J. Bax: Various MRI approaches have been proposed to assess cardiac dyssynchrony before CRT. However, MRI cannot be routinely applied after CRT implantation, and therefore, follow-up studies are often not feasible.
Multiple LV Leads Alternatively, the role of using multiple LV leads has also gained some interest. In the TRIP-HF multicenter study with 40 patients, LeClerq et al.50 used 2 LV leads in comparison with the standard 1 lead and found no difference in quality of life or 6-minute walk distance; however, there was a significant difference in the LV remodeling and ejection fraction. The hemodynamic improvement of triple-site pacing appears to be most beneficial to individuals with large LV end-diastolic volumes.51 Triplesite pacing is not standard care, but it is an innovative approach that deserves more research.
Multipolar Leads and Phrenic Nerve Stimulation Phrenic nerve stimulation from the LV lead is a significant problem that can lead to dislodgement, discontinuation of LV pacing, and need for surgical repositioning. Phrenic nerve stimulation can sometimes be avoided with a lower pacing output or using multipolar or dual cathode Curr Probl Cardiol, June 2013
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leads, as they can offer multiple vector configurations.52 The recent ELECTION study was a prospective trial that evaluated the utility of multiple LV pacing configurations with bipolar leads. The study revealed that electronic repositioning improved suboptimal pacing thresholds that would result in phrenic nerve stimulation and also reduced lead dislodgment or need for surgical repositioning.53 In another recent prospective trial, Forleo et al.54 demonstrated that quadripolar leads could be safely implanted with low rates of lead dislocation and phrenic nerve stimulation. Recent experimental models suggest that multipolar LV leads can be used to adjust the LV pacing site to further reduce dyssynchrony. Although promising, this approach has not yet been proven to improve outcomes in extensive human studies.
Lead Placement and LV Scar In patients with an ischemic cardiomyopathy who meet criteria for CRT, scarring mediated by previous myocardial infarctions provides a unique challenge for LV lead placement. It is suggested that in approximately one-third of nonresponders to CRT, the nonresponse may be due to previous scar.3,18 Using MRI to identify scar, Bleeker et al.55 found a lower response rate to CRT in patients with transmural, posterolateral scar, and found no improvement in echocardiographic parameters. In another study that used myocardial perfusion imaging to identify scar, higher scar burden and scar density near the LV lead tip indicated an unfavorable response to CRT in patients with an ischemic cardiomyopathy.56 Additionally, it has also been shown that higher scar burden quantified by using single-photon emission computed tomography (SPECT)-myocardial perfusion imaging had unfavorable clinical and LV functional outcomes regardless of baseline dyssynchrony, and those with lower scar burden had outcomes similar to individuals with nonischemic cardiomyopathy.57 Despite these studies, it is still unclear whether we should avoid placement of the LV lead electrodes in areas of scar, or if scar in the posterior lateral region is simply a marker of poor response. Further prospective studies are needed. Jeroen J. Bax: MRI with contrast-enhanced assessment of myocardial scar tissue may be important in prediction of nonresponse to CRT. It has been shown that transmural scar tissue in the region where the LV lead is positioned will result in nonresponse; it is currently not clear whether CRT may still be effective in regions of nontransmural scar tissue. Independent of where the LV lead is positioned, it was shown that the extent of scar tissue in the LV is also important for CRT response. The more 222
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scar tissue is present in the LV, the lower the likelihood of response to CRT. Finally, the integrated assessment of scar tissue and cardiac dyssynchrony with MRI may be particularly useful to predict response to CRT. In addition to MRI, SPECT/positron emission tomography imaging using perfusion tracers or F18-fluorodeoxyglucose has also been used for assessment of scar tissue.
Device Programming to Maximize Biventricular Pacing Although lead placement strategies described previously may improve response rates, currently, approximately 20%-30% patients will derive no benefit or have a suboptimal response to CRT and are labeled “nonresponders”.3,17,58 Challenges remain in attempts to convert patients from “non-responders” to “responders.” Device programming features that can be attempted to optimize response to CRT include promoting CRT pacing and optimizing the AV and VV timing. Unlike conventional pacing, the goal of CRT is to encourage pacing close to 100% of the time. During interrogation, the frequency of the ventricular pacing should be confirmed. Adjustments to various parameters may be necessary to maintain maximum ventricular pacing.
Maximum Tracking Rate The maximum tracking rate (MTR) sets the highest rate at which the ventricles will be paced in response to intrinsic atrial activity. However, if the patient has high intrinsic atrial rates that exceed the MTR with normal AV conduction, the patient may not likely be paced all the time, particularly during exercise. Thus, clinical judgment should be used to ensure that the MTR is high enough to maximize pacing without getting to such high pacing rates that may not be well tolerated by the patient.
Mode Switching Mode switching turns off atrial tracking during high-rate atrial episodes. This prevents rapid ventricular pacing when patients go into atrial arrhythmias such as AF and atrial flutter. However, ventricular pacing is lost if the intrinsic rate is higher than the programmed mode switch ventricular pacing rate. Therefore, if the intrinsic rate during the atrial arrhythmia is not high (ie, under 80 bpm), the mode switch ventricular pacing rate can be programmed higher to maintain pacing and maximize the benefits of CRT.
AV Delay The programmed AV delay represents the time between the atrial beat and the corresponding paced ventricular event. There are 2 types of programmed Curr Probl Cardiol, June 2013
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AV delay: (1) sensed AV delay is the time interval from a sensed atrial event to the next paced ventricular event, and (2) paced AV delay is the time interval from a paced atrial event to the next paced ventricular event. Paced AV delay is typically programmed slightly longer than the sensed AV delay owing to interatrial conduction delay from atrial pacing. Atrial sensing or atrial pacing therefore results in different AV delays that should be evaluated during AV delay optimization. For CRT, both types of AV delay should be programmed short enough to ensure that the ventricle is paced on every or nearly every beat. Jeroen J. Bax: Various automated programs have been introduced to optimize CRT settings. It remains difficult, however, to demonstrate whether these optimization programs contribute to improved long-term survival.
Dynamic AV Delay As conduction through the AV node shortens with increased sympathetic tone, there may be intrinsic conduction to the ventricle during emotional stress or exercise, which overrides biventricular pacing. To avoid this reduction of biventricular pacing at a time when maintaining cardiac output may be most critical, the dynamic AV delay or rateresponsive AV delay feature should be turned ON. This feature automatically shortens the AV delay of the device at times of high intrinsic or paced atrial rates. This reduces the chance that intrinsic conduction will be rapid enough to depolarize the ventricles before the CRT device.
Negative Hysteresis In contrast to conventional AV hysteresis, which encourages intrinsic activity and thus is not compatible with CRT, there is also a negative AV hysteresis, which is a feature that encourages pacing. Negative AV hysteresis prevents intrinsic conduction to the ventricle by automatically shortening the AV delay whenever a nonpaced ventricular event is sensed (Fig 1). This feature causes the device to automatically adjust the AV delay to ensure biventricular pacing when intrinsic AV delay shortens unexpectedly.
Rate Responsive Mode in CRT In patients with advanced heart failure and severe chronotropic incompetence, defined as a failure to achieve at least 70% of age-predicted heart rate, the use of the rate-responsive mode in CRT demonstrated an incremental benefit in exercise capacity.59 However, the recent PE224
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Fig 1. Negative atrioventricular (AV) hysteresis. Negative AV hysteresis prevents intrinsic conduction to the ventricle by automatically shortening the AV delay whenever a nonpaced ventricular event is sensed. This feature causes the device to automatically abbreviate the AV delay to ensure biventricular pacing when intrinsic AV delay shortens unexpectedly. In this example, the ventricular sensed event leads to abrupt shortening of the paced AV delay to 135 ms (Courtesy of St. Jude Medical, Inc).
GASUS-CRT multicenter trial was designed to evaluate the effect of atrial support pacing among heart failure patients receiving a CRT defibrillator. This study randomized patients to DDD mode at a lower rate of 40 bpm (DDD-40; control arm), or one of the following 2 treatment arms: (1) DDD-70 or (2) DDDR-40. The latter 2 modes led to significantly more atrial support pacing, yet the investigators found no difference in patient outcomes when compared with control.60 The lack of improvement may be partly attributed to a low prevalence of chronotropic incompetence or sinus node dysfunction in this study population, as the inclusion criteria required patients to tolerate a lower rate of 40 bpm.
Device Programming to Optimize Timing Most studies point to a benefit in adjusting the AV and VV timing in CRT. However, there is much variability on the best approach to make these adjustments and how often it should be done.
AV Optimization As described previously, it is standard practice in CRT to shorten the programmed AV delay to ensure nearly complete ventricular pacing. However, how short to program the AV delay to optimize cardiac output has been a focus of much research. Multiple studies have shown hemodynamic improvements in patients with CRT who have a Curr Probl Cardiol, June 2013
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programmed optimal AV delay. This is typically achieved by changing the AV delay to the timing that maximizes cardiac output based on imaging. The 2008 guidelines from the American Society of Echocardiography recommend doing AV optimization after CRT device implant, particularly if the post-CRT implant Doppler echo of the mitral inflow suggests suboptimal diastolic filling patterns. In patients with an excessively long A-V interval, Doppler echo will display fused E and A waves with evidence of mitral regurgitation during diastole. Additionally, a prolonged AV delay allows the ventricle to initiate its own beat before receiving a pacing impulse. By contrast, those with an excessively short AV interval have a truncated A wave resulting in a loss of the atrial kick, resulting in reduced contribution from the atria and reduced ventricular filling time. Optimal AV timing can be identified with aortic systole that begins at the end of A wave.10,58 The optimal AV delay should allow for adequate time for passive filling of the ventricles (atrial diastole) and allow adequate time to complete atrial contraction (atrial systole). Diastolic filling patterns suggestive of either a pseudonormal (stage II) or restrictive (stage III) pattern as demonstrated by pulse Doppler echo should have adjustments made to the AV delay. Those who demonstrate milder diastolic filling patterns with mitral E-A reversal (stage I) can maintain the baseline AV delay setting.61 (Fig 2). Additionally, the aortic velocity time integral (VTI), which is a surrogate for cardiac output, can be used for AV optimization. The optimal AV delay is determined by adjusting the AV delay until the largest aortic VTI is achieved (Fig 3). Although echo AV optimization is the current standard, some have questioned its necessity. In a recent prospective trial of 28 patients, Gold et al.62 determined that there is wide range of optimal AV delay among patients and using an electrogram-based optimization method accurately predicts the optimal hemodynamic AV delay in both atrial sensed and atrial paced modes. Additionally, programming empiric AV delays or optimization with echo-based methods were inferior to the electrogram method. This study suggests that a more simplified technique using electrograms may obviate the need for echo optimization. Furthermore, in evaluating the best strategy to optimize AV delay, the SMART-AV trial compared 3 different strategies, including fixed AV delay (120 ms), device algorithm-based, and echo-guided, and found no differences in the primary end point of LV end-systolic volume.63 226
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Fig 2. AV delay screening. Simplified AV delay screening using mitral inflow Doppler velocities. Sample volume is placed within mitral valve to see closure click. AV optimization may not be necessary if E and A waves are separated, and termination of A wave is before QRS onset or mitral closure click aligned with end of A and QRS complex (usually type I diastolic dysfunction with E lower than A) (top). AV optimization is indicated if A wave is truncated, E and A waves are merged, or A wave is absent (bottom) (Courtesy of Gorcsan III J, Abraham T, Agler DA, et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group. Journal of the American Society of Echocardiography 2008).
Jeroen J. Bax: Various AV optimization protocols have been introduced; echocardiography may be particularly useful in AV optimization. The iterative approach is often used with stepwise increments (usually 10 ms) in AV delay, ranging from a short AV interval (eg, 80 ms) to a relatively long AV interval (eg, 140 ms). With pulsed-wave Doppler echocardiography, the mitral inflow is assessed (E and A waves). The balance is sought between avoiding fusion of the E and A wave (too long AV interval) and truncation of the A wave (AV interval too short). Usually the optimal AV interval is detected at around 120 ms. Again, it is currently unclear whether AV optimization will improve long-term outcome.
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Fig 3. Interventricular optimization using aortic velocity time integral (VTI). Interventricular interval delay optimization using left ventricular outflow tract (LVOT measurements of blood flow velocities for estimation of stroke volume (SV). Stroke volume is exponentially related to the left ventricular outflow tract diameter and directly to the VTI of the left ventricular outflow tract. Variation of the interventricular interval (VV) interval affects the stroke volume, as evidenced by varying volume–time integral measurements. The optimal interventricular interval in this example is obtained when pacing the right ventricle (RV) 40 ms before the left ventricle (LV) (Modified with permission from Waggoner AD, de las Fuentes L, Davila-Roman VG. Doppler echocardiographic methods for optimization of the atrioventricular delay during cardiac resynchronization therapy. Echocardiography 2008;25:1047-55).
VV Optimization VV timing refers to the synchronization of the RV and LV contractions. The goal of VV optimization is to have the ventricles contract in unison. Pulsed-wave Doppler echo has been typically used for evaluation of baseline VV dyssynchrony. Pulsed-wave Doppler uses the difference in time between the LV and RV pre-ejection intervals. The measurement is taken from the onset of the QRS complex from the electrocardiogram, which correlates with the end-diastolic filling period, to the onset of aortic and pulmonary ejection. A delayed interval of ⬎40-50 ms has been accepted as being indicative of VV dyssynchrony.15,64,65 In the MIRACLE trial, the measurement of VV mechanical delay was reduced by approximately 19% after CRT.66 Similarly, Yu et al.30 reported normalization in dyssynchrony in patients who previously had significant mechanical delay in the lateral wall of the LV and RV. Programmable features of CRT allow for simultaneous pacing (RV and LV together) or for offset pacing (one ventricle before the other). For example, the presence of scar from an ischemic cardiomyopathy may require longer VV intervals.67 228
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In a small study of 21 CRT patients, Sogaard et al.36 used 3-dimensional echo with tissue tracking Doppler and found that offset RV and LV pacing significantly improved LV systolic and diastolic performance and tissue tracking was effective to select optimum VV delay during CRT. Additionally, using other echo parameters such as LV dP/pt max and aortic VTI can also be used to optimize VV timing. Programming the optimal VV interval can be accomplished by the similar technique used to optimize AV delay optimization. The VTI as measured from the LV outflow tract can be used to estimate the stroke volume. By adjusting the VV delay on the CRT device and measuring the LV outflow tract VTI on echo, the VV time corresponding to the highest stroke volume can be identified.68,69 The value of VV timing optimization has been hotly debated. In a systematic review on ventricular optimization, Lim et al.70 highlight that various nonrandomized trials demonstrated incremental improvements with VV optimization and the 2 randomized control trials failed to demonstrate any significant improvement in functional status, LV dimensions, and quality of life.71,72 Alternatively, the use of optimization during exercise may yield hemodynamic benefits in patients with exacerbation of dyssynchrony during exercise73 (Fig 4). Jeroen J. Bax: Similarly to AV optimization, VV optimization has been proposed to improve CRT response. Echocardiography has been shown particularly useful in VV optimization; most often, VV intervals are stepwise changed from RV stimulation first, followed by simultaneous RV and LV, and ended by LV stimulation first. The intervals are usually 10- or 20-ms intervals, increasing from 0 ms (LV and RV pacing simultaneous) to 60 or 80 ms (RV or LV first). Some studies have demonstrated benefit from VV optimization, but larger randomized controlled studies failed to demonstrate improved longterm outcome.
Automated Programmer-Based Optimization Some device manufacturers have automated programmer-based IEGM method that provides a much simpler and efficient alternative to standard techniques for the optimization of AV and VV delay settings in patients with CRT. The software takes the intrinsic AV delay and the timing of RV and LV depolarization as measured from the CRT device leads. These data are then fed into a formula, which estimates the optimal AV and VV settings. This method has been shown to have high correlation with echo parameters of optimization techniques,74,75 but not yet shown to improve outcomes. Curr Probl Cardiol, June 2013
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Fig 4. Optimizing AV delay using VTI. Measurements of the continuous-wave Doppler-derived VTI to program AV delay. Before CRT (top left panel), the aortic VTI was 31 cm. The subsequent panels demonstrate the effect of various programmed AV delays and the maximal increase (ie, 36 cm) was determined at an AV delay of 140 ms (Modified with permission from Gassis S, León AR. Cardiac resynchronization therapy: strategies for device programming, troubleshooting and follow-up. Journal of Interventional Cardiac Electrophysiology 2005;13:209-22).
How Often to Optimize CRT Devices The optimal follow-up and long-term programming for CRT devices is uncertain. In a 2005 study by O’Donnell, timing cycles began to change as early as 24 hours and then as often as every 2-3 weeks. Less than 5% of patients did not need any significant changes. In contrast, 18 of the 63 patients required adjustment at every follow-up76 (Fig 5). In another study with 22 patients, the myocardial perfusion index was evaluated during follow-up of 6 and 12 months. Reoptimization of the AV and VV delays was required in 21 of 22 patients at 6 months; however, there was no difference in clinical symptoms or reverse LV remodeling at 6 and 12 months.77 These studies suggest that frequent monitoring and adjustment is needed to maintain optimal AV and VV timings. The ongoing FREEDOM trial will determine whether frequent optimization of CRT, using a new device-based algorithm, is associated with better clinical outcomes than current standard of care.78 230
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Fig 5. Changes in AV and VV delay over time. Temporal variation in optimal V-V and AV delays over the 8 postimplant visits over a period of 9 months in the overall patient cohort. There is a significant reduction in LV predominance of the V-V delay and a significant increase in optimal AV delay (Courtesy of O’Donnell D, Nadurata V, Hamer A, et al. Long-term variations in optimal programming of cardiac resynchronization therapy devices. Pacing and Clinical Electrophysiology 2005).
Jeroen J. Bax: Another important issue in AV and VV optimization remains when to perform these optimizations; should these be performed immediately after CRT implantation? Or some weeks-months later? Another question is whether optimizations should be repeated (and when)? At present, these questions remain largely unanswered.
Conclusions CRT in heart failure patients with mechanical dyssynchrony is an effective means of improving symptoms and reducing mortality. There are now several recognized approaches to optimize CRT. Imaging modalities can assist with identifying the myocardium with latest mechanical activation for targeted LV lead implantation. Device programming can be tailored to maximize biventricular pacing and thereby its benefit. Cardiac imaging has shown that AV and VV intervals can be adjusted to further reduce dyssynchrony. Optimization of CRT devices continues to be an area of active research. Therefore, we expect many more advances in this field over the next several years. Jeroen J. Bax: Over the recent years, the clinical value of CRT in patients with severe heart failure has been demonstrated, initially in small singlecenter studies, followed by large multicenter trials. For example, the CARE-HF study demonstrated a clear survival benefit with CRT as compared with optimized medical therapy alone (Cleland et al. N Engl J Med 2005). In Curr Probl Cardiol, June 2013
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the early studies, only patients with severe heart failure (NYHA class III-IV) were included, but more recently, the benefit of CRT was also demonstrated in patients with mild heart failure (Linde et al. J Am Coll Cardiol 2008). In the current issue of the Journal, Drs Duggirala and Lee have provided an excellent review on the selection of CRT patients and optimization of device settings. At present, patients are selected based on the symptoms, the QRS duration, and the LV ejection fraction (McMurray et al. Eur Heart J 2012). Most patients respond well to CRT, but a substantial percentage of patients may not benefit from CRT. The response to CRT is defined according to different criteria; often the improvement in symptoms or 6-minute walk distance is used, but echocardiographic criteria (improvement in LV ejection fraction, reduction in LV volumes) are also frequently used. As discussed previously, the improvement in echocardiographic criteria is observed less often as compared with improvement in symptoms. The optimal end point would be long-term survival. As pointed out in the current article, an important challenge remains the prediction of response to CRT. In addition to symptoms, QRS duration, and LVEF, other factors are also important, such as age, gender, comorbidity (diabetes, renal failure), and AF. Specific criteria that may be of value for enriching the population that may benefit from CRT include cardiac dyssynchrony and the presence/absence of scar tissue, as carefully outline in this article. Various imaging modalities can provide this information, including echocardiography, MRI, and gated SPECT. It has also been suggested that the LV lead position is important, particularly in relation to the area of latest mechanical activation and the location of scar tissue. Integration (or fusion) of the different imaging modalities may eventually be of use in the combined assessment of dyssynchrony, site of latest mechanical activation, and extent and location of scar tissue. Finally, Drs Duggirala and Lee have carefully discussed the value and available technology for AV and VV optimization. They have provided a good summary on the different programs for AV and VV optimization, with careful explanations on the use of echocardiography in this field. Although often applied in clinical practice, the precise value of these optimization techniques remains unclear.
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