Cardiac Resynchronization Therapy Part 1 Issues Before Device Implantation

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1 Journal of the American College of Cardiology Vol. 46, No. 12, by the American College of Cardiology Foundation ISSN /05/$30.00 Published by Elsevier Inc. doi: /j.jacc FOCUS ISSUE: CARDIAC RESYNCHRONIZATION THERAPY STATE-OF-THE-ART PAPERS Cardiac Resynchronization Therapy Part 1 Issues Before Device Implantation 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, Cheuk-Man Yu, MD Leiden, the Netherlands; Baltimore, Maryland; Tampa, Florida; Mannheim and Bielefeld, Germany; Hong Kong, China; Pessac and Rennes, France; Pittsburgh, Pennsylvania; Rochester, Minnesota; Turku, Finland; Stockholm, Sweden; Durham, North Carolina; and London, United Kingdom Cardiac resynchronization therapy (CRT) has been used extensively over the last years in the therapeutic management of patients with end-stage heart failure. Data from 4,017 patients have been published in eight large, randomized trials on CRT. Improvement in clinical end points (symptoms, exercise capacity, quality of life) and echocardiographic end points (systolic function, left ventricular size, mitral regurgitation) have been reported after CRT, with a reduction in hospitalizations for decompensated heart failure and an improvement in survival. However, individual results vary, and 20% to 30% of patients do not respond to CRT. At present, the selection criteria include severe heart failure (New York Heart Association functional class III or IV), left ventricular ejection fraction 35%, and wide QRS complex ( 120 ms). Assessment of inter- and particularly intraventricular dyssynchrony as provided by echocardiography (predominantly tissue Doppler imaging techniques) may allow improved identification of potential responders to CRT. In this review a summary of the clinical and echocardiographic results of the large, randomized trials is provided, followed by an extensive overview on the currently available echocardiographic techniques for assessment of LV dyssynchrony. In addition, the value of LV scar tissue and venous anatomy for the selection of potential candidates for CRT are discussed. (J Am Coll Cardiol 2005;46: ) 2005 by the American College of Cardiology Foundation Cardiac resynchronization therapy (CRT) has changed the treatment of patients with end-stage, drug-refractory heart failure. To date, eight large randomized, clinical trials in CRT have been completed (1 8). A summary of these trials, with a total of 4,017 patients, is provided in Table 1. The inclusion criteria in these trials were: Severe heart failure, New York Heart Association (NYHA) functional class III and IV Depressed systolic left ventricular (LV) function, LV ejection fraction (LVEF) 35% Wide QRS complex: 120 ms with interventricular conduction disorder From the *Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Johns Hopkins University, Baltimore, Maryland; University of South Florida, Tampa, Florida; University of 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; and Stadtische Kliniken Bielefeld, Bielefeld, Germany. Dr. Abraham receives honoraria from GE, Guidant, Medtronic, 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. Manuscript received April 19, 2005; revised manuscript received September 19, 2005, accepted September 19, 2005.

2 2154 Bax et al. JACC Vol. 46, No. 12, 2005 Issues Before Device Implantation December 20, 2005: Abbreviations and Acronyms CMR cardiovascular magnetic resonance CRT cardiac resynchronization therapy LV left ventricle/ventricular LVEF left ventricular ejection fraction MIRACLE Multicenter InSync Randomized Clinical Evaluation study MSCT multislice computed tomography NYHA New York Heart Association tissue Doppler imaging TSI tissue synchronization imaging The Cardiac Resynchronization-Heart Failure (CARE- HF) study is the only study that, to some extent, has included the presence of LV dyssynchrony in the inclusion criteria. In these large trials, the most frequently used primary end points mainly reflect the functional status (6-min walk test,, quality of life score, and peak O 2 ) and should be considered clinical end points. The vast majority of studies demonstrated improvement in 6-min walking distance,, and quality of life score. In addition, the majority of studies that evaluated peak O 2 reported an improvement in this parameter after CRT. Few studies have focused on morbidity and mortality. In particular, the recent CARE-HF study has focused primarily on morbidity and mortality (6). Inconsistency on the reduction in hospital admissions has been reported. While a reduction in hospitalizations was observed in the Multisite Simulation in Cardiomyopathies (MUSTIC) and Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trials (2,3), this was not the case in the CONTAK-Cardiac Defibrillator (CONTAK-CD) and MIRACLE-Implantable Cardioverter Defibrillator trials (4,8). The Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial demonstrated a reduction in the composite end point of all-cause mortality or hospitalization during 16 months follow-up (5). The CARE-HF study subsequently demonstrated a clear survival benefit after CRT as compared to optimized medical therapy (6). Secondary end points in the studies were predominantly echocardiographic measurements including: LV systolic function, LVEF, LV reverse remodeling, LV volumes, Mitral regurgitation In these large randomized trials, detailed information on echocardiographic data is not consistently available, but detailed echocardiographic studies have been performed. In general, LV systolic function improved, LV reverse remodeling occurred, and mitral regurgitation decreased. However, the extent of improvement in LVEF and reduction in LV volumes varied substantially among studies. Based on the available trials, the current American College of Cardiology/American Heart Association/North American Society of Pacing and Electrophysiology guidelines state that CRT is beneficial in patients with heart failure, severe systolic LV dysfunction, and wide QRS complex (level of evidence class IB). Although the results are indeed promising, analysis of individual responses revealed that 20% to 30% of patients do not respond to CRT (3,9). Accordingly, emphasis has shifted towards selection of potential responders to CRT, before device implantation. Before discussing the identification of responders, the definition of a responder should be addressed. WHO IS A RESPONDER TO CRT? Small studies have initially used invasive methods to assess acute hemodynamic response to CRT. Long-term response (usually assessed at three to six months of CRT) is mainly evaluated by clinical or echocardiographic parameters (Table 2). The relationship between acute hemodynamic response and chronic outcomes is still not entirely clear. Clinical parameters are subjective and mainly reflect symptoms; a substantial placebo effect may be present in 40% of individuals (3). Still, these are the criteria that are traditionally used to evaluate patients with heart failure, and may be most relevant from a patient perspective. The ultimate clinical end points include a reduction in hospitalization and mortality rate. Echocardiographic parameters may be more objective. Improvements in LV systolic function (mainly expressed as LVEF) have been reported in most studies, but the absolute increase in LVEF varied substantially among studies (3,6,8). Reverse LV remodeling (indicated by a decrease in LV systolic and diastolic diameters and volumes) has been reported consistently in CRT studies and often used as an indicator of response (2,3,6,8). Indeed, molecular changes in the lateral wall of the LV such as increased stress kinase levels may decrease after CRT. Whether these changes contribute to the reverse LV remodeling or are merely a result of the reverse remodeling is yet unclear. Echocardiography has also been used to demonstrate improvements in inter- and intraventricular dyssynchrony (10). Clinical non-responders have also been reported when correlated with echocardiographic results. Yu et al. (11) used a 15% improvement in LV end-systolic volume index after CRT and demonstrated non-response in 13 of 30 (43%) patients. Moreover, clinical and echocardiographic response to CRT may not always appear simultaneously, and patients who respond clinically may not exhibit reverse LV remodeling and vice versa. It appears that more patients exhibit improvement in clinical parameters as compared to echocardiographic markers. This discrepancy may even further complicate the definition of response to CRT. QRS DURATION TO PREDICT RESPONSE TO CRT The response to CRT was initially considered to result in part from resynchronization of interventricular dyssyn-

3 JACC Vol. 46, No. 12, 2005 December 20, 2005: Bax et al. Issues Before Device Implantation 2155 Table 1. CRT in Randomized Clinical Trials End Points Trials Design Patients (n) Primary PATH-CHF (1) Crossover 41 6MWT Peak VO 2 Secondary Hospitalizations MUSTIC-SR (2) Crossover 58 6MWT Peak VO 2 LV volumes MR Hospitalizations Total mortality MIRACLE (3) Parallel arms 453 6MWT MIRACLE-ICD (4) Parallel arms 555 6MWT COMPANION (5) Parallel arms 1,520 All-cause mortality or hospitalization CARE-HF (6) Open label, randomized PATH-CHF II (7) CONTAK-CD (8) Crossover (no pacing vs. LV pacing) Crossover, parallel controlled Peak VO 2 LVEF LVEDD MR Clinical composite response Peak VO 2 LVEF LV volumes MR Clinical composite response All-cause mortality and cardiac morbidity 814 All-cause mortality LVEF LVESV Hospitalization for heart failure 86 6MWT Peak VO MWT LVEF LV volumes Composite of mortality, hospitalizations, VT/VF Results Summary Improvement in 6MWT Less hopitalizations Improvement in 6MWT Peak VO 2 LV volumes MR Less hospitalizations Improvement in 6MWT LVEF LVEDD MR Improvement in Reduced all-cause mortality/ hospitalization Reduced mortality/morbidity Improvement in LVEF LVESV Improvement in 6MWT Peak VO 2 Improvement in 6MWT LVEF LV volumes CARE-HF Cardiac Resynchronization-Heart Failure; CONTAK-CD CONTAK-Cardiac Defibrillator; COMPANION Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure; CRT cardiac resynchronization therapy; LV left ventricular; LVEDD left ventricular end-diastolic dimension; LVEF left ventricular ejection fraction; LVESV left ventricular end-systolic volume; MIRACLE Multicenter InSync Randomized Clinical Evaluation; MIRACLE-ICD Multicenter InSync Implantable Cardioverter Defibrillator trial; MR mitral regurgitation; MUSTIC Multisite Simulation in Cardiomyopathies; NYHA New York Heart Association; PATH-CHF Pacing Therapies in Congestive Heart Failure trial; quality-of-life score; VF ventricular fibrillation; VO 2 volume of oxygen; VT ventricular tachycardia; 6MWT 6-min walk test. chrony (dyssynchrony between the left and right ventricle). Thus, patients with interventricular dyssynchrony were selected for CRT. This selection was based on the QRS duration, because this parameter is considered to reflect interventricular dyssynchrony. Indeed, Rouleau et al. (12) demonstrated a good relation between interventricular dyssynchrony (assessed by tissue Doppler imaging []) and QRS duration. Accordingly, patients with wide QRS were considered candidates for CRT. In general, studies used QRS duration 120 to 130 ms as a selection criterion. The initial studies required the presence of a left bundle branch block pattern on the electrocardiogram, whereas more recent studies also included patients with non-specific interventricular conduction delay (a poorly defined entity) or even right bundle branch block pattern. The beneficial effect of CRT on symptoms, exercise capacity, systolic LV function, and hospitalization rate was demonstrated in these patients with wide QRS complex, as outlined in the preceding text (Table 1). In addition, data from the Pacing Therapies in Congestive Heart Failure (PATH-CHF) II trial demonstrated that the benefit of CRT was most pronounced in patients with QRS duration 150 ms (as compared to patients with QRS

4 2156 Bax et al. JACC Vol. 46, No. 12, 2005 Issues Before Device Implantation December 20, 2005: Table 2. Markers of Chronic Response to CRT Clinical parameters Quality-of-life score 6-min walk distance, exercise capacity peak VO 2 (Heart failure) hospitalizations (Cardiac) mortality Echocardiographic parameters Left ventricular ejection fraction Left ventricular dimensions/volumes Mitral regurgitation Interventricular resynchronization Left ventricular resynchronization CRT cardiac resynchronization therapy; NYHA New York Heart Association; VO 2 volume of oxygen. duration 120 to 150 ms) (13). These observations tend to support the use of the QRS duration for patient selection. However, careful analysis of the individual patients in many CRT studies demonstrated that 20% to 30% of the patients failed to respond to CRT, despite prolonged QRS duration. In particular, Reuter et al. (14) evaluated 102 patients undergoing CRT and reported non-response in 18% of patients. These observations prompted Molhoek et al. (15) to analyze the precise value of the QRS duration to predict response to CRT. Their study included 61 patients, and 45 (74%) responded to CRT. The QRS duration at baseline before pacing was similar between the responders and non-responders ( ms vs ms; p NS). However, a significant shortening in QRS duration after six months of CRT was observed only in responders. Receiver operating characteristic curve analysis showed that a reduction in QRS duration 10 ms had a high sensitivity (73%) with low specificity (44%) (Fig. 1) in prediction of responders. Conversely, a reduction in QRS duration 50 ms was highly specific (88%) but not sensitive (18%) to predict response to CRT. Comparable findings were recently reported by Lecoq et al. (16). Figure 1. Receiver operating characteristic curve analysis on the change in QRS duration after six months of cardiac resynchronization therapy (CRT) demonstrated an optimal sensitivity of 58% and 56% (using a cutoff value of 30 ms) to predict response to CRT. Adapted from Molhoek et al. (15). Figure 2. The QRS duration does not relate with the extent of left ventricular (LV) dyssynchrony as assessed with tissue Doppler imaging. Adapted from Bleeker et al. (17). It has subsequently been suggested that intraventricular dyssynchrony may predict response to CRT more accurately (10). In this respect, studies using demonstrated that patients with intraventricular dyssynchrony had a high likelihood of a positive response to CRT (10). Bleeker et al. (17) evaluated the relation between QRS duration and LV dyssynchrony (assessed by ) in 90 patients with severe heart failure; LVEF 35%; and narrow ( 120 ms), intermediate (120 to 150 ms), or wide ( 150 ms) QRS complexes. Substantial LV dyssynchrony on was present in 27%, 60%, and 70% of patients, respectively. When QRS duration was considered as a continuous variable, no relation between QRS duration and LV dyssynchrony could be demonstrated (Fig. 2). Ghio et al. (18) confirmed the absence of LV dyssynchrony in 48% of patients with an intermediate (120 to 150 ms) QRS complex and in 28% of patients with a wide ( 150 ms) QRS complex. These observations indicate that patients with a wider QRS complex have a higher likelihood of LV dyssynchrony, although 30% of patients with wide ( 150 ms) QRS complex lack LV dyssynchrony. This 30% may partially explain a similar percentage of non-responders in the large trials. These observations have resulted in many echocardiographic studies evaluating different echocardiographic parameters to detect LV dyssynchrony and predict response to CRT. ECHOCARDIOGRAPHIC SELECTION OF RESPONDERS TO CRT: ROLE OF INTERVENTRICULAR DYSSYNCHRONY Echocardiography is the most practical approach to evaluate dyssynchrony and predict response to CRT. Initial studies have focused on assessment of interventricular (left-right) dyssynchrony to predict response. Interventricular dyssynchrony can be evaluated by pulsed-wave Doppler echocardiography assessing the extent of interventricular mechanical delay defined as the time-difference between left and right ventricular pre-ejection intervals; a delay of 40 ms or

5 JACC Vol. 46, No. 12, 2005 December 20, 2005: Bax et al. Issues Before Device Implantation 2157 more has been proposed as a marker of interventricular dyssynchrony (10). Bordachar et al. (19), however, reported that interventricular dyssynchrony was not related to hemodynamic improvement during CRT. Tissue Doppler imaging has also been used to assess interventricular dyssynchrony (11,20,21). Three studies used to compare the delay between peak systolic velocity of the right ventricular free wall and the LV. Although Penicka et al. (21) suggested that assessment of interventricular delay by contributed to the prediction of response to CRT, this was not confirmed by two different studies where was used (11,20). Bax et al. (20) evaluated 80 patients undergoing CRT and demonstrated a similar extent of interventricular dyssynchrony in the 59 responders and the 21 non-responders (47 34 ms vs ms; p NS). Yu et al. (11) demonstrated that interventricular dyssychrony was not predictive of response to CRT in 54 patients undergoing CRT. Thus, most evidence suggests that interventricular dyssynchrony is not useful in the prediction of response to CRT. ECHOCARDIOGRAPHIC SELECTION OF RESPONDERS TO CRT: ROLE OF LV DYSSYNCHRONY ON M-MODE, TWO-DIMENSIOL ECHOCARDIOGRAPHY, AND A variety of echocardiographic techniques have been suggested for the assessment of LV dyssynchrony and prediction of response to CRT. These techniques include M-mode assessment, two-dimensional echocardiography using phase imaging or intravenous contrast,, and potentially three-dimensional echocardiography (10). Tissue Doppler imaging is the most extensively tested technique, and different methods have been proposed, including pulsedwave, color-coded, tissue tracking, displacement mapping, strain and strain rate imaging, and, most recently, tissue synchronization imaging (TSI). A comprehensive summary of the merits of the different techniques to predict response to CRT is provided in Table 3. M-mode echocardiography. Using an M-mode recording from the parasternal short-axis view (at the level of the papillary muscles), the septal-to-posterior wall motion delay can be obtained, and a cutoff value of 130 ms or more was proposed as a marker of intraventricular dyssynchrony. Pitzalis et al. (22) evaluated 20 patients and reported a sensitivity and specificity of 100% and 63%, respectively, to predict response to CRT. In addition, the authors recently demonstrated the prognostic value of the septal-to-posterior wall motion delay (23). However, this parameter is often difficult to obtain. Rose et al. (24) evaluated the feasibility of obtaining this parameter in the patients of the CONTAK-CD database. A clear definition of the systolic deflection of both the septal and posterior wall was possible in only 45% of 79 patients. Moreover, the septal-toposterior wall motion delay did not correlate with LV reverse remodeling. Most importantly, the sensitivity and specificity to predict response (both clinical and echocardiographic) were 24% and 66%. These findings were similar in patients with ischemic and dilated cardiomyopathy. Two-dimensional echocardiography. The first use of two-dimensional echocardiography was that of a semiautomatic method for endocardial border delineation (25). The degree of LV dyssynchrony was quantified in twodimensional echocardiographic sequences from the apical four-chamber view, focusing on the septal-lateral relationships. Computer-generated regional wall movement curves were compared by a mathematical phase analysis, based on Fourier transformation. The resulting septal-lateral phase angle difference is a quantitative measure for intraventricular (dys)synchrony. Using this approach, patients with extensive LV dyssynchrony between the septum and lateral wall exhibited an immediate improvement in hemodynamics after CRT. The second approach utilized echo contrast (Optison, Mallinckrodt, Hazelwood, Missouri) to optimize LV border detection (26). With the improved LV border detection, regional fractional area changes were determined and plotted versus time, yielding displacement maps. From these maps, the LV dyssynchrony between the septum and lateral wall was determined. The authors observed an acute reduction in LV dyssynchrony after biventricular pacing, which correlated with an acute increase in LVEF. No studies on the two-dimensional techniques for prediction of long-term outcome have been published., strain, and strain rate imaging. Tissue Doppler imaging measures the velocity of longitudinal cardiac motion and allows comparison of timing of motion in relation to electrical activity (QRS complex). Different parameters can be derived, and the most frequently used include the peak systolic velocity, the time to onset of systolic velocity, and the time to peak systolic velocity. The measurements can be obtained directly using pulsed-wave and using color-coded, which needs post-processing. With pulsed-wave, only one region can be interrogated at a time making the procedure timeconsuming and precludes comparison of segments simultaneously. Because measurements are influenced by differences in heart rate, loading conditions and respiration measurements that are not simultaneous may be less meaningful. In addition, the timing of peak systolic velocity is often difficult to identify, resulting in imprecise information on LV dyssynchrony. There is limited evidence of pulsed-wave to predict response to CRT. Two studies have demonstrated a relation between LV dyssynchrony on pulsedwave and improvement in symptoms and/or LVEF after CRT (27,28), but prediction of response was not addressed. Bordachar et al. (19) showed that LV dyssynchrony assessed by pulsed-wave correlated with an improvement in cardiac output and reduction in mitral regurgitation after CRT. Penicka et al. (21) used pulsedwave (with an integration of interventricular and LV dyssynchrony) and reported a sensitivity of 96% with a specificity of 77% to predict response to CRT.

6 2158 Bax et al. JACC Vol. 46, No. 12, 2005 Issues Before Device Implantation December 20, 2005: Table 3. Echocardiographic Studies on LV Dyssynchrony to Predict Response to CRT Authors Patients (n) Follow-Up Period (month) Echo Technique Methodology for LV Dyssynchrony Pitzalis et al. (22) 20 1 M-mode Septal-to-posterior wall motion delay Pitzalis et al. (23) M-mode Septal-to-posterior wall motion delay Rose et al. (24) 79 6 M-mode Septal-to-posterior wall motion delay Breithardt et al. (25) 34 Acute 2D phase imaging Kawaguchi et al. (26) 10 9 Contrast echo Penicka et al. (21) 49 6 Pulsed-wave Ansalone et al. (27) 21 1 Pulsed-wave Garrigue et al. (28) Pulsed-wave Bordachar et al. (19) 41 3 Pulsed-wave, M-mode, pulsedwave Doppler Yu et al. (29) 25 3 Color-coded Bax et al. (30) 25 Acute Color-coded Yu et al. (31) 30 3 Color-coded Bax et al. (20) Color-coded Notabartolo et al. (32) 49 3 Color-coded Yu et al. (11) 54 3 Color-coded, SRI Difference between the lateral and septal wall motion phase angles Septal and lateral fractional area changes Ts(onset) of 3 basal LV and 1 basal RV segments Systolic dyssynchrony among 5 basal segments Ts(onset) between septum and lateral wall Maximal difference in 12 LV segments for Ts, Ts(onset), Ts-SD, and DLC Ts of 12 LV segments in ejection phase Septal-to-lateral delay of Ts in ejection phase Ts-SD of 12 LV segments in ejection phase Septal-to-lateral delay of Ts in ejection phase Maximal difference in Ts in 6 basal segments (both ejection phase and post-systolic shortening) Ts-SD of 12 LV segments in ejection phase (and 17 other parameters) DLC Sogaard et al. (33) Color-coded, SRI Sogaard et al. (34) 20 Acute Color-coded TT and DLC, TT, SRI Main Findings Septal-to-posterior delay 130 ms predicted LV reverse remodeling Septal-to-posterior delay 130 ms predicted event-free survival Septal-to-posterior delay 130 ms insufficient to predict LV reverse remodeling Delayed lateral wall motion predicted acute hemodynamic improvement 1 Septal inward motion, 2 spatial and temporal LV dyssynchrony by 40%, and correlated with 1 LVEF Summation of inter- and intra(lv)-ventricular delay 102 ms predicted 1 LVEF Extensive LV dyssynchrony resulted in 1 in symptoms, and 1 LVEF Post-CRT reduction in LV dyssynchrony and improvement in symptoms Maximal difference in 12 LV segments for Ts, T(onset), Ts-SD closely correlated with improvement of MR and CO, but not interventricular delay by pulsed-wave Doppler echo Improve LV dyssynchrony by delaying Ts in 12 LV segments globally resulting in homogenous Ts Septal-to-lateral delay of Ts 60 ms predicted 1 LVEF Ts-SD of 12 LV segments 33 ms predicted LV reverse remodeling Septal-to-lateral delay of Ts 65 ms predicted LV reverse remodeling; and associated with lower event rate Maximal difference in Ts in 6 basal segments 110 ms predicted reverse remodeling Ts-SD of 12 LV segments 31 ms predicted LV reverse remodeling Number of basal segments with DLC predicted 1 LVEF Optimization of V-V timing by TT resulted in 2 DLC and 1 LVEF Sensitivity (%) Specificity (%) Continued on next page

7 JACC Vol. 46, No. 12, 2005 December 20, 2005: Bax et al. Issues Before Device Implantation 2159 Table 3. Continued Authors Patients (n) Follow-Up Period (month) Echo Technique Methodology for LV Dyssynchrony Breithardt et al. (35) 18 Acute Strain, SRI Strain and SRI at septal and lateral walls Sun et al. (36) 34 Acute Displacement, Strain, SRI, and strain, and SRI displacement at septal and lateral walls Popović et al. (37) Displacement and strain Dohi et al. (38) 38 Acute TSI and strain Strain at septal and lateral walls Peak radial strain septum versus posterior wall Gorcsan III et al. (39) 29 Acute TSI Septal-posterior delay (both ejection phase and post-systolic shortening) Yu et al. (40) 56 3 TSI Ts-SD of 12 LV segments in ejection phase (inclusion of post-systolic shortening) Zhang et al. (43) D echo Time to minimal systolic volume (Tmsv) in 6, 12, and 16 LV segments Main Findings Baseline: lateral wall strain and strain rate higher than septal; CRT: septal wall strain and strain rate higher than lateral 1 LVEF and 1 peak strain rate at lateral wall by CRT; 1 Septal and inferior wall displacement by LV pacing 1 Global LV peak strain, 2 coefficient of change in LV strain, no change in septal or lateral wall displacement Delay in septal-posterior strain 130 ms, predicted 1 stroke volume Septal-posterior delay 65 ms predicted 1 stroke volume Ts-SD of 12 LV segments in ejection phase 34 ms predicted reverse LV remodeling Improvement of Tmsv parameters during CRT Tmsv of 16 LV segments by 3D echo correlated closely with Ts-SD of 12 LV segments by Sensitivity (%) Specificity (%) CO cardiac output; CRT cardiac resynchronization therapy; DLC delayed longitudinal contraction; LV left ventricular; LVEF left ventricular ejection fraction; MR mitral regurgitation; RV right ventricular; SRI strain rate imaging; tissue Doppler imaging; TMSV time to minimal systolic volume; Ts time to peak myocardial systolic velocity; TSI tissue synchronization imaging; Ts(onset) time to onset of myocardial systolic velocity; Ts-SD standard deviation of time to peak myocardial systolic velocity; TT tissue tracking; V-V interventricular. Eight studies have used color-coded to assess LV dyssynchrony and predict outcome (Table 3)(11,20,29 34). From these color-coded images, tracings can be obtained by post-processing, and the majority of studies have used time to peak systolic velocity to assess LV dyssynchrony. Initially, investigators focused on the four-chamber view to identify LV dyssynchrony by color-coded (Fig. 3). Velocity tracings were derived from the basal septal and lateral segments, and the septal-to-lateral delay was measured. It was shown that a delay 60 ms was predictive of acute response to CRT (30). Subsequently, a four-segment model was applied, which included four basal segments (septal, lateral, inferior, and anterior) (20). It was shown that a delay 65 ms allowed prediction of response to CRT. Using this cutoff value, sensitivity/specificity for prediction of clinical improvement (defined by an improvement in and 6-min walking distance) were both 80% whereas sensitivity/specificity for LV reverse remodeling (defined as a 15% reduction in LV endsystolic volume) were both 92%. In addition, patients with LV dyssynchrony 65 ms had a favorable prognosis after CRT. The extensive studies by Yu et al. (11,29,31) have used a 12-segment model. Tracings were derived from 12 segments, and an LV dyssynchrony index was derived from the standard deviation of all 12 time intervals demonstrating that a dyssynchrony index 31 ms yielded a sensitivity and specificity of 96% and 78% to predict LV reverse remodeling (11). In general, prediction of response to CRT based on time to peak systolic velocity (using a varying number of segments) yields a high sensitivity (ranging from 76% to 97%) and specificity (ranging from 55% to 92%) (Table 3). Seven studies have used tissue tracking, strain, and/or strain rate imaging (11,33 38). Tissue tracking (GE Vingmed, Horten, Norway) provides a color-coded display of myocardial displacement, allowing for easy visualization LV dyssynchrony and the region of latest activation. Sogaard et al. (34) pioneered this approach and demonstrated that the number of segments with delayed longitudinal contraction was related to the improvement in LVEF during CRT. Strain and strain rate analysis is performed by off-line analysis of the color-coded tissue Doppler images. Strain analysis allows direct assessment of the extent and timing of myocardial deformation during systole and is expressed as

8 2160 Bax et al. JACC Vol. 46, No. 12, 2005 Issues Before Device Implantation December 20, 2005: Figure 3. Color-coded four-chamber tissue Doppler image (upper left). Post-processing yields velocity tracings (right); severe left ventricular dyssynchrony is present as indicated by the delay in the peak systolic velocity of the septum (yellow curve) as compared to the lateral wall (green curve). the percentage of segmental shortening or lengthening in relation to its original length (10). The main advantage over is that strain analysis allows differentiation between active systolic contraction and passive motion. This is important in patients with ischemic cardiomyopathy with the presence of scar tissue. Breithardt et al. (35) showed that CRT reversed the pathologic septal-lateral strain relationships and reduced the incidence of early systolic pre-stretch Figure 4. Tissue synchronization imaging, four-chamber view. (Left) The color represents timing: green normal timing; red severe delay. Color-guided visual identification of the site of latest activation facilitates sample-placement to derive the tissue Doppler imaging () velocity tracings. In this patient, the earliest activation (green) is in the lateral wall, and the latest activation is in the lateral wall (red); the velocity tracings (right) confirm the delay between the septum and lateral wall.

9 JACC Vol. 46, No. 12, 2005 December 20, 2005: Bax et al. Issues Before Device Implantation 2161 Figure 5. Four-dimensional tissue synchronization imaging (TSI) of a normal individual. From the different views (left), a three-dimensional impression of the left ventricle is reconstructed (middle). The entire three-dimensional image of the left ventricle is green indicating no dyssynchrony. Post- processing allows the display of the different segments in a polar map format (right) to further facilitate identification of the site of latest activation. in the late activated wall and of post-systolic shortening. However, no study with strain or strain rate imaging has so far reported on the actual prediction of response to CRT (Table 3), except for Yu et al. (11), who demonstrated that strain rate imaging could not predict LV reverse remodeling. Despite the technical advantages of the strain imaging, the technique has not become routine practice in the evaluation of patients considered for CRT. The main limitations are the time-consuming aspect of the technique, the high operator dependency, and the moderate reproducibility. Only one direct comparison between and strain rate imaging has been reported in 54 patients undergoing Figure 6. Four-dimensional tissue synchronization imaging (TSI) of a patient with left ventricular dyssynchrony. From the different views (left), a three-dimensional impression of the left ventricle is reconstructed (middle). The region of latest activation is indicated in red. Post-processing yields the polar-map format (upper right) indicating in red the site of latest activation (anteroseptal), and further calculations can be performed (lower right) to further quantify the extent of left ventricular dyssynchrony using different parameters.

10 2162 Bax et al. JACC Vol. 46, No. 12, 2005 Issues Before Device Implantation December 20, 2005: Figure 7. Real-time three-dimensional full volume analysis of regional left ventricular function showing (top left) the reconstructed left ventricular cast and the bulls-eye display (bottom left) of the 16 segments. Changes in regional volume (color-matched) for each of the 16 segments is displayed in the upper right. The anteroseptal and septal segments (light blue and green) show poor function and significant delay in achieving a minimum volume compared to other segments. A first derivative display of the regional volume curves is shown in the lower right panel and also demonstrates significant dispersion in the timing of minimal regional volume (indicated by the zero crossing points). CRT (11). Left ventricular dyssynchrony on was predictive of LV reverse remodeling, but strain rate imaging failed to predict response to CRT (11). TSI TO ASSESS LV DYSSYNCHRONY A recent addition to the tissue Doppler approach to quantify LV dyssynchrony has been the automated color-coding of time to peak longitudinal velocities. This color-coding of temporal velocity data is superimposed on the routine two-dimensional echocardiographic images to provide visual mechanical information on the anatomical regions. Tissue synchronization imaging (GE Vingmed) (38 40) is a signal-processing algorithm of the tissue Doppler data to automatically detect peak positive velocity and then colorcode the time to peak velocities in green for normal timing, yellow-orange for moderate delay, and red for severe delays in peak longitudinal velocity (Fig. 4). Interval start time is manually fine-tuned to begin with aortic valve opening to exclude isovolumic contraction velocity and extended to rapid filling (E-wave) to include post-systolic LV dyssynchrony; TSI color-coding is then used to guide placement of 7 15 mm oval regions of interest in the basal and mid-segments from apical views. Regions of interest are localized where the color-coding of timing is most representative for the anatomical segment for time-velocity curve analysis. Although the color-coding information is very useful, it is considered important to continue to use the time-velocity tracings to correctly identify the peak velocities for LV dyssynchrony analysis. Left ventricular dyssynchrony can be defined as difference in time to peak velocity of opposing walls: inferoseptal to lateral wall (four-chamber view), anterior to inferior wall (two-chamber view), and anteroseptal to posterior wall (long-axis view). In a pilot series of 29 patients, TSI was assessed before CRT, and acute response (defined as an immediate increase in LV stroke volume by 15% or more) was observed in 21 patients (39). Differences in baseline TSI time to peak velocity of opposing LV walls (three views average) were greater in acute responders than non-responders: ms versus ms (p 0.05). When delays between individual walls were compared, dyssynchrony between the anteroseptal and posterior wall (assessed from the apical long-axis

11 JACC Vol. 46, No. 12, 2005 December 20, 2005: Bax et al. Issues Before Device Implantation 2163 Figure 8. Parametric polar-map displays (lower left and lower right panels) of left ventricular dyssynchrony of the real-time three-dimensional images; blue indicates early activation, red indicates late activation. Left ventricular dyssynchrony is present before cardiac resynchronization therapy (CRT) in the anteroseptal region (red, lower left panel); almost complete resynchronization has occurred after CRT, with disappearance of red regions (lower right). view) had the greatest ability to separate acute responders from non-responders after CRT. A cutoff value of 65 ms had a sensitivity and specificity of 87% and 100%, respectively, to predict acute response to CRT (39). The cutoff value of 65 ms is in agreement with other results (20) using color-coded. In addition, a recent study by Yu et al. (40) used TSI in 56 patients to predict LV reverse remodeling after three months of CRT, and a sensitivity of 87% with a specificity of 81% was demonstrated. Recent technological enhancements include multiplane TSI imaging to keep frame rates high with threedimensional reconstruction of color-coded temporal LV activation; imaged in the time-domain, this allows actual four-dimensional information. Examples of four-dimensional TSI in a normal individual and a patient with LV dyssynchrony are demonstrated in Figures 5 and 6. Anglecorrected tissue Doppler data for color-coded temporal activation, known as Dyssynchrony Imaging (Toshiba, Tokyo, Japan), also have the potential to provide radial dyssynchrony data that may be additive to dyssynchrony analysis of longitudinal velocities alone. In 38 patients undergoing CRT, Dohi et al. (38) showed a sensitivity of 95% with a specificity of 88% to predict acute response to CRT using radial dyssynchrony. THREE-DIMENSIOL ECHOCARDIOGRAPHY TO ASSESS LV DYSSYNCHRONY Three-dimensional echocardiography has evolved from a technique based on reconstruction of multiple twodimensional scan planes to an almost real-time methodology. Left ventricular volumes and LVEF can be assessed with high accuracy (41). In the context of LV dyssynchrony, analysis of regional function in the time-domain is important (10), and a series of plots is obtained representing the change in volume for each segment (usually 16 or 17 segments) throughout the cycle (Fig. 7). With synchronous contraction of all segments, each segment would be expected to achieve the minimum volume at almost the same point in the cardiac cycle. In LV dyssynchrony, dispersion exists in the timing of the point of minimum volume for each of the segments. The degree of dispersion reflects the severity of LV dyssynchrony (42). Parametric polar-map displays (of the three-dimensional data) of the timing of LV contraction have been developed to facilitate interpretation of data. This methodology examines regional LV contraction at approximately 3,000 points over the endocardial surface rather than in 16 or 17 segments. Color-coding is used to identify the region/site of latest

12 2164 Bax et al. JACC Vol. 46, No. 12, 2005 Issues Before Device Implantation December 20, 2005: Figure 9. Noninvasive multislice computed tomography of the venous anatomy. (Left) Three-dimensional volume rendered reconstruction. (Right) Multiplanar curved reconstruction (MPR) of the coronary sinus (CS). Indicated on the three-dimensional reconstruction (left) are the CS, the posterior interventricular vein (PIV), the posterior vein of the left ventricle (PVLV), and the great cardiac vein (GCV). LA left atrium; LV left ventricle; RA right atrium; RV right ventricle. activation, and this is potentially useful for electrophysiologists to select the optimal LV lead position. Examples of parametric polar-map images (of the three-dimensional data) pre- and post-crt are displayed in Figure 8. Zhang et al. (43) used three-dimensional echocardiography in 13 patients who had previously received CRT; when CRT was withheld, significant LV dyssynchrony occurred, associated with a decrease in LVEF. Currently, no extensive data are available on the prediction of response to CRT using three-dimensional echocardiography. OTHER FACTORS RELATED TO RESPONSE: VENOUS ATOMY AND SCAR TISSUE Besides LV dyssynchrony, other factors are important for success of CRT. In particular, the venous anatomy is important. Considerable variability exists in the venous system (44) as well as variability in the nomenclature used to designate specific coronary veins. The authors evaluated venous anatomy by retrograde venography in 129 consecutive patients referred for implantable cardioverter defibrillator implantation. In 5 (4%) patients coronary sinus cannulation failed, and in 38 (29%) visualization was suboptimal and/or venograms were incomplete. In the remaining 86 patients, the anterior interventricular vein and middle cardiac vein could be visualized in 99% and 100% of patients, respectively. The veins (posterior or left marginal veins) between these two veins are mostly used for LV lead placement in CRT. Only one prominent vein was present in 51% of patients, two veins in 46% of patients, whereas more than two veins were present in only 2% of patients. When patients would be considered for CRT only in the presence of the posterior veins, 55% would be acceptable. When patients would be considered for CRT in the presence of the posterior or the left marginal veins, 99% would be acceptable. Ideally, venous anatomy should be assessed noninvasively, at the outpatient clinic, to determine whether a transvenous approach is feasible, or whether a (minimal invasive) surgical approach should be used for LV lead Figure 10. Resting single-photon emission computed tomography images (using technetium-99m tetrofosmin) of a patient with a previous inferoposterolateral infarction. A severe defect in tracer uptake is visible on the mid-ventricular short-axis slice (SA) (left) in the inferior and posterolateral regions, which is confirmed on the horizontal long-axis (HLA) (middle) and vertical long-axis (VLA) (right) projections.

13 JACC Vol. 46, No. 12, 2005 December 20, 2005: Bax et al. Issues Before Device Implantation 2165 Figure 11. Contrast-enhanced cardiovascular magnetic resonance short-axis slices illustrating the presence and transmural extent of scar tissue. (Left) Non-transmural scar tissue in the posterolateral wall as indicated by the hyperenhanced (white) region. (Right) Transmural scar formation in the posterolateral region. implantation. The feasibility of multislice computed tomography (MSCT) to visualize the venous anatomy was recently demonstrated (45). The variability in venous anatomy was confirmed, and findings were in line with previous invasive observations; MSCT allowed not only precise determination of coronary sinus and its tributaries, but also assessment of distances between veins and ostial size of the coronary sinus. An example of an MSCT depicting venous anatomy is demonstrated in Figure 9. Although information on venous anatomy is needed, it is really the integrated information on the site of latest activation (maximum LV dyssynchrony) and venous anatomy that determines the approach for LV lead implantation (transvenous versus surgical). Accordingly, it would be desired for example to fuse the three-dimensional TSI images (Figs. 5 and 6) with the MSCT images (Fig. 9), in order to co-registrate electromechanical delays with venous anatomy. Another factor that is important for success of CRT is whether scar tissue is present in the region of latest activation (where the LV lead should be positioned). Currently, no solid data on this issue are available. One anecdotal report, however, demonstrated that initial response to CRT was reversed after acute infarction in the territory of the LV lead (46). It would, therefore, be of potential interest to evaluate non-invasively, before CRT implantation, whether the target region for LV lead positioning contains viable tissue or whether scar tissue is present. Various techniques are available, including nuclear imaging techniques, echocardiographic techniques, or cardiovascular magnetic resonance (CMR). Routine resting single-photon emission computed tomography imaging with a technetium-99m-labeled tracer would provide the requested information, as indicated in Figure 10, showing a large defect in the inferior and posterolateral regions, indicating scar tissue. Contrast-enhanced CMR may eventually provide the optimal information, because it allows precise depiction of the extent, and transmurality of scar tissue (Fig. 11). CONCLUSIONS In large clinical trials, the beneficial effect of CRT has been demonstrated. On an individual basis, however, 20% to 30% of patients still do not respond to CRT. Observational echocardiographic studies have clearly demonstrated that the presence of LV dyssynchrony is an important factor determining response to CRT, whereas interventricular dyssynchrony appears of less importance. Various studies using different echocardiographic approaches have subsequently aimed at prediction of response to CRT, and the available literature suggests that using 2-, 4-, or 12-segment models of LV dyssynchrony may represent the best method to predict response to CRT. Careful analysis of the literature also reveals the limitations of published studies. The number of patients is small in most studies, a lack of consensus exists in assessment of response (in particular clinical parameters vs. echocardiographic parameters), the measurements of LV dyssynchrony are different among studies, and direct comparisons between LV dyssynchrony parameters to predict response are virtually absent. The Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study is underway to examine if prospectively defined echocardiographic parameters of systolic dyssynchrony are able to predict a favorable response to CRT, and the latter includes both clinical composite end points and LV reverse remodeling (47). Still, from the existing evidence, it appears mandatory to expand current guidelines for patient selection for CRT, and to include assessment of LV dyssynchrony. In addition to LV dyssynchrony, information on venous anatomy and the presence of scar tissue may further optimize response to CRT, but further studies are needed to fully appreciate the clinical importance of these issues.

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