Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy

Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient... Abstract Aim To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. Methods and results Echocardiography was performed in 1060 patients before and 12 ± 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as ≥15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37–86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline-based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines. Conclusion Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony. guidelines, CRT, mechanical dyssynchrony, heart failure, apical rocking Introduction Guidelines aim at translating inclusion criteria of high-quality clinical landmark trials into indications for treatment recommendations in order to guarantee a solid evidence base for the clinical practice. In the field of cardiac resynchronization therapy (CRT), the inclusion criteria of landmark trials that impacted the current recommendations for patient selection were left ventricular ejection fraction (≤30%,1,2 ≤35%3,4, ≤40%5), New York Heart Association (NYHA) Class (I–II,1,5 II,4 II–III,2 III,3 II–IV,6 III–IV7,8), and QRS width (≥120 ms,2,5 ≥130 ms,4,7,9 ≥150 ms3,10). Recommendations have been further influenced by study results showing a better response of patients with left bundle branch block (LBBB) than non-LBBB morphology.11 The suggested possible harm of CRT implantation in patients with QRS duration less than 130 ms by some studies12 has led to increasing the threshold for CRT implantation from 120 ms in 2013 guidelines13 to 130 ms in the 2016 edition of the European guidelines.14 While this approach ensures a strong evidence base for a certain treatment, it does not necessarily guarantee the optimal strategy for patient selection, as relevant or potentially favourable selection criteria might not have been tested. In the case of CRT, which has become an established treatment option for patients with heart failure, left ventricular (LV) dysfunction and conduction delays, still approximately one-third of the patients remain non-responders to this costly and invasive therapy.15 One such potential selection criterion, which is not considered in current guidelines is mechanical dyssynchrony. This is in particular due to the disappointing results of studies that tested the additional predictive value of parameters derived from the timing of longitudinal myocardial velocity peaks as surrogate of mechanical dyssynchrony, which failed to show any additional value over conventional guideline criteria despite promising results from single-centre studies.16 In the meantime, however, there is growing evidence that advanced concepts such as the detection of specific motion patterns could be a potential guide for CRT candidate selection.17,18 The PREDICT-CRT trial investigated the association between CRT outcome and a novel parameter of mechanical dyssynchrony, characterized by a short septal contraction pulling the apex septally [‘septal flash’ (SF)] followed by a delayed lateral wall contraction which causes a lateral motion of the apex [‘apical rocking’ (ApRock)]. This specific pattern of contraction in addition to similar parameters which rely on the same phenomena, have been shown to be strongly associated with better survival and CRT response.17,19–26 In this study, we relate current CRT guideline recommendations for patient selection with patient outcome and investigate the potential additive prognostic value of echocardiographic markers of mechanical dyssynchrony. Methods Study population We analysed data from the PREDICT-CRT database17 which comprises data of 1060 patients who received CRT between 1999 and 2012 in six European centres. The indication for CRT implantation was a clinical decision of the treating physician. All patients were on optimized pharmacologic therapy for at least 3 months before CRT. Ischaemic origin of heart failure was proven by coronary angiography and/or records of myocardial infarction. At the time of inclusion, none of the candidates required interventional or surgical treatment for coronary disease. For follow-up, we collected data on mortality from medical records, by interviews with the patient’s general practitioner or relatives, and/or from national death registries. The study was approved by the Ethics Committee of the University Hospitals Leuven. Patient classification For the current analysis, patients were retrospectively classified following the recommendations for CRT implantation as published in the 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure14 and according to the 2012 guideline published by the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society (ACCF/AHA/HRS).23 First, we excluded data sets of 286 patients from our database, for which not all parameters used in the guideline classification scheme were available. The remaining data sets were then assigned to a guideline indication class when they met all criteria of that specific class. This assignment was performed by converting the guideline statements into Boolean expressions (Supplementary material online, Figure S1) and applying them to our database, thus avoiding any clinical interpretation of patient characteristics. In this way, 4.1% and 1.4% of patients were classified as Class III, while 4.9% and 9.4% of the patients remained unclassifiable according to the European and American guidelines, respectively. In the following text, these patients are referred to as CRT-not recommended (Supplementary material online, Figure S2). Echocardiography Patients underwent echocardiography before and 12 ± 6 months after CRT implantation. LV volumes and ejection fractions were measured using the modified biplane Simpson’s method. Patients with LV end-systolic volume (LVESV) decrease of ≥15% at the time of the follow-up visit were considered as volume responders. Mechanical dyssynchrony was visually assessed by analysing the presence of ApRock and SF (Supplementary material online, Videos S1 and S2). All echocardiographic measurements were performed by two experienced readers. A blinded third reader was asked in case of disagreement.17 Resynchronization therapy All patients received biventricular pacing, in 399 (40%) with defibrillator (CRT-D). LV pacing leads were positioned, guided by coronary venography, preferably in the lateral and postero-lateral venous branches. Device settings were optimized within a week of CRT device implantation, as deemed clinically appropriate, based on surface electrocardiogram (ECG) or Doppler echocardiography.24 Statistical analysis Continuous data are expressed as mean ± standard deviation. Normally distributed data were compared between groups using unpaired Student’s t-test for continuous variables and χ2 test for categorical variables. If not normally distributed, median and interquartile range (IQR) and a Wilcoxon rank sum test were used. Survival rates were assessed using the Kaplan–Meier method, and differences in survival were compared between groups by a Log-rank test. Predictors of long-term survival were analysed in Cox’s proportional hazards models. Data were processed using SPSS (IBM, Chicago, IL, USA) version 24.0. Two-sided P-value of <0.05 was considered significant. Results Study population Characteristics of the study population are summarized in Table 1. Applying the European and American guidelines retrospectively, 63.4% and 52.6% of the patients had a Class I indication, 18.2% and 33.9% a Class IIa and 9.4% and 2.6% a Class IIb indication at the time of CRT implantation, respectively. Nine percent of the patients had in retrospect no treatment recommendation according to current European guidelines and 10.8% according to the American counterpart (Figure 1). Patients who had to be excluded from this analysis due to missing data showed on average no significant difference in survival compared to the analysed study population (Supplementary material online, Figure S3). Table 1 Baseline clinical and echocardiographic characteristics of the study population (n = 774) EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF, ejection fraction; LBBB, left bundle branch block; Dyss, mechanical dyssynchrony at baseline; AF, atrial fibrillation; NYHA, New York Heart Association. Table 1 Baseline clinical and echocardiographic characteristics of the study population (n = 774) EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF, ejection fraction; LBBB, left bundle branch block; Dyss, mechanical dyssynchrony at baseline; AF, atrial fibrillation; NYHA, New York Heart Association. Figure 1 View largeDownload slide Percentage assignment of the study population to recommendations classes for CRT implantation according to the European and the American guidelines. CRT-not recommended (grey) refers to the patients who were either classified as Class III or met no recommendation class. Figure 1 View largeDownload slide Percentage assignment of the study population to recommendations classes for CRT implantation according to the European and the American guidelines. CRT-not recommended (grey) refers to the patients who were either classified as Class III or met no recommendation class. The intraobserver agreement for visual assessment of ApRock and SF had been reported earlier17 and was 93% [k = 0.81 95% confidence interval (95% CI) 0.66–0.95] and 93% [k = 0.80 (95% CI 0.66–0.95)], respectively. The interobserver agreement was 86% [k = 0.71 (95% CI 0.67–0.76) for both ApRock and SF]. Volumetric response From our study population, 65% of patients who had a Class I recommendation according to current European guidelines showed a volumetric response to CRT, 50% with Class IIa, 38% with Class IIb, and 40% of the CRT-not recommended (P < 0.0001, Figure 2). Comparable response rates were observed according to the American classification, 66% in Class I, 51% in Class IIa, 25% in Class IIb, and 40% in the CRT-not recommended (P < 0.0001, Supplementary material online, Figure S4). Figure 2 View largeDownload slide Volumetric response of patients assigned to the different European recommendation classes for CRT implantation. See Supplementary material online, Figure S4 for similar results applying the respective American guidelines. Figure 2 View largeDownload slide Volumetric response of patients assigned to the different European recommendation classes for CRT implantation. See Supplementary material online, Figure S4 for similar results applying the respective American guidelines. Adding mechanical dyssynchrony as an additional selection criterion to each guideline class led to a better discrimination between volume responders and non-responders within all European classes (77% in Class I, 75% in Class IIa, 62% in Class IIb, and 69% in the CRT-not recommended, Figure 3) and American guideline Classes I (76%), IIa (75%), IIb (75%), and the CRT-not recommended (70%), Supplementary material online, Figure S5. Figure 3 View largeDownload slide Volumetric response of patients assigned to the European recommendation classes, separated by the presence (+Dyss) or absence (−Dyss) of mechanical dyssynchrony at baseline. The respective result using the American guideline recommendations are shown in Supplementary material online, Figure S5. Figure 3 View largeDownload slide Volumetric response of patients assigned to the European recommendation classes, separated by the presence (+Dyss) or absence (−Dyss) of mechanical dyssynchrony at baseline. The respective result using the American guideline recommendations are shown in Supplementary material online, Figure S5. Survival analysis During a median follow-up of 59 months (IQR 37–86 months), no significant difference was found in survival among patient’s classes defined by the European guidelines (Log-rank P = 0.2). The survival of the classes defined by the American guidelines was significantly different between Classes I and IIa (P = 0.002) but not among the other classes (Figure 4). In both guidelines, there was no significant difference in survival between patients in whom CRT was recommended (Classes I, IIa, and IIb together) vs. those in whom it was not recommended (Figure 5). Figure 4 View largeDownload slide The Kaplan–Meier curves depicting long-term survival of patients after CRT implantation, stratified by the different recommendation classes of the European and the American guidelines. Note that there is no significant difference in survival among European guideline classes (Log-rank P = 0.2), while only Classes I and IIa in the American guidelines showed significant survival difference (P = 0.002). N.S, non-significant; N.R., not recommended for CRT implantation. Figure 4 View largeDownload slide The Kaplan–Meier curves depicting long-term survival of patients after CRT implantation, stratified by the different recommendation classes of the European and the American guidelines. Note that there is no significant difference in survival among European guideline classes (Log-rank P = 0.2), while only Classes I and IIa in the American guidelines showed significant survival difference (P = 0.002). N.S, non-significant; N.R., not recommended for CRT implantation. Figure 5 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing no significant difference between patients with (Classes I, IIa, and IIb) and those without recommendation for therapy (Class III and unclassifiable) according to both the European and American guidelines. Figure 5 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing no significant difference between patients with (Classes I, IIa, and IIb) and those without recommendation for therapy (Class III and unclassifiable) according to both the European and American guidelines. For the entire study cohort, the presence of mechanical dyssynchrony before CRT implantation was associated with favourable outcome (Log-rank P < 0.0001) due to a lower all-cause mortality [hazard ratio (HR) 0.30, 95% CI 0.24–0.39; P < 0.0001, Figure 6]. Also within each European guideline recommendation class, the presence of mechanical dyssynchrony was associated with more favourable outcome (Log-rank P < 0.0001, 0.006, 0.004, 0.02 for Classes I, IIa, IIb, and the CRT-not recommended, respectively, Figure 7) due to a lower all-cause mortality (HR 0.21, 95% CI 0.15–0.30; P < 0.0001 in Class I; HR 0.47, 95% CI 0.27–0.82; P = 0.007 in Class IIa, HR 0.35, 95% CI 0.14–0.87; P = 0.02 in Class IIb, and HR 0.29, 95% CI 0.12–0.68; P = 0.004 in the CRT-not recommended). In American recommendation classes, mechanical dyssynchrony had a similarly favourable impact on outcome (Log-rank P < 0.0001, HR 0.40; 95% CI 030–0.54; P < 0.0001 for Class I; Log-rank P < 0.0001, HR 0.52; 95% CI 0.35–0.77; P = 0.001 for Class IIa; and Log-rank P 0.03; HR 0.37; 95% CI 0.18–0.76; P = 0.007 for the CRT-not recommended, Supplementary material online, Figure S6). Figure 6 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing the association of baseline mechanical dyssynchrony with favourable overall survival (hazard ratio 0.30, P < 0.0001). Figure 6 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing the association of baseline mechanical dyssynchrony with favourable overall survival (hazard ratio 0.30, P < 0.0001). Figure 7 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation for each European recommendation class. Note that within each guideline recommendation class, the presence of baseline mechanical dyssynchrony (+Dyss) was associated with a better long-term survival while its absence (−Dyss) was associated with less favourable outcome. N.R., not recommended for CRT implantation. Figure 7 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation for each European recommendation class. Note that within each guideline recommendation class, the presence of baseline mechanical dyssynchrony (+Dyss) was associated with a better long-term survival while its absence (−Dyss) was associated with less favourable outcome. N.R., not recommended for CRT implantation. Discussion In this study, we retrospectively applied the latest European and American guideline recommendations for CRT implantation to a large database of CRT recipients. We found a relation between response rate to CRT and guideline recommendation class. The survival of patients with and without a recommendation for CRT implantation according to the current guidelines; however, was not significantly different. In each guideline recommendation class, mechanical dyssynchrony (ApRock and/or SF) was strongly associated with better volumetric response and more favourable patient outcome after CRT implantation. Guideline recommendation classes and volumetric response We found a significant relation between guideline recommendation classes and volumetric response to CRT (Figure 2 and Supplementary material online, Figure S4). This behaviour might be expected, as a lower recommendation class should imply a lower likelihood that a certain therapy is effective. Aiming at better identification of potential responders to CRT, the updates of the guidelines have introduced more strict criteria in Class I recommendation regarding QRS width and morphology. However, we found that 35% and 34% of patient with Class I recommendation according to the European and American guidelines, respectively, were non-responders. This observation is in concordance with other CRT studies which repetitively find a volumetric non-responder rate of around one-third of the implanted patients.25 These non-responders have significantly more often an ischaemic aetiology of heart failure, more scarred segments, a higher NYHA functional class, and less mechanical dyssynchrony (Supplementary material online, Tables S1 and S2). Although a lack of volumetric response does not necessarily equal a therapy failure, it is an indication that current recommendations for CRT implantation might lack specificity. Our analysis also revealed that 40% and 42% of the patients who were not recommended for CRT implantation according to current European and American guideline recommendations, respectively, showed a volume response. Most of these patients showed non-ischaemic aetiology of cardiomyopathy and mechanical dyssynchrony at baseline (Dyss) echocardiographic examination (see supplementary subanalysis of the CRT-not recommended). This observation indicates a potential room for improving the sensitivity of the current guideline criteria. Mechanical dyssynchrony and volumetric response Mechanical dyssynchrony, on the other hand, was closely linked with volumetric response. For both guidelines, the additional consideration of mechanical dyssynchrony led to a better association with volumetric response in all recommendation classes (Figure 3 and Supplementary material online, Figure S5). Our data are in contrast to the predominant notion that the role of baseline mechanical dyssynchrony assessment might be of limited value in patients with LBBB and QRS ≥ 150 ms (Class I recommendation), as these patients already have the largest likelihood of response.5 We found, however, that even in this group, the selection of patients could be further improved when baseline mechanical dyssynchrony is considered in addition to the respective European and American guideline criteria (from 65% to 77% and from 66% to 76%, respectively). Our data are also in contrast to the notion that patients with QRS duration between 120 and 150 ms are less likely to respond to therapy26 which are classified depending on the pattern of the bundle branch block into Classes IIa and IIb by both guidelines. Considering mechanical dyssynchrony increased the number of correctly classified volume responders in the European recommendation Classes IIa by 25% and IIb by 24% and in the American guideline Class IIa by 24% and IIb by 50%. Our data are in-line with other studies, which have demonstrated an added prognostic value of mechanical dyssynchrony assessment in patients with moderately wide QRS complex (120–150 ms).27 Guideline-based selection criteria, room for improvement Our data show that specific signs of mechanical dyssynchrony, reflecting typical LBBB contraction pattern is closely linked to volumetric response regardless of QRS width. QRS width measurements have been shown to be associated with low reproducibility and high inter- and intraobserver variability,28 which might in part explain patient miss-classifications and along with our findings doesn’t make it the ideal surrogate to describe the mechanical dyssynchrony of the LV which is the pathophysiologic mechanism underlying the ventricular failure and the main target of a resynchronization therapy. Furthermore we were able to confirm the negative impact of a ischaemic aetiology of heart failure and scar burden, which has been shown to be associated with poor CRT response in addition to masking or modulating myocardial deformation patterns.29,30 Our data consequently suggest that the additional consideration of scar localization and extent would improve patient selection even further. Guideline recommendation classes and patient survival Our data showed a non-significant difference in survival between patients who were recommended for therapy according to the guidelines (recommendation Classes I, IIa, and IIb) and the CRT-not recommended, a finding that may indicate that there might be shortcomings in both specificity and sensitivity in the current guideline criteria. However, it is noteworthy that according to our analysis, 53% and 85% of CRT-not recommended patients were in fact unclassifiable mainly due to having EF > 35%, and showed on average a QRS width of 167 ± 20 ms and 151 ± 34 ms considering the European and American guidelines, respectively. It is therefore very likely, that those patients have an intraventricular dyssynchrony and will benefit from therapy despite of formally missing the EF cut-off for inclusion. Furthermore, CRT-not recommended patients were in better general condition compared to patients with other recommendation classes as reflected by higher EF and lower NYHA class at baseline examination which would improve their outcome31 (EF: 34 ± 10 vs. 26 ± 6 and 36 ± 9 vs. 25 ± 5 and NYHA class 2.6 ± 0.7 vs. 3.0 ± 0.5 and 2.7 ± 0.8 vs. 3.0 ± 0.5, P < 0.0001, for CRT-not recommended vs. other classes according to the European and American guidelines, respectively, see Supplementary material online for a detailed subanalysis of the CRT-not recommended). On the other hand, adding mechanical dyssynchrony to both the European and the American guideline recommendations for CRT implantation was associated with more favourable survival and lower all-cause mortality. Our findings are in-line with other studies implementing the concept of LV mechanical dyssynchrony as selection criterion.17,27,32–34 In all these studies, the proof of specific patterns of Dyss was associated with better survival after CRT than the summarized mortalities of CARE-HF,8 COMPANION,35 and MADIT-CRT.36 Considering only patients with no baseline mechanical dyssynchrony, there was also non-significant difference in survival between guideline classes (Log-rank P = 0.17 and 0.24 for the European and American guideline classes, respectively, Supplementary material online, Figure S7). However, a tendency of worse outcome for patients with Class I indication in both guidelines might be noted at the first sight. This tendency may not only be attributed to the significantly worse general condition of Class I patients, as reflected by lower baseline EF and older age (EF: 27 ± 6 vs. 29 ± 7 and 26 ± 5 vs. 29 ± 7, and age 66 ± 8 vs. 63 ± 16 and 66 ± 8 vs. 63 ± 11; P < 0.05 for all comparisons for Class I vs. other classes according to the European and American guidelines, respectively, Supplementary material online, Tables S3 and S4) but also would shed some light on the potential undesirable outcome of CRT in patients who do not manifest true dyssynchrony that is amendable to therapy beyond ECG criteria,19,37 a finding that corresponds to consistently showing that one-third of patients do not respond to therapy in the previous studies.15 Future steps to improve selection of CRT candidates Integrating both temporal and functional inhomogeneity, visual assessment of ApRock and SF has been shown to be superior to Doppler velocity-based assessments of mechanical dyssynchrony in predicting response to therapy,38 overcoming their limitations and reflecting true LBBB contraction pattern. Previous data showed that ApRock and SF can be easily detected and yield comparable accuracy if quantitatively assessed.17,38,39 Our data suggest that baseline assessment of ApRock and SF as a parameter of mechanical dyssynchrony could be a valuable supplement to the current guidelines resulting in better survival and increasing response rates. This strongly indicates the need for a further investigation of specific mechanical dyssychrony parameters through larger prospective studies. Study limitations The study was retrospective and observational, leaving gaps in our knowledge, where a control group would have been needed. Although ethically difficult, only prospective randomized studies could fill these gaps and clarify with confidence the added value of specific mechanical dyssynchrony patterns. In our study, we assessed echocardiographic volumetric response to therapy, other indices of clinical response like improvement of NYHA class or 6 min walk test were not investigated. Volumetric response was assessed after 1 year of device implantation which according to some publications may underestimate response rates due to potential late responders.40 However, we have analysed long-term outcome data which are hard endpoints and might provide even more insight than a short-term volumetric or clinical response. Conclusion Our data indicate that current guideline criteria for CRT candidate selection leave room for improvement of both sensitivity and specificity. Incorporating the assessment of specific mechanical dyssynchrony patterns amendable by CRT is a promising tool to do so and should be considered for future evaluation through prospective randomized trials. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements We would like to thank Ann Belmans, MSc, PhD, University of Leuven, for her invaluable statistical advice and support. Conflict of interest: A.S.B. received research grant from the Egyptian ministry of high education. J.-U.V. holds a personal research mandate of the Flemish Research Fund (FWO) and received a research grant from the University Leuven. S. Ü. and I.S. received research grants of the European Association of Cardiovascular Imaging. R.W. receives research funding, consulting fees and speaker’s fees from Biotronik, Boston Scientific, St. Jude Medical and Medtronic. He is further supported as post-doctoral clinical researcher by the Flemish Research Fund. References 1 Singh JP , Klein HU , Huang DT , Reek S , Kuniss M , Quesada A et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial . Circulation 2011 ; 123 : 1159 – 66 . Google Scholar CrossRef Search ADS PubMed 2 Tang ASL , Wells GA , Talajic M , Arnold MO , Sheldon R , Connolly S et al. 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Electrocardiographic correlates of mechanical dyssynchrony in recipients of cardiac resynchronization therapy devices . Arch Cardiovasc Dis 2015 ; 108 : 617 – 25 . Google Scholar CrossRef Search ADS PubMed 23 Epstein AE , DiMarco JP , Ellenbogen KA , Estes NA 3rd , Freedman RA , Gettes LS et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities . J Am Coll Cardiol 2013 ; 61 : e6 – 75 . Google Scholar CrossRef Search ADS PubMed 24 Vardas P , Auricchio A , Blanc J , Daubert J , Drexler H , Ector H. Guidelines for cardiac pacing and cardiac resynchronization therapy: the Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association . Eur Heart J 2007 ; 2256 – 95 . 25 Bax JJ , Gorcsan J. Echocardiography and noninvasive imaging in cardiac resynchronization therapy. Results of the PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) Study in Perspective . J Am Coll Cardiol 2009 ; 53 : 1933 – 43 . Google Scholar CrossRef Search ADS PubMed 26 Sipahi I , Carrigan TP , Rowland DY , Stambler BS , Fang JC. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials . Arch Intern Med 2011 ; 171 : 1454 – 62 . Google Scholar CrossRef Search ADS PubMed 27 Risum N , Williams ES , Khouri MG , Jackson KP , Olsen NT , Jons C et al. Mechanical dyssynchrony evaluated by tissue Doppler cross-correlation analysis is associated with long-term survival in patients after cardiac resynchronization therapy . Eur Heart J 2013 ; 34 : 48 – 56 . Google Scholar CrossRef Search ADS PubMed 28 Guillebon MDE , Thambo J , Ploux S , Deplagne A , Sacher F , Jais P et al. Reliability and reproducibility of QRS duration in the selection of candidates for cardiac resynchronization therapy . J Cardiovasc Electrohysiol 2010 ; 21 : 890 – 2 . 29 Steelant B , Stankovic I , Roijakkers I , Aarones M , Bogaert J , Desmet W et al. The impact of infarct location and extent on LV motion patterns: implications for dyssynchrony assessment . J Am Coll Cardiol Cardiovasc Imaging 2016 ; 9 : 655 – 64 . Google Scholar CrossRef Search ADS 30 Angermann CE , Stoerk S , Gelbrich G , Faller H , Jahns R , Frantz S et al. Mode of action and effects of standardized collaborative disease management on mortality and mobidity in patient with systolic heart . Circ Heart Fail 2012 ; 5 : 25 – 35 . Google Scholar CrossRef Search ADS PubMed 31 Kutyifa V , Kloppe A , Zareba W , Solomon SD , McNitt S , Polonsky S et al. The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: mADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) . J Am Coll Cardiol 2013 ; 61 : 936 – 44 . Google Scholar CrossRef Search ADS PubMed 32 Delgado V , Van Bommel RJ , Bertini M , Borleffs CJW , Marsan NA , Ng ACT et al. Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy . Circulation 2011 ; 123 : 70 – 8 . Google Scholar CrossRef Search ADS PubMed 33 Tanaka H , Nesser HJ , Buck T , Oyenuga O , Jánosi RA , Winter S et al. Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: results of the Speckle Tracking and Resynchronization (STAR) study . Eur Heart J 2010 ; 31 : 1690 – 700 . Google Scholar CrossRef Search ADS PubMed 34 Gorcsan J , Oyenuga O , Habib PJ , Tanaka H , Adelstein EC , Hara H et al. Relationship of echocardiographic dyssynchrony to long-term survival after cardiac resynchronization therapy . Circulation 2010 ; 122 : 1910 – 8 . Google Scholar CrossRef Search ADS PubMed 35 Bristow M , Michael R , Saxon LLA , Boehmer J , Krueger S , Kass DA et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure . N Engl J Med 2004 ; 350 : 2140 – 50 . Google Scholar CrossRef Search ADS PubMed 36 Moss AJ , Hall WJ , Cannom DS , Klein H , Brown MW , Daubert JP , MADIT-CRT Trial Investigators et al. Cardiac-resynchronization therapy for the prevention of heart-failure events . N Engl J Med 2009 ; 361 : 1329 – 38 . Google Scholar CrossRef Search ADS PubMed 37 Menet A , Bernard A , Tribouilloy C , Guyomar Y , Leclercq C , Castel A et al. Clinical significance of septal deformation patterns in heart failure patients receiving cardiac resynchronization therapy. Eur Heart J Cardiovasc Imaging 2017 ; 18 : 1388 – 97 . 38 Szulik M , Tillekaerts M , Vangeel V , Ganame J , Willems R , Lenarczyk R et al. Assessment of apical rocking: a new, integrative approach for selection of candidates for cardiac resynchronization therapy . Eur J Echocardiogr 2010 ; 11 : 863 – 9 . Google Scholar CrossRef Search ADS PubMed 39 Tournoux F , Singh JP , Chan RC , Chen-Tournoux A , McCarty D , Manzke R et al. Absence of left ventricular apical rocking and atrial-ventricular dyssynchrony predicts non-response to cardiac resynchronization therapy . Eur Heart J Cardiovasc Imaging 2012 ; 13 : 86 – 94 . Google Scholar CrossRef Search ADS PubMed 40 Burns K , Gage RM , Curtin AE , Bank AJ. Long-term echocardiographic response to cardiac resynchronization therapy in initial nonresponders . J Am Coll Cardiol Heart Fail 2015 ; 3 : 990 – 7 . Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. 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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aim To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. Methods and results Echocardiography was performed in 1060 patients before and 12 ± 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as ≥15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37–86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline-based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines. Conclusion Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony. guidelines, CRT, mechanical dyssynchrony, heart failure, apical rocking Introduction Guidelines aim at translating inclusion criteria of high-quality clinical landmark trials into indications for treatment recommendations in order to guarantee a solid evidence base for the clinical practice. In the field of cardiac resynchronization therapy (CRT), the inclusion criteria of landmark trials that impacted the current recommendations for patient selection were left ventricular ejection fraction (≤30%,1,2 ≤35%3,4, ≤40%5), New York Heart Association (NYHA) Class (I–II,1,5 II,4 II–III,2 III,3 II–IV,6 III–IV7,8), and QRS width (≥120 ms,2,5 ≥130 ms,4,7,9 ≥150 ms3,10). Recommendations have been further influenced by study results showing a better response of patients with left bundle branch block (LBBB) than non-LBBB morphology.11 The suggested possible harm of CRT implantation in patients with QRS duration less than 130 ms by some studies12 has led to increasing the threshold for CRT implantation from 120 ms in 2013 guidelines13 to 130 ms in the 2016 edition of the European guidelines.14 While this approach ensures a strong evidence base for a certain treatment, it does not necessarily guarantee the optimal strategy for patient selection, as relevant or potentially favourable selection criteria might not have been tested. In the case of CRT, which has become an established treatment option for patients with heart failure, left ventricular (LV) dysfunction and conduction delays, still approximately one-third of the patients remain non-responders to this costly and invasive therapy.15 One such potential selection criterion, which is not considered in current guidelines is mechanical dyssynchrony. This is in particular due to the disappointing results of studies that tested the additional predictive value of parameters derived from the timing of longitudinal myocardial velocity peaks as surrogate of mechanical dyssynchrony, which failed to show any additional value over conventional guideline criteria despite promising results from single-centre studies.16 In the meantime, however, there is growing evidence that advanced concepts such as the detection of specific motion patterns could be a potential guide for CRT candidate selection.17,18 The PREDICT-CRT trial investigated the association between CRT outcome and a novel parameter of mechanical dyssynchrony, characterized by a short septal contraction pulling the apex septally [‘septal flash’ (SF)] followed by a delayed lateral wall contraction which causes a lateral motion of the apex [‘apical rocking’ (ApRock)]. This specific pattern of contraction in addition to similar parameters which rely on the same phenomena, have been shown to be strongly associated with better survival and CRT response.17,19–26 In this study, we relate current CRT guideline recommendations for patient selection with patient outcome and investigate the potential additive prognostic value of echocardiographic markers of mechanical dyssynchrony. Methods Study population We analysed data from the PREDICT-CRT database17 which comprises data of 1060 patients who received CRT between 1999 and 2012 in six European centres. The indication for CRT implantation was a clinical decision of the treating physician. All patients were on optimized pharmacologic therapy for at least 3 months before CRT. Ischaemic origin of heart failure was proven by coronary angiography and/or records of myocardial infarction. At the time of inclusion, none of the candidates required interventional or surgical treatment for coronary disease. For follow-up, we collected data on mortality from medical records, by interviews with the patient’s general practitioner or relatives, and/or from national death registries. The study was approved by the Ethics Committee of the University Hospitals Leuven. Patient classification For the current analysis, patients were retrospectively classified following the recommendations for CRT implantation as published in the 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure14 and according to the 2012 guideline published by the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society (ACCF/AHA/HRS).23 First, we excluded data sets of 286 patients from our database, for which not all parameters used in the guideline classification scheme were available. The remaining data sets were then assigned to a guideline indication class when they met all criteria of that specific class. This assignment was performed by converting the guideline statements into Boolean expressions (Supplementary material online, Figure S1) and applying them to our database, thus avoiding any clinical interpretation of patient characteristics. In this way, 4.1% and 1.4% of patients were classified as Class III, while 4.9% and 9.4% of the patients remained unclassifiable according to the European and American guidelines, respectively. In the following text, these patients are referred to as CRT-not recommended (Supplementary material online, Figure S2). Echocardiography Patients underwent echocardiography before and 12 ± 6 months after CRT implantation. LV volumes and ejection fractions were measured using the modified biplane Simpson’s method. Patients with LV end-systolic volume (LVESV) decrease of ≥15% at the time of the follow-up visit were considered as volume responders. Mechanical dyssynchrony was visually assessed by analysing the presence of ApRock and SF (Supplementary material online, Videos S1 and S2). All echocardiographic measurements were performed by two experienced readers. A blinded third reader was asked in case of disagreement.17 Resynchronization therapy All patients received biventricular pacing, in 399 (40%) with defibrillator (CRT-D). LV pacing leads were positioned, guided by coronary venography, preferably in the lateral and postero-lateral venous branches. Device settings were optimized within a week of CRT device implantation, as deemed clinically appropriate, based on surface electrocardiogram (ECG) or Doppler echocardiography.24 Statistical analysis Continuous data are expressed as mean ± standard deviation. Normally distributed data were compared between groups using unpaired Student’s t-test for continuous variables and χ2 test for categorical variables. If not normally distributed, median and interquartile range (IQR) and a Wilcoxon rank sum test were used. Survival rates were assessed using the Kaplan–Meier method, and differences in survival were compared between groups by a Log-rank test. Predictors of long-term survival were analysed in Cox’s proportional hazards models. Data were processed using SPSS (IBM, Chicago, IL, USA) version 24.0. Two-sided P-value of <0.05 was considered significant. Results Study population Characteristics of the study population are summarized in Table 1. Applying the European and American guidelines retrospectively, 63.4% and 52.6% of the patients had a Class I indication, 18.2% and 33.9% a Class IIa and 9.4% and 2.6% a Class IIb indication at the time of CRT implantation, respectively. Nine percent of the patients had in retrospect no treatment recommendation according to current European guidelines and 10.8% according to the American counterpart (Figure 1). Patients who had to be excluded from this analysis due to missing data showed on average no significant difference in survival compared to the analysed study population (Supplementary material online, Figure S3). Table 1 Baseline clinical and echocardiographic characteristics of the study population (n = 774) EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF, ejection fraction; LBBB, left bundle branch block; Dyss, mechanical dyssynchrony at baseline; AF, atrial fibrillation; NYHA, New York Heart Association. Table 1 Baseline clinical and echocardiographic characteristics of the study population (n = 774) EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF (%) 26 ± 7 QRS width (ms) 170 ± 29 AF, n (%) 176 (23) LBBB, n (%) 687 (89) Dyss, n (%) (n = 744) 534 (72) Male sex, n (%) 582 (75) Ischaemic aetiology, n (%) 334 (43) NYHA 2.9 ± 0.5 Age at implantation (years) 64 ± 11 Scarred segments 0.8 ± 1.9 EF, ejection fraction; LBBB, left bundle branch block; Dyss, mechanical dyssynchrony at baseline; AF, atrial fibrillation; NYHA, New York Heart Association. Figure 1 View largeDownload slide Percentage assignment of the study population to recommendations classes for CRT implantation according to the European and the American guidelines. CRT-not recommended (grey) refers to the patients who were either classified as Class III or met no recommendation class. Figure 1 View largeDownload slide Percentage assignment of the study population to recommendations classes for CRT implantation according to the European and the American guidelines. CRT-not recommended (grey) refers to the patients who were either classified as Class III or met no recommendation class. The intraobserver agreement for visual assessment of ApRock and SF had been reported earlier17 and was 93% [k = 0.81 95% confidence interval (95% CI) 0.66–0.95] and 93% [k = 0.80 (95% CI 0.66–0.95)], respectively. The interobserver agreement was 86% [k = 0.71 (95% CI 0.67–0.76) for both ApRock and SF]. Volumetric response From our study population, 65% of patients who had a Class I recommendation according to current European guidelines showed a volumetric response to CRT, 50% with Class IIa, 38% with Class IIb, and 40% of the CRT-not recommended (P < 0.0001, Figure 2). Comparable response rates were observed according to the American classification, 66% in Class I, 51% in Class IIa, 25% in Class IIb, and 40% in the CRT-not recommended (P < 0.0001, Supplementary material online, Figure S4). Figure 2 View largeDownload slide Volumetric response of patients assigned to the different European recommendation classes for CRT implantation. See Supplementary material online, Figure S4 for similar results applying the respective American guidelines. Figure 2 View largeDownload slide Volumetric response of patients assigned to the different European recommendation classes for CRT implantation. See Supplementary material online, Figure S4 for similar results applying the respective American guidelines. Adding mechanical dyssynchrony as an additional selection criterion to each guideline class led to a better discrimination between volume responders and non-responders within all European classes (77% in Class I, 75% in Class IIa, 62% in Class IIb, and 69% in the CRT-not recommended, Figure 3) and American guideline Classes I (76%), IIa (75%), IIb (75%), and the CRT-not recommended (70%), Supplementary material online, Figure S5. Figure 3 View largeDownload slide Volumetric response of patients assigned to the European recommendation classes, separated by the presence (+Dyss) or absence (−Dyss) of mechanical dyssynchrony at baseline. The respective result using the American guideline recommendations are shown in Supplementary material online, Figure S5. Figure 3 View largeDownload slide Volumetric response of patients assigned to the European recommendation classes, separated by the presence (+Dyss) or absence (−Dyss) of mechanical dyssynchrony at baseline. The respective result using the American guideline recommendations are shown in Supplementary material online, Figure S5. Survival analysis During a median follow-up of 59 months (IQR 37–86 months), no significant difference was found in survival among patient’s classes defined by the European guidelines (Log-rank P = 0.2). The survival of the classes defined by the American guidelines was significantly different between Classes I and IIa (P = 0.002) but not among the other classes (Figure 4). In both guidelines, there was no significant difference in survival between patients in whom CRT was recommended (Classes I, IIa, and IIb together) vs. those in whom it was not recommended (Figure 5). Figure 4 View largeDownload slide The Kaplan–Meier curves depicting long-term survival of patients after CRT implantation, stratified by the different recommendation classes of the European and the American guidelines. Note that there is no significant difference in survival among European guideline classes (Log-rank P = 0.2), while only Classes I and IIa in the American guidelines showed significant survival difference (P = 0.002). N.S, non-significant; N.R., not recommended for CRT implantation. Figure 4 View largeDownload slide The Kaplan–Meier curves depicting long-term survival of patients after CRT implantation, stratified by the different recommendation classes of the European and the American guidelines. Note that there is no significant difference in survival among European guideline classes (Log-rank P = 0.2), while only Classes I and IIa in the American guidelines showed significant survival difference (P = 0.002). N.S, non-significant; N.R., not recommended for CRT implantation. Figure 5 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing no significant difference between patients with (Classes I, IIa, and IIb) and those without recommendation for therapy (Class III and unclassifiable) according to both the European and American guidelines. Figure 5 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing no significant difference between patients with (Classes I, IIa, and IIb) and those without recommendation for therapy (Class III and unclassifiable) according to both the European and American guidelines. For the entire study cohort, the presence of mechanical dyssynchrony before CRT implantation was associated with favourable outcome (Log-rank P < 0.0001) due to a lower all-cause mortality [hazard ratio (HR) 0.30, 95% CI 0.24–0.39; P < 0.0001, Figure 6]. Also within each European guideline recommendation class, the presence of mechanical dyssynchrony was associated with more favourable outcome (Log-rank P < 0.0001, 0.006, 0.004, 0.02 for Classes I, IIa, IIb, and the CRT-not recommended, respectively, Figure 7) due to a lower all-cause mortality (HR 0.21, 95% CI 0.15–0.30; P < 0.0001 in Class I; HR 0.47, 95% CI 0.27–0.82; P = 0.007 in Class IIa, HR 0.35, 95% CI 0.14–0.87; P = 0.02 in Class IIb, and HR 0.29, 95% CI 0.12–0.68; P = 0.004 in the CRT-not recommended). In American recommendation classes, mechanical dyssynchrony had a similarly favourable impact on outcome (Log-rank P < 0.0001, HR 0.40; 95% CI 030–0.54; P < 0.0001 for Class I; Log-rank P < 0.0001, HR 0.52; 95% CI 0.35–0.77; P = 0.001 for Class IIa; and Log-rank P 0.03; HR 0.37; 95% CI 0.18–0.76; P = 0.007 for the CRT-not recommended, Supplementary material online, Figure S6). Figure 6 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing the association of baseline mechanical dyssynchrony with favourable overall survival (hazard ratio 0.30, P < 0.0001). Figure 6 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation showing the association of baseline mechanical dyssynchrony with favourable overall survival (hazard ratio 0.30, P < 0.0001). Figure 7 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation for each European recommendation class. Note that within each guideline recommendation class, the presence of baseline mechanical dyssynchrony (+Dyss) was associated with a better long-term survival while its absence (−Dyss) was associated with less favourable outcome. N.R., not recommended for CRT implantation. Figure 7 View largeDownload slide The Kaplan–Meier curves depicting long-term survival after CRT implantation for each European recommendation class. Note that within each guideline recommendation class, the presence of baseline mechanical dyssynchrony (+Dyss) was associated with a better long-term survival while its absence (−Dyss) was associated with less favourable outcome. N.R., not recommended for CRT implantation. Discussion In this study, we retrospectively applied the latest European and American guideline recommendations for CRT implantation to a large database of CRT recipients. We found a relation between response rate to CRT and guideline recommendation class. The survival of patients with and without a recommendation for CRT implantation according to the current guidelines; however, was not significantly different. In each guideline recommendation class, mechanical dyssynchrony (ApRock and/or SF) was strongly associated with better volumetric response and more favourable patient outcome after CRT implantation. Guideline recommendation classes and volumetric response We found a significant relation between guideline recommendation classes and volumetric response to CRT (Figure 2 and Supplementary material online, Figure S4). This behaviour might be expected, as a lower recommendation class should imply a lower likelihood that a certain therapy is effective. Aiming at better identification of potential responders to CRT, the updates of the guidelines have introduced more strict criteria in Class I recommendation regarding QRS width and morphology. However, we found that 35% and 34% of patient with Class I recommendation according to the European and American guidelines, respectively, were non-responders. This observation is in concordance with other CRT studies which repetitively find a volumetric non-responder rate of around one-third of the implanted patients.25 These non-responders have significantly more often an ischaemic aetiology of heart failure, more scarred segments, a higher NYHA functional class, and less mechanical dyssynchrony (Supplementary material online, Tables S1 and S2). Although a lack of volumetric response does not necessarily equal a therapy failure, it is an indication that current recommendations for CRT implantation might lack specificity. Our analysis also revealed that 40% and 42% of the patients who were not recommended for CRT implantation according to current European and American guideline recommendations, respectively, showed a volume response. Most of these patients showed non-ischaemic aetiology of cardiomyopathy and mechanical dyssynchrony at baseline (Dyss) echocardiographic examination (see supplementary subanalysis of the CRT-not recommended). This observation indicates a potential room for improving the sensitivity of the current guideline criteria. Mechanical dyssynchrony and volumetric response Mechanical dyssynchrony, on the other hand, was closely linked with volumetric response. For both guidelines, the additional consideration of mechanical dyssynchrony led to a better association with volumetric response in all recommendation classes (Figure 3 and Supplementary material online, Figure S5). Our data are in contrast to the predominant notion that the role of baseline mechanical dyssynchrony assessment might be of limited value in patients with LBBB and QRS ≥ 150 ms (Class I recommendation), as these patients already have the largest likelihood of response.5 We found, however, that even in this group, the selection of patients could be further improved when baseline mechanical dyssynchrony is considered in addition to the respective European and American guideline criteria (from 65% to 77% and from 66% to 76%, respectively). Our data are also in contrast to the notion that patients with QRS duration between 120 and 150 ms are less likely to respond to therapy26 which are classified depending on the pattern of the bundle branch block into Classes IIa and IIb by both guidelines. Considering mechanical dyssynchrony increased the number of correctly classified volume responders in the European recommendation Classes IIa by 25% and IIb by 24% and in the American guideline Class IIa by 24% and IIb by 50%. Our data are in-line with other studies, which have demonstrated an added prognostic value of mechanical dyssynchrony assessment in patients with moderately wide QRS complex (120–150 ms).27 Guideline-based selection criteria, room for improvement Our data show that specific signs of mechanical dyssynchrony, reflecting typical LBBB contraction pattern is closely linked to volumetric response regardless of QRS width. QRS width measurements have been shown to be associated with low reproducibility and high inter- and intraobserver variability,28 which might in part explain patient miss-classifications and along with our findings doesn’t make it the ideal surrogate to describe the mechanical dyssynchrony of the LV which is the pathophysiologic mechanism underlying the ventricular failure and the main target of a resynchronization therapy. Furthermore we were able to confirm the negative impact of a ischaemic aetiology of heart failure and scar burden, which has been shown to be associated with poor CRT response in addition to masking or modulating myocardial deformation patterns.29,30 Our data consequently suggest that the additional consideration of scar localization and extent would improve patient selection even further. Guideline recommendation classes and patient survival Our data showed a non-significant difference in survival between patients who were recommended for therapy according to the guidelines (recommendation Classes I, IIa, and IIb) and the CRT-not recommended, a finding that may indicate that there might be shortcomings in both specificity and sensitivity in the current guideline criteria. However, it is noteworthy that according to our analysis, 53% and 85% of CRT-not recommended patients were in fact unclassifiable mainly due to having EF > 35%, and showed on average a QRS width of 167 ± 20 ms and 151 ± 34 ms considering the European and American guidelines, respectively. It is therefore very likely, that those patients have an intraventricular dyssynchrony and will benefit from therapy despite of formally missing the EF cut-off for inclusion. Furthermore, CRT-not recommended patients were in better general condition compared to patients with other recommendation classes as reflected by higher EF and lower NYHA class at baseline examination which would improve their outcome31 (EF: 34 ± 10 vs. 26 ± 6 and 36 ± 9 vs. 25 ± 5 and NYHA class 2.6 ± 0.7 vs. 3.0 ± 0.5 and 2.7 ± 0.8 vs. 3.0 ± 0.5, P < 0.0001, for CRT-not recommended vs. other classes according to the European and American guidelines, respectively, see Supplementary material online for a detailed subanalysis of the CRT-not recommended). On the other hand, adding mechanical dyssynchrony to both the European and the American guideline recommendations for CRT implantation was associated with more favourable survival and lower all-cause mortality. Our findings are in-line with other studies implementing the concept of LV mechanical dyssynchrony as selection criterion.17,27,32–34 In all these studies, the proof of specific patterns of Dyss was associated with better survival after CRT than the summarized mortalities of CARE-HF,8 COMPANION,35 and MADIT-CRT.36 Considering only patients with no baseline mechanical dyssynchrony, there was also non-significant difference in survival between guideline classes (Log-rank P = 0.17 and 0.24 for the European and American guideline classes, respectively, Supplementary material online, Figure S7). However, a tendency of worse outcome for patients with Class I indication in both guidelines might be noted at the first sight. This tendency may not only be attributed to the significantly worse general condition of Class I patients, as reflected by lower baseline EF and older age (EF: 27 ± 6 vs. 29 ± 7 and 26 ± 5 vs. 29 ± 7, and age 66 ± 8 vs. 63 ± 16 and 66 ± 8 vs. 63 ± 11; P < 0.05 for all comparisons for Class I vs. other classes according to the European and American guidelines, respectively, Supplementary material online, Tables S3 and S4) but also would shed some light on the potential undesirable outcome of CRT in patients who do not manifest true dyssynchrony that is amendable to therapy beyond ECG criteria,19,37 a finding that corresponds to consistently showing that one-third of patients do not respond to therapy in the previous studies.15 Future steps to improve selection of CRT candidates Integrating both temporal and functional inhomogeneity, visual assessment of ApRock and SF has been shown to be superior to Doppler velocity-based assessments of mechanical dyssynchrony in predicting response to therapy,38 overcoming their limitations and reflecting true LBBB contraction pattern. Previous data showed that ApRock and SF can be easily detected and yield comparable accuracy if quantitatively assessed.17,38,39 Our data suggest that baseline assessment of ApRock and SF as a parameter of mechanical dyssynchrony could be a valuable supplement to the current guidelines resulting in better survival and increasing response rates. This strongly indicates the need for a further investigation of specific mechanical dyssychrony parameters through larger prospective studies. Study limitations The study was retrospective and observational, leaving gaps in our knowledge, where a control group would have been needed. Although ethically difficult, only prospective randomized studies could fill these gaps and clarify with confidence the added value of specific mechanical dyssynchrony patterns. In our study, we assessed echocardiographic volumetric response to therapy, other indices of clinical response like improvement of NYHA class or 6 min walk test were not investigated. Volumetric response was assessed after 1 year of device implantation which according to some publications may underestimate response rates due to potential late responders.40 However, we have analysed long-term outcome data which are hard endpoints and might provide even more insight than a short-term volumetric or clinical response. Conclusion Our data indicate that current guideline criteria for CRT candidate selection leave room for improvement of both sensitivity and specificity. Incorporating the assessment of specific mechanical dyssynchrony patterns amendable by CRT is a promising tool to do so and should be considered for future evaluation through prospective randomized trials. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements We would like to thank Ann Belmans, MSc, PhD, University of Leuven, for her invaluable statistical advice and support. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Feb 22, 2018

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