Role of myocardial constructive work in the identification of responders to CRT

Role of myocardial constructive work in the identification of responders to CRT Abstract Aims Cardiac resynchronization therapy (CRT) plays a pivotal role in the management of patients with heart failure (HF) and wide QRS complex. However, the treatment is plagued by numerous non-responders. Aim of the study is to evaluate the role myocardial work estimated by pressure-strain loops (PSLs) in the comprehension of physiological mechanisms associated with CRT and in the prediction of CRT response. Methods and results Ninety-seven patients with symptomatic HF (ejection fraction: 27 ± 6%, QRS duration 164 ± 18 ms) undergoing CRT implantation according to current recommendations were retrospectively included in the study. Standard 2D and speckle tracking echocardiography were performed before CRT and at the 6-month follow-up (FU). PSL analysis allowed the calculation of global and regional myocardial constructive work (CW) and wasted work (WW). A > 15% reduction in left ventricular (LV) end-systolic volume at FU defined CRT-positive response (CRT-PR). At FU, 63 (65%) patients responded to CRT. Global CW (CWtot) was significantly increased in CRT-responders. At multivariate analysis, CWtot > 1057 mmHg% (OR 14.69, P = 0.005) and septal flash (OR 8.05, P = 0.004) were the only significant predictors of CRT-PR. CWtot was associated with the entity of CRT-induced myocardial remodelling in both ischaemic (r = −0.55, P < 0.0001) and non-ischaemic patients (r = 0.65, P < 0.0001). A CWtot < 1057 mmHg% identified 85% of non-responders with a positive predictive value of 88%. Conclusion Patients with higher CWtot exhibit a favourable response to CRT. These data encourage further studies for the assessment of the myocardial substrate related to the functional response to CRT. cardiac resynchronization therapy, heart failure, pressure-strain loops, cardiac work Introduction Cardiac resynchronization therapy (CRT) plays a pivotal role in the management of patients with severe left ventricular (LV) dysfunction, persistent dyspnoea despite optimal medical therapy, and wide QRS complex.1 Despite this, approximately 30% of patients undergoing CRT do not properly respond to therapy. Imaging approaches have been proposed to facilitate the detection of CRT responders. Despite the initial promising results, randomized multicentre studies have demonstrated that dyssynchrony parameters assessed by echocardiography cannot predict CRT response2 and that their application for the selection of CRT candidates is even detrimental in the case of normal QRS.3 A potential explanation for these results is that the assessment of myocardial dyssynchrony markers does not take into account the role of residual myocardial contractility4,5 as a potential source for LV functional restoration after CRT. Recently, Russel et al.6,7 demonstrated that pressure strain loops (PSLs) estimate LV performance in a non-invasive manner and that the corresponding PSLs area is directly correlated with the residual myocardial metabolic activity assessed by FDG positron emission tomography in CRT candidates.6 The aim of the present study is to evaluate the role of global and regional myocardial work estimated by PSLs in the prediction of CRT response. Methods Population Ninety-seven patients with ischaemic or dilated cardiomyopathy undergoing CRT implantation according to current guidelines1 were retrospectively included in the study. At the moment of CRT implantation, all patients received optimized medical therapy. Clinical data, including age, gender, New York Heart Association (NYHA) functional class, systolic and diastolic blood pressure, NTproBNP, and creatinine were assessed for each patient. An ischaemic aetiology for LV failure was claimed in cases with a history of myocardial infarction or revascularization, angiographic evidence of multiple vessel disease or single-vessel disease with ≥75% stenosis of the left main or proximal left anterior descending artery.8 The study was reviewed by an independent ethics committee (regional ethic committee validation number: 35RC14-9767) and conducted in accordance with the ‘Good Clinical Practice’ Guidelines in the Declaration of Helsinki. All patients provided written informed consent. Electrocardiogram data The 12-lead surface electrocardiogram (ECG) was recorded at 25 and 50 mm/s during spontaneous rhythm before implantation of the CRT device. The method used for QRS duration analysis was previously reported.9 Left bundle branch block (LBBB) was defined by a QRS duration ≥ 120 ms with the following characteristics: QS or rS in lead V1; broad R waves in leads I, aVL, V5, or V6; and no q waves in leads V5 and V6. Echocardiography All patients underwent standard transthoracic echocardiography using a Vivid 7 or Vivid E9 ultrasound system (GE Healthcare, Horten, Norway) equipped with a 3S or M5S 3.5-mHz transducer. The M-mode, 2D, colour Doppler, pulsed-wave, and continuous-wave Doppler data were stored on a dedicated workstation for off-line analysis (EchoPAC, GE Healthcare, Horten, Norway). LV volumes and function were measured by the biplane method as recommended.10 The presence of myocardial scar was assessed by echocardiography and was defined by an end-diastolic wall thickness ≤5 mm associated with increased acoustic reflectance and concomitant akinesia/dyskinesia.11 Septal flash (SF) was defined by the presence of early septal thickening/thinning detected by M-mode within the isovolumetric contraction period or by the presence of a rapid change of colour in tissue Doppler imaging related to the early and fast contraction of the septum occurring during the isovolumetric period.12 The systolic delay between the lateral and septal wall at tissue-Doppler imaging was measured to quantify intraventricular delay according to recommendations.13 2D-speckle tracking echocardiography 2D greyscale images were acquired in the standard apical four-, three- and two-chamber views at a frame rate ≥ 60 frames/s. The recordings were processed using acoustic tracking-dedicated software (EchoPAC version 112.99, Research Release, GE Healthcare, Horten, Norway), which allowed for an off-line semi-automated analysis of speckle-based strain. To calculate the LV global longitudinal strain (GLS), a line was traced along the LV endocardium’s inner border in each of the three apical views on an end-systolic frame, and a region of interest was automatically defined between the endocardial and epicardial borders with GLS then automatically calculated from the strains in the three apical views.14 Image quality for the enrolled patients was optimal, and no LV segments were excluded from the analysis. Quantification of cardiac work Myocardial work and related indices were calculated using a costumed software. As previously described by Russel et al.,6 myocardial work was measured as a function of time throughout the cardiac cycle by the combination of LV strain data obtained by STE and a non-invasively estimated LV pressure curve. Peak systolic LV pressure was assumed to be equal to peak arterial pressure measured with a cuff manometer. The average of three blood pressure measures taken at rest was retained and inserted in the custom software. The non-invasive LV pressure curve (Figure 1A, left panel) was then obtained using an empiric, normalized reference curve that was adjusted according to the duration of the isovolumetric and ejection phases defined by the timing of aortic and mitral valve events by echocardiography. The reliability of this non-invasively estimated LV pressure curve was previously validated in a dog model and in patients with various cardiac disorders.6 Figure 1 View largeDownload slide (A) Example of LV pressure curve estimation. The timing of mitral and aortic valve events is indicated (left panel). Pressure data are then combined with LV global longitudinal strain data (right panel) using the R-wave onset in electrocardiogram as a common time reference. (B) Representative traces showing pressure–strain loops measured at the infero-basal septal LV segment (left panel) and infero-lateral segment (right panel) in a patient with a left bundle branch block. Figure 1 View largeDownload slide (A) Example of LV pressure curve estimation. The timing of mitral and aortic valve events is indicated (left panel). Pressure data are then combined with LV global longitudinal strain data (right panel) using the R-wave onset in electrocardiogram as a common time reference. (B) Representative traces showing pressure–strain loops measured at the infero-basal septal LV segment (left panel) and infero-lateral segment (right panel) in a patient with a left bundle branch block. Strain and pressure data were synchronized by aligning the valvular event times (Figure 1A, right and left panels). Myocardial work is approximated as the area of the pressure-strain loop (PSL) (Figure 1B). Mathematically this area was calculated by computing the rate of segmental shortening by differentiation of the strain curve and multiplying this value with instantaneous LV-pressure. This product is a measure of instantaneous power, which was integrated over time to obtain myocardial work as a function of time in systole, which is defined as the time interval from mitral valve closure to mitral valve opening.6,7,15 During the LV ejection period, work performed by the myocardium during segmental elongation represents energy loss, which is defined as wasted work (WW). Myocardial work performed during segmental shortening represented constructive work (CW). During isovolumetric relaxation, this definition was reversed such that myocardial work during shortening was considered WW and work during lengthening was considered CW. CW and WW were calculated for each LV segment. The mean CW and WW at the level of the lateral (CWlat and WWlat) and septal (CWsept and WWsept) walls and for the entire LV (CWtot and WWtot) were subsequently calculated. Figure 1B presents an example of the PSL traces obtained at the infero-basal and latero-basal segments of a patient with dilated cardiomyopathy and SF. Supplementary data online, Figure S1 shows segmental PSLs curves obtained in a CRT responder before and after resynchronisation. Supplementary data online, Figure S2 shows the bull’s eye for CW, WW and LV GLS obtained from the same patient. Cardiac resynchronization therapy delivery CRT delivery followed a standardized protocol. The right atrial and ventricular leads were positioned conventionally. Preferred localization of the LV lead was a lateral or postero-lateral vein. The position was chosen according to the width of QRS, with the goal of obtaining the thinnest one at the end of the procedure. No imaging data were used to identify the site of CRT delivery. After implantation, atrioventricular delay was programmed individually to reach the optimal diastolic filling using the Doppler mitral inflow before discharge, and ventriculo-ventricular timing was programmed to be simultaneous. After CRT implantation, the LV lead position was confirmed from the chest X-ray as previously described.16 The presence of a >15% reduction in LV end-systolic volume (ESV) at follow-up (FU) defined the CRT positive response (CRT-PR).2 Statistical analysis Continuous variables are expressed by means ± standard deviation. Non-continuous variables are expressed as numbers and percentages. Comparisons between the continuous variables were performed using the two-tailed t-test. Comparisons between the categorical variables were performed using the χ2 test. Linear regression analysis was used to assess the correlation between continuous variables. The inter-observer and intra-observer agreement for CW and WW was assessed on 15 randomly selected subjects by Bland–Altman plot analysis. Interclass coefficients (ICC) were then calculated as appropriate. Univariate logistic regression analysis was performed to assess the predictive value of clinical features, ECG, and echocardiographic parameters with respect to CRT response. Variables with a P-value <0.1 at univariate analysis were then inserted in the multivariate analysis (forward stepwise method). Receiver operator characteristic (ROC) analysis was used to identify the best cut-off values of CW to predict CRT response. Statistical analysis was performed using SPSS Version 20.0 (IBM, Chicago, IL, USA). Results Clinical, echocardiographic, and myocardial work data from the overall population and based on CRT response are presented in Table 1. Table 1 Characteristics of the entire population and based on CRT response Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 CW, constructive work; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; GLS, global longitudinal strain; LBBB, left bundle branch block; LV, left ventricle; NYHA, New York Heart Association functional class; WW, wasted work. Table 1 Characteristics of the entire population and based on CRT response Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 CW, constructive work; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; GLS, global longitudinal strain; LBBB, left bundle branch block; LV, left ventricle; NYHA, New York Heart Association functional class; WW, wasted work. Ischaemic cardiomyopathy was diagnosed in 35 (36%) patients. At echocardiography, a myocardial scar that extended to at least 2 myocardial segments was observed in 21 patients (15 anterior, 3 lateral, 3 inferior myocardial infarction). In three cases, the LV lead was placed at the site of previous myocardial infarction, and all patients were non-responders to CRT. After a 6.1 (5.5–6.9) months FU, a CRT-PR was observed in 63 (65%) patients. CRT-responders exhibited an increased prevalence of dilated cardiomyopathy, less dilated LV, more preserved GLS, and an increased prevalence of SF. Higher values for CWtot, CWlat, WWtot, WWlat, and WWsept were observed in CRT-responders. Estimation of myocardial work and reproducibility The estimation of myocardial work was possible in all patients. Inter-observer and intra-observer variability is depicted in Figure 2A–D. The ICC for the inter-observed and intra-observer variability were 0.92 (95% CI: 0.76–0.97, P < 0.0001) and 0.89 (95% CI: 0.68–0.96, P < 0.0001) for CW and 0.91 (95% CI: 0.73–0.96, P < 0.0001) and 0.91 (95% CI: 0.72–0.97, P < 0.0001) for WW. Figure 2 View largeDownload slide Bland–Altman plot analysis for intra-observer and inter-observer agreement for constructive work (A and B) and wasted work (C and D). CWA, WWA: measures performed by the echocardiographer A. CWB, WWB: measure performed by the echocardiographer B. CW1, WW1, CW2, WW2: first and second measure performed by the same echocardiographer to test intra-observer agreement. Figure 2 View largeDownload slide Bland–Altman plot analysis for intra-observer and inter-observer agreement for constructive work (A and B) and wasted work (C and D). CWA, WWA: measures performed by the echocardiographer A. CWB, WWB: measure performed by the echocardiographer B. CW1, WW1, CW2, WW2: first and second measure performed by the same echocardiographer to test intra-observer agreement. Predictors of CRT response At univariable logistic regression analysis, LV end-diastolic volume, ischaemic aetiology, SF, CWtot, CWlat, WWtot, WWlat, and WWsept were significant predictors of CRT-PR (P < 0.05). In multivariable logistic regression analysis, only SF (OR 5.07, P = 0.007) and CWtot (OR 1.003, P < 0.036) remained significant predictors of CRT-PR (Table 2). At ROC analysis, a cut-off value of 1057 mmHg% for CWtot was predictor of CRT response (Figure 3A). When this value was inserted in the multivariable analysis, SF and CWtot > 1057 mmHg% remained the only predictors of CRT (OR 8.05, P = 0.005 and OR 14.69, P = 0.005, respectively). The AUC’s comparison did not reveal a significant difference between SF and CWtot for the identification of CRT-responders (Figure 3B). A CW < 1057 mmHg% identified 29 (85%) of 34 non-responders with good positive predictive value (PPV) of 88% and negative predictive value of 51%. Table 2 Predictors of positive response to CRT in univariable and multivariable logistic regression analysis OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 Table 2 Predictors of positive response to CRT in univariable and multivariable logistic regression analysis OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 Figure 3 View largeDownload slide (A) ROC curve analysis for constructive work. (B) ROC curves for CW > 1057 mmHg% and septal flash. Figure 3 View largeDownload slide (A) ROC curve analysis for constructive work. (B) ROC curves for CW > 1057 mmHg% and septal flash. Constructive myocardial work and clinical and echocardiographic data The studied population was divided in two groups: CWtot ≤ 1057 mmHg% and CWtot > 1057 mmHg%. The group with a higher CWtot exhibited less dilated LV and better LVEF and GLS values. Both groups exhibited similar NYHA functional class levels and prevalence of ischaemic cardiomyopathy. The entity of dyssynchrony expressed by QRS durations, LV septo-lateral delay and the prevalence of SF was the same in the two groups (Table 3). Table 3 Characteristics of the entire population according to global constructive work values Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 Table 3 Characteristics of the entire population according to global constructive work values Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 LV reverse remodelling at follow-up CWtot was significantly correlated with the entity of LV remodelling after CRT (Figure 4A–G). Interestingly, CWtot also correlated with LV remodelling in ischaemic patients, and the correlation coefficients were increased compared with those observed in the overall population (Table 4). Table 4 Correlations between global constructive work and left ventricular remodelling at follow-up in the overall population and in patients with ischaemic cardiomyopathy Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 EDD, end-diastolic diameter; ESD, end-systolic diameter; FU, follow-up; Δ, percentage of variation in LV-ESV before and after CRT. Table 4 Correlations between global constructive work and left ventricular remodelling at follow-up in the overall population and in patients with ischaemic cardiomyopathy Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 EDD, end-diastolic diameter; ESD, end-systolic diameter; FU, follow-up; Δ, percentage of variation in LV-ESV before and after CRT. Figure 4 View largeDownload slide (A–G) Correlations between global constructive work and left ventricular size and function parameters at follow-up. Figure 4 View largeDownload slide (A–G) Correlations between global constructive work and left ventricular size and function parameters at follow-up. Discussion In the present study we showed that in CRT-candidates, the amount of total myocardial CW is a predictor of CRT response and is correlated with the entity of LV remodelling after CRT. Pressure-strain loop curves PSL curves are a recently introduced tool that allows a non-invasive estimation of myocardial work. The reliability of this method with respect to the invasive estimation of myocardial work has been validated by experimental studies and mathematical models.6,7 Moreover, in 21 CRT-candidates, Vecera et al.17 were able to demonstrate that WWsept is a predictor CRT-PR. Regional differences in myocardial work assessed by PSLs have a strong correlation with the entity of myocardial glucose metabolism evaluated by FDG-PET.6 These results support the hypothesis that the differences in CW detected by PSLs before CRT correspond to myocardial residual metabolic activity and contractile reserve and might therefore explain the role of baseline CW in predicting CRT-PR. Role of total myocardial constructive work in CRT response Previous studies have demonstrated that the contractile reserve has a prognostic role in patients with reduced LVEF and ischaemic cardiomyopathy18; low-flow/low-gradient aortic stenosis19; and LV dyssynchrony.5 In patients with HF undergoing CRT, Ciampi et al.5 demonstrated that the presence of contractile reserve assessed by dobutamine stress echocardiography was associated with CRT-PR independently of the entity of LV electrical dyssynchrony. These findings shift the focus of CRT from electrical dyssynchrony to the myocardial substrate of functional response. Most CRT studies demonstrated that up to 40% of patients are not responders to CRT probably because mechanical dyssynchrony was absent despite a wide QRS. These results were attributed to the limited accuracy and reproducibility of the Doppler technique in HF patients.20 Another potential explanation is that the assessment of LV time delays does not correspond to the degree of residual myocardial contractility in the failing LV. The possibility that LV stimulation might gradually recruit viable myocardium might be the key to obtain significant LV remodelling after CRT. The entity of viability is associated with the entity of the myocardial scar21 and to a lower extent of heart remodelling before CRT.22 In our population, CRT-responders exhibited dilated cardiomyopathy more often and dilated LV less often. Moreover, CWtot emerged as a significant predictor of CRT response at multivariate regression analysis and was significantly associated with the entity of myocardial remodelling after CRT in both ischaemic and non-ischaemic patients. Ischaemic patients are often non-responders to CRT despite the presence of a wide QRS. This finding might be attributable to the presence of a myocardial scar in the area of CRT delivery21 but also to the presence of extensive myocardial remodelling and fibrosis,23 which limits the beneficial effect of CRT.22 As a matter of fact, in our study three patients who were non-responders to CRT had a myocardial scar located in the site of CRT delivery. Moreover, ischaemic patients responding to CRT had higher CWtot at baseline (1014 ± 354 vs. 816 ± 34 mmHg%, P = 0.05), and a greater correlation between CWtot and LV remodelling was observed after CRT in patients with ischaemic cardiomyopathy. Scar and viability can be investigated by cardiac MRI, stress echo, and nuclear imaging. PSLs allow the assessment of myocardial performance in a rapid and effective manner and might therefore have a complementary role with respect to other costly investigations. In our study, regional analysis of myocardial work revealed a significant reduction of CW in the septum with respect to the lateral wall (771 ± 332 vs. 1398 ± 529 mmHg%, P < 0001). In contrast, the amount of WW was significantly increased in the septum compared with lateral wall (498 ± 235 vs. 341 ± 177 mmHg/%, P < 0.0001). This regional difference in myocardial performance was particularly evident in CRT-responders compared with non-responders and is partially attributed to the electrical delay observed in CRT candidates (Figure 1). Despite this, with the only exception of SF, no parameter of regional myocardial performance was able to predict CRT response at multivariable analysis. Noteworthy, in our study the performance of CW in predicting CRT was similar to that observed for SF, which is a well know parameter of LV dyssynchrony,12 which underscores the importance of global myocardial performance as a substrate of the electromechanical delay.5,20 With respect to SF, which is a qualitative parameter, myocardial work is obtained from an automatic and quantitative analysis of LV function. This quantitative approach has some important advantages: (i) the assessment of myocardial performance is independent of afterload data, which are already included in the calculation of myocardial work; (ii) LV performance can be measured simultaneously on a global or segmental basis; (iii) data analysis is not influenced by the operator’s experience. In our survey, a CWtot < 1057 mmHg% identified 85% of non-responders with a PPV of 88% but with a reduced negative predictive value of 51%, indicating that the assessment of the contractile reserve might help but should not be the only parameter to consider for the selection of CRT candidates. The existence of multiple independent mechanism governing CRT response (e.g., electro-mechanical delay, residual contractility, and extension and localization of myocardial scar)5,21,20 supports the hypothesis that a multimodal stepwise approach which combines clinical, electrocardiographic, and echocardiographic data might be more effective for the identification of CRT-responders.12,24,25 We believe the assessment of myocardial performance before CRT implantation might be useful in the identification of patients26 with minimal residual contractility who are less likely to improve with CRT. This parameter combined with other data might represent a useful tool for the selection of CRT candidates. Limitations This is a monocentric, retrospective study involving a limited number of CRT candidates. No validation cohort was created to replicate our findings on myocardial work, which currently limit their application in everyday clinical practice. The definition of CRT-PR in our study was exclusively based on LV remodelling and not on clinical improvement. Anyway, the placebo effect in CRT, is a well-known phenomenon (40% of CRT-off patients in the Miracle trial27), which limits the application of the clinical status criteria for the detection of ‘true’ responders. The FU period we chosen to assess the reduction in LV-ESV was limited to 6 months after device implantation, which can represent a limit because some patients might have a delayed response to CRT.28 Anyway, this criterion has already been adopted by many renowned studies on this topic,2 and this is the reason why it was applied in our population. Several recent publications have documented a significant relationship between mechanical dyssynchrony and mortality in CRT-candidates.21,29 The association between myocardial work and prognosis has not been assessed in the present study. This is an interesting issue that merits further analysis in a larger cohort with a longer FU. Atrial fibrillation patients were not included given the difficulty in obtaining strain traces and myocardial work in the case of significant R–R variability. Despite the relative elevated prevalence of atrial fibrillation in CRT candidates, these patients were normally excluded by the landmark trials on CRT.1 In our study, myocardial scar was assessed by echocardiography using the motion score index, and imaging data were not used to guide CRT delivery. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Conflict of interest: S.O.A. is co-inventor of a patent: ‘Method for myocardial segmental work analysis’. D.E. received a research grant from General Electric Healthcare. S.E. is employed by General Electric Healthcare. Other authors have no conflicts of interests to declare. Funding The study was made possible thanks to a grant obtained from General Electric Healthcare by DE. References 1 Brignole M , Auricchio A , Baron-Esquivias G , Bordachar P , Boriani G , Breithardt O-A et al. 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Long-term follow-up of cardiac resynchronization therapy in patients with end-stage heart failure . J Cardiovasc Electrophysiol 2005 ; 16 : 701 – 7 . Google Scholar CrossRef Search ADS PubMed 17 Vecera J , Penicka M , Eriksen M , Russell K , Bartunek J , Vanderheyden M et al. Wasted septal work in left ventricular dyssynchrony: a novel principle to predict response to cardiac resynchronization therapy . Eur Heart J Cardiovasc Imaging 2016 ; 17 : 624 – 32 . Google Scholar CrossRef Search ADS PubMed 18 Picano E , Sicari R , Landi P , Cortigiani L , Bigi R , Coletta C et al. Prognostic value of myocardial viability in medically treated patients with global left ventricular dysfunction early after an acute uncomplicated myocardial infarction: a dobutamine stress echocardiographic study . Circulation 1998 ; 98 : 1078 – 84 . Google Scholar CrossRef Search ADS PubMed 19 Monin J-L , Quéré J-P , Monchi M , Petit H , Baleynaud S , Chauvel C et al. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics . Circulation 2003 ; 108 : 319 – 24 . Google Scholar CrossRef Search ADS PubMed 20 Lim P , Buakhamsri A , Popovic ZB , Greenberg NL , Patel D , Thomas JD et al. Longitudinal strain delay index by speckle tracking imaging: a new marker of response to cardiac resynchronization therapy . Circulation 2008 ; 118 : 1130 – 7 . Google Scholar CrossRef Search ADS PubMed 21 Delgado V , Bommel RJ , van 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 22 Reant P , Zaroui A , Donal E , Mignot A , Bordachar P , Deplagne A et al. Identification and characterization of super-responders after cardiac resynchronization therapy . Am J Cardiol 2010 ; 105 : 1327 – 35 . Google Scholar CrossRef Search ADS PubMed 23 Chen Z , Sohal M , Sammut E , Child N , Jackson T , Claridge S et al. Focal but not diffuse myocardial fibrosis burden quantification using cardiac magnetic resonance imaging predicts left ventricular reverse modeling following cardiac resynchronization therapy: focal but not diffuse fibrosis burden predicts CRT remodeling response . J Cardiovasc Electrophysiol 2016 ; 27 : 203 – 9 . Google Scholar CrossRef Search ADS PubMed 24 Lafitte S , Reant P , Zaroui A , Donal E , Mignot A , Bougted H et al. Validation of an echocardiographic multiparametric strategy to increase responders patients after cardiac resynchronization: a multicentre study . Eur Heart J 2009 ; 30 : 2880 – 7 . Google Scholar CrossRef Search ADS PubMed 25 Brunet-Bernard A , Maréchaux S , Fauchier L , Guiot A , Fournet M , Reynaud A et al. Combined score using clinical, electrocardiographic, and echocardiographic parameters to predict left ventricular remodeling in patients having had cardiac resynchronization therapy six months earlier . Am J Cardiol 2014 ; 113 : 2045 – 51 . Google Scholar CrossRef Search ADS PubMed 26 Lecoq G , Leclercq C , Leray E , Crocq C , Alonso C , de Place C , et al. Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure . Eur Heart J 2005 ; 26 : 1094 – 100 . Google Scholar CrossRef Search ADS PubMed 27 Abraham WT , Fisher WG , Smith AL , Delurgio DB , Leon AR , Loh E et al. Multicenter InSync Randomized Clinical Evaluation . Cardiac resynchronization in chronic heart failure . N Engl J Med 2002 ; 346 : 1845 – 53 . Google Scholar CrossRef Search ADS PubMed 28 Burns KV , Gage RM , Curtin AE , Bank AJ. Long-term echocardiographic response to cardiac resynchronization therapy in initial nonresponders . JACC Heart Fail 2015 ; 3 : 990 – 7 . Google Scholar CrossRef Search ADS PubMed 29 Tayal B , Gorcsan J , Delgado-Montero A , Marek JJ , Haugaa KH , Ryo K et al. Mechanical dyssynchrony by tissue Doppler cross-correlation is associated with risk for complex ventricular arrhythmias after cardiac resynchronization therapy . J Am Soc Echocardiogr 2015 ; 28 : 1474 – 81 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Role of myocardial constructive work in the identification of responders to CRT

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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 2017. For permissions, please email: journals.permissions@oup.com.
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10.1093/ehjci/jex191
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Abstract

Abstract Aims Cardiac resynchronization therapy (CRT) plays a pivotal role in the management of patients with heart failure (HF) and wide QRS complex. However, the treatment is plagued by numerous non-responders. Aim of the study is to evaluate the role myocardial work estimated by pressure-strain loops (PSLs) in the comprehension of physiological mechanisms associated with CRT and in the prediction of CRT response. Methods and results Ninety-seven patients with symptomatic HF (ejection fraction: 27 ± 6%, QRS duration 164 ± 18 ms) undergoing CRT implantation according to current recommendations were retrospectively included in the study. Standard 2D and speckle tracking echocardiography were performed before CRT and at the 6-month follow-up (FU). PSL analysis allowed the calculation of global and regional myocardial constructive work (CW) and wasted work (WW). A > 15% reduction in left ventricular (LV) end-systolic volume at FU defined CRT-positive response (CRT-PR). At FU, 63 (65%) patients responded to CRT. Global CW (CWtot) was significantly increased in CRT-responders. At multivariate analysis, CWtot > 1057 mmHg% (OR 14.69, P = 0.005) and septal flash (OR 8.05, P = 0.004) were the only significant predictors of CRT-PR. CWtot was associated with the entity of CRT-induced myocardial remodelling in both ischaemic (r = −0.55, P < 0.0001) and non-ischaemic patients (r = 0.65, P < 0.0001). A CWtot < 1057 mmHg% identified 85% of non-responders with a positive predictive value of 88%. Conclusion Patients with higher CWtot exhibit a favourable response to CRT. These data encourage further studies for the assessment of the myocardial substrate related to the functional response to CRT. cardiac resynchronization therapy, heart failure, pressure-strain loops, cardiac work Introduction Cardiac resynchronization therapy (CRT) plays a pivotal role in the management of patients with severe left ventricular (LV) dysfunction, persistent dyspnoea despite optimal medical therapy, and wide QRS complex.1 Despite this, approximately 30% of patients undergoing CRT do not properly respond to therapy. Imaging approaches have been proposed to facilitate the detection of CRT responders. Despite the initial promising results, randomized multicentre studies have demonstrated that dyssynchrony parameters assessed by echocardiography cannot predict CRT response2 and that their application for the selection of CRT candidates is even detrimental in the case of normal QRS.3 A potential explanation for these results is that the assessment of myocardial dyssynchrony markers does not take into account the role of residual myocardial contractility4,5 as a potential source for LV functional restoration after CRT. Recently, Russel et al.6,7 demonstrated that pressure strain loops (PSLs) estimate LV performance in a non-invasive manner and that the corresponding PSLs area is directly correlated with the residual myocardial metabolic activity assessed by FDG positron emission tomography in CRT candidates.6 The aim of the present study is to evaluate the role of global and regional myocardial work estimated by PSLs in the prediction of CRT response. Methods Population Ninety-seven patients with ischaemic or dilated cardiomyopathy undergoing CRT implantation according to current guidelines1 were retrospectively included in the study. At the moment of CRT implantation, all patients received optimized medical therapy. Clinical data, including age, gender, New York Heart Association (NYHA) functional class, systolic and diastolic blood pressure, NTproBNP, and creatinine were assessed for each patient. An ischaemic aetiology for LV failure was claimed in cases with a history of myocardial infarction or revascularization, angiographic evidence of multiple vessel disease or single-vessel disease with ≥75% stenosis of the left main or proximal left anterior descending artery.8 The study was reviewed by an independent ethics committee (regional ethic committee validation number: 35RC14-9767) and conducted in accordance with the ‘Good Clinical Practice’ Guidelines in the Declaration of Helsinki. All patients provided written informed consent. Electrocardiogram data The 12-lead surface electrocardiogram (ECG) was recorded at 25 and 50 mm/s during spontaneous rhythm before implantation of the CRT device. The method used for QRS duration analysis was previously reported.9 Left bundle branch block (LBBB) was defined by a QRS duration ≥ 120 ms with the following characteristics: QS or rS in lead V1; broad R waves in leads I, aVL, V5, or V6; and no q waves in leads V5 and V6. Echocardiography All patients underwent standard transthoracic echocardiography using a Vivid 7 or Vivid E9 ultrasound system (GE Healthcare, Horten, Norway) equipped with a 3S or M5S 3.5-mHz transducer. The M-mode, 2D, colour Doppler, pulsed-wave, and continuous-wave Doppler data were stored on a dedicated workstation for off-line analysis (EchoPAC, GE Healthcare, Horten, Norway). LV volumes and function were measured by the biplane method as recommended.10 The presence of myocardial scar was assessed by echocardiography and was defined by an end-diastolic wall thickness ≤5 mm associated with increased acoustic reflectance and concomitant akinesia/dyskinesia.11 Septal flash (SF) was defined by the presence of early septal thickening/thinning detected by M-mode within the isovolumetric contraction period or by the presence of a rapid change of colour in tissue Doppler imaging related to the early and fast contraction of the septum occurring during the isovolumetric period.12 The systolic delay between the lateral and septal wall at tissue-Doppler imaging was measured to quantify intraventricular delay according to recommendations.13 2D-speckle tracking echocardiography 2D greyscale images were acquired in the standard apical four-, three- and two-chamber views at a frame rate ≥ 60 frames/s. The recordings were processed using acoustic tracking-dedicated software (EchoPAC version 112.99, Research Release, GE Healthcare, Horten, Norway), which allowed for an off-line semi-automated analysis of speckle-based strain. To calculate the LV global longitudinal strain (GLS), a line was traced along the LV endocardium’s inner border in each of the three apical views on an end-systolic frame, and a region of interest was automatically defined between the endocardial and epicardial borders with GLS then automatically calculated from the strains in the three apical views.14 Image quality for the enrolled patients was optimal, and no LV segments were excluded from the analysis. Quantification of cardiac work Myocardial work and related indices were calculated using a costumed software. As previously described by Russel et al.,6 myocardial work was measured as a function of time throughout the cardiac cycle by the combination of LV strain data obtained by STE and a non-invasively estimated LV pressure curve. Peak systolic LV pressure was assumed to be equal to peak arterial pressure measured with a cuff manometer. The average of three blood pressure measures taken at rest was retained and inserted in the custom software. The non-invasive LV pressure curve (Figure 1A, left panel) was then obtained using an empiric, normalized reference curve that was adjusted according to the duration of the isovolumetric and ejection phases defined by the timing of aortic and mitral valve events by echocardiography. The reliability of this non-invasively estimated LV pressure curve was previously validated in a dog model and in patients with various cardiac disorders.6 Figure 1 View largeDownload slide (A) Example of LV pressure curve estimation. The timing of mitral and aortic valve events is indicated (left panel). Pressure data are then combined with LV global longitudinal strain data (right panel) using the R-wave onset in electrocardiogram as a common time reference. (B) Representative traces showing pressure–strain loops measured at the infero-basal septal LV segment (left panel) and infero-lateral segment (right panel) in a patient with a left bundle branch block. Figure 1 View largeDownload slide (A) Example of LV pressure curve estimation. The timing of mitral and aortic valve events is indicated (left panel). Pressure data are then combined with LV global longitudinal strain data (right panel) using the R-wave onset in electrocardiogram as a common time reference. (B) Representative traces showing pressure–strain loops measured at the infero-basal septal LV segment (left panel) and infero-lateral segment (right panel) in a patient with a left bundle branch block. Strain and pressure data were synchronized by aligning the valvular event times (Figure 1A, right and left panels). Myocardial work is approximated as the area of the pressure-strain loop (PSL) (Figure 1B). Mathematically this area was calculated by computing the rate of segmental shortening by differentiation of the strain curve and multiplying this value with instantaneous LV-pressure. This product is a measure of instantaneous power, which was integrated over time to obtain myocardial work as a function of time in systole, which is defined as the time interval from mitral valve closure to mitral valve opening.6,7,15 During the LV ejection period, work performed by the myocardium during segmental elongation represents energy loss, which is defined as wasted work (WW). Myocardial work performed during segmental shortening represented constructive work (CW). During isovolumetric relaxation, this definition was reversed such that myocardial work during shortening was considered WW and work during lengthening was considered CW. CW and WW were calculated for each LV segment. The mean CW and WW at the level of the lateral (CWlat and WWlat) and septal (CWsept and WWsept) walls and for the entire LV (CWtot and WWtot) were subsequently calculated. Figure 1B presents an example of the PSL traces obtained at the infero-basal and latero-basal segments of a patient with dilated cardiomyopathy and SF. Supplementary data online, Figure S1 shows segmental PSLs curves obtained in a CRT responder before and after resynchronisation. Supplementary data online, Figure S2 shows the bull’s eye for CW, WW and LV GLS obtained from the same patient. Cardiac resynchronization therapy delivery CRT delivery followed a standardized protocol. The right atrial and ventricular leads were positioned conventionally. Preferred localization of the LV lead was a lateral or postero-lateral vein. The position was chosen according to the width of QRS, with the goal of obtaining the thinnest one at the end of the procedure. No imaging data were used to identify the site of CRT delivery. After implantation, atrioventricular delay was programmed individually to reach the optimal diastolic filling using the Doppler mitral inflow before discharge, and ventriculo-ventricular timing was programmed to be simultaneous. After CRT implantation, the LV lead position was confirmed from the chest X-ray as previously described.16 The presence of a >15% reduction in LV end-systolic volume (ESV) at follow-up (FU) defined the CRT positive response (CRT-PR).2 Statistical analysis Continuous variables are expressed by means ± standard deviation. Non-continuous variables are expressed as numbers and percentages. Comparisons between the continuous variables were performed using the two-tailed t-test. Comparisons between the categorical variables were performed using the χ2 test. Linear regression analysis was used to assess the correlation between continuous variables. The inter-observer and intra-observer agreement for CW and WW was assessed on 15 randomly selected subjects by Bland–Altman plot analysis. Interclass coefficients (ICC) were then calculated as appropriate. Univariate logistic regression analysis was performed to assess the predictive value of clinical features, ECG, and echocardiographic parameters with respect to CRT response. Variables with a P-value <0.1 at univariate analysis were then inserted in the multivariate analysis (forward stepwise method). Receiver operator characteristic (ROC) analysis was used to identify the best cut-off values of CW to predict CRT response. Statistical analysis was performed using SPSS Version 20.0 (IBM, Chicago, IL, USA). Results Clinical, echocardiographic, and myocardial work data from the overall population and based on CRT response are presented in Table 1. Table 1 Characteristics of the entire population and based on CRT response Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 CW, constructive work; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; GLS, global longitudinal strain; LBBB, left bundle branch block; LV, left ventricle; NYHA, New York Heart Association functional class; WW, wasted work. Table 1 Characteristics of the entire population and based on CRT response Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 Variable Entire population n = 97 Non-responders n = 34 (35%) Responders n = 63 (65%) P-value Clinical data  Age (years) 65 ± 10 65 ± 10 65 ± 9 0.71  Male sex, n (%) 67 (69) 27 (79) 40 (63) 0.08  Heart rate (bpm) 67 ± 12 66 ± 9 67 ± 14 0.18  Ischaemic aetiology, n (%) 35 (36) 47 (74) 15 (44) 0.003  Systolic blood pressure (mmHg) 119 ± 23 105 ± 5 131 ± 28 0.18  Diastolic blood pressure (mmHg) 74 ± 10 72 ± 3 76 ± 16 0.71  Creatinine (μmol/L) 102 ± 33 112 ± 29 97 ± 34 0.05  lnNT-proBNP (ng/L) 7.2 ± 1.1 7.5 ± 1.1 7.0 ± 1.1 0.05  NYHA class 2.6 ± 0.5 2.6 ± 0.5 2.6 ± 0.5 0.87 LV dyssynchrony  QRS (ms ) 164 ± 18 159 ± 19 166 ± 17 0.09  LBBB, n (%) 48 (49) 16 (47) 32 (51) 0.11  LV septo-lateral delay (ms) 122 ± 92 120 ± 83 123 ± 97 0.88  Septal flash, n (%) 62 (64) 12 (35) 50 (79) <0.0001 Echocardiographic data  LV-EDV (mL) 227 ± 78 249 ± 83 215 ± 73 0.04  LV-ESV (mL) 168 ± 68 183 ± 74 159 ± 63 0.09  LV-EF (%) 27 ± 6 27 ± 5 27 ± 6 0.63  GLS (%) −8.1 ± 3.1 −6.9 ± 2.1 −8.8 ± 3.4 0.005 Cardiac work  Total CW (mmHg%) 980 ± 362 805 ± 252 1074 ± 379 <0.0001  Septal CW (mmHg%) 732 ± 366 666 ± 351 768 ± 372 0.19  Lateral CW (mmHg%) 1398 ± 519 1148 ± 390 1532 ± 533 0.001  Total WW (mmHg%) 313 ± 141 254 ± 105 346 ± 150 0.002  Septal WW (mmHg%) 498 ± 236 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 342 ± 177 280 ± 117 374 ± 195 0.013 CW, constructive work; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; GLS, global longitudinal strain; LBBB, left bundle branch block; LV, left ventricle; NYHA, New York Heart Association functional class; WW, wasted work. Ischaemic cardiomyopathy was diagnosed in 35 (36%) patients. At echocardiography, a myocardial scar that extended to at least 2 myocardial segments was observed in 21 patients (15 anterior, 3 lateral, 3 inferior myocardial infarction). In three cases, the LV lead was placed at the site of previous myocardial infarction, and all patients were non-responders to CRT. After a 6.1 (5.5–6.9) months FU, a CRT-PR was observed in 63 (65%) patients. CRT-responders exhibited an increased prevalence of dilated cardiomyopathy, less dilated LV, more preserved GLS, and an increased prevalence of SF. Higher values for CWtot, CWlat, WWtot, WWlat, and WWsept were observed in CRT-responders. Estimation of myocardial work and reproducibility The estimation of myocardial work was possible in all patients. Inter-observer and intra-observer variability is depicted in Figure 2A–D. The ICC for the inter-observed and intra-observer variability were 0.92 (95% CI: 0.76–0.97, P < 0.0001) and 0.89 (95% CI: 0.68–0.96, P < 0.0001) for CW and 0.91 (95% CI: 0.73–0.96, P < 0.0001) and 0.91 (95% CI: 0.72–0.97, P < 0.0001) for WW. Figure 2 View largeDownload slide Bland–Altman plot analysis for intra-observer and inter-observer agreement for constructive work (A and B) and wasted work (C and D). CWA, WWA: measures performed by the echocardiographer A. CWB, WWB: measure performed by the echocardiographer B. CW1, WW1, CW2, WW2: first and second measure performed by the same echocardiographer to test intra-observer agreement. Figure 2 View largeDownload slide Bland–Altman plot analysis for intra-observer and inter-observer agreement for constructive work (A and B) and wasted work (C and D). CWA, WWA: measures performed by the echocardiographer A. CWB, WWB: measure performed by the echocardiographer B. CW1, WW1, CW2, WW2: first and second measure performed by the same echocardiographer to test intra-observer agreement. Predictors of CRT response At univariable logistic regression analysis, LV end-diastolic volume, ischaemic aetiology, SF, CWtot, CWlat, WWtot, WWlat, and WWsept were significant predictors of CRT-PR (P < 0.05). In multivariable logistic regression analysis, only SF (OR 5.07, P = 0.007) and CWtot (OR 1.003, P < 0.036) remained significant predictors of CRT-PR (Table 2). At ROC analysis, a cut-off value of 1057 mmHg% for CWtot was predictor of CRT response (Figure 3A). When this value was inserted in the multivariable analysis, SF and CWtot > 1057 mmHg% remained the only predictors of CRT (OR 8.05, P = 0.005 and OR 14.69, P = 0.005, respectively). The AUC’s comparison did not reveal a significant difference between SF and CWtot for the identification of CRT-responders (Figure 3B). A CW < 1057 mmHg% identified 29 (85%) of 34 non-responders with good positive predictive value (PPV) of 88% and negative predictive value of 51%. Table 2 Predictors of positive response to CRT in univariable and multivariable logistic regression analysis OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 Table 2 Predictors of positive response to CRT in univariable and multivariable logistic regression analysis OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 OR (95% CI) P-value OR 95% (CI) P-value Age (per year) 0.99 (0.95–1.04) 0.71 Male sex 2.21 (0.84–5.89) 0.11 LV-EDV (per mL) 0.99 (0.98–1.00) 0.04 1.02 (0.98–1.07) 0.34 LV-ESV (per mL) 0.99 (0.98–1.00) 0.10 0.98 (0.95–1.02) 0.98 LV-EF (per %) 0.63 (0.92–1.05) 0.63 Ischaemic aetiology 0.27 (0.11–0.65) 0.004 0.44 (0.12–1.60) 0.22 QRS width (per ms) 1.02 (0.99–1.05) 0.09 1.02 (0.98–1.06) 0.36 LBBB 2.20 (0.77–6.26) 0.14 Septal flash, n (%) 7.29 (2.82–18.83) 0.0001 5.7 (1.60–20.52) 0.007 LV septo-lateral delay (per ms) 1.00 (0.99–1.01) 0.88 Total CW (per mmHg%) 1.003 (1.001–1.004) 0.001 1.003 (1.001–1.005) 0.036 Septal CW (per mmHg%) 1.001 (1.000–1.002) 0.19 Lateral CW (per mmHg%) 1.002 (1.001–1.003) 0.001 0.99 (0.99–1.00) 0.54 Total WW (per mmHg%) 0.99 (0.99–1.00) 0.004 0.99 (0.99–1.01) 0.72 Septal WW (per mmHg%) 1.005 (1.002–1.007) <0.0001 1.00 (0.99–1.01) 0.24 Lateral WW (per mmHg%) 1.004 (1.001–1.007) 0.02 1.00 (0.99–1.01) 0.38 Figure 3 View largeDownload slide (A) ROC curve analysis for constructive work. (B) ROC curves for CW > 1057 mmHg% and septal flash. Figure 3 View largeDownload slide (A) ROC curve analysis for constructive work. (B) ROC curves for CW > 1057 mmHg% and septal flash. Constructive myocardial work and clinical and echocardiographic data The studied population was divided in two groups: CWtot ≤ 1057 mmHg% and CWtot > 1057 mmHg%. The group with a higher CWtot exhibited less dilated LV and better LVEF and GLS values. Both groups exhibited similar NYHA functional class levels and prevalence of ischaemic cardiomyopathy. The entity of dyssynchrony expressed by QRS durations, LV septo-lateral delay and the prevalence of SF was the same in the two groups (Table 3). Table 3 Characteristics of the entire population according to global constructive work values Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 Table 3 Characteristics of the entire population according to global constructive work values Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 Variable CWtot ≤ 1057 mmHg/% n = 57 (59%) CWtot > 1057 mmHg/% n = 40 (41%) P-value Demographic data  Age (years) 65 ± 10 65 ± 9 0.66  Male sex, n (%) 42 (74) 25 (63) 0.17  Ischaemic aetiology, n (%) 33 (58) 29 (72) 0.19  NYHA class 2.6 ± 0.5 2.6 ± 0.5 0.96 LV dyssynchrony  QRS (ms) 165 ± 18 161 ± 17 0.19  LBBB, n (%) 31 (54) 17 (41) 0.54  LV septo-lateral delay (ms) 120 ± 95 124 ± 89 0.86  Septal flash, n (%) 32 (56) 30 (75) 0.07 Echocardiographic data  LV-EDV (mL) 250 ± 85 195 ± 54 <0.0001  LV-ESV (mL) 188 ± 74 138 ± 44 <0.0001  LV-EF (%) 26 ± 6 29 ± 5 0.01  GLS (%) −6.5 ± 2.3 −10.5 ± 2.5 <0.0001  Responders, n (%) 28 (49) 35 (88) <0.0001 Cardiac work  Septal CW 612 ± 294 904 ± 393 <0.0001  Lateral CW (mmHg%) 1201 ± 482 1678 ± 445 <0.0001  Total WW (mmHg%) 306 ± 137 324 ± 150 0.54  Septal WW (mmHg%) 363 ± 163 571 ± 238 <0.0001  Lateral WW (mmHg%) 321 ± 183 373 ± 166 0.16 LV reverse remodelling at follow-up CWtot was significantly correlated with the entity of LV remodelling after CRT (Figure 4A–G). Interestingly, CWtot also correlated with LV remodelling in ischaemic patients, and the correlation coefficients were increased compared with those observed in the overall population (Table 4). Table 4 Correlations between global constructive work and left ventricular remodelling at follow-up in the overall population and in patients with ischaemic cardiomyopathy Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 EDD, end-diastolic diameter; ESD, end-systolic diameter; FU, follow-up; Δ, percentage of variation in LV-ESV before and after CRT. Table 4 Correlations between global constructive work and left ventricular remodelling at follow-up in the overall population and in patients with ischaemic cardiomyopathy Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 Overall population N = 97 Ischaemic patients r P-value r P-value LV-EDDFU −0.52 <0.0001 −0.63 0.0001 LV-ESDFU −0.43 <0.0001 −0.61 0.0001 LV-EDVFU −0.55 <0.0001 −0.47 0.0001 LV-ESVFU −0.55 <0.0001 −0.65 0.0001 ΔLV-ESV −0.27 <0.01 −0.38 0.02 LV-EFFU 0.46 <0.0001 −0.56 0.0001 GLSFU −0.59 <0.0001 0.61 0.0001 EDD, end-diastolic diameter; ESD, end-systolic diameter; FU, follow-up; Δ, percentage of variation in LV-ESV before and after CRT. Figure 4 View largeDownload slide (A–G) Correlations between global constructive work and left ventricular size and function parameters at follow-up. Figure 4 View largeDownload slide (A–G) Correlations between global constructive work and left ventricular size and function parameters at follow-up. Discussion In the present study we showed that in CRT-candidates, the amount of total myocardial CW is a predictor of CRT response and is correlated with the entity of LV remodelling after CRT. Pressure-strain loop curves PSL curves are a recently introduced tool that allows a non-invasive estimation of myocardial work. The reliability of this method with respect to the invasive estimation of myocardial work has been validated by experimental studies and mathematical models.6,7 Moreover, in 21 CRT-candidates, Vecera et al.17 were able to demonstrate that WWsept is a predictor CRT-PR. Regional differences in myocardial work assessed by PSLs have a strong correlation with the entity of myocardial glucose metabolism evaluated by FDG-PET.6 These results support the hypothesis that the differences in CW detected by PSLs before CRT correspond to myocardial residual metabolic activity and contractile reserve and might therefore explain the role of baseline CW in predicting CRT-PR. Role of total myocardial constructive work in CRT response Previous studies have demonstrated that the contractile reserve has a prognostic role in patients with reduced LVEF and ischaemic cardiomyopathy18; low-flow/low-gradient aortic stenosis19; and LV dyssynchrony.5 In patients with HF undergoing CRT, Ciampi et al.5 demonstrated that the presence of contractile reserve assessed by dobutamine stress echocardiography was associated with CRT-PR independently of the entity of LV electrical dyssynchrony. These findings shift the focus of CRT from electrical dyssynchrony to the myocardial substrate of functional response. Most CRT studies demonstrated that up to 40% of patients are not responders to CRT probably because mechanical dyssynchrony was absent despite a wide QRS. These results were attributed to the limited accuracy and reproducibility of the Doppler technique in HF patients.20 Another potential explanation is that the assessment of LV time delays does not correspond to the degree of residual myocardial contractility in the failing LV. The possibility that LV stimulation might gradually recruit viable myocardium might be the key to obtain significant LV remodelling after CRT. The entity of viability is associated with the entity of the myocardial scar21 and to a lower extent of heart remodelling before CRT.22 In our population, CRT-responders exhibited dilated cardiomyopathy more often and dilated LV less often. Moreover, CWtot emerged as a significant predictor of CRT response at multivariate regression analysis and was significantly associated with the entity of myocardial remodelling after CRT in both ischaemic and non-ischaemic patients. Ischaemic patients are often non-responders to CRT despite the presence of a wide QRS. This finding might be attributable to the presence of a myocardial scar in the area of CRT delivery21 but also to the presence of extensive myocardial remodelling and fibrosis,23 which limits the beneficial effect of CRT.22 As a matter of fact, in our study three patients who were non-responders to CRT had a myocardial scar located in the site of CRT delivery. Moreover, ischaemic patients responding to CRT had higher CWtot at baseline (1014 ± 354 vs. 816 ± 34 mmHg%, P = 0.05), and a greater correlation between CWtot and LV remodelling was observed after CRT in patients with ischaemic cardiomyopathy. Scar and viability can be investigated by cardiac MRI, stress echo, and nuclear imaging. PSLs allow the assessment of myocardial performance in a rapid and effective manner and might therefore have a complementary role with respect to other costly investigations. In our study, regional analysis of myocardial work revealed a significant reduction of CW in the septum with respect to the lateral wall (771 ± 332 vs. 1398 ± 529 mmHg%, P < 0001). In contrast, the amount of WW was significantly increased in the septum compared with lateral wall (498 ± 235 vs. 341 ± 177 mmHg/%, P < 0.0001). This regional difference in myocardial performance was particularly evident in CRT-responders compared with non-responders and is partially attributed to the electrical delay observed in CRT candidates (Figure 1). Despite this, with the only exception of SF, no parameter of regional myocardial performance was able to predict CRT response at multivariable analysis. Noteworthy, in our study the performance of CW in predicting CRT was similar to that observed for SF, which is a well know parameter of LV dyssynchrony,12 which underscores the importance of global myocardial performance as a substrate of the electromechanical delay.5,20 With respect to SF, which is a qualitative parameter, myocardial work is obtained from an automatic and quantitative analysis of LV function. This quantitative approach has some important advantages: (i) the assessment of myocardial performance is independent of afterload data, which are already included in the calculation of myocardial work; (ii) LV performance can be measured simultaneously on a global or segmental basis; (iii) data analysis is not influenced by the operator’s experience. In our survey, a CWtot < 1057 mmHg% identified 85% of non-responders with a PPV of 88% but with a reduced negative predictive value of 51%, indicating that the assessment of the contractile reserve might help but should not be the only parameter to consider for the selection of CRT candidates. The existence of multiple independent mechanism governing CRT response (e.g., electro-mechanical delay, residual contractility, and extension and localization of myocardial scar)5,21,20 supports the hypothesis that a multimodal stepwise approach which combines clinical, electrocardiographic, and echocardiographic data might be more effective for the identification of CRT-responders.12,24,25 We believe the assessment of myocardial performance before CRT implantation might be useful in the identification of patients26 with minimal residual contractility who are less likely to improve with CRT. This parameter combined with other data might represent a useful tool for the selection of CRT candidates. Limitations This is a monocentric, retrospective study involving a limited number of CRT candidates. No validation cohort was created to replicate our findings on myocardial work, which currently limit their application in everyday clinical practice. The definition of CRT-PR in our study was exclusively based on LV remodelling and not on clinical improvement. Anyway, the placebo effect in CRT, is a well-known phenomenon (40% of CRT-off patients in the Miracle trial27), which limits the application of the clinical status criteria for the detection of ‘true’ responders. The FU period we chosen to assess the reduction in LV-ESV was limited to 6 months after device implantation, which can represent a limit because some patients might have a delayed response to CRT.28 Anyway, this criterion has already been adopted by many renowned studies on this topic,2 and this is the reason why it was applied in our population. Several recent publications have documented a significant relationship between mechanical dyssynchrony and mortality in CRT-candidates.21,29 The association between myocardial work and prognosis has not been assessed in the present study. This is an interesting issue that merits further analysis in a larger cohort with a longer FU. Atrial fibrillation patients were not included given the difficulty in obtaining strain traces and myocardial work in the case of significant R–R variability. Despite the relative elevated prevalence of atrial fibrillation in CRT candidates, these patients were normally excluded by the landmark trials on CRT.1 In our study, myocardial scar was assessed by echocardiography using the motion score index, and imaging data were not used to guide CRT delivery. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Conflict of interest: S.O.A. is co-inventor of a patent: ‘Method for myocardial segmental work analysis’. D.E. received a research grant from General Electric Healthcare. S.E. is employed by General Electric Healthcare. Other authors have no conflicts of interests to declare. Funding The study was made possible thanks to a grant obtained from General Electric Healthcare by DE. References 1 Brignole M , Auricchio A , Baron-Esquivias G , Bordachar P , Boriani G , Breithardt O-A et al. 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Journal

European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Sep 1, 2018

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