Introduction. CLINICAL RESEARCH Pacing and resynchronization therapy

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1 Europace (216) 18, doi:1.193/europace/euv145 CLINICAL RESEARCH Pacing and resynchronization therapy Quantitative assessment of cardiac mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy in patients with non-ischaemic dilated cardiomyopathy using equilibrium radionuclide angiography Anirban Mukherjee 1, Chetan D. Patel 1 *, Nitish Naik 2, Gautam Sharma 2, and Ambuj Roy 2 1 Department of Nuclear Medicine, Cardio-Thoracic Centre, All India Institute of Medical Sciences, Room No. 36, New Delhi 1129, India; and 2 Department of Cardiology, Cardio-Thoracic Centre, All India Institute of Medical Sciences, New Delhi, India Received 6 January 215; accepted after revision 27 April 215; online publish-ahead-of-print 7 June 215 Aims The aim of this study was to evaluate equilibrium radionuclide angiography (ERNA) in prediction of response to cardiac resynchronization therapy (CRT) in non-ischaemic dilated cardiomyopathy (DCM) patients.... Methods Thirty-two patients (23 males, years) were prospectively included. Equilibrium radionuclide angiography and results and clinical evaluation were performed before and 3 months after CRT implantation. Standard deviation of left ventricle mean phase angle (SD LVmPA) and difference between LV and right ventricle mpa (LV RVmPA) expressed in degrees (8) were used to quantify left intraventricular synchrony and interventricular synchrony, respectively. Left ventricular ejection fraction (LVEF) was also evaluated. At the baseline, mean NYHA class was , LVEF %, mean QRS duration ms, SD LVmPA , and LV RVmPA At 3-month follow-up, 22 patients responded to CRT with improvement in NYHA class 1 and EF.5%. Responders had significantly larger SD LVmPA ( vs ) and LV RVmPA ( vs ) than non-responders. Receiveroperating characteristic curve analysis demonstrated 95% sensitivity and 8% specificity at a cut-off value of 38 for SD LVmPA, and 81% sensitivity and 8% specificity at a cut-off value of 238 for LV RVmPA in prediction of response to CRT.... Conclusion Baseline SD LVmPA and LV RVmPA derived from ERNA are useful for prediction of response to CRT in nonischaemic DCM patients Keywords Equilibrium radionuclide angiography Cardiac mechanical dyssynchrony Cardiac resynchronization therapy Non-ischaemic dilated cardiomyopathy Introduction Cardiac resynchronization therapy (CRT) has emerged as an exciting treatment option for the subset of heart failure (HF) patients who remain symptomatic despite optimal medical management. 1 The American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines recommend CRT in patients with end-stage drug-refractory HF (NYHA class II IV), depressed left ventricular ejection fraction (LVEF 35%), and prolonged QRS duration ( 15 ms). 2 TheresponsetoCRTwasinitially considered to result in part from correction of interventricular dyssynchrony (IVD; conduction delay). Since QRS duration was considered to reflect interventricular delay, patients with wide QRS complex ( ms) or left bundle branch block (LBBB) * Corresponding author. B-54, South Extension Part-1, New Delhi 1149, India. Tel: ; fax: address: cdpatel9@gmail.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 215. For permissions please journals.permissions@oup.com.

2 852 A. Mukherjee et al. What s new? The QRS duration shows strong association with interventricular dyssynchrony, but not with left intraventricular dyssynchrony. Left intraventricular dyssynchrony appears to be the major determinant of left ventricular function compared with QRS duration and interventricular dyssynchrony. Responders had larger cardiac mechanical dyssynchrony (both left intraventricular and interventricular dysssynchrony) parameters at baseline compared with non-responders. Standard deviation of left ventricle mean phase angle (SD LVmPA) and difference between LV and right ventricle mpa (LV RVmPA) measured by phase analysis of equilibrium radionuclide angiography (ERNA) have a good predictive value for response to cardiac resynchronization therapy (CRT) with high sensitivity and specificity. Both SD LVmPA and LV RVmPA were univariate predictors for response to CRT. On multivariate analysis, SD LVmPA was found to be the most important independent predictor for response to CRT. QRS duration was not found to be a predictor for response to CRT on both uni- and multivariate analyses. were considered candidates for CRT. However, using these conventional criteria for selection of patients for CRT, it was noted that 2 4% of patients did not respond to CRT. 3,4 Owing to high cost of device therapy and associated procedural complications, the quest is to refine the selection criteria and to define an objective parameter which can accurately predict the response to therapy prior to device implantation. Mechanical cardiac dyssynchrony has been recognized as an additional and essential criterion for response to CRT. 5,6 Therefore, assessment of cardiac mechanical dyssynchrony has gained considerable attention over recent years with the aim to distinguish CRT responders from non-responders with a high degree of accuracy. A variety of imaging techniques have been used for assessment of mechanical dyssynchrony, which include echocardiography, cardiac magnetic resonance, equilibrium radionuclide angiography (ERNA), gated blood pool single-photon emission computed tomography, gated myocardial perfusion SPECT (GMPS), and positron emission tomography. 7 Though echocardiography has been used most commonly to measure both interventricular and intraventricular mechanical dyssynchrony due to its wide availability, it has limited reproducibility and high operator dependency. The PROSPECT trial revealed that the available echocardiographic techniques including tissue Doppler imaging are not ready for routine clinical practice to assess LV dyssynchrony. 8 There is a need for better standardization and refinements of the screening tools for the evaluation of LV dyssynchrony. Therefore, there is an ample scope and a need to search for more reproducible modalities of measuring LV dyssynchrony. The potential of ERNA as a tool for assessment of cardiac mechanical dyssynchrony has been recognized for many years. 9 Being less subjective than echocardiography, ERNA is a promising tool to objectively quantify mechanical dyssynchrony. Recently, an article published from our centre has established normal values of mechanical synchrony using ERNA in a larger population using the commercially available software. 7 Using these normal values, we designed this study to evaluate ERNA to detect mechanical dyssynchrony in patients submitted for CRT and to establish the cut-off values of dyssynchrony to predict response to CRT in these patients. Methods Study population This was a single-centre study performed at cardiothoracic centre at AIIMS. We prospectively included 34 patients between the period of January 213 and August 214, who were implanted CRT as per the standard protocol followed at our institute. The study was approved by the Institute s Ethics Committee and informed consent was taken from all the patients. Patients diagnosed with non-ischaemic dilated cardiomyopathy (DCM) with a duration of symptoms greater than 1 year, LVEF 35%, QRS duration 13 ms, NYHA class III and IV, and with normal sinus rhythm were included. Patients with coronary artery disease, congenital heart disease, valvular heart disease, and restrictive and hypertrophic cardiomyopathies were excluded from the study. All the 34 recruited patients underwent a baseline ERNA study within 1 week before CRT. The patients were also clinically evaluated by the referring cardiologist who was unaware of the result of phase analysis of ERNA. Two patients were excluded due to failed quality control as a result of high percentage of rejected beat on an ERNA study. So, a total of 32 patients were included in the final study. The patients then underwent CRT as per the standard institute procedure. Equilibrium radionuclide angiography was performed on each patient at 3 months post-crt for assessment of dyssynchrony and function and also clinically evaluated at the same time. Equilibrium radionuclide angiography acquisition All patients underwent technetium99m-labelled red blood cell (Tc99m-RBC)-gated blood pool ERNA. RBC labelling was performed by an in vivo method. Stannous ions (stannous chloride,.5.9 mg, 15 mg/kg body weight) were injected intravenously. Tc99m pertechnetate [15 2 mci (55 74 MBq)] was injected intravenously 1 15 min later. Rest ERNA acquisition was performed after 1 15 min. A dual head gamma camera (Infinia Hawkeye 4, GE Medical Systems, Waukesha, WI, USA) was used for image acquisition using a parallel hole, low-energy, high-resolution collimator. Images were acquired in the left anterior oblique (best septal) view to provide optimal RV and LV blood pool discrimination, using energy discrimination centred on 14 kev and 2% energy window. Images were acquired in a matrix of 32 gated frames, for 3 4 s ( 5 6 Kcts). The ECG was monitored continuously to ensure R-wave gating of the QRS complex with a window threshold of 2% around the mean R R interval. Images were acquired for each patient in sinus rhythm. Equilibrium radionuclide angiography processing Equilibrium radionuclide angiography studies were processed using the commercially available XT-ERNA software (GE Medical Systems) on a Xeleris Workstation (GE Medical Systems).

3 Assessment of cardiac mechanical dyssynchrony and cardiac resynchronization therapy 853 Image processing Ejection fraction calculation and phase analysis We assessed LVEF and derived cardiac synchrony from phase analysis. The software generates LV region of interest (ROI) automatically, but the RV ROI is not generated automatically. Therefore, manual image processing was done in all studies for both LV and RV ROI. In the first step, LV centre was manually chosen on the end-diastolic frame. The software image display shows four images simultaneously: the filtered end-diastolic image, Laplace image (highlights region with a rapid change in counts, used for edge detection), amplitude image (showing a relative change in counts over time on a pixel basis), and the phase image. The LV and RV end-diastolic ROI is drawn interactively on all four images and one can jump between the images to fine tune the ROI. The ventricular ROI was drawn carefully to exclude atrial and extracardiac activity. Left ventricular ejection fraction was computed as a percentage using formula: LVEF ¼ (end-diastolic ROI counts 2 background counts) 2 (end-systolic ROI counts 2 background counts)/(end-diastolic ROI counts 2 background counts) 1. 7 The phase analysis software applies a first Fourier harmonic fit of the blood pool time vs. radioactive curve to measure the magnitude and sequence of ventricular contraction in each pixel of the image. 1 A phase angle is assigned (between and 368 depending on the relative time delay from the R-wave to the start of the cardiac cycle for each pixel). A phase histogram is constructed corresponding to the sequence of ventricular contraction during cardiac cycle. Phase images were generated using a continuous colour scale, corresponding to phase angles from to 368. The mean phase angle (mpa) relates to the mean time of onset of the ventricular contraction, and standard deviation of the ventricular mean phase angle measures the synchrony of the ventricular contraction. 11 Parameter derived from phase analysis Mean phase angle was computed for both the LV and RV blood pools as the arithmetic mean of the phase angle for all pixels in the corresponding ventricular ROI. The difference between the mean phase angles of the two ventricles, i.e. LV RVmPA signifies dyssynchrony between the ventricles, denotes IVD. On the other hand, standard deviation of the mpa of LV blood pool, i.e. SD LVmPA, represents contractile synchrony within the left ventricle and denotes intra LV dyssynchrony (ILVD). Standard deviation of left ventricle mean phase angle and LV RVmPA can be expressed in degree/angle (8) and time in milliseconds (ms) (time in ms ¼ mean of the cardiac cycle duration during acquisition angle/36). Expressing SD of mpa in degrees is considered more accurate since it negates the effect of different heart rates (and thus R R interval) among individuals. 12 Therefore, in our study, we only used degrees to measure SD LVmPA and LV RVmPA. We used cut-off values of ERNA, which are established at our centre to detect the presence of dyssynchrony (Table 1). 7 Table 1 Proposed cut-off values of dyssynchrony 7 Left intraventricular dyssynchrony (SD LVmPA).27.1 ms, Right intraventricular dyssynchrony (SD RVmPA).68.7 ms, Interventricular dyssynchrony (LV RVmPA).47.3 ms, LV, left ventricle; RV, right ventricle; mpa, mean phase angle; SD, standard deviation; ms, milliseconds. Methods of cardiac resynchronization therapy implantation Cardiac resynchronization therapy implantation was performed through the subclavian or axillary vein access. Coronary sinus venogram was obtained using occlusive balloon angiography to define the venous anatomy. The LV lead was inserted preferably into a posterolateral vein whenever a suitable vein was available and amenable for cannulation and stable lead positioning. In patients with unsuitable anatomy, leads were positioned in lateral veins either through tributaries draining from lateral sites or by surgical epicardial lead placement. The optimal position of the LV lead was defined according to LV lead impedance, threshold, and the absence of phrenic nerve stimulation. The right atrial lead was conventionally positioned in the right atrium appendage and right ventricular lead into the ventricular septum or right ventricular apex. Finally, all leads were connected to a dual-chamber biventricular CRT device. The optimal atrioventricular (AV) delay was determined during simultaneous biventricular pacing by the simplified mitral inflow method: a long AV interval (2 ms) was programmed and gradually reduced by 2 ms, until A-wave truncation was observed. All patients received St Jude Medical devices and underwent auto AV/VV optimization using QuickOpt w programming at initial implant and on follow-up. Statistical analysis Data are presented as mean with standard deviations or median with ranges where appropriate. Chi-squared test/fisher s exact test was used for comparison of categorical (qualitative) data between groups. For continuous variables, the Student s t-test/mann Whitney U-test were applied for comparison between the means of two groups. Pearson s r/spearman s r was used to assess correlation between quantitative variables where appropriate. Receiver-operating characteristic (ROC) curves were analysed to determine the optimal cut-off values to predict response to CRT. Uni- and multivariate analyses were done using the stepwise logistic regression method to find out the most important predictor for response to CRT. A value of P,.5 was considered as statistically significant. All the data analyses were performed using the statistical software packages SPSS 17 (SPSS, Inc., Chicago, IL, USA) and MedCalc 11.3 (MedCalc Software, Mariakerke, Belgium). Results Study population The baseline characteristics of the 32 patients (23 males, years) are summarized in Table 2. Of 32 patients, 2 had LBBB and mean QRS duration was ms. All patients had severe HF with LVEF,35% (mean LVEF %). Of 32 patients, 9 had NYHA class IV and 23 had NYHA class III (mean NYHA functional class ). All the 32 patients were on optimal medical therapy, all the patients were on diuretics, 31 (97%) were on b-blocker and inotropes, and 16 (5%) were taking ACE inhibitor. All patients underwent baseline pre-crt ERNA. On ERNA, SD LVmPA was the measure of ILVD and difference between left ventricular mean phase angle and right ventricular mean phase angle (LV RVmPA) was the measure of IVD. Values of SD LVmPA and LV RVmPA higher than the normal values (Table 1) were considered dyssynchronous. In our study, of 32 patients, 31 (97%) had ILVD and 23 (72%) had IVD on ERNA.

4 854 A. Mukherjee et al. Table 2 Clinical characteristics of the study population (n 5 32) Clinical characteristics Value Age years Sex (M/F) 23/9 Diabetes 14 (44%) Hypertension 13 (41%) Smoking 16 (5%) LBBB 2 (63%) NYHA class QRS interval ms LVEF % Dyssynchrony parameters SD LVmPA (ILVD) LV RVmPA (IVD) Data are presented as mean + SD or as n (%). LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; SD LVmPA, standard deviation of left ventricle mean phase angle; ILVD, intra LV dyssynchrony; IVD, interventricular dyssynchrony; LV RVmPA, difference between LV and right ventricle mpa. Table 3 Baseline characteristics of responders (n 5 22) vs. non-responders (n 5 1) to CRT Baseline Responder Non-responder P-value characteristics Age Sex (M/F) 15/7 8/2.79 Diabetes 1 (45%) 4 (4%).92 Hypertension 1 (45%) 3 (3%).66 Smoking 11 (5%) 5 (5%).7 b-blocker 21 (95%) 1 (1%) 1. Inotropes 22 (1%) 9 (9%) 1. Diuretic 22 (1%) 1 (1%) 1. ACE-I 12 (54%) 4 (4%).7 LBBB 16 (72%) 4 (4%).16 NYHA QRS (ms) LVEF % %.15 Dyssynchrony parameters SD LVmPA (ILVD) LV RVmPA (IVD) A NYHA class C Degrees NYHA SD LVmPA Post CRT NYHA Post CRT SD LVmPA B (%) D Degrees LVEF LV RVmPA Post CRT EF Post CRT LV RVmPA Data are presented as mean + SD or as n (%). LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; SD LVmPA, standard deviation of left ventricle mean phase angle; ILVD, intra LV dyssynchrony; IVD, interventricular dyssynchrony; LV RVmPA, difference between LV and right ventricle mpa. Post-cardiac resynchronization therapy assessment A follow-up ERNA was performed in all the patients 3 months post-crt (range 3 4 months). Patients were clinically evaluated by the cardiologists who were unaware of the result of baseline ERNA. At the follow-up evaluation, the NYHA functional class improved significantly [ vs (P,.1)]. There was a significant improvement in LVEF [ vs % (P,.1)]. Comparison of mechanical dyssynchrony parameters showed that both ILVD [ vs (P,.1)] and IVD [ vs (P,.1)] improved significantly in post-crt assessment when compared with baseline (Figure 1 ). Figure 1 Significant improvement in NYHA class (A), LVEF (B), SD LVmPA (ILVD) and LV RVmPA (IVD) (C and D, respectively) in post-crt follow-up assessment compared with the baseline. At the baseline evaluation, no significant correlation was noted between QRS interval and ILVD (r ¼.8, 95% CI 2.28 to.42, P ¼.66). However, there was a significant correlation between QRS interval and IVD (r ¼.74, 95% CI.52.86; P,.1). No significant correlation was observed between patient s QRS duration and LVEF (r ¼.1; P ¼.58). A significant negative correlation was noted between LVEF and ILVD (r ¼ 2.6, 95% CI 2.78 to 2.31, P ¼.3). However, no statistically significant correlation was noted between LVEF and IVD (r ¼ 2.12, 95% CI 2.45 to.23, P ¼.5). Identifying responders and non-responders Patients were classified as responders if there was an improvement in NYHA functional class 1 and an increase in LVEF.5% on follow-up ERNA. 13 Twenty-two (69%) patients were classified as responders and 1 (31%) patients as non-responders according to these criteria. At baseline, there were no significant differences in clinical characteristics between the responders and nonresponders, except for dyssynchrony parameters. Both ILVD and IVD were significantly larger in responders when compared with non-responders (Table 3). In the responders, the NYHA functional class, LVEF, and dyssynchrony parameters improved significantly, whereas it remains almost unchanged in the non-responders. Details are summarized in Table 4.

5 Assessment of cardiac mechanical dyssynchrony and cardiac resynchronization therapy 855 Table 4 Comparison of LVEF, NYHA class, and dyssynchrony parameters between baseline and post-crt in responders and non-responders Baseline Post-CRT P-value NYHA class Responder <.1 Non-responder LVEF Responder % % <.1 Non-responder % %.6 Dyssynchrony parameters SD LVmPA (ILVD) Responder <.1 Non-responder LV RVmPA (IVD) Responder <.1 Non-responder Data are presented as mean + SD. LVEF, left ventricular ejection fraction; CRT, cardiac resynchronization therapy; SD LVmPA, standard deviation of left ventricle mean phase angle; ILVD, intra LV dyssynchrony; IVD, interventricular dyssynchrony; LV RVmPA, difference between LV and right ventricle mpa. Bold value indicates significant difference. Prediction of cardiac resynchronization therapy response Both ILVD and IVD were higher in responders compared with the non-responders. ROC curve analysis demonstrated an optimal sensitivity of 95% and specificity of 8% at a cut-off value of 38 for SD LVmPA and an optimal sensitivity of 81% and specificity of 8% at a cut-off value of 238 for LV RVmPA for prediction of response to CRT. The area under curve was.9 and.832 for SD LVmPA and LV RVmPA, respectively, which indicates a good predictive value (Figure 2). Using the cut-off values obtained using ROC analysis, out of total of 32 patients, 17 patients had SD LVmPA.38 and LV RVmPA.238. All these patients responded to CRT. Five patients with both SD LVmPA and LV RVmPA values less than the above cut-offs did not respond to CRT (Figures 3 and 4). In six patients with only SD LVmPA.38, 4 responded to CRT (66%) and in remaining four patients with only LV RVmPA.238, 1 (25%) responded to CRT. Uni- and multivariate analyses using stepwise logistic regression was performed between QRS duration, ILVD, and IVD to find out the most important predictors for response to CRT. Both ILVD and IVD detected to be univariate predictors of response to CRT, but QRS duration was not. On multivariate analysis, ILVD was found to be most important independent predictors for response to CRT (Table 5). Discussion Equilibrium radionuclide angiography provides a relatively simple, reproducible, and non-invasive method to assess ventricular function and wall motion, in particular LVEF. 9 In our study, we evaluated the role of ERNA in detecting the presence of cardiac mechanical A Sensitivity B Sensitivity SD LVmPA Specificity LV RVmPA Specificity Figure 2 Receiver-operating characteristic curves analysis of ERNA for SD LVmPA (ILVD; A) and for LV RVmPA (IVD; B) for prediction of response to CRT. dyssynchrony in patients with non-ischaemic DCM and determined the cut-off value of dyssynchrony to predict the response to CRT. In our study, QRS duration was found to have a strong correlation with IVD, but not with ILVD. Correlation of QRS duration with IVD is consistently reported. Fauchier et al. 12 found significantly higher values of IVD on ERNA in patients with QRS.12 ms than in those with QRS,12 ms. Marcassa et al. 14 divided patients into three groups with QRS,12 ms, between and.15 ms, respectively. The values of IVD were , , and ms, respectively (P,.5). On the other hand, there are conflicting data on the exact relationship of QRS duration with ILVD. Fauchier et al. 12 reported that the value of SD-LVmPA differed significantly in patients with QRS lesser than and greater than 12 ms, whereas Marcassa et al. 14 reported only a weak correlation between QRS duration and SD LVmPA (r ¼.51). The other important criterion for selecting patients for CRT is LVEF. In our study, on baseline ERNA evaluation, we found no significant relation between the duration of QRS complex and IVD with LVEF. But, we observed a negative correlation between ILVD and LVEF. Several workers in the past have reported similar results. Bode-Schnurbus et al. 15 found no significant difference in mean LVEF between HF patients with QRS, or.15 ms. Fauchier et al. 12 reported that a degradation of the haemodynamic status was associated with an increase in ILVD, but not in IVD. Marcassa et al. 14 reported a significant non-linear inverse relation of LVEF with ILVD (r ¼ 2.68, P,.1), but not with IVD, which is consistent with our findings. The relation between QRS, LVEF, and cardiac mechanical dyssynchrony is important as both QRS duration and LVEF are essential criteria for the selection of patients for CRT. The above findings suggest that ILVD is more important than IVD or QRS duration in determining LV function and the subsequent prognosis. The lack of correlation between QRS duration and ILVD as well as QRS

6 856 A. Mukherjee et al. A C LV mpa-236 SD LVmPA-65 LV mpa-15 SD LVmPA-11 B D RV mpa-22 SD RVmPA-68 RV mpa-17 SD RVmPA-13 Table 5 Odd ratio (and 95% confidence intervals) in uni- and multivariate analyses of predictors of response to CRT Univariate analysis Multivariate analysis ILVD 1.14 ( ), P ¼.5 IVD 1.12 ( ), P ¼ ( ), P ¼.5 Not significant QRS duration Not significant Not significant CRT, cardiac resynchronization therapy; ILVD, intra LV dyssynchrony; IVD, interventricular dyssynchrony. Figure 3 Pre-CRT phase histogram of LV (A) and RV (B) ina 6-year-old female patient presented with LVEF 2% and NYHA class IV showing both ILVD (SD LVmPA) and IVD (LV RVmPA) abovethecut-offvalue.thepatientrespondedfavourablyto CRT with post-crt LVEF of 32% and NYHA class of II. Post-CRT phase histogram of LV (C) and RV (D) showed significant reduction in ILVD and IVD. A LV mpa-27 SD LVmPA-21 C LV mpa-155 SD LVmPA-26 duration and LVEF may explain the reason behind the considerable proportion of patients being non-responders to CRT. In our study, 22 (69%) of 32 patients were classified as responders and 1 (31%) as non-responders. At baseline, there were no significant differences B RV mpa-196 SD RVmPA-56 D RV mpa-156 SD RVmPA-66 Figure 4 Pre-CRT phase histogram of LV (A) and RV (B) ina 2-year-old male patient presented with LVEF 22% and NYHA class III showing both ILVD (SD LVmPA) and IVD (LV RVmPA) below the cut-off value for response to CRT. The patient did not respond to CRT with post-crt LVEF of 24% and NYHA class remains at III. Post-CRT phase histogram of LV (C) and RV (D) showed that both ILVD and IVD did not reduce when compared with baseline. in QRS ( vs ms, P ¼.13) and LVEF ( vs %, P ¼.15) between the responders and nonresponders. Only differentiating parameters between responders and non-responders were SD LVmPA (ILVD) and LV RVmPA (IVD), which were significantly larger in the responders. ROC curve analysis shows a sensitivity of 95% and a specificity of 8% at a cut-off value of 38 for SD LVmPA and a sensitivity of 81% and a specificity of 8% at a cut-off value of 238 for LV RVmPA for prediction of response to CRT. Dauphin et al. 16 studied the role of ERNA for predicting CRT response in 74 patients with DCM (both ischaemic and non-ischaemic) and QRS.13 ms. They have found that IVD was the only parameter that was significantly higher in responders compared with non-responders, prior to implantation, whereas ILVD was comparable in the two groups prior to therapy. Subsequent ROC curve analysis showed that an IVD value of was associated with a sensitivity of 91.4% and a specificity of 84.4% to predict CRT response. They concluded that in patients with wide QRS, IVD may predict response to resynchronization therapy. In another study by Toussaint et al., 17 it was noted that together, an LVEF of.15% and a significant IVD at D have a sensitivity of 79% and a positive predictive value of 83% to predict response to CRT. In contrast, in our study, we found that both ILVD and IVD were significantly larger in responders. The possible explanation of these findings may be due to the fact that the above mentioned studies assessed both ischaemic and non-ischaemic DCM patients in contrast to our study, which included only non-ischaemic DCM patients. The presence of scar will cause regional wall motion abnormality, which may subsequently alter both ILVD and IVD. Our study shows that both ILVD and IVD parameters need to be evaluated in non-ischaemic DCM patients. Between QRS duration, ILVD, and IVD, we found that both ILVD and IVD are univariate predictors for response to CRT, whereas QRS duration was not. However, on multivariate analysis, ILVD found to be most important independent predictors of response to CRT. The possible explanation that QRS duration was not a predictor for response to CRT may be due to the fact that all the patients submitted for CRT had long QRS duration (.12 ms). However, in our study, all 17 patients who had both IVD and ILVD above the cut-off value responded to CRT (1%). The response rate decreased to 66% when patients had only ILVD above the cut-off value (4/6 ¼ 66%) and to 25% when only IVD was found

7 Assessment of cardiac mechanical dyssynchrony and cardiac resynchronization therapy 857 to be more than the derived cut-off value. So, the presence of IVD along with ILVD certainly improves the accuracy for prediction of response to CRT. This study strongly suggests that both ILVD and IVD should be measured for prediction of response to CRT. This finding is of special importance as in recent years, focus on dyssynchrony assessment has shifted from ERNA to GMPS as it can assess myocardial perfusion, wall motion, synchrony, and function in a single study. But, by GMPS, one can only evaluate ILVD. So, ERNA definitely holds a significant advantage over GMPS as it can provide more comprehensive assessment of dyssynchrony (both ILVD and IVD). In addition, regional Fourier analysis of the ERNA helps to determine local mechanical activation and thereby can guide optimal lead positioning in CRT. 18 The presence of a transmural infarction does not compromise the ability of ERNA phase analysis to generate accurate results because ERNA measurements are based on volumes, 19 which is contrast with GMPS. However, ERNA phase analyses have several limitations. Inadequate RBC labelling and low-count images can compromise the image quality. Improper separation of the ventricles resulting in overlapping of cardiac structures and gating errors from irregular heart rate can adversely affect phase analysis results and lead to high variability. Also, a kinetic region with absent amplitude requires the phase method to fit a flat line, where noise could obscure the signal leading to inaccurate phase analysis. 2 There were few limitations in the present study. It was a singlecentre study with a relatively less number of patients. We have not studied the dyssynchrony and response to CRT in ischaemic DCM patients. We have not compared the mechanical dyssynchrony with the most commonly used method, i.e. echocardiography. Clinical status is only evaluated by the NYHA class. Other parameters like 6-min walk test and quality-of-life score were not assessed. Conclusions Both intraventricular dyssynchrony and IVD can be used to predict response to CRT, with high sensitivity and specificity. Between QRS duration, intraventricular dyssynchrony, and IVD, left intraventricular dyssynchrony is the single most important independent predictor for response to CRT. Though the current results need confirmation in larger patient populations, results of the study suggest that ERNA can play an important role in determining the responders to CRT therapy. Conflict of interest: none declared. References 1. Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 25;352: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH et al. 213 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 213;62:e Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 22;346: Fox DJ, Fitzpatrick AP, Davidson NC. Optimization of cardiac resynchronization therapy: addressing the problem of nonresponders. Heart 25;91: Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 24;44: Leclercq C, Faris O, Tunin R, Johnson J, Kato R, Evans F et al. Systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block. Circulation 22;16: Singh H, Singhal A, Sharma P, Patel CD, Seth S, Malhotra A. Quantitative assessment of cardiac mechanical synchrony using equilibrium radionuclide angiography. J Nucl Cardiol 213;2: Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J et al. Results of the predictors of response to CRT (PROSPECT) trial. Circulation 28;117: Botvinick EH. Scintigraphic blood pool and phase image analysis: the optimal tool for the evaluation of resynchronization therapy. J Nucl Cardiol 23;1: Botvinick EH, Frais M, O Connell JW, Faulkner D, Scheinman M, Morady F et al. Phase image evaluation of patients with ventricular pre-excitation syndromes. J Am Coll Cardiol 1984;3: Botvinick EH, Dunn R, Frais M, O Connell W, Shosa D, Herfkens R et al. The phase image: its relationship to patterns of contraction and conduction. Circulation 1982; 65: Fauchier L, Marie O, Casset-Senon D, Babuty D, Cosnay P, Fauchier JP. Interventricular and intraventricular dyssynchrony in idiopathic dilated cardiomyopathy: a prognostic study with Fourier phase analysis of radionuclide angioscintigraphy. J Am Coll Cardiol 22;4: Bleeker GB, Bax JJ, Fung JW, van der Wall EE, Zhang Q, Schalij MJ et al. Clinical versus echocardiographic parameters to assess response to cardiac resynchronization therapy. Am J Cardiol 26;97: Marcassa C, Campini R, Verna E, Ceriani L, Giannuzzi P. Assessment of cardiac asynchrony by radionuclide phase analysis: correlation with ventricular function in patients with narrow or prolonged QRS interval. Eur J Heart Fail 27;9: Bode-Schnurbus L, Böcker D, Block M, Gradaus R, Heinecke A, Breithardt G et al. QRS duration: a simple marker for predicting cardiac mortality in ICD patients with heart failure. Heart 23;1: Dauphin R, Nonin E, Bontemps L, Vincent M, Pinel A, Bonijoly S et al. Quantification of ventricular resynchronization reserve by radionuclide phase analysis in heart failure patients a prospective long-term study. Circ Cardiovasc Imaging 211;4: Toussaint JF, Lavergne T, Kerrou K, Froissart M, Ollitrault J, Darondel JM et al. Basal asynchrony and resynchronization with biventricular pacing predict long-term improvement of LV function in heart failure patients. Pacing Clin Electrophysiol 23;26: Somsen GA, Verberne HJ, Burri H, Ratib O, Righetti A. Ventricular mechanical dyssynchrony and resynchronization therapy in heart failure: a new indication for Fourier analysis of gated blood-pool radionuclide ventriculography. Nucl Med Commun 26;27: Port SC. Timing is everything. J Nucl Cardiol 28;15: O Connell JW, Schreck C, Moles M, Badwar N, DeMarco T, Olgin J et al. A unique method by which to quantitate synchrony with equilibrium radionuclide angiography. J Nucl Cardiol 25;12:441 5.