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European Journal of Heart Failure 2009 11(1):58-67; doi:10.1093/eurjhf/hfn010
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Effects of global longitudinal strain and total scar burden on response to cardiac resynchronization therapy in patients with ischaemic dilated cardiomyopathy

Antonello D'Andrea1,*, Pio Caso2, Raffaella Scarafile1, Lucia Riegler1, Gemma Salerno1, Francesca Castaldo1, Rita Gravino1, Rosangela Cocchia1, Luca Del Viscovo3, Giuseppe Limongelli1, Giovanni Di Salvo1, Luigi Ascione4, Raffaele Iengo4, Sergio Cuomo1, Lucio Santangelo1 and Raffaele Calabrò1

1 Department of Cardiology, Second University of Naples, Martucci 35, 80121 Naples, Italy
2 Department of Cardiology, Monaldi Hospital, Naples, Italy
3 Dipartimento di Internistica Clinica e Sperimentale—Sezione Scientifica di Diagnostica per Immagini, Second University of Naples, Naples, Italy
4 Department of Interventional Cardiology, Santa Maria di Loreto Hospital, Naples, Italy

* Corresponding author. Tel: +39 (0) 817 618525, Fax: +39 (0) 817 145205, Email: antonellodandrea{at}libero.it


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 References
 
Aims: To evaluate whether quantification of the extent of scarred left ventricular (LV) tissue by speckle-tracking strain echo (2DSE) can predict response to cardiac resynchronization therapy (CRT) in patients with ischaemic dilated cardiomyopathy (DCM).

Methods and results: Forty-five patients (58.3 ± 8.3 years; 24 males) with ischaemic DCM scheduled for CRT, and 25 controls were studied. A week before implantation all the patients underwent standard Doppler echo, 2DSE, and contrast-enhanced magnetic resonance (MR). Clinical and echocardiographic evaluation was repeated 6 months after CRT. The patients were considered as responders to CRT if LV end-systolic volume decreased by 15%. In DCM patients, LV ejection fraction was 29.2 ± 5.1%. By evaluating the 765 segments with MR, subendocardial infarct was identified in 17.0% and transmural infarct in 18.3%. With 2DSE, the average global longitudinal strain (GLS) was –23.1 ± 3.6% in controls and –15.1 ± 5.1% in DCM (P = 0.001). GLS showed a close correlation with total scar burden using MR (r = 0.64, P < 0.001). At follow-up, patients were subdivided into responders (n = 30; 66.7%) and non-responders (n = 15; 33.3%) to CRT. GLS was significantly different in non-responders than in responders (GLS: –10.4 ± 5.1 in non-responders vs. –18.4 ± 14% in responders, P < 0.001). In a multivariable analysis, GLS (P < 0.0001) and radial intraventricular dyssynchrony (P < 0.001) were powerful independent determinants of response to CRT.

Conclusion: GLS is strongly associated with total scar burden assessed by MR, and is an excellent independent predictor of response to CRT.

Key Words: Heart failure • Resynchronization therapy • Ischaemic dilated cardiomyopathy • Two-dimensional strain imaging • Cardiac magnetic resonance • Myocardial scar • Global strain

Received April 23, 2008; Revised July 16, 2008; Accepted August 29, 2008


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Study limitations
 Conclusions
 References
 
Cardiac resynchronization therapy (CRT) has become an attractive therapeutic option for patients with end-stage chronic heart failure (HF), left ventricular (LV) dilatation and left bundle branch block (LBBB) with wide QRS duration.1,2 Currently, patients are selected for CRT on the basis of clinical and ECG criteria and standard LV echocardiographic indexes.3,4 However, up to 30% of these carefully selected patients do not benefit from this invasive and costly intervention, with up to 40% having a progressive worsening of their HF.1,2

Patients with ischaemic HF often show heterogeneous patterns of myocardial scarring despite similar degrees of myocardial dysfunction. Recently, Bleeker et al.5 suggested that in addition to the presence of LV dyssynchrony, transmural scar tissue in the region of the LV pacing lead may prohibit functional and clinical response to CRT. Furthermore, Woo et al.6 showed that reverse remodelling and improvement in LV ejection fraction (EF) after CRT were greater in non-ischaemic patients than in ischaemic patients. This may imply that not only the location, but also the size of infarcted myocardium (total scar burden) is important for response to CRT.

Growing evidence that QRS duration poorly predicts acute and chronic response to CRT suggests that other parameters might identify candidates better. Myocardial dyssynchrony (i.e. the disparity in regional contraction timing) was proposed as an alternative. Among various echocardiographic techniques, tissue velocity imaging (TVI) and strain rate imaging have gained acceptance by virtue of their ability to define myocardial timing, contractility, and deformation in patients with LBBB and HF.7–19 Although TVI and Doppler strain measures have been used most often in this clinical setting, they are limited by the Doppler angle of incidence. A novel approach to quantify regional LV function from routine grey-scale two-dimensional echocardiographic images, known as speckle tracking two-dimensional strain echocardiography (2DSE), calculates myocardial strain independent of the angle of incidence, and has recently been validated against sonomicrometry and tagged magnetic resonance (MR) imaging.16–19 In addition, recent reports have demonstrated that global longitudinal strain (GLS) measured by 2DSE is an excellent predictor of myocardial infarct size in both acute and chronic ischaemic heart disease.20–23

On these grounds, the aims of the present study were: (i) to detect global and regional myocardial dysfunction in patients with ischaemic dilated cardiomyopathy (DCM) using 2DSE; (ii) to assess whether echocardiographic quantification of the extent of the scarred ventricular tissue by 2DSE can predict response to CRT during a 6-month follow-up.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Study limitations
 Conclusions
 References
 
Study population
From January 2005 to December 2006, 485 ambulatory HF patients with known LV systolic dysfunction were referred to our echocardiographic laboratory. Of these, patients with idiopathic DCM (n = 150), QRS<120 ms (n = 92), atrial fibrillation (n = 69), inducible myocardial ischaemia (n = 25), poor echocardiographic window (n = 11), and mildly impaired LVEF (>40%) (n = 36) were ineligible for our study. Of the remaining 102 patients with ischaemic DCM, 45 patients were scheduled for implantation of a CRT device and were prospectively enrolled in this study. Selection criteria were: (i) ischaemic, drug-refractory HF (NYHA class III); (ii) LVEF <35%; and (iii) QRS duration >120 ms.

Ischaemic aetiology was defined as the presence of significant coronary artery disease (>50% stenosis in more than one major epicardial coronary artery) on coronary angiographic examination and a history of myocardial infarction, and/or previous percutaneous coronary intervention, or coronary artery bypass graft surgery. None of the patients had experienced a recent myocardial infarction (<3 months) or presented with acute HF. Patients with pacemakers or intracranial clips were excluded. This study was approved by the Hospital Ethics Committee and all patients gave written informed consent to participate in the study.

Since 2DSE represents a novel technique with few clinical applications, we also studied myocardial function in 25 age- and sex-matched control subjects without detectable cardiovascular risk factors. All volunteer controls were recruited in Naples (Italy), and were selected from subjects undergoing investigation in our Cardiology department for work eligibility. All control subjects were examined in a single centre (Monaldi Hospital, Naples, Italy). None of the control subjects had cardiovascular structural or functional abnormalities or received any medication. We ensured comparability of the two groups using frequency-matching. Baseline characteristics such as family history of atherosclerotic disease, smoking behaviour, eating habits, physical activity, and body mass index were assessed. There were no significant differences between the two groups for any of these parameters.

Study protocol
A week before implantation, all patients underwent a clinical examination, 12-lead ECG, standard Doppler echo, two-dimensional Strain by Vivid 7 ultrasound system (GE Vingmed Ultrasound, MI, USA), contrast-enhanced MR. Clinical and echocardiographic evaluation was repeated 6 months after CRT. The patients were considered as responders to CRT if the LV end-systolic volume decreased by 15% and as non-responders in all other cases.3

Clinical evaluation
An independent physician blinded to all other data performed the clinical evaluation including NYHA class and 6 min walking test. QRS duration was measured from the surface ECG using the widest QRS complex from leads II, V1, and V6.

Conventional echocardiographic measurements
Standard Doppler echocardiography and 2DSE were performed with the subjects in the partial left decubitus position. A variable frequency phased-array transducer (2.5–3.5–4.0 MHz) was used for two-dimensional and Doppler imaging. Doppler echocardiographic tracings were recorded on magneto-optical disks. All measurements were analysed by two experienced readers, for an average of ≥3 cardiac cycles. Stroke volume was obtained using the LV outflow Doppler method as the product of outflow tract area and LV output time–velocity integral. Tricuspid annular plane systolic excursion was calculated as the index of right ventricular global systolic function from the difference between end-diastolic and end-systolic measurements (in millimetres). The early (Ea) and late (Aa) diastolic annular velocities were measured at the lateral corner of the mitral annulus by pulsed TVI, in accordance with the method proposed by Nagueh et al.24 Mitral E velocity, corrected for the influence of relaxation (i.e. the E/Ea ratio), was calculated to estimate LV-filling pressures.

The proximal flow convergence (PFC) technique has been validated as a quantitative Doppler method to calculate regurgitant volume of flow and orifice area [effective regurgitant orifice (ERO)]. The regurgitant flow is measured as 2{pi}xr2xVr, where r is the radius of the hemispheric PFC region and Vr is the aliasing velocity. The following parameter was calculated: ERO=regurgitant flow/maximal regurgitant velocity. At least three consecutive beats of sinus rhythm were measured and the average value taken.25

Analysis of mechanical dyssynchrony
Recent results from the PROSPECT study illustrated that technical factors of individual echocardiographic Doppler methods, such as feasibility and reproducibility, affect results in a multicentre setting.26 Quantifying mechanical dyssynchrony in a series of patients with HF is complex, and no single ideal method currently exists.27,28 As a result, in accordance with the recommendations for performance of echocardiography for CRT, recently proposed by the American Society of Echocardiography Dyssynchrony Writing Group,29 in our study protocol the following dyssynchrony measures were performed:

  1. Interventricular (VV) dyssynchrony: time difference between RV to LV ejection. This was determined as the time from the onset of the QRS to the onset of LV ejection vs. RV ejection, measured as the onset of pulsed Doppler flow velocities in the LV and RV outflow tracts, respectively (cut-off ≥40 ms is consistent with significant dyssynchrony).
  2. Longitudinal intraventricular dyssynchrony (by the opposing wall delay method). Myocardial Doppler velocity profile signals were reconstituted off-line from the TVI colour images that provided regional myocardial velocity curves. From the apical four-chamber, two-chamber, and long-axis views, this index was simply measured as the time from the Sm wave of one wall to the Sm wave of the opposing wall on the same cineloops. At least three consecutive beats were stored and the images were digitized and computer-analysed offline (EchoPac 5.0.1, GE-Vingmed, MI, USA). As previously reported,27,28 longitudinal intraventricular delay was considered significant in case of maximal difference ≥65 ms25 (Figure 1A).
  3. Radial intraventricular dyssynchrony. 2DSE uses grey scale (B-Mode) sector image and is based on frame-by-frame tracking of small rectangular image blocks with stable speckle pattern. A minimum frame rate of 30 Hz was required for reliable operation of this programme and frame rates of 50–90 Hz were used for routine grey-scale imaging. Speckle tracking applied to routine midventricular short-axis images determines radial strain from multiple points averaged to six standard segments. Baseline speckle-tracking radial dyssynchrony was defined as a time difference in peak septal-to-posterior wall strain ≥130 ms19 (Figure 1B).


Figure 1
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  		Figure 1 Echocardiographic analysis of myocardial dyssynchrony. (A) Longitudinal intraventricular dyssynchrony. Colour-coded tissue velocity imaging study from standard four-chamber apical view of a dilated cardiomyopathy patient. Time–velocity curves from representative basal levels are shown. Maximum opposing wall delay was seen between septum and posterior wall, consistent with significant dyssynchrony (≥65 ms). (B) Radial intraventricular dyssynchrony. Radial dyssynchrony is determined as the differences in peak strain between the anterior septum and posterior wall. Speckle-tracking images demonstrate severe dyssynchrony in a patient with heart failure and left bundle branch block referred for cardiac resynchronization therapy.

 
Two-dimensional segmental longitudinal strain and global longitudinal strain
To further facilitate clinical application, speckle tracking technique has been simplified and integrated into echocardiographic instruments to generate a parametric image of myocardial strain throughout the LV, called automated function imaging (AFI).21 In our study, digital loops with three successive cardiac cycles were acquired from apical two-, three-, and four-chamber views. Analysis was performed directly on the echocardiographic system for each of the three apical views, with the operator manually identifying three points: two on each side of the mitral valve, and a third at the apex of the LV. The two-dimensional loops from the routine echocardiographic examination are processed offline. The end-systolic frame is first defined in the apical long-axis (three-chamber) view, where the aortic valve is directly visible. Aortic valve closure time is marked. The R wave to aortic valve closure time is then measured by the software. Subsequently, the same R wave to aortic valve closure time distance is used as a reference on the other loops. The time distance is also checked against mitral valve opening, which is easily seen in any apical plane. This allows accurate timing of systole, diastole, and aortic valve closure on all views.

As a result, the software detected the endocardium at end-systole, tracked myocardial motion during the entire cardiac cycle, and created U-shaped regions of interest (ROI) that encompassed basal, middle, and apical segments of two opposite LV walls (Figures 2 and 3). Tracking quality was assessed by the operator and scored by the software. If the tracking was poor, the operator could repeat the imaging, readjusting the endocardial tracing, or changing the software parameters such as ROI width and smoothing until a better score was achieved. Inadequately tracked segments were automatically excluded from the analysis.


Figure 2
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  		Figure 2 An example of longitudinal left ventricular two-dimensional strain curves in a control subject from an apical four-chamber view. (A) Global longitudinal strain showing a normal global ventricular deformation. (B) Strain curves colour-coded by the defined myocardial segment. (C) Peaks of systolic strain in a six-segment model (all ≥19%). (D) Corresponding contrast-enhanced magnetic resonance image from the same patient shown for comparison.

 


Figure 3
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  		Figure 3 Longitudinal left ventricular two-dimensional strain curves and magnetic resonance (MR) images in patients with ischaemic dilated cardiomyopathy. Upper panels: transmural scar (previous anterior-septal myocardial infarction). (A) Global longitudinal strain (GLS) showing impaired global ventricular deformation. (B) Peaks of systolic strain in a six-segment model; note the severe impairment of myocardial deformation in transmural-infarcted apical segments. (C) Corresponding contrast-enhanced MR image from the same patient confirming apical transmural scar. Lower panels: subendocardial scar (previous lateral myocardial infarction). (D) GLS showing an impaired global ventricular deformation. (E) Peaks of systolic strain in a six-segment model; note that the impairment of LV segmental deformation is less severe than in the DCM patient with transmural scar. (F) Corresponding contrast-enhanced MR image from the same patient confirming subendocardial scar.

 
Longitudinal strains for each individual segment were measured and the software calculated GLS by averaging local strains along the entire LV.

Since in dilated ventricles with electromechanical delay myocardial shortening may peak before (early segments) or after (late segments) AVC, in accordance with previous reports we calculated both a segmental post-systolic shortening index (measured in each segment as the ratio of post-systolic strain divided by the maximal strain), and also an average global post-systolic shortening index in a 16-segment model.23,30

Magnetic resonance imaging, data acquisition, and analysis
A 1.5-T scanner (Harmony, Siemens, Erlangen, Germany) equipped with cardiac software by Siemens with system MRease SYNGO 2002B was used. Patients were positioned in a supine position, and images were acquired during breath-holds of approximately 12–15 s. The heart was imaged from apex to base, with 10–12 imaging levels (dependent on heart size) in the short-axis view using a steady-state free procession sequence (True FISP). Contrast-enhanced images were acquired 15 min after bolus injection of a gadolinium-based contrast agent (gadobenate dimeglumine, Multihance—Bracco, Milan, Italy; 0.2 mmol/kg of body weight) with a segmented gradient-echo inversion-recovery turbo FLASH sequence; inversion time (TI) was determined using a real-time scan plan. Contrast-enhanced images were scored visually by two experienced observers (blinded to all other data). Segmental scar score was recorded as: 0: absence of hyperenhancement, 1: hyperenhancement of 1–25% of LV wall thickness, 2: hyperenhancement extending 26–50%, 3: hyperenhancement extending 51–76%, and 4: hyperenhancement extending 76–100%. Number of affected segments was considered to reflect the spatial extent of scar tissue. Number of segments with segmental scar scores of 3 and 4 was considered to reflect the transmurality of scar tissue in the infarct zone. Patients' segmental scores were summed and divided by 17 to yield total scar burden (which reflected damage per patient).31,32

Implantation technique and LV lead position
CRT was initiated with implantation of a biventricular pacing system (CONTAK CD H115, CD II H119, RENEWAL H135, or III H170, H175, H177, Guidant Corp; InSync ICD 7272, Marquis 7277, or InSync ICD II Marquis 7289, Medtronic). Left ventricular leads were positioned as follows: posterior-lateral or lateral in 38 patients, and anterior or anterior-lateral in 7 patients.

In order to optimize benefit from CRT in all patients, we performed echo-guided positioning of the LV pacing lead, determined using two-dimensional strain at the site of latest mechanical activation.19 In addition, pre-implantation evaluation of myocardial scar in the region targeted for LV pacing was assessed by MR. In our population, myocardial scar was observed in the anterior/anterior–lateral position in 38 ischaemic patients, and in the posterior/posterior–lateral position in seven patients. As a consequence, in 36/38 patients with anterior/anterior–lateral scar, the LV lead was implanted in the posterior–lateral position, while in five of seven patients with posterior/posterior–lateral scar, the LV lead was implanted in the anterior–lateral position. In the remaining four patients, patient-tailored LV lead positioning was not possible because of the limited number of suitable branches of the coronary sinus.

The CRT device was programmed in DDD mode and adjustment of the atrioventricular (AV) delay was performed during simultaneous pacing. Optimal AV delay was first determined using Ritter's method33 followed by optimization of VV delay. Post-optimization mean AV delay was 120 ± 55 ms, with a wide variability of optimized AV delay intervals (60–180 ms) among the patient cohort, while post-optimization mean VV delay was ±35 ms (±15).

Statistical methods
All the analyses were performed using a commercially available package (SPSS, Rel 11.0 2002, SPSS Inc, Chicago, IL, USA). Variables are presented as mean ± SD. Two-tailed t-tests for paired and unpaired data were used to assess changes between groups. Linear regression analyses and partial correlation tests by Pearson's method were done to assess univariate relations.

To identify significant independent determinants of response to CRT in patients with DCM, their individual association with clinically relevant and instrumental variables was assessed by multivariable logistic regression analysis. The following variables were included in the analysis: clinical data [age, sex, body surface area (BSA), risk factors], standard echocardiographic indexes (LV volumes, LVEF, Doppler transmitral inflow measurements, mitral valve ERO), TVI, and 2DSE indexes (intraventricular delay, GLS, post-systolic shortening index), MR measurements (total score burden). These variables were selected according to their clinical relevance and potential impact on response to CRT, as shown by earlier studies.17 Variable selection was performed in the multivariable logistic regression as an interactive stepwise backward elimination method, each time excluding the one variable with the highest P-value according to Wald statistics. The assumption of linearity was checked graphically by studying the smoothed martingale residuals from the null model plotted against the covariate variables. The linearity assumptions were satisfied. The Hosmer–Lemeshow goodness-of-fit test was used to check that the model adequately fit the data. The model also underwent bootstrap validation (200 runs). In order to decrease the inflation of the Type 1 error rate due to multiple testing, the statistical significance was defined as two-sided P-value <0.01.

Receiver-operating characteristic (ROC) curve analysis was performed to select optimal cut-off values of echocardiographic measurements.

Reproducibility of 2DSE measurements was determined in all the subjects. Inter- and intra-observer variability was examined using both Pearson's bivariate two-tailed correlations and Bland–Altman analysis. Relation coefficients, 95% CI, and percent errors were reported.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Study limitations
 Conclusions
 References
 
Patient characteristics
A total of 45 patients with ischaemic DCM, and 25 healthy controls were prospectively studied. All the DCM patients were in NYHA class III before CRT implantation, and received optimized medical therapy if tolerated (Table 1).


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  		Table 1 Demographic and clinical characteristics of the study population (n = 45)

 
In DCM patients, the LVEF assessed by echocardiography was 29.2 ± 5.1% and the LVEF assessed by MR was 28.4 ± 6.1% (Table 2).


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  		Table 2 Measured characteristics of the study population of ischaemic dilated cardiomyopathy patients (n=45)

 
Overall, LV speckle tracking was possible in 97% of 720 attempted segments from the 45 subjects with technically adequate images, with only 3% of segments eliminated. Mean strain calculation time using GLS was <60 s, allowing a rapid and real-time analysis of global systolic function.

Of the 765 myocardial segments evaluated by MR, subendocardial scar was identified in 131 segments (17.0%), transmural infarct in 140 segments (18.3%), and no infarct in 494 segments.

Segmental analyses
Peak systolic strain measured by 2DSE differentiated significantly (P < 0.001) between non-infarcted segments (–19.1 ± 3.9%), segments with subendocardial infarcts (–12.8 ± 6.1%), and transmurally infarcted segments (–8.5 ± 3.8%). A segmental strain value of –10% identified transmural infarction with a sensitivity of 78% and a specificity of 83% (AUC = 0.88; 95% CI 0.70–0.99; P < 0.001), and a value of –15% predicted a non-transmural infarction with a sensitivity of 73% and a specificity of 81% (AUC = 0.81; 95% CI 0.66–0.97; P < 0.01) (Figures 2 and 3).

Global analyses
Peak systolic segmental strains were averaged into a global strain value for each study object as a parameter for global LV performance. The average global strain was –23.1 ± 3.6% in normal individuals and –15.1 ± 5.1% in patients with DCM (P = 0.001) (Figures 2 and 3). By univariate analysis, total scar burden by MR showed a close correlation with GLS (r = 0.64, P < 0.0001), and a weak association with LVEF (r = –0.32, P < 0.05). By multivariable analysis, after adjusting for potential determinants such as age, heart rate, BSA, LV volumes, and LVEF, in the overall population of DCM patients the independent association between total scar burden and GLS was confirmed (β coefficient = 0.54; P < 0.001).

Clinical and echocardiographic response to cardiac resynchronization therapy
Device implantation was successful in all patients and no complication was observed.

Six months after CRT, 33 patients (73.3%) were in NYHA functional class I–II, while seven (15.5%) and five (11.2%) were in NYHA class III and IV, respectively. QRS duration was significantly reduced from 148.2 ± 26.1 to 127 ± 24 ms (P < 0.01), while a significant increase in 6 min walking distance was seen (from 221.7 ± 18 to 347 ± 75 m; P < 0.001). LV end-diastolic volume and LV end-systolic volume decreased from 227.7 ± 34.3 mL to 207.2 ± 78.1 mL (P < 0.005) and from 156.6 ± 27.5 to 143.1 ± 71.2 mL (P < 0.001), respectively, while LVEF increased from 29.2 ± 5.1% to 34.6 ± 11.1% (P < 0.001).

Responders and non-responders to cardiac resynchronization therapy
The patients were subdivided into echocardiographic responders (n = 30; 66.7%) and non-responders (n = 15; 33.3%) to CRT based on a reduction of LV end-systolic volume ≥15% after 6 months of CRT. No significant differences were found between the two groups in terms of NYHA functional class, 6 min walking distance, coronary risk factors, and pharmacological treatment before CRT. Also LV systolic function parameters and post-systolic shortening index (10.6 ± 7.4 in responders vs. 9.8 ± 6.3 in non-responders) were not significantly different between the two groups. Conversely, both longitudinal and radial intraventricular dyssynchrony and mean GLS were significantly different in non-responders than in responders (longitudinal intraventricular dyssynchrony: 78.4 ± 12.4 in non-responders vs. 96.2 ± 8.9 ms in responders, P < 0.01; radial intraventricular dyssynchrony: 152.4 ± 54.2 in non-responders vs. 226.2 ± 58.9 ms in responders, P < 0.0001; global strain: –10.4 ± 5.1 in non-responders vs. –18.4 ± 4.4% in responders, P < 0.001). Furthermore, patients not responding to CRT had significantly more scar tissue than responders, as shown by significantly higher total scar burden by MR (1.6 ± 0.3 in non-responders vs. 0.6 ± 0.3 in responders; P < 0.001).

To define the optimal cut-off value of global strain to predict LV remodelling, an ROC curve analysis was performed. A GLS ≤12% showed a sensitivity and a specificity, respectively, of 84.7% and 88.8% (AUC 0.88; 95% CI 0.80–0.95; P < 0.0001) to predict response to CRT (Figure 4). On the other hand, none of the patients with a total scar burden >1.30 responded to CRT. In a stepwise forward multiple logistic regression analysis, after adjusting for potential determinants, GLS (OR 4.1; 95% CI 3.1–5.5; P < 0.0001) and radial intraventricular dyssynchrony (OR 0.5; 95% CI 0.3–0.9; P < 0.001) were powerful independent determinants of response to CRT.


Figure 4
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  		Figure 4 Interactive plots diagrams (receiver-operating characteristic curve analyses) of global longitudinal strain (GLS) in dilated cardiomyopathy patients. A GLS <12% showed a sensitivity and a specificity, respectively, of 84.7% and 88.8% [area under curve 0.88; 95% CI 0.80–0.95; P < 0.0001) to predict response to cardiac resynchronization therapy.

 
Reproducibility of two-dimensional strain echocardiography and magnetic resonance measurements
Intra-observer variability
Pearson's correlations: GLS: r = 0.91; P < 0.00001; total scar burden: r = 0.88; P < 0.00001.

Bland–Altman analysis: GLS (95% CI ±1.2; percent error 3.1%), total scar burden (95% CI ±0.5; percent error 3.6%).

Inter-observer variability
Pearson's correlations: GLS: r = 0.88; P < 0.00001, total scar burden: r = 0.86; P < 0.00001.

Bland–Altman analysis: GLS (95% CI ±1.9; percent error 3.4%), total scar burden (95% CI ±0.4; percent error 3.9%).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Study limitations
 Conclusions
 References
 
The results of the present study confirm the usefulness of 2DSE in analysing LV longitudinal global and regional myocardial function in patients with ischaemic DCM undergoing CRT.

The following lists the main findings of our study: (i) 2DSE detected at baseline impaired myocardial systolic function more in transmural-infarcted compared with subendocardial-infarcted segments; (ii) a significant association between GLS measured by 2DSE and total scar burden assessed by MR was observed; (iii) GLS was a powerful independent determinant of response to CRT.

Advantages of 2DSE in the study of left ventricular myocardial function and dyssynchrony in ischaemic DCM
Previous reports have documented that echocardiography with its newer applications such as TVI and strain imaging may represent useful techniques to evaluate myocardial dyssynchrony in candidates for CRT.10,18,19 However, a recent study by Miyazaki et al.34 in 120 patients outlined how a substantial proportion of normal subjects have TVI-derived dyssynchrony indexes higher than the cut-off value proposed for predicting beneficial effect of CRT, while strain-derived timing index appears to be more specific for dyssynchrony in patients with systolic dysfunction and LBBB. In particular, myocardial strain is a dimensionless index of change in myocardial length in response to an applied force, and is expressed as fractional or percent change. This technique has a theoretical advantage over TVI in that it is relatively immune to cardiac translational motion and tethering allowing differentiation between active systolic contraction and passive motion. However, in patients with DCM and large and spherical ventricles, Doppler strain estimation with its angle dependency represents an important limitation owing to a poor alignment between Doppler beam and myocardial wall.13,35 Conversely, in our study we used 2DSE, a novel approach to quantify regional myocardial deformation within a scan plane that is inherently two-dimensional and independent of interrogation angle as it tracks speckle patterns (acoustic markers) within serial B-Mode sector scans.16,17 In addition, a recent study in patients with DCM has demonstrated that dyssynchrony indexes derived from the novel speckle-tracking radial 2DSE predicts response to CRT.19 To the best of our knowledge, the present paper is the first report analysing the possible role of GLS in predicting response to CRT in ischaemic DCM.

The association between GLS and total scar burden
In our study protocol, peak systolic strain from all LV segments was averaged into a GLS. Contrast-enhanced MR was used as a reference method for the determination of the extent of scar.

Our findings show that global 2DSE provides additional information regarding the extent of myocardial scar tissue function when compared with LVEF in patients with ischaemic DCM. In fact, the LV longitudinal function measured by 2DSE correlates well with the scar tissue as seen by MR over a wide range of infarct sizes and anatomical locations. This relationship was found at both global and segmental level. In fact, 2DSE values revealed reduced contractility in LV segments with greater transmural scar extent, and the optimal cut-off values for identifying scar were –10% for transmural scar and –15% for subendocardial scar. Furthermore, the best echocardiographic parameter to predict the total scar burden was GLS.

Such findings are in accordance with several recent reports about the usefulness of GLS in both acute or chronic ischaemic heart disease. In particular, Vartdal et al.22 reported in 30 patients with acute anterior myocardial infarction that global strain assessed 1.5 h after reperfusion therapy can predict the final infarct size as measured by MR. Furthermore, Gjesdal et al.23 showed that GLS correlated with infarct mass assessed by MR in 38 chronic ischaemic patients 9 months after a first myocardial infarction.

The independent roles of mechanical dyssynchrony and GLS in predicting response to CRT
In our study, among the echocardiographic indexes selected for mechanical dyssynchrony analysis, only radial intraventricular dyssynchrony was an independent predictor of response to CRT. Such findings are in accordance with a recent article by Delgado et al.,36 who reported in a population of 161 DCM patients how differences in baseline LV dyssynchrony between responders and non-responders to CRT were noted only for radial strain and not for circumferential and longitudinal strain. In particular, a cut-off value of radial dyssynchrony ≤130 ms was able to predict response to CRT with a sensitivity of 83% and a specificity of 80%.

Our results also show that GLS measured by 2DSE is an important independent determinant of response to CRT in patients with ischaemic systolic HF. This novel parameter was found to be superior to the more traditional echocardiographic methods such as LVEF. Strain values were obtained in 97% of all LV segments, demonstrating that the 2DSE technique is feasible for most patients. In particular, a GSA value ≤12% accurately identified patients without significant LV remodelling after 6 months from CRT.

Since GLS was closely associated with total scar burden in our study population, these findings further confirm that the benefits of CRT in patients with ischaemic HF depends not only on myocardial dyssynchrony, but also on the extent of scarred LV myocardium. Therefore, the ability of diseased myocardium to respond to and propagate electrical stimulation during CRT can be influenced by the underlying pathology. These findings are not surprising, considering that patients with ischaemic DCM have heterogeneous patterns of myocardial scarring despite similar alterations in contractile function.37,38 In patients with severe LV dysfunction, the percentage of patients with detectable scar by MR ranges from 12–100% depending on the underlying cause of HF. The volume, location, and transmurality of this scarring are similarly heterogeneous between individuals.

Some recently published data based on the assessment of myocardial viability using different techniques are presently available in HF patients undergoing CRT. In particular, both White et al.31 and Ypenburg et al.32 reported that total scar burden, determined by contrast-enhanced MR is linearly related to relative changes in LV end-systolic volume after 6 months of CRT. Using contrast echocardiography, Hummel et al.39 showed that a perfusion score index reflecting the extent of viable myocardium was related to LV reverse remodelling after CRT, thus the greater the amount of viable myocardium present, the larger the reverse remodelling. Sciagra et al.40 showed that large resting perfusion defects on single-photon emission computed tomography perfusion imaging predicted a lack of ventricular remodelling with CRT. Finally, in a very recent article Ypenburg et al.41 demonstrated that myocardial contractile reserve (>7.5% increase in LVEF during low-dose dobutamine infusion) predicts LV reverse remodelling after CRT.


   Study limitations
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
Conclusions
 References
 
This study was performed in a small patient population. In particular, there were few patients with large-sized myocardial scar in territories outside the anterior and septal walls. This may reflect a higher likelihood of referral for CRT in patients with large anterior-septal myocardial infarctions because of more severe LV dysfunction.

A technical limitation is that speckle-tracking echocardiography is dependent on frame rate as well as image resolution.16,17 Low frame rate results in the speckle pattern changing too much from frame to frame, which prevents the precise characterization of regional myocardial motion and impacts the overall temporal resolution of the regional strain map. In contrast, increasing the frame rate reduces scan line density, which reduces image resolution. Frame rate in our setting ranged from 50 frame/s to 90 frame/s; this value is lower than the frame rates available with Doppler strain, however indexes of LV function used in this study did not rely on difference in the timing of contraction.

GLS is measured as the average strain at the time of AVC. It estimates global function available for ejection before the aortic valve closes.20–23 However, one of the hallmarks of intra-ventricular dyssynchrony consists of strongly decreased deformation (strain) amplitudes in the early activated regions and early stretching in the delayed regions, and post-systolic shortening is common to ischaemia as well as dyssynchrony.30 This could potentially change results considerably, influencing the calculation of GLS. Therefore, in our study protocol we calculated both a segmental post-systolic shortening index and an average global post-systolic shortening index in a 16-segment model. In addition, even considering these technical limitations, a good correlation between GLS and myocardial fibrosis has already been reported by others, in patients with both acute or chronic ischaemic heart disease.22,23

Changes in preload and afterload are important determinants of myocardial deformation. The possibility that reduction in strain could be owing to an increased wall stress cannot be entirely excluded. LV end-diastolic dimensions were comparable in both groups, suggesting comparable preload. Thus, although strain is load-dependent, abnormal loading conditions should not have had a major impact on our results.

In our study protocol, MR contrast-enhancement images were scored visually. This is a crude but simple and largely available method to detect myocardial scar tissue in ischaemic patients, as previously reported by Ypenburg et al.32 using a qualitative analysis. In addition, MR analysis was performed by two experienced observers, blinded to all other data, and the reproducibility was good.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
References
 
Our study confirms that a novel speckle tracking algorithm applied to routine grey-scale two-dimensional images represents a promising and feasible non-invasive and easily repeatable technique to assess myocardial global and regional function in patients with DCM. Peak systolic strain measured by 2DSE discriminates between non-infarcted, transmural-infarcted, and subendocardial-infarcted segments. In addition, GLS is strongly associated with total scar burden assessed by MR, and is an excellent independent predictor of response to CRT.

Future longitudinal studies are warranted to further our understanding of the natural history of myocardial deformation, the extent of reversibility of myocardial dysfunction with medical therapy, and/or CRT, and the possible long-term impact of such changes on outcomes in patients with HF.


   Acknowledgements
 
The authors are grateful to Dr Ercole Volpe (Boston Scientific) and to Dr Marco Maglione (General Electric) for their technical support in the preparation and development of the study protocol.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 References
 

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A. D'Andrea, R. Scarafile, L. Riegler, G. Salerno, R. Gravino, R. Cocchia, F. Castaldo, F. Allocca, G. Limongelli, G. Di Salvo, et al.
Right atrial size and deformation in patients with dilated cardiomyopathy undergoing cardiac resynchronization therapy
Eur J Heart Fail, December 1, 2009; 11(12): 1169 - 1177.
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