European Heart Journal

European Heart Journal Advance Access originally published online on July 3, 2006
European Heart Journal 2006 27(15):1818-1823; doi:10.1093/eurheartj/ehl133

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Utility of a new left ventricular asynchrony index as a predictor of reverse remodelling after cardiac resynchronization therapy

Maria Cristina Porciani^*, Alessio Lilli, Roberto Macioce, Francesco Cappelli, Gabriele Demarchi, Alessia Pappone, Giuseppe Ricciardi and Luigi Padeletti

Department of Heart and Vessels, University of Florence, Viale Morgagni 85, Florence 50134, Italy

Received 31 January 2006; revised 8 May 2006; accepted 2 June 2006; online publish-ahead-of-print 3 July 2006.

^* Corresponding author. Tel: +39 0557947514; fax: +39 0554378638. E-mail address: cporciani{at}hotmail.com

	Abstract

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
Aims The majority of tissue Doppler indexes proposed to predict left ventricular (LV) reverse remodelling in cardiac resynchronization therapy (CRT) reflects LV asynchrony as assessed in ejection phase. We evaluated the predictive value of a new strain-imaging parameter reflecting the total amount of time spent by 12 LV segments in contracting after aortic valve closure.

Methods and results Fifty-nine patients who fulfilled current treatment recommendations were studied before and 6 months after CRT. Time to tissue Doppler systolic peak velocity (Ts) and time exceeding aortic closure (ExcT) in strain curves were measured in 12 LV segments. Ts standard deviation (Ts-SD) and sum of ExcT of overall 12 LV segments (oExcT) were analysed. After 6 months, responders were defined according to 15% LV end-systolic volume reduction. Responders (47%) when compared with non-responders (53%) had significantly higher baseline Ts-SD and oExcT values. Receiver operating characteristic (ROC) curve analysis demonstrated that an optimal cutoff value of 760 ms for oExcT yielded 93.5% sensitivity and 82.8% specificity. For Ts-SD at the cutoff of 32 ms, 82% sensitivity and 39% specificity were obtained. Area under ROC was significantly larger for oExcT than for Ts-SD.

Conclusion o-ExcT is able to predict LV reverse remodelling after CRT.

Key Words: Cardiac resynchronization therapy • Left ventricular diastolic asynchrony • Strain imaging • Reverse remodelling

	Introduction

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
In the last few years, cardiac resynchronization therapy (CRT) has been widely used as an effective therapy for patients with heart failure (HF) and LV conduction disturbances.^1–5 However, despite enthusiasm regarding the use of therapy for patients who fulfill current treatment recommendations,⁶ about 50%^7,8 of patients may not show clinical or left ventricular (LV) reverse remodelling response. The reasons for lack of response are not well known. From the initial focus on electrical markers, recent interest has shifted towards a more direct assessment of mechanical dyssynchrony by means of tissue Doppler imaging (TDI). At present, many predictors of CRT response indexes have been proposed, the majority of them reflecting LV asynchrony as assessed in the ejection phase.^9–12 Among them, the standard deviation of the time to the systolic peak velocity (Ts-SD) has been demonstrated to be the most powerful predictor of LV reverse remodelling.⁷ Only few previous studies showed the finding of LV contraction in diastolic phase to be useful in determining haemodynamic improvement after CRT.^13,14 Using strain imaging that reflects myocardial deformation, we proposed a new index quantitatively reflecting the whole temporal amount spent by 12 LV segments in contracting after aortic valve closure. In our study, we prospectively compared the relative predictive value of this new index and of Ts-SD on the CRT-induced reverse remodelling.

	Methods

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
Inclusion criteria and study protocol
The study population comprised 59 patients who (from January 2004 to October 2005) underwent biventricular pacing device implantation for HF according to current guidelines.⁶ Briefly, inclusion criteria were New York Heart Association (NYHA) classes III–IV despite maximum well-tolerated medical therapy, LVEF35%, and QRS duration 130 ms. They were treated with maximal tolerable doses of HF medications and remained clinically stable for 1 month before enrolment. Patients with atrial fibrillation (AF) or with a previously implanted pacemaker were excluded.

Standard and TDI echocardiography was performed before and 6 months after biventricular pacing device implant. At the 6-month follow-up, patients were divided into responders and non-responders on the basis of at least 15% LV end-systolic volume (ESV) reduction according to the literature data.^15,16 Our Institutional Review Board approved the study and witnessed informed consent was obtained from each patient.

Biventricular pacemaker implantation
Three transvenous pacing leads were inserted. The right atrial and ventricular leads were positioned conventionally. The LV lead was inserted through the coronary sinus into either the lateral (28 patients, 47%) or posterolateral cardiac vein (31 patients, 53%). The biventricular devices used were InSynch (Medtronic Inc., Minneapolis, MN, USA) in 25 patients and Contak TR CHFD (Guidant Inc., St Paul, MN, USA) in 34 patients. After implantation, the atrioventricular interval was optimized for maximal diastolic filling using Doppler echocardiography.¹⁷

Echocardiography
Standard echocardiography, including Doppler studies, was performed using a Vivid 7 System (Vingmed-General Electric, Horten, Norway). The following parameters were evaluated: LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) assessed by Simpson's equation using the apical four-chamber view,¹⁸ myocardial performance index (MPI) as the sum of isovolumic contraction and relaxation times divided by ejection time,¹⁹ where the ejection time was evaluated as the interval between the beginning and the end of aortic flow and the sum of isovolumic contraction and relaxation time was derived from the interval between the end of mitral inflow and the onset of the next mitral inflow signal minus ejection time, the ratio of peak flow velocity in early diastole and peak flow velocity in late diastole during atrial contraction (E/A), deceleration time of E-wave (DTE), isovolumic relaxation time (IVRT) as the interval between the end of aortic flow and the beginning of mitral inflow, and the jet mitral regurgitant area (JA) relative to left atrial size in the apical four-chamber view (JA/LAA) as mitral regurgitation severity parameter.²⁰ The interventricular electromechanical delay (IVD) was also calculated as the time difference between the aortic and pulmonary pre-ejection time intervals where aortic and pulmonary ejection flows were recorded in the five-chamber apical and parasternal views, respectively.

Tissue Doppler and strain Doppler imaging evaluation
TDI and strain Doppler colour imaging (SDI) were performed with a 2.5 or 3.5 MHz phase array transducer for the long axis motion of the ventricles. Gain setting, filters, and pulse repetition frequency were adjusted to optimize colour saturation; sector size and depth were optimized for the highest frame rate. At least three consecutive beats were stored, and the images were digitized and computer-analysed offline (EchoPac 6.3.6, Vingmed- General Electric, Horten, Norway). Myocardial pulse-Doppler velocity profile signals were reconstituted offline from the TDI colour images that provided regional myocardial velocity curves.

From the apical four-chamber, two-chamber, and long-axis views, a six-basal and six-mid segmental models were obtained in the LV, namely the septal, lateral, anteroseptal, posterior, anterior, and inferior segments at both basal and mid-levels. The time to the systolic peak velocity (Ts) was measured in every segment. For Ts, the beginning of the QRS complex was used as the reference point. Ts-SD was assumed as LV asynchrony index as proposed by Yu et al.⁹

For SDI, the image sector width was set as narrow as possible to allow a frame rate acquisition >140 frames/s. As with the TDI measurements, three beats were measured and averaged for each measurement. A region of interest (ROI), 6x6 mm² sized, was used with careful alignment of the cursor with the wall direction in any given region measured. A semi-automatic tracking algorithm was applied to maintain the sample volume in the ROI throughout the cardiac cycle. Myocardial strain is a measure of the regional deformation, and by definition, for the apical views, negative strain reflects shortening, whereas positive strain indicates elongation.^21,22 The time of strain tracing exceeding aortic valve closure (ExcT) was measured in each segment as the interval between the marker of aortic closure and the nadir of the strain tracing as illustrated in Figure 1. ExcT was considered 0 when the nadir of strain curve did not exceed aortic valve closure. The overall time of strain exceeding aortic valve closure (oExcT) was computed as the sum of the 12 segmental ExcTs. Reproducibility of oExcT was assessed in 10 randomly chosen baseline echocardiograms by Bland–Altman method. Mean±SD difference between two expert echocardiographers for oExcT was 95±124 ms (r=0.97) (95% CI 6.1–183.8 ms).

View larger version (58K): [in this window] [in a new window]   Figure 1 Method employed to measure time of exceeding aortic valve closure contraction. The peak myocardial strain was evaluated at the centre of 12 LV segments during a stable cardiac cycle. The time of strain tracing exceeding aortic valve closure was measured in each segment as the interval between the marker of aortic closure and the nadir of the strain tracing.

 

	Statistical analysis

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
Continuous variables are expressed as mean±SD. Baseline categorical data were compared by means of the ² test. For the comparison of continuous variables before and after CRT, paired sample t-test was performed. The comparison of clinical and echocardiographic parameters between responder and non-responder groups was performed by unpaired t-test. Linear regression analysis was performed to assess the relationship between the two chosen parameters of LV asynchrony (i.e. Ts-SD and oExcT) at baseline and changes in ESV. Receiver operating curve (ROC) analysis was performed to determine sensitivity and specificity of Ts-SD and oExcT in predicting CRT response. The value corresponding with the highest accuracy (i.e. minimal false negative and false positive result) was choosen as the optimal cutoff. The reliability of the cutoff was validated using bootstrap resampling (n=5000) (90% confidence intervals are presented). CMDT software (version 1.0 ß, Berlin University) was used for bootstrapping analysis.

We derived from our previously published population study⁸ an area under curve (AUC) of 0.68 for Ts-SD and decided to enrol at least 50 patients (80% of power with a difference between AUC of 0.17, given a one-sided value of 0.05 and responders of 50%). For all tests, a P-value <0.05 was considered significant.

	Results

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
Of 69 initially assessed patients, seven had poor echocardiographic images (bad alignment in five cases and missed anterior wall in two cases) and strain analysis was not possible with a final feasibility of 89%. Three patients died before the 6-month follow-up visit. Fifty-nine patients constitute the final population. The baseline characteristics are shown in Table 1. Pacemaker implantation was successful in all patients and no procedure-related complications were observed.

View this table: [in this window] [in a new window]   Table 1 Responder and non-responder patient baseline characteristics

 
After 6 months of CRT, among the 59 patients, there were 28 responders (47%) to LV reverse remodelling with reduction of >15% ESV and 31 non-responders (53%) in whom the reduction in ESV was 15%. No significant differences were observed in baseline clinical and demographic characteristics between the two groups (Table 2).

View this table: [in this window] [in a new window]   Table 2 Conventional and tissue Doppler echocardiographic parameters of responders and non-responders at baseline and at the 6-month follow-up

 
Among the baseline echocardiographic parameters, in responders when compared with non-responders, DTE and IVRT were significantly longer and MPI significantly higher, and LV dyssynchrony resulted more extensively as indicated by significantly larger Ts-SD and oExcT values (Table 2).

At the 6-month follow-up, in responders, ESV was reduced by 20% in all patients with a mean reduction of 36±11% (20–61%). In non-responders, ESV was stable in 12 patients and further dilated in the remaining 19 patients with a mean increase of 16±12% (2–41%). Both EDV and ESV were significantly decreased in responders when compared with baseline, whereas in non-responders, they were significantly further dilated. In responders, EF (P=0.000), MPI (P=0.000), and MR (P=0.0005) improved and IVRT shortened (P=0.015); in non-responders, all these parameters remained unchanged, with exception for MR, which significantly improved (P=0.03). Intraventricular synchronism improved only in responder group, as indicated by a significant reduction in Ts-SD and oExcT (P=0.002 and P=0.000, respectively). No significant changes in IVD were observed in the both groups (Table 2).

In overall population, linear regression analysis showed a significant correlation between changes in ESV and baseline Ts-SD and oExcT (r=–0.32, P=0.01 and r=–0.48, P=0.0001, respectively) (Figure 2).

View larger version (11K): [in this window] [in a new window]   Figure 2 Linear regression analysis between changes of oExcT and ESV (P<0.00001) and between Ts-SD and ESV (P<0.005).

 

	Prediction of response

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
ROC analysis showed that oExcT had 93.5% of sensitivity and 82.8% of specificity to predict CRT response with an optimal cutoff value of 760 ms (90% CI by boostrapping 725–879.5) (area under curve 0.86; 95% CI 0.75–0.94, P=0.000). Ts-SD with a cutoff of 32 ms as proposed²⁰ had 82% of sensitivity and 39% of specificity (area under curve 0.69; 95% CI 0.56–0.8, P=0.004). Area under the ROC curves was significantly larger for oExcT than for Ts-SD (P=0.03) (Figure 3).

View larger version (8K): [in this window] [in a new window]   Figure 3 Comparison of ROC curve analysis between oExcT and Ts-SD showed better sensitivity and specificity for the first (P<0.05 between curves).

 

	Discussion

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
In this study, for the first time, a parameter measuring the overall time wasted by the LV in contracting after aortic valve closure has been introduced for LV dyssynchrony evaluation. Our data show that this parameter can predict LV reverse remodelling in patients treated with CRT. Previously, several TDI parameters, generally using the variation or the difference in time to the peak of systolic sustained velocity, were proposed for asynchrony evaluation.^9–12 Of them, the Ts-SD has been recently demonstrated to be the most powerful predictor of LV reverse remodelling.¹⁶ All these parameters have the common attribute of focusing exclusively on the mechanical asynchrony in the ejective phase. They do not take into account the contractile events occurring after aortic valve closure. Sogaard et al.¹³ for the first time highlighted the presence of delayed longitudinal contraction and demonstrated that the greater the number of segments displaying longitudinal contraction during diastole, the more severe is the degree of dyssynchrony. This finding was shown to be predictive of CRT efficacy. In this study, the authors performed a dichotomic analysis of each segment on the basis of the presence or absence of delayed longitudinal contraction using tissue-tracking technique. Although this method immediately shows the region with delayed longitudinal contractions, it cannot evaluate the degree of the temporal delay. To better describe such phenomenon, we proposed a quantitative parameter. Using strain imaging, we measured the total amount of time spent by 12 LV segments in contracting after aortic valve closure. Thus, a quantitative measurement in time domain of the whole LV segmental deformation occurring outside ejective phase was obtained. This parameter reflects a severe asynchrony degree in which regional electromechanical delays are prolonged to an extent that some regional contractile events are shifted in diastolic phase. We considered two different patterns of contractile asynchrony: a ‘systolic contractile asynchrony’ in which there is a temporal dispersion of the regional electromechanical delays although they remain confined inside ejective phase and a ‘contractile diastolic asynchrony’ in which the contractile events exceed ejective phase. The latter cannot be disclosed analysing only the ejection phase. Figure 4 shows an example of patient with baseline low Ts-SD (left side) and prolonged oExcT (right side) in whom after 6 months of CRT, a 32% LV ESV reduction was observed. According to the Ts-SD criterion, this patient should not have benefited from CRT.

View larger version (74K): [in this window] [in a new window]   Figure 4 Example of a patient with baseline low Ts-SD (left panel) and prolonged oExcT (right panel) in whom after 6 months of CRT a 32% ESV reduction was observed.

 
Strain is a measure of a true myocardial deformation. Although it can reflect both active contraction and passive recoil, it is less influenced by overall heart motion and tethering effects than TDI. Strain imaging in patients treated with CRT has been already studied: Breithardt et al.²³ demonstrated that CRT can acutely reduce the regional delay between QRS onset and the peak of strain and Popovic et al.²⁴ found the coefficient of variation of myocardial strain can detect patients with the largest degree of myocardial dyssynchrony who are likely to benefit most from CRT. On the contrary, recently Yu et al.¹⁶ demonstrated that TDI is superior to strain rate imaging in predicting reverse remodelling after CRT. However, strain rate signal is more disturbed by noising artefacts than the strain that we used,^20,21,25 and this could explain the discordant results. We found ExcT a better predictor of positive response to CRT than Ts-SD. The longer IVRT observed at baseline in responders compared with non-responders is likely due to contrasting effects of the diastolic contraction in the rate of the LV falling pressure.

An asynchronous contraction occurring after LV systolic ejection has been largely described in experimental and clinical studies.^26–28 This phenomenon defined as postsystolic shortening (PSS) can occur independently of delayed activation in different conditions such as ischemia, LV hypertrophy, or LV overload.²⁶

In our study, in computing oExcT, we did not differentiate the various underlining mechanisms of PSS. However, the good predictive value found confirms the assertion that PSS could be considered an expression of myocardial asynchrony as postulated by some authors.²⁶ Further studies are required to evaluate the impact of the different underlining mechanisms of PSS on CRT response.

	Conclusions

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 
Currently, in the setting of CRT responders' identification, attention is focused on LV dyssynchrony analysis, as assessed in the systolic phase. This study highlights the importance of LV dissynchrony occurring in the diastolic phase. The presence of delayed longitudinal contraction had been previously demonstrated to be useful in predicting CRT benefits, but the semi-quantitative nature of the method employed may limit its efficacy.¹³ In our cohort of patients, we found that a quantitative measurement in the time domain of the whole LV segmental deformation occurring after aortic valve closure is able to predict LV functional recovery and reversal remodelling after CRT.

Conflict of interest: none declared.

	References

Top Abstract Introduction Methods Statistical analysis Results Prediction of response Discussion Conclusions References

 

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