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European Heart Journal Advance Access originally published online on March 30, 2007
European Heart Journal 2007 28(8):1004-1011; doi:10.1093/eurheartj/ehm021
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effect of dynamic myocardial dyssynchrony on mitral regurgitation during supine bicycle exercise stress echocardiography in patients with idiopathic dilated cardiomyopathy and ‘narrow’ QRS

Antonello D'Andrea1,*, Pio Caso2, Sergio Cuomo1, Raffaella Scarafile1, Gemma Salerno1, Giuseppe Limongelli1, Giovanni Di Salvo1, Sergio Severino2, Luigi Ascione3, Paolo Calabrò1, Massimo Romano1, Gianpaolo Romano4,5, Lucio Santangelo1, Ciro Maiello4,5, Maurizio Cotrufo4,5 and Raffaele Calabrò1

1 Chair of Cardiology, Second University of Naples, Italy
2 Department of Cardiology, Monaldi Hospital Naples, Italy
3 Department of Interventional Cardiology, Santa Maria di Loreto Hospital, Naples, Italy
4 Department of Cardiothoracic and Respiratory Sciences, Monaldi Hospital, Second University of Naples, Italy
5 Department of Cardiovascular Surgery and Transplant, Monaldi Hospital, Second University of Naples, Italy

Received 7 September 2006; revised 22 January 2007; accepted 15 February 2007; online publish-ahead-of-print 30 March 2007.

* Corresponding author. Tel: +39 0817618525; fax: +39 0817145205. E-mail address: antonellodandrea{at}libero.it

See page 924 for the editorial comment on this article (doi:10.1093/eurheartj/ehm079)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Supplementary material
 Acknowledgements
 References
 
Aims: Cardiac resynchronization therapy (CRT) has become an attractive therapeutic option for patients with end-stage heart failure (HF). Currently, patients are selected for CRT on ECG and on echocardiographic criteria analysed at rest. Whether the physical effort may further increase myocardial dyssynchrony is not fully established. The aim of the study was to test by the use of Doppler myocardial imaging (DMI) if dynamic left ventricular (LV) dyssynchrony during physical effort may be a determinant of dynamic mitral regurgitation in patients with dilated cardiomyopathy and ‘narrow’ QRS.

Methods and results: Sixty patients (62.3 ± 8.3 years) with idiopathic dilated cardiomyopathy and narrow QRS duration ( < 120 ms) were selected. All the patients underwent standard Doppler echo, colour DMI, supine bicycle exercise stress echocardiography, and cardiopulmonary exercise testing. Cardiac synchronicity was assessed, at rest and at peak exercise, from measurements of time intervals (Ts) between the onset of the QRS complex and the peak myocardial systolic velocity, in a six-basal-six-mid-segmental model. Standard deviation of Ts of the 12 LV segments (Ts-SD-12) was also calculated. In baseline conditions, HF patients showed an LV ejection fraction of 30.1 ± 4%, and a significant electromechanical delay (Ts-SD-12 ≥ 34.4 ms) in 20 patients (33.3%). At peak of physical exercise, a significant electromechanical delay was detected in 35 patients (58.3%), whereas in 47 patients (78.3%) exercise-induced increase in mitral valve effective regurgitant orifice (ERO) was observed. By multivariable analysis, an independent positive association between changes in Ts-SD-12 and in mitral valve ERO (P < 0.0001), as well as an independent inverse correlation of the same changes in Ts-SD-12 with LV stroke volume (P < 0.0001) were detected. In addition, changes in Ts-SD-12 were also independent determinants of peak VO2 (P < 0.0001) during cardiopulmonary exercise testing.

Conclusion: Colour DMI is an effective technique for assessing the severity of regional delay in activation of LV walls in HF patients with narrow QRS both at rest and during stress test. The increase in LV dyssynchrony during exercise strongly correlates with the increase in mitral regurgitation severity and with the impairment of LV stroke volume.

Key Words: Dynamic myocardial dyssynchrony • Mitral regurgitation • Heart failure • Resynchronization therapy • Supine bicycle exercise stress echocardiography • Idiopathic dilated cardiomyopathy • Narrow QRS • Doppler myocardial imaging


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Supplementary material
 Acknowledgements
 References
 
Chronic heart failure (HF) is an active disease process characterized by progressive remodelling of the ventricles, even in patients with stable symptoms. In ~30% of patients, HF not only determines impaired cardiac systolic function, but also affects the conduction pathways causing a delay in the onset of both right and left ventricular (LV) systole. Such dyssynchrony is visible on the electrocardiogram as a QRS interval lasting more than 120 ms.1,2

Cardiac resynchronization therapy (CRT) has become an attractive therapeutic option for patients with left bundle branch block (LBBB), wide QRS duration and end-stage HF.3–5 Currently, patients are selected for CRT mainly on ECG criteria and on echocardiographic indexes analysed at rest. Whether the physical effort may further increase myocardial dyssynchrony is not fully established.

Increased tenting area resulting from LV remodelling has been identified as a determinant of the severity of resting and exercise functional mitral regurgitation (MR) in patients with LV systolic dysfunction.6–9 Besides reducing cardiac performance, myocardial asynchronism may decrease mitral valve closing forces, thereby exacerbate functional MR during dynamic exercise in patients with HF.10,11

Among various echocardiographic techniques, Doppler myocardial imaging (DMI) has gained its acceptance by virtue of the ability to define myocardial timing and contractility in patients with LBBB and HF and is highly feasible and reproducible.12–17

Several recent reports have underlined that the relation between QRS duration and LV myocardial mechanical dyssynchrony is poor, since significant mechanical dyssynchrony is absent in nearly 30% of patients with prolonged QRS duration.4,5,18 Furthermore, CRT determined clinical and functional benefit also in HF patients with ‘narrow’ QRS.19

On these grounds, the aim of the present study was to test by the use of DMI the hypothesis that dynamic LV dyssynchrony, intermittent changes in LV synchronicity during physical effort, may be a determinant of dynamic MR in patients with idiopathic dilated cardiomyopathy and incomplete LBBB (‘narrow’ QRS).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Supplementary material
 Acknowledgements
 References
 
Study population
From January 2005 to March 2006, 455 ambulatory HF patients with known LV systolic dysfunction and MR were referred to our echocardiographic laboratory. Patients with QRS > 120 ms (n = 120), ischaemic cardiomyopathy (n = 202), atrial fibrillation (n = 29), orthopaedic limitation (n = 14), inducible myocardial ischaemia (n = 11), or poor echocardiographic window (n = 4) and improved LV ejection fraction (LVEF) > 40% (n = 15) were ineligible for the study. No patients refused to give their consent. The remaining 60 patients were able to perform a symptom-limited exercise. The study was approved by the local Ethics Committee.

The final study population therefore included 60 patients (62.3 ± 8.3 years) with idiopathic dilated cardiomyopathy (angiographically normal coronary arteries). Inclusion criteria were: New York Heart Association (NYHA) classes II–III refractory HF, LV end-diastolic diameter > 55 mm, LVEF < 35%, ‘narrow’ QRS interval ( < 120 ms), sinus rhythm, at least least mild functional MR.

All the patients underwent standard Doppler echo, colour DMI by Vivid 7 ultrasound system (GE Vingmed Ultrasound), coronary angiography, and supine bicycle exercise stress echocardiography (ESE). Peak oxygen consumption (peak VO2) was assessed by cardiopulmonary exercise test the day before or after the echocardiographic study.

Standard echocardiography
Standard Doppler echocardiography and DMI were performed with the subjects in partial left decubitus. A variable frequency phased-array transducer (2.5–3.5–4.0 MHz) was used for two-dimensional and Doppler imaging. Doppler echocardiographic and DMI tracings were recorded on magneto-optical disk. All the measurements were analysed by two experienced readers, on the average of three or more cardiac cycles. Stroke volume was obtained at rest at peak effort by LV outflow Doppler method as the product between outflow tract area and LV output time–velocity integral.20 LVEF was measured using a commercially available software program that applied modified Simpson's rule on the two-chamber and four-chamber views.

The proximal flow convergence (PFC) technique has been validated as a quantitative Doppler method to calculate regurgitant volume (RV) of flow and orifice area [effective regurgitant orifice (ERO)] at rest and during exercise. The regurgitant flow is measured as 2{pi} x r2 x Vr, where r is the radius of the hemispheric PFC region and Vr is the aliasing velocity. The following parameters are calculated: ERO = regurgitant flow/maximal regurgitant velocity, and RV = ERO x RTVI, where RTVI being the regurgitant time–velocity integral. At least three consecutive beats of sinus rhythm were measured and the average value taken.21–23

Colour Doppler myocardial imaging
DMI was performed using apical four-chamber, apical two-chamber, and apical long-axis views for the long-axis motion of the ventricles.10 Two-dimensional echocardiography with DMI-color imaging views was optimized for pulse repetition frequency, colour saturation, and sector size and depth and allowed a highest possible frame rate. At least three consecutive beats were stored and the images were analysed offline. Tissue synchronization imaging (TSI) is a parametric imaging tool derived from two-dimensional DMI images.24 It automatically calculates and colour-codes the time to peak tissue velocity (Ts) in every position in the image with reference to the QRS signal. The TSI algorithm detects positive velocity peaks within a specified time interval, and the colour coding ranges from green (earliest), yellow, orange, to red (latest) within this interval. The algorithm uses the automatically detected QRS onset as a reference. With the event timing tool, the time from the onset of the QRS to the aortic valve opening or closure was first measured in a separately recorded Doppler spectrum or M-mode through the valve.

A quantitative measurement tool allowed numerical calculation of the median time to peak velocity within a 6 mm diameter circular region of interest manually positioned within the two-dimensional TSI image. The six-basal-six-mid-segmental model was used.15 The myocardial velocity curves were constructed with the TSI images simultaneously when necessary to confirm the pattern of myocardial motion.

Cardiac synchronicity was assessed from measurements of time intervals, obtained in 12 LV segments and two lateral right ventricular segments, between the onset of the QRS complex and the peak myocardial sustained systolic velocity. LV intraventricular dyssynchrony was determined as the difference, among the 12 LV walls, between the longest and the shortest times to peak myocardial sustained systolic velocity. Interventricular dyssynchrony was determined as the difference between the time interval in the lateral segment of the right ventricle and of the left ventricle. Standard deviation of Ts of the 12 LV segments (Ts-SD) was also calculated.15 LV and intraventricular and interventricular dyssynchrony were calculated at rest and at peak exercise (Figure 1).


Figure 1
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  		Figure 1 Doppler myocardial imaging echocardiograms depicting exercise-induced changes in left ventricular dyssynchrony as estimated by the differences in time to peak velocities between two basal segments at rest (A) and at peak exercise (B) in a patient with significant dynamic left ventricular dyssynchrony. See online Supplementary material for a colour version of this figure.

 
Exercise stress echocardiography
Symptom-limited (fatigue or dyspnoea) exercise was performed in supine position on a semi-recumbent and tilting bicycle ergometer with a 20 W/3 min step protocol starting from 25 W. Beta-blockers were discontinued 24 h before the test. After recording a resting two-dimensional echocardiogram, the heart rate was continuously monitored and 12-lead electrocardiogram, echocardiographic images, and blood pressure were recorded at every step. Criteria for test interruption were: achievement of maximal heart rate, onset of new or worsening wall motion abnormalities, severe chest pain or dyspnoea, horizontal or down-sloping ST-segment depression ≥ 2 mm, ST-segment elevation ≥ 1.5 mm, systolic blood pressure > 220 mmHg, diastolic blood pressure > 120 mmHg, reduction in systolic blood pressure ≥ 30 mmHg, supraventricular or ventricular tachyarrhythmias. Two-dimensional images were obtained in apical-chamber views, at each exercise step and during recovery, and recorded using a quad-screen cine-loop system.

Statistical methods
All the analyses were performed using a commercially available package (SPSS, Rel 11.0 2002, Chicago: SPSS Inc.) except bootstrap analysis, which was performed with R (R Foundation for Statistical Computing). Variables are presented as mean ± SD.

Two-tailed t-test for paired data was used to assess changes between rest and peak effort. Linear regression analyses and partial correlation test by Pearson's method were done to assess univariate relations.

To identify significant independent predictors of changes in mitral valve regurgitation and LV stroke volume during effort in patients with dilated cardiomyopathy, their individual association with clinical relevant and echocardiographic variables was assessed by multivariable Cox regression analysis. The following variables were included in the analysis: clinical data (age, heart rate, QRS width), standard echocardiographic indexes (LV volumes, LVEF, systolic tenting area), and DMI measurements (LV intra- and interventricular dyssynchrony, Ts-SD-12). These variables were selected according to their clinical relevance and potential impact on cardiac performance, as shown by earlier studies. Variable selection was performed in the multivariable Cox 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.25 The linearity assumptions were satisfied. The Hosmer–Lemeshow goodness-of-fit test was used to check that the model adequately fit the data.26 The model also underwent bootstrap validation (200 runs), with the calculation of the c-statistic to evaluate discrimination and the shrinkage coefficient to evaluate calibration; in both cases, the closer the value to 1, the better.

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 < 0.01.

Reproducibility of DMI measurements was determined in all the subjects. Inter- and intraobserver variability was examined using both Pearson's bivariate two-tailed correlations and Bland–Altman analysis. Relation coefficients, 95% confidence limits, and per cent errors were reported.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Supplementary material
 Acknowledgements
 References
 
Demographic and clinical characteristics are summarized in Table 1. Our patients were mildly symptomatic, since only 20 patients (33.3%) were in NYHA functional class III. All patients were receiving ACE-inhibition and beta-adrenergic blockade except for eight patients who could not tolerate beta-adrenergic blockade because of excessive bradycardia or clinical deterioration. Width of QRS was 109.6 ± 9.4 ms. By cardiopulmonary exercise testing, the mean absolute value of peak VO2 of 16.8 ± 3.2 mL/kg/min.


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  		Table 1 Demographic and clinical characteristics of the study population (n = 60)

 
In baseline conditions, dilated patients showed a resting LVEF of 30.1 ± 4%, and mild both intraventricular and interventricular delay by DMI analysis (Table 2). According to the Ts-SD-12 cut-off value of 34.4 ms previously reported by Yu et al.,15 a significant electromechanical delay was detected at rest in 20 patients (33.3%) (12 in NYHA class II, eight in NYHA class III).


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  		Table 2 Baseline and exercise echocardiography results of the study population

 
At peak of physical exercise, most of dilated patients showed an increase in LVEF, stroke volume, as well as in both mitral valve ERO and electromechanical dyssynchrony, with respect to baseline measurements (Table 2). A significant electromechanical delay (Ts-SD-12 ≥ 34.4 ms) was detected during effort in 35 patients (58.3%) (22 in NYHA class II, 13 in NYHA class III). In particular, during effort, LV dyssynchrony increased in 76.7%, remained stable in 5%, and decreased in 18.3%. In 47 patients (78.3%), exercise-induced increase in MR was observed.

None of the included patients had chest pain, significant ST-segment depression, or echocardiographic evidence of ischaemia during exercise. Severe dyspnoea (46 patients), leg fatigue (11 patients), reduction in systolic blood pressure ≥ 30 mmHg (two patients), ventricular tachyarrhythmias (one patient) were the causes of exercise cessation.

By univariate analysis, in our population of dilated patients, changes in Ts-SD-12 during effort were positively associated with changes in mitral valve ERO (r = 0.78, P < 0.00001) (Figure 2) and inversely related to changes in LV stroke volume (r = –0.74, P < 0.00001) (Figure 3). Of note, correlations between changes in Ts-SD-12 and in mitral ERO were highly significant in patients with an increase in LV dispersion (r = 0.82, P < 0.00001) and non-significant in patients with a decrease in LV dispersion (r = 0.31, P = 0.26). Changes in LV dispersion were also significantly associated with changes in systolic tenting area (r = 0.52, P < 0.001), a determinant of tethering force. Conversely, no significant correlation was observed between changes in Ts-SD-12, changes in heart rate, and QRS duration. Also exercise-induced changes in ERO were not associated with changes in heart rate, LV volumes, and EF, whereas they were strongly correlated with changes in the systolic tenting area (r = 0.79, P < 0.00001).


Figure 2
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  		Figure 2 Scatter plot between changes in systolic asynchrony (Ts-SD-12) and changes in mitral valve effective regurgitant orifice.

 

Figure 3
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  		Figure 3 Scatter plot between changes in systolic asynchrony (Ts-SD-12) and changes in left ventricular stroke volume.

 
By multivariable analyses, after adjusting for potential determinants such as age, heart rate, QRS width, and LV volumes, in the overall population of patients, the independent positive association between changes in Ts-SD-12 and in mitral valve ERO (ß cofficient in the final model = 0.62; P < 0.0001; ß cofficient estimate averaged across bootstrap samples = 0.61; P < 0.0001) and the independent inverse correlation of the same changes in Ts-SD-12 with changes in LV stroke volume (ß coefficient in the final model = –0.53; P < 0.0001; ß cofficient estimate averaged across bootstrap samples: = –0.53; P < 0.0001) were confirmed. In multivariable analysis, also an increase in systolic tenting area emerged as independent determinants of ERO changes during exercise (ß = 0.73; P < 0.00001). In addition, changes in Ts-SD-12 were also independent determinants of peak VO2 (ß cofficient = –0.49; P < 0.0001) during cardiopulmonary exercise testing.

For the models about changes in mitral valve ERO and in LV stroke volume during effort, each of the variables in the final models appeared in the bootstrap models over 90% of the time. According to model validation statistics, discrimination of both models was adequate:

  1. changes in mitral valve ERO during effort: c-statistic = 0.773; calibration, shrinkage coefficient = 0.79; Hosmer–Lemeshow P = 0.83).
  2. changes in LV stroke volume during effort: c-statistic: 0.781; calibration, shrinkage coefficient = 0.773; Hosmer–Lemeshow P = 0.73.

Reproducibility of Doppler myocardial imaging measurements
Interobserver variability
Pearson's correlations
Intraventricular delay: r = 0.88; P < 0.00001; interventricular delay: r = 0.90; P < 0.00001; Ts-SD-12: r = 0.86; P < 0.00001.

Bland–Altman analysis
Intraventricular delay (95% CI ± 1.8; per cent error 3.3%); interventricular delay (95% CI ± 1.2; per cent error 3.1%); Ts-SD-12 (95% CI ± 3.5; per cent error 4.3%).

Intraobserver variability
Pearson's correlations
Intraventricular delay: r = 0.91; P < 0.00001; interventricular delay: r = 0.92; P < 0.00001; Ts-SD-12: r = 0.87; P < 0.00001.

Bland–Altman analysis
Intraventricular delay (95% CI ± 1.9; per cent error 3.4%); interventricular delay (95% CI ± 1.1; per cent error 3.0%); Ts-SD-12 (95% CI ± 3.2; per cent error 4.1%).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Supplementary material
 Acknowledgements
 References
 
The result of the present study demonstrates the usefulness of colour DMI in analysing dynamic variations of myocardial electromechanical delay during physical effort in patients with impaired LV global systolic function and incomplete LBBB.

The following lists the main findings of our study: (i) physical effort unmasked a significant dynamic LV systolic dyssyncrony, independent of QRS width, in more than 50% of our dilated patients; (ii) such increase in intraventricular activation delay was an independent determinant of both functional mitral valve regurgitation and of LV stroke volume at peak effort; (iii) increased LV dyssynchrony during effort was associated with impaired exercise capacity.

Dynamic left ventricular dyssynchrony and narrow QRS
One of the most critical questions to emerge from the recent clinical trial data is how should one best target CRT therapy, since CRT devices are complex, invasive, and expensive. The percentage of non-responding patients as indexed by clinical symptoms or objective evidence of the absence of reverse chamber remodelling is 25–30% of recipients.4,5 The major entry criteria to date have been the presence of severe dilated HF (NYHA classes III–IV), sinus rhythm, and evidence of a wide QRS complex on the electrocardiogram.

Although the available data in literature highlight a positive correlation between QRS duration and interventricular dyssynchrony,5 one problem with QRS duration is that it incorporates total ventricular activation (right and left) and rapid right ventricular activation can be offset by delayed LV activation to yield a normal-range QRS, despite considerable mechanical dyssynchrony. Conversely, QRS widening can reflect more diffuse conduction abnormalities or predominantly right ventricular delays, but not belie physiologically significant LV intraventricular delay. Several echocardiographic studies have confirmed a presence of intraventricular dyssynchrony ranging from 36 to 51% in patients with LBBB and QRS duration < 120 ms.27–29 As a result, more sophisticated imaging techniques may be necessary to disclose intraventricular dyssynchrony.

One of the implications of the lack of a consistent relationship between QRS duration and CRT response is that patients could well exist with narrow QRS durations yet significant mechanical dyssynchrony. Even if most of such patients would not have qualified for entry into prior clinical CRT trials, on the basis of recent data, they could well be predicted to benefit from CRT.5,18,19 In our study population, physical effort determined an increase in the prevalence of LV dyssynchrony from 33.3% at rest to 58.3% during ESE. The further impairment of intraventricular systolic synchronicity during physical effort was also strongly related to exercise capacity and to the impairment of LV stroke volume. Since CRT may be helpful in HF patients with incomplete LBBB and echocardiographic evidence of intraventricular dyssynchrony, DMI in conjunction with physical effort may represent a valid non-invasive means for improving the selection of patients with dilated cardiomyopathy and incomplete LBBB suitable for CRT.

Dynamic left ventricular dyssynchrony and dynamic functional mitral regurgitation
In dilated patients, the degree of resting functional MR is related to mitral valvular deformation that is dependent on local rather than global LV remodelling. In fact, LV dilation produces distortion of ventricular geometry, since the apical and outward displacement of the mitral leaflets restricts their ability to close through tethering forces.30–32

During exercise, the dynamic changes in MR are correlated to changes in mitral valve configuration and mitral apparatus geometry at both ends of the tethered leaflets. In patients with normal QRS duration but reduced LV contraction, exercise-induced changes in MR are associated neither to the degree of MR at rest nor to the changes in global LV function, but are related to the changes in local LV distortion and in mitral deformation.9,11

Several recent observational studies have underlined also an association between functional mitral regurgitation and LV electromechanical delay in dilated patients with prolonged QRS. In particular, Ennezat et al.33 studied 70 HF patients (51% with ischaemic cardiomyopathy; width of QRS > 120 ms in 68% of cases). Pulsed-wave DMI was performed to assess and quantify LV dyssynchrony at rest. Worsening of functional MR during exercise was individually variable and was associated with the presence and the degree of LV dyssynchrony at rest. Of note, in this study, the DMI pulsed-wave mode did not allow assessment of regional timing differences during a single beat and was technically challenging to catch during exercise.

Conversely, colour-coded measurements, although not necessarily more accurate, are obtainable during exercise to reconstitute pulsed-wave Doppler velocity profiles and to analyse them offline. By the use of this DMI modality, Lancellotti et al. were the first authors to document a dynamic LV dyssynchrony in patients with HF due to coronary disease. In fact, they studied at rest and during effort 35 patients with chronic ischaemic LV dysfunction (mean QRS duration: 118 ± 34 ms) by the use of a DMI six-basal-segmental mode, showing important changes in LV synchronicity during exercise in most patients, strongly correlated with those in MR and in forward stroke volume.10

Very recently, also Lafitte et al. analysed by colour DMI 65 patients with compensated HF at rest and during exercise echocardiography. The origin of HF was ischaemic in 33 patients (50.7%) and 22 patients (33.8%) manifested a narrow QRS complex. During effort, LV dyssynchrony increased by at least 20% in 34%, remained stable in 37%, and decreased by at least 20% in 29%. Moreover, 26% of HF had either exercise induction or normalization of ventricular dyssynchrony. A significant association was found between exercise-induced changes in dyssynchrony and the presence of ischaemic cardiomyopathy (P < 0.05). Rest–exercise differences in ventricular dyssynchrony were correlated with changes in cardiac output and mitral regurgitation (r = –0.63 and 0.56, respectively).34

In accordance with these recent reports,15,24,34 in our study protocol, we used a colour DMI six-basal-six-mid-segmental model and Ts-SD-12 index to assess significant LV dyssynchrony. In act, such measurements had demonstrated a higher predictive value for LV reverse remodelling and improvement of systolic function in dilated patients. By the use of this DMI modality, we confirmed in a larger selected population of patients with idiopathic cardiomyopathy and narrow QRS that asynchronous activation of LV segments during exercise may increase and may contribute to exercise-induced changes in MR and LV stroke volume. This suggests that systolic displacement of the mitral leaflet body into the LV cavity can be accentuated at least in part by the disturbed activation sequence of the left ventricle.

Clinical implications
A large rise in MR during exercise is associated with more frequent hospital admission for decompensated HF or flash pulmonary oedema. Furthermore, CRT is able to decrease MR, improving mitral valve closing force and coordinated timing of the papillary muscle insertion sites, not only at rest but also during exercise.35,36 As a consequence, a practical implication of our results is that dynamic testing and careful recording and interpretation of Doppler echocardiographic and DMI parameters should be encouraged to unmask what might be otherwise considered a mild MR or a relatively synchronized LV.

Study limitations
Patients in NYHA class IV were excluded. However, dynamic LV dyssynchrony can be more severe in these patients.

Although Doppler methods performed to quantify MR have some pitfalls, the quantitative method used in this study has been validated at rest and during exercise in previous reports.21–23

Our assessment of dynamic changes in LV synchronicity was based on a colour DMI six-basal-six-mid-segmental model and on Ts-SD-12 index to assess significant LV dyssynchrony. This technique may be more time-consuming than other easier methods to evaluate LV electromechanical delay. However, with the pre-installation of equations to compare various parameters of dyssynchrony and the advancement of computer hardware, it takes only few minutes to measure Ts of 12 segments from three apical views and to calculate the Ts-SD-12 automatically. In addition, such measurements have demonstrated a higher predictive value for LV reverse remodelling and improvement in systolic function in dilated patients.15,24,34 Therefore, if the time spent in these measurements is going to predict a positive response to CRT more accurately, it will be highly justified when balancing between the time and efficacy of the procedure.

No evaluation of strain and strain rate parameters was performed to differentiate myocardial passive from active motion.37 However, DMI in dilated patients has been shown to be superior to strain rate imaging in clinical practice.15 What's more, the evaluation of strain and strain rate measurements during physical effort have shown low feasibility as an increased signal noise precludes adequate data acquisition during exercise.38

As a single-centre observational study, some biases might be inevitable in the present study. To reduce the small sample bias, we used the bootstrap technique, a data-based simulation method for statistical inference. Random samples are produced from the original data by sampling with replacement. Each of these ‘bootstrap’ samples provides estimate of the parameter of interest. Repeating the sampling a large number of times provides information on the variability of the estimator and on the robustness of the predictive model.39


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Supplementary material
 Acknowledgements
 References
 
Colour DMI is an effective technique for assessing the severity of regional delay in activation of LV walls in HF patients with narrow QRS both at rest and during stress test. The increase in LV dyssynchrony during exercise strongly correlates with the increase in mitral regurgitation severity and with the impairment of LV stroke volume. Since CRT may be helpful in HF patients with echocardiographic evidence of intraventricular dyssynchrony, further longitudinal studies will be needed to clarify the potential role of DMI in conjunction with exercise echocardiography for improving the selection of HF patients with narrow QRS suitable for resynchronization therapy.


   Supplementary material
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Supplementary material
Acknowledgements
 References
 
Supplementary material is available at European Heart Journal online.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Supplementary material
 Acknowledgements
References
 
The authors are grateful to Mrs Daniela Lafera, Mrs Assunta Di Vaio, Mrs Clotilde Del Vecchio, Mrs Michela Piscopo, and Mr Riccardo Braun for excellent nursing and technical support during the study protocol.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Supplementary material
 Acknowledgements
 References
 

  1. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. (1989) Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation 79:845.[Abstract/Free Full Text]
  2. Baldasseroni S, Opasich C, Gorini M, Lucci D, Marchionni N, Marini M, Campana C, Perini G, Deorsola A, Masotti G, Tavazzi L, Maggioni AP. Italian Network on Congestive Heart Failure Investigators. (2002) Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 143:398.[CrossRef][ISI][Medline]
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