Echo Assessment of Intraventricular Dyssynchrony

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Brief Title

Echo Assessment of Intraventricular Dyssynchrony

Official Title

Italian Multicenter PROject on Echo Assessment of Left VEntricular (IMPROVE) Dyssynchrony Study

Brief Summary

      Background. Clinical benefits of cardiac resynchronization therapy (CRT) have been clearly
      demonstrated in heart failure (HF) patients with severe left ventricular (LV) dysfunction and
      wide QRS at surface electrocardiogram. However, there is a growing evidence that QRS duration
      poorly predicts responses to CRT, and that ~30% of patients do not experience any benefit
      from CRT when pre-implant dyssynchrony is defined according to electrocardiographic criteria.
      A number of echocardiographic criteria have been proposed to assess mechanical LV
      dyssynchrony, but at present there is no consensus on their use to predict response to CRT.

      Study Design. The Italian Multicenter PROject on echo assessment of left VEntricular
      (IMPROVE) dyssynchrony study is a prospective, multicenter, observational study aimed to
      assess feasibility and predictive power of mechanical dyssynchrony assessed by
      echocardiography in consecutive consenting patients candidate to CRT by clinical and
      electrocardiographic criteria. IMPROVE will enroll 120 healthy subjects and 216 HF patients
      in 6 sites in Italy. CRT response criteria will be based on improvement in NYHA class and LV
      reverse remodeling evaluated by 3D-echocardiography. Enrollment is expected to conclude early

      Implications. CRT is today part of the therapeutic armamentarium for symptomatic HF patients
      refractory to medical therapy, with wide QRS complex and severe LV systolic dysfunction. The
      IMPROVE study has been designed to evaluate reference values of indexes of ultrasound
      mechanical dyssynchrony that have been proposed in the literature and compare their ability
      to predict response to CRT in HF patients.

Detailed Description

      The IMPROVE study has 3 main purposes:

        1. definition of reference values of echocardiographic mechanical dyssynchrony (DYS)
           indexes in a population of healthy subjects;

        2. definition of the feasibility and reproducibility of such indexes in healthy subjects
           and in HF patients undergoing implantation of a biventricular pacemaker;

        3. definition of the accuracy of such indexes for predicting response to CRT.

           STUDY DESIGN. Multicenter, prospective, observational study that will be carried out in
           6 Italian sites of acknowledged expertise in LV DYS evaluation and biventricular
           pacemaker implantation. At least 120 healthy subjects (about 20 per site) and 216 HF
           patients candidates to CRT (about 36 per site) will be enrolled. With this sample volume
           it is possible to test statistically significative differences of about 7%, with an
           alfa=0.05 and beta=0.50. Definition of healthy subject includes absence of history and
           symptoms of any cardiovascular disease, normal physical examination and ECG. The same
           commercial ultrasound equipment will be used for image acquisition in each investigating
           center and echo studies will be sent to a core-lab for analysis.

           Both ischemic and non ischemic etiology of HF will be considered. Patients with
           permanent or persistent atrial fibrillation or flutter will be excluded, as these
           patients cannot benefit from the atrial-ventricular component of resynchronization.

           The following evaluations:

           - clinical examination, including NYHA class estimate;

             -  12-lead standard ECG;

             -  echocardiographic examination. will be performed within 7 days before CRT and
                repeated after 3 months of CRT. Patients will receive all appropriate treatments
                for HF, which include a diuretic, an ACE- inhibitor, or an angiotensin receptor
                blocker and usually digitalis and a beta-blocker. Doses of these background
                medications will be kept maximized during the follow-up period.

           Response to CRT will be assessed after 3 months of CRT as follows:

             -  CRT response: combined end-point defined as NYHA class improvement by at least one
                grade and echocardiographic LV end-systolic volume decrease by at least 10% with
                respect to baseline (variations are considered as relative values);

             -  CRT non-response: death for cardiac causes or failure to reach the above
                pre-specified NYHA class and echocardiographic changes.

           Patients who will die for non-cardiac causes will not be considered as non-responders
           but will exit the study.


           - Image acquisition. Conventional M-mode and B-mode two-dimensional (2D)
           echocardiography, conventional pulsed (PW), continuous (CW) wave and color Doppler,
           tissue Doppler imaging (TDI), triplane tissue synchronization imaging (TSI) and RT3DE
           techniques will be used for data acquisition in each site using a GE-Vingmed Vivid 7
           Dimension echo scanner (GE Healthcare, Horten, Norway), equipped with a broad-band M3s
           probe (2.5 MHz) and a matrix-array 3V probe (2.5 MHz), and the EchoPAC software v. BT05
           or more.

           Ultrasound scanning will be performed after 10 min rest with the patient in left lateral
           decubitus position (unless differently specified). Standard parasternal, apical and
           subcostal views will be acquired in conventional 2D modality. From the parasternal
           approach the 3 standard short-axis views (basal, mid-ventricle and apical) will be
           collected. The mid-LV short-axis view will be selected with the papillary muscle as a
           consistent internal anatomic landmark, and great care will be taken to orient the image
           to the most circular geometry possible. Oblique views with elliptical geometry will not
           be recorded. From the apical approach, the 3 standard apical views (4-chamber,
           2-chamber, long-axis) will be acquired also in triplane mode. Using this technique, once
           the apical 4-chamber view is optimized similar to the one obtained with the traditional
           2D transducer, secondary image planes (i.e., apical 2-chamber and long-axis views) are
           automatically displayed in a quad screen view. The relative angles between the 3 image
           planes will be adjusted to acquire the 3 standard apical views according to anatomical
           landmarks. All apical images (2D and triplane) will be collected in gray-scale, color
           TDI and TSI modality. Gain settings will be adjusted for routine clinical gray-scale 2D
           imaging to optimize endocardial definition; frame rates will be kept between 55 and 70
           fps to allow subsequent speckle tracking analysis (see below). Sector angle, depth, and
           Doppler pulse repetition frequency will be optimized to obtain the highest possible
           frame rate (>100 fps) avoiding loss of spatial data and aliasing in the TDI modality.
           RT3DE datasets will be obtained from the apical approach immediately after acquisition
           of 2D apical views, with the patient in the same position. In order to include the
           entire LV into the 3D dataset, a full-volume acquisition mode will be used. Using this
           approach it is possible to "stitch" together 4 sub-volumes obtained in real-time over
           consecutive cardiac cycles according to a previously described technique and protocol.
           This will create an on-line rendered image of the scanning sector with a time resolution
           of around 40-50 ms equivalent to a volume rate of 20-25 volumes per second. Measurements
           of RT3DE volumes will be performed off-line (4D analysis, TomTec Gmbh, Ubterschlessheim,

           For the study of MR, the standard color Doppler examination will be performed in the
           apical 4- and 2-chamber views to visualize the regurgitant jet; the flow convergence
           area will be recorded in the apical 4-chamber view in zoom mode, with color bar baseline
           set between 30 and 40 cm/s; finally, the CW Doppler tracing of the regurgitant jet will
           be acquired in the 4-chamber view.

           The PW Doppler examination will be performed positioning the sample volume at the level
           of the valve tips in the apical 4-chamber view for assessment of mitral inflow and at
           the level of the aortic anulus for assessment of aortic outflow.

           All conventional and TDI images will be acquired in a cineloop format during hold
           end-expiration (unless differently specified). Each cineloop and Doppler tracing will
           contain 3 cardiac cycles. All images and tracings will be stored on a CD-ROM for
           subsequent analysis. At the time of the echo examination blood pressure will be also

           - Measurements. LV size will be evaluated measuring the end-diastolic and end-systolic
           diameters (EDD, ESD, cm) on 2D parasternal short-axis view images and calculating the
           end-diastolic and end-systolic volumes (EDV, ESV, ml) using RT3DE. The EDD and EDV will
           be indexed for body surface area. LV systolic function will be evaluated using both the
           ejection fraction (EF, %) calculated from volumes and the Doppler dP/dt (mmHg/ms)
           calculated from the CW MR tracing, when available. MR severity will be evaluated by: (1)
           the maximal regurgitant jet area visualized by color Doppler in the apical 4- and
           2-chamber views (the average value of the two views will be calculated); (2) the PISA
           method; (3) the duration of the CW Doppler tracing of the regurgitant flow. Systolic
           pulmonary artery pressure (sPAP) will be calculated from the CW tricuspid regurgitation

           Several indexes of LV DYS have been selected based on published validation studies in
           which LV reverse remodeling has been considered as an end-point (single or combined) and
           at least 3 months of follow-up after CRT have been used. Dyssynchrony indexes will be
           calculated as previously reported in the literature (the respective cut-off value to
           predict positive response to CRT is shown in parentheses).

           M-mode indexes

             -  Septal-to-posterior wall motion delay (cut-off value= 130 ms): measurement will be
                obtained from the M-mode tracing of the LV as the time interval between the maximal
                inward motion of the septum and the left posterior wall.

             -  Lateral wall postsystolic displacement: difference of intervals from QRS onset to
                maximal systolic displacement of the basal LV lateral wall (assessed by M-mode in
                apical 4-chamber view) and from QRS onset to the beginning of the E wave (assessed
                by PW Doppler of mitral inflow); a positive value identifies a pathologic
                post-systolic contraction.

           TDI time intervals and indexes

           - Time to peak systolic velocity: the interval from onset of the QRS to the maximum
           positive velocity during the ejection period. The velocities in the isovolumic
           contraction and relaxation periods will not be used in this measurement. The region of
           interest (ROI) (6 x 6-mm circular shape) will be positioned in the middle of each
           segment. Time to peak velocity (Tv) will be measured on each curve from the beginning of
           the Q (or R)-wave on the ECG to the peak positive systolic velocity during the ejection
           phase, previously defined by the aortic valve opening and closure times. If a positive
           velocity will not be observed, the segment will be excluded from the calculation. If
           there will be multiple peaks in ejection period with the same velocity, the earliest
           peak will be chosen.

             -  Time to peak velocity, including the postejection period: the interval from onset
                of the QRS to the maximum positive velocity, including the period after aortic
                valve closure. Everything else as above.

             -  Time to peak strain: the interval from onset of the QRS to peak negative strain
                throughout the cardiac cycle, including postsystolic shortening. The region of
                interest (ROI) (6 x 12-mm oval shape) will be positioned in the middle of each
                segment. If negative strain will not be identified, the segment will be excluded
                from the calculation.

             -  Time to peak strain exceeding aortic valve closure (ExcT: exceeding time): the
                interval between the marker of aortic closure and the nadir of the strain tracing.
                ExcT will be considered 0 when the nadir of strain curve will not exceed aortic
                valve closure. Everything else as above.

           In addition to the time intervals described above, the triplane TSI display of LV
           electro-mechanical delays will be evaluated visually (VT-TSI) during the systolic
           ejection phase to identify a severe lateral wall delay, marked by the presence of red
           color on the lateral wall (alone or in association with other severely delayed

           Using the above described time intervals, the following DY indexes reported in the
           literature will be measured:

             -  Septal-lateral delay (cut-off value= 65 ms): maximum time delay between peak
                systolic velocities among four basal segments in 4 chamber and 2 chamber view.

             -  Anteroseptal-posterior delay (cut-off value= 65 ms): absolute time difference in
                time to peak systolic velocity, including the postejection period, between the
                basal inferolateral and basal anteroseptal segments.

             -  Standard deviation in time to peak systolic velocity in the 12 basal and mid
                segments using both the two-dimensional tissue Doppler (cut-off value= 33.6 ms) and
                the novel triplane TSI modality (Tv-SD index).

             -  Standard deviation in time to peak strain (cut-off value= 60 ms) among 12 basal and
                mid segments as a strain-derived dyssynchrony index (11).

             -  Overall time of strain exceeding aortic valve closure (cut-off value= 760 ms) as
                the sum of 12 basal and mid segments ExcTs (10).

           Also, the combined approach based on the Tv-SD index (cut-off value= 34.4 ms) and VT-TSI
           severe lateral wall delay will be tested as described by Yu et al.

           RT3DE For each of the 16 LV segment, the time taken to reach the minimum regional volume
           will be measured and expressed as a percentage of the cardiac cycle. Then, the systolic
           dyssynchrony index (cut-off value= 8.3%) will be calculated as the standard deviation in
           time to minimum regional volume.

           Speckle-tracking analysis For each of the 6 segments of the mid-ventricle short-axis
           view, the time to peak radial strain will be measured. Then, the radial strain DYS
           (cut-off value= 130 ms) index will be calculated as the difference between earliest and
           latest time to peak strain.

           Echo core and peripheral laboratory. All investigators must obtain the approval of the
           core laboratory before participating in the study by sending a test CD-ROM of adequate
           quality to the core laboratory. The core laboratory will be located in Udine (L.P.
           Badano). A number of ultrasound images and tracings will be read in 2 peripheral
           laboratories to test the interlaboratory reproducibility for evaluation of dyssynchrony

           Optimization of atrio-ventricular delay will be performed at pre-discharge using Doppler
           echocardiography of transmitral flow to provide the maximum LV filling time without
           compromising cardiac resynchronization.

           Statistical analysis plan.

             -  Descriptive statistics. Continuous variables will be described as mean and standard
                deviation and categorical variables as counts and percentages.

             -  Statistical analysis: generality. The analysis for the continuous variables will be
                conducted by standard methods, unless there is evidence of important deviation from
                assumptions of normality, in which case non-parametric "bootstrap" methods will be
                used to generate confidence intervals. A two-sided p-value<0.05 will be considered
                statistically significant.

                1) Evaluation of feasibility and reproducibility of DYS indexes

             -  Feasibility. Feasibility is defined for each DYS index by the number of patients in
                whom the index was actually measured or calculated relative to the number of
                patients in whom the measure or calculation was attempted. Feasibility will be
                evaluated separately in normals and in patients.

             -  Measurements of DYS indexes will be repeated in 15 baseline normal studies and 15
                baseline patient studies by the same and a second observer at least one week after
                the first assessment in the core laboratory to test intra and interobserver
                variability. The same normal and patient studies will be read in two peripheral
                laboratories to test the interlaboratory variability. All observers will be unaware
                of the patients' characteristics, including ECG data. The Lin correlation
                coefficient and the Bland-Altman limits of agreement (LOA) will be used to evaluate
                intraobserver, interobserver and interlaboratory variabilities.

             -  To evaluate the strength of the association between dyssynchrony indexes values at
                baseline both in normals and in patients, the Pearson R and its 95% confidence
                interval (95% C.I.) will be computed.

                2) Evaluation of the effects of CRT

             -  Variations over time. A paired Student t test or an exact symmetry homogeneity test
                will be used to compare baseline and 3-month continuous and categorical values,

                3) Evaluation of the predictive value of the dyssynchrony indexes

             -  Association with CRT response and power analysis. The association between baseline
                dyssynchrony indexes, considered as continuous variables, and CRT response after 3
                months will be assessed by means of a logistic model. With the available sample
                size and an alpha of 5%, the power for detecting the observed association of the
                dyssynchrony indexes with CRT response is computed to 80% for each parameter.

             -  Association with CRT response based on DYS cut-off values. DYS parameters will also
                be dichotomized according to the pre-specified cut-off values derived from previous
                reports (see above). Model performances will be empirically compared through the c
                statistics for the discriminating ability (corresponding to the model based area
                under the ROC curve: the closer to 1, the better the model). Sensitivity and
                specificity of the dichotomized dyssynchrony parameters with respect to response
                will be computed.

             -  Association with echocardiographic changes. The association of baseline
                dyssynchrony indexes on a continuous scale with the relative changes in
                echocardiographic EF and ESV after 3 months of CRT will be assessed by means of
                Pearson R.

Study Type


Primary Outcome

Prediction of the combined end-point defined as NYHA class improvement by at least one grade and echocardiographic left ventricular end-systolic volume decrease by at least 10% with respect to baseline (variations are considered as relative values);

Secondary Outcome

 Feasibility and repeatibility of echocardiographic indexes of intraventricular dyssynchrony


Chronic Heart Failure

Study Arms / Comparison Groups

 1 Heart Failure
Description:  216 consecutive consenting patients with refractory heart failure candidate to cardiac resynchronization therapy by clinical and electrocardiographic criteria


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

March 2008

Completion Date

March 2009

Eligibility Criteria

        Inclusion Criteria:

          -  Age > 18 years.

          -  Sinus rhythm.

          -  Chronic heart failure (>6 weeks duration) refractory to maximized drug therapy.

          -  NYHA class III-IV.

          -  LV ejection fraction less than 35% by RT3DE.

          -  Indexed LV end-diastolic diameter >3.2 cm/m2 by 2D echocardiography and/or indexed
             end-diastolic volume >75 ml/m2 by 3D echocardiography.

        Exclusion Criteria:

          -  Hypertrophic, restrictive, obstructive cardiomyopathy.

          -  Primitive and hemodynamically significant valve disease (defined as valvular stenosis
             greater than mild, and 3+ or 4+/4+ valvular regurgitations).

          -  Constrictive pericarditis.

          -  Primitive pulmonary hypertension.

          -  Uncorrected congential heart disease.

          -  Patients candidate to heart surgery.

          -  Patients with acute myocardial infarction, severe unstable angina and stroke that
             occurred within 6 weeks prior the study enrollment.

          -  Patients with life expectation <1 year due to disease unrelated to the heart failure.

          -  Pregnant women.

          -  Refusal to give the informed consent.




18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Luigi P. Badano, M.D., +39 0432 554557, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Study Sponsor

Italian Society of Cardiology

Study Sponsor

Luigi P. Badano, M.D., Principal Investigator, Ospedale Universitario di Udine

Verification Date

March 2008