Results of the PROspective MInnesota Study of ECHO/TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) Study

Journal of Cardiac Failure Vol. - No. - 2009

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Results of the PROspective MInnesota Study of ECHO/TDI inCardiac Resynchronization Therapy (PROMISE-CRT) Study

ALAN J. BANK, MD,1,2,4 CHRISTOPHER L. KAUFMAN, PhD,2 AARON S. KELLY, PhD,2,4 KEVIN V. BURNS, BS,2 STUARTW. ADLER, MD,2 TOM S. RECTOR, PhD,3,4 STEVEN R. GOLDSMITH, MD,1,4 MARIA-TERESA P. OLIVARI, MD,1 CHUEN TANG,

MD,1 LINDA NELSON, RN,2 AND ANDREA METZIG, MA,2

ON BEHALF OF THE PROMISE-CRT INVESTIGATORS

Minneapolis, Minnesota

From the 1Minnta; 2The St. Paul Hical Center and 4U

Manuscript receDecember 12, 200

CorrespondenceSmith Avenue, #4651-233-5080. E-

Supported by aDrs Bank, Kauf

grant support fromrently an employeof interest.

1071-9164/$ - s� 2009 Elseviedoi:10.1016/j.ca

ABSTRACT

Background: Retrospective single-center studies have shown that measures of mechanical dyssynchronybefore cardiac resynchronization therapy (CRT), or acute changes after CRT, predict response better thanQRS duration. The Prospective Minnesota Study of Echocardiographic/TDI in Cardiac ResynchronizationTherapy (PROMISE-CRT) study was a prospective multicenter study designed to determine whether acute(1 week) changes in mechanical dyssynchrony were associated with response to CRT.Methods and Results: Nine Minnesota Heart Failure Consortium centers enrolled 71 patients withstandard indications for CRT. Left ventricular (LV) size, function, and mechanical dyssynchrony (echocar-diography [ECHO], tissue Doppler imaging [TDI], speckle-tracking echocardiography [STE]) as well as6-minute walk distance and Minnesota Living with Heart Failure Questionnaire scores were measured atbaseline and 3 and 6 months after CRT. Acute change in mechanical dyssynchrony was not associated withclinical response to CRT. Acute change in STE radial dyssynchrony explained 73% of the individual var-iation in reverse remodeling. Baseline measures of mechanical dyssynchrony were associated with reverseremodeling (but not clinical) response, with 4 measures each explaining 12% to 30% of individual vari-ation.Conclusions: Acute changes in radial mechanical dyssynchrony, as measured by STE, and other baselinemechanical dyssynchrony measures were associated with CRT reverse remodeling. These data support thehypothesis that acute improvement in LV mechanical dyssynchrony is an important mechanism contrib-uting to LV reverse remodeling with CRT. (J Cardiac Fail 2009;-:1e9)Key Words: heart failure, pacemakers, echocardiography, reverse remodeling.

Cardiac resynchronization therapy (CRT) improvessymptoms, functional status, ventricular size and function,hospitalization rate, and mortality in patients with advancedheart failure.1e4 However, approximately 25% to 30% of

esota Heart Failure Consortium, Minneapolis, Minneso-eart Clinic, St. Paul, Minnesota; 3Minneapolis VA Med-niversity of Minnesota, Minneapolis, Minnesota.ived November 24, 2008; revised manuscript received8; revised manuscript accepted December 17, 2008.to: Alan J. Bank, MD, St. Paul Heart Clinic, 225 N.

00, St. Paul, MN 55102. Phone: 651-726-6767; Fax:mail: [email protected] from Guidant Corporation (now Boston Scientific).man, Kelly, and Adler receive honoraria and/or research

Medtronic and Boston Scientific. Linda Nelson is cur-e at Medtronic, Inc. All other authors report no conflict

ee front matterr Inc. All rights reserved.rdfail.2008.12.009

1

patients who meet standard criteria for CRT fail to derivesubstantial benefit. One potential explanation is that electri-cal dyssynchrony, as measured by QRS duration, ratherthan mechanical dyssynchrony, has been used as a majorcriterion for receiving a CRT device. Several retrospectivestudies have shown that, as compared with QRS duration,preimplant tissue Doppler imaging (TDI)5e7 or speckletracking echocardiography (STE)8e10 indices of mechani-cal dyssynchrony have superior sensitivity and specificityfor identifying patients who benefit. The only prospectivemulticenter trial examining preimplant echocardiographic/TDI measures of mechanical dyssynchrony failed to showclinically significant sensitivity and specificity for predict-ing response to CRT.11

Previous retrospective analyses have shown that acute re-synchronization of LV mechanical dyssynchrony is associ-ated with LV reverse remodeling12 and long-term clinicalresponse.13 However, no prospective studies have examinedthe relationship between acute resynchronization and

mailto:[email protected]

2 Journal of Cardiac Failure Vol. - No. - - 2009

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response to CRT. Therefore, the purpose of the ProspectiveMinnesota Study of Echocardiographic/TDI in CardiacResynchronization Therapy (PROMISE-CRT) study wasto assess the relationship between acute changes in me-chanical dyssynchrony, as measured by STE and TDI, andresponse to CRT in patients with heart failure who met stan-dard criteria for this therapy.

Methods

Study Design

The PROMISE-CRT study was a multicenter observational co-hort study designed to test the primary hypothesis that acutechanges in echocardiographic/TDI measures of left ventricular(LV) mechanical dyssynchrony would correlate with clinical re-sponse as measured by the 6-minute walk test (6MWT) and theMinnesota Living with Heart Failure Questionnaire (MLHFQ) af-ter 3 months of CRT. The secondary hypothesis was that acutechanges in echocardiographic/TDI measures of LV mechanicaldyssynchrony would correlate with reverse remodeling responsesas measured by change in LV end-systolic volume (LVESV) after6 months of CRT.

Eligibility criteria were based on standard indications for CRT(LV ejection fraction #35%, New York Heart Association(NYHA) Class III or IV symptoms of heart failure, and QRS du-ration $120 ms). Patients were required to be stable on optimalmedical therapy and in sinus rhythm with a heart rate $50 beatsper minute. Exclusion criteria included advanced renal disease(Cr O 3.5), recent (within 30 days) myocardial infarction, unsta-ble angina, or coronary revascularization procedure, previouspacemaker or CRT, primary valvular heart disease, dyspneafrom lung disease, inability to perform a 6MWT, or a life expec-tancy of less than 6 months.

Device Implant

Patients were implanted with the Guidant models H170, H177,H210 (Guidant Corp, St. Paul, MN) and Medtronic model 7304(Medtronic, Inc, Minneapolis, MN) using standard procedures.Right ventricular and LV lead position and postimplant device set-tings were based on the implanting physician’s preference andavailable coronary veins. The LV lead was placed in a lateral orposterolateral position whenever possible. The implanters didnot have any knowledge of mechanical dyssynchrony to influencelead placement. The AV delay was programmed using the formuladescribed and used in the Comparison of Medical Therapy, Pac-ing, and Defibrillation in Heart Failure (ie, COMPANION) study.4

AV and/or VV optimization was not performed because of the dif-ficulty of performing this consistently at all sites and the lack ofgeneral consensus on the best methodology.

Measurement of Clinical Response

Clinical response was assessed by the MLHFQ and the 6MWT.The NYHA functional Class was also determined. Clinical assess-ments were made before CRT and at 3- and 6-month follow-upvisits by the same individual at each site. These individualswere blinded to the echocardiographic data.

Echocardiography and Measurement of MechanicalDyssynchrony

Echocardiographic information was collected using the samecommercially available equipment (Vivid 7, GE Vingmed

Ultrasound, Milwaukee, WI) for all patients. Images were ob-tained in end-expiratory apnea using a 3.5-MHz transducer atdepths of 12 to 20 cm. Mitral regurgitation (MR) was assessed us-ing a semiquantitative visual ranking system (0 5 none through6 5 severe MR). For TDI, ultrasound settings were optimized toprovide maximum frame rates (80 to 135 frames/second, velocityrange of 616 cm/second). Digital routine gray-scale 2-dimen-sional and TDI cine loops from 3 consecutive beats were obtainedfrom apical 4-chamber, 2-chamber, long-axis, and mid-LV short-axis views. Pulsed Doppler echocardiography of transmitral andtransaortic blood flow was recorded for a minimum of 5 beatsfor determining timing of valve opening and closure.

All echocardiographic analysis was performed at a single corelaboratory (St Paul Heart Clinic Echo Core Laboratory). One indi-vidual (K.V.B.) performed the 2-dimensional and TDI analysesand a second individual (C.L.K.) performed the STE analysis. Im-ages were analyzed offline with commercially available software(Echopac 6.3.6, GE Vingmed Ultrasound). LVEF was calculatedusing the biplane Simpson’s method. Sphericity index was calcu-lated as the ratio of LV length to width at end-diastole. TDI wasused to determine LV longitudinal displacement (tissue tracking,TT), velocity (tissue velocity imaging, TVI) and dyssynchrony.Sample volumes for both modalities were the same (8� 8 mm).STE analyses were performed on mid-LV (papillary muscle level)short axis images as described by others.9 Markers were placedalong the LV endocardial border and the LV was divided into 6standard segments (anteroseptum, anterior, lateral, posterior, infe-rior, and septum). An algorithm within the software tracksspeckles created by the ultrasonic interference pattern of the myo-cardium. The software provides a yes/no indication of adequatemyocardial segment tracking. Only patients with adequate track-ing for all segments were included in the analysis. Of the 64patients included in the final analysis, 43 patients (67%) had ade-quate analyzable images for STE analysis of both the preimplantand 1-week echocardiograms. The 43 patients with adequateimages were no different with respect to age, LVEF, LVESV, orlongitudinal dyssynchrony than the 21 patients without adequateimages for STE.

To characterize LV longitudinal myocardial function, systolicdisplacement at aortic valve closure and peak systolic velocity(PSV; peak velocity during systole) were identified for 6 basaland 6 mid-LV segments. Segmental values were averaged to de-rive 2 separate longitudinal function scores. Global systolic con-traction amplitude was calculated as the average longitudinaldisplacement of 12 segments.5 Mean PSV (PSVmean) was calcu-lated as the average velocity of 12 segments.7 Radial LV systolicfunction was calculated as the average strain of 6 segments. Exam-ples of the curves generated for the three main TDI/STE modali-ties are shown in Fig. 1.

LV mechanical dyssynchrony was evaluated using multiple pre-viously published, and a few novel, measures (Table 1). Mitralvalve closure was used as the zero reference point for all timingevents because it marks the end of mechanical diastole and is in-dependent of QRS morphology or ECG lead placement. Repro-ducibility indices from 15 randomly selected heart failurepatients for the major TDI and STE measurements are summa-rized in Table 2.

Determination of Lead Position

Biplane radiographs were reviewed by a single physician. Rightventricular lead location was described as either high, mid, or

Fig. 1. Tissue tracking, tissue velocity, and speckle tracking mea-sures of mechanical dyssynchrony. Tissue Doppler Imaging (TDI)curves in the longitudinal plane as either displacement (A) or ve-locity (B). (C) Speckle-tracking echocardiography (STE) radialstrain curves. All 3 modalities indicate a delayed lateral or poste-rior wall.

PROMISE-CRT Study Results � Bank et al 3

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apical septum. LV lead location was categorized as anterior (0 to45 degrees), lateral (45 to 135 degrees), or posterior (135 to 180degrees) and as basal, mid, or apical.

Data Analysis

Patient characteristics and responses to CRT are described asmeans and standard deviations or percentages. Repeated measure-ments during follow-up were compared by analysis of varianceand post hoc paired t-tests using the Bonferroni correction for 2comparisons to baseline values. Friedman’s rank-based analysisof variance and the Wilcoxon signed-ranks tests were used forordinal variables.

The primary study objective was to test for associationsbetween changes in measures of mechanical dyssynchrony andresponses to CRT. Changes in 6MWT distance, and the MLHFQscores at 3 months and changes in LVESV at 6 months were theprimary and secondary endpoints. These longitudinal measureswere analyzed using growth curve models with random coeffi-cients representing individual variation in baseline values and re-sponses to CRT using xtmixed in Stata software, version 9.0. TheLVESV data were fit to a linear growth model where the estimatedslope (change in ESV per 6 months) represents the response toCRT. The MLHFQ scores and 6MWT data were fit using a growthmodel with dummy variables representing the changes from base-line to 3 months and from 3 months to 6 months. Variation in theestimated individual responses was hierarchically modeled as themean value plus a random parameter for individual variation aboutthe mean. Measures of cardiac dyssynchrony were then enteredinto the second level models of individual variation in interceptsand slopes and tested for significance using Wald tests. EstimatedP values are cited without adjustment for multiple comparisons.Relationships between individual responses to CRT and echocar-diographic variables are summarized as regression coefficientswith 95% confidence intervals that indicate the estimated differ-ence in response per 1-unit increase in an explanatory variable.Whenever a difference of 1 unit was implausibly large or smallthe regression coefficients were rescaled to provide more mean-ingful values. The percent reduction in the variance of the esti-mated random individual effects was calculated as an indicatorof how much of the individual variation in responses was relatedto an explanatory variable. The covariance (correlation) betweenindividual random intercept and response effects was includedin the model and provides an assessment of how individual re-sponses were related to initial values. The authors had full accessto the data and take responsibility for its integrity. All authors haveread and agreed to the manuscript as written.

Results

Patient Characteristics

There were 71 patients enrolled in the study. Twopatients were withdrawn because of pocket infection and2 from lead dislodgement. One implant was unsuccessful,1 patient voluntarily withdrew, and 1 patient died duringthe 6-month follow-up period. Therefore, 64 patients com-pleted the study and were included in the final analyses.

Preimplant patient characteristics are summarized inTable 3. On average, the subjects exhibited substantial elec-trical dyssynchrony as measured by the QRS duration.More than 90% of patients were receiving b-blocker ther-apy and either an angiotensin-converting enzyme inhibitoror an angiotensin II receptor blocker.

Table 1. Measures of Mechanical Dyssynchrony

Variable Definition

Standard echocardiographyIVCT Time between

mitral valve closureand aortic valve opening

AV-PV delay Time delaybetween aortic valve

opening and pulmonicvalve opening

(ie, interventricular dyssynchrony measure)Tissue trackingTTS-L delay Time delay

between peak displacementof septal and lateral wall

No. wallswith DLC

Number of segments(out of 12) with

peak longitudinal displacementoccurring after aortic

valve closureTotal time DLC Time (ms) from

aortic valve closureto peak longitudinal

displacement summed for eachof 12 possible segments

No. wallswith DOA

Number of segmentsdisplaying an initial

negative displacement $0.5 mmSD TT-12 Standard deviation

of time to peakdisplacement of 6 basaland 6 mid-LV segments

Tissue velocity imagingTVIS-L delay Time delay

between peak systolic(between aortic valve opening and closure)

velocity of septaland lateral wall

SD TVI-12 Standard deviationof time to peak

systolic velocity of 6 basaland 6 mid-LV

segments(ie, Yu index or Ts-SD)

Speckle trackingSD Rad-6 Standard deviation

of time to peakradial strain of 6 mid-LV

short-axis segments

Table 2. Reproducibility of Dyssynchrony Variables(n 5 15)

Difference Mean 6 SD Correlation Intraclass

Intraobserver variabilityIVCT (ms) 2 6 30 0.56AV-PV delay (ms) �1 6 5 0.97TTS-L delay (ms) 5 6 21 0.92TT: no. walls

with DLC0.3 6 2.3 0.89

TT: no. wallswith DOA

0.3 6 1.0 0.40

SD TT-12 (ms) 3 6 22 0.88TVIS-L delay (ms) �7 6 34 0.68SD TVI-12 (ms) �0.7 6 14 0.77SD Rad-6 �0.4 6 7.4 0.97Interobserver variabilityIVCT (ms) �16 6 34 0.36AV-PV delay (ms) �0.8 6 8 0.95TTS-L delay (ms) 4 6 32 0.86TT: no. walls

with DLC0.3 6 2.2 0.85

TT: no. wallswith DOA

0.3 6 1.0 0.82

SD TT-12 (ms) �7 6 18 0.90TVIS-L delay (ms) �11 6 35 0.53SD TVI-12 (ms) �6 6 14 0.74SD Rad-6 �0.7 6 9.7 0.96

IVCT, isovolumic contraction time; AV-PV, aortic value-pulmonic valve;DLC, delayed longitudinal contraction; DOA, delayed onset activation;TT, tissue tracking.

Data are presented as mean 6 standard deviation. Abbreviations aresame as Table 1.


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Clinical Response

On average, the MLHFQ score improved significantlyfrom 46 6 20 to 29 6 17 over the first 3 months (P !.01), then remained stable (31 6 21) at 6 months. The6MWT averaged 349 6 99 meters at baseline and increasedsignificantly to 381 6 94 meters at 3 months (P ! .01) andwas maintained at 382 6 107 meters after 6 months. All but1 patient (NYHA Class IV) was classified as NYHA ClassIII at baseline. The NYHA classification improved signifi-cantly (P ! .05) after 3 months (47% Class II, 7% ClassI) and 6 months (32% Class II, 14% Class I). No subjectdeteriorated to NYHA Class IV.

Echocardiographic Response

Table 4 summarizes echocardiographic variables at base-line and during follow-up. At baseline, LVEF was 28 6 7%.

Measures of LV systolic function and mechanical dyssyn-chrony in the longitudinal and radial planes were abnormal,consistent with moderate-to-severe heart failure.

Overall, as compared with baseline, LVEF and LV vol-umes improved significantly at 3 and 6 months. Figure 2shows the overall mean and individual estimated changesin the ESV end point over the 6-month follow-up period.Mitral regurgitation was significantly reduced at 1 weekand remained reduced at 3 and 6 months. The TDI-basedindices of longitudinal mechanical dyssynchrony were notsignificantly better at any time over the 6-month follow-up period. However, radial dyssynchrony as determinedby STE, tended to be reduced after 1 week with continuedimprovement resulting in a significant (P ! .05) reductionat 6 months as compared with baseline. Isovolumic contrac-tion time and interventricular dyssynchrony were signifi-cantly improved within 1 week and remained sothroughout follow-up.

Responses in Relation to Mechanical Dyssynchrony

Neither the baseline nor 1-week changes in mechanicaldyssynchrony were related to the individual variation inthe clinical response variables (6MWT or MLHFQ).

Table 5 shows the univariate 1-week changes in variablesand baseline variables that were significantly related to theindividual variation in LVESV response to CRT. Thechange in radial dyssynchrony (SD Rad-6) at 1 week ex-plained 73% of the individual variation in LVESV response

Table 3. Preimplant Clinical Characteristics of StudyCohort

Variable

Male/female (n) 49/15Age (y) 67 6 10HF ischemic etiology (n, %) 40 (63%)HF duration (y) 5.6 6 4.8QRS duration (ms) 155 6 25Diuretic therapy (n, %) 55 (86%)ACE/ARB therapy (n, %) 59 (92%)b-Blocker therapy (n, %) 59 (92%)6-minute walk distance (m) 349 6 99MLHFQ score 45 6 20

HF, heart failure; ACE, angiotensin-converting enzyme inhibitor; ARB,angiotensin II receptor blocker; MLHFQ, Minnesota Living with HeartFailure Questionnaire.

Data are mean 6 standard deviation.


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to CRT. The estimated SD Rad-6 regression coefficient of0.36 mL/6 months indicates that a patient with a 20-ms de-crease in SD RAD-6 at 1 week (approximately the averagechange observed in this study) would be expected to havea 7.2 mL greater decrease in ESV over 6 months. Figure 3depicts a scatter plot of the changes in radial dyssynchronyafter 1 week and the estimated change in ESV at 6 months.Of the 27 patients who had an improvement in radial dys-synchrony 1 week post-CRT, 18 (67%) had an estimateddecrease in LVESV of O15 mL (positive predictive value)and only 1 (3.7%) had an increase in LVESV. Of the 16 pa-tients who had a worsening of radial dyssynchrony 1 weekafter CRT, 11 (69%) had an estimated decrease in LVESVof !15 mL (negative predictive value).

Decreases in time between mitral valve closure and aor-tic valve opening (IVCT) after 1 week were also signifi-cantly related to the individual variation in LVESVresponse, explaining 13% of the individual variation. In-creases in the sphericity index (an increase indicatesa less spherical LV) were also associated with decreasesin LVESV.

Table 4. Echocardiograp

Variable Pre-CRT

EF (%) 28 6 7LVEDV (mL) 170 6 69 1LVESV (mL) 125 6 60 1Moderate or worse MR (%) 30%GSCS (mm) 4.7 6 9.1PSVmean (cm/s) 2.8 6 0.9Radial strain (%) 15.7 6 11.0 1IVCT (ms) 96 6 46AV-PV (ms) 29 6 39TTS-L Delay (ms) 33 6 91SD TT-12 (ms) 78 6 33TVIS-L Delay (ms) 34 6 75SD TVI-12 (ms) 49 6 20SD Rad-6 (ms) 65 6 56

Data are presented as mean 6 standard deviation unless otherwise noted.Abbreviations are same as Table 1.*p ! 0.05 as compared to baseline after Bonferroni adjustment for multiple c

Four baseline measures of mechanical dyssynchronywere also associated with LVESV response to CRT: SDRad-6, TTS-L delay, TVIS-L delay, and IVCT. These vari-ables each explained 12% to 30% of the individual varia-tion in LVESV changes to CRT. The estimated regressioncoefficient for TTS-L delay was e0.14, indicating a patientwith a 50 ms greater baseline TTS-L delay had a 7 mLgreater decrease in ESV over 6 months. Figure 4 showsbaseline radial dyssynchrony measurements (n 5 51) ver-sus estimated change in LVESV over 6 months. We dividedpatients into responders and nonresponders using a cutoffvalue of 15 mL change in LVESV. We chose a cutoff valuefor SD Rad-6 of 55 ms based on a previous retrospectivestudy performed in our laboratory.14 Of the 24 patientswith SD Rad-6 O 55 ms, 18 (75%) had a decrease inLVESV O15 mL (positive predictive value). Of the 27 pa-tients with SD Rad-6 ! 55 ms, 16 (59%) had a decrease inLVESV !15 mL (negative predictive value).

Other baseline variables that were associated with im-provements in LVESV included younger age, the absenceof ischemic heart disease, lower EF, a wider QRS, andlower sphericity index (more spherical LV). BaselineQRS duration did not significantly correlate with any ofthe 4 baseline measures of mechanical dyssynchrony thatwere significant predictors of LVESV response. The base-line LVESV was also related to the changes in LVESV(r 5�0.36).

Lead Position

The LV lead was placed in a lateral position in 57/64(89%) patients. Eleven of these patients had a basal LVlead location, 34 a mid-LV lead location, and 12 an apicalLV lead location. Four patients had an anterior and 3 hada posterior lead position. Approximately 50% of patientswith LV leads in each of the lateral positions or in the an-terior positions had a decrease in LVESV O15 mL. Noneof the 3 patients with a posterior lead location had anLVESV response of this magnitude.

hic Measurements

1 Week 3 Month 6 Month

30 6 9 33 6 8* 34 6 8*69 6 68 159 6 64* 154 6 62*21 6 63 110 6 58* 105 6 57*14%* 11%* 16%*

4.5 6 2.2 4.8 6 2.2 4.8 6 2.12.9 6 1.2 3.2 6 1.9 3.1 6 1.47.6 6 10.6 21.1 6 14.6 22.2 6 14.3*73 6 29* 73 6 29* 71 6 29*15 6 24* 15 6 24* 14 6 25*48 6 89 38 6 77 48 6 8378 6 31 73 6 29 74 6 2521 6 63 26 6 66 37 6 6952 6 36 47 6 18 48 6 1944 6 38 52 6 45 40 6 40*

omparisons.

Fig. 2. Estimated mean and individual change in left ventricularend-systolic volume (ESV) over 6 months. Individual estimatedESV lines are shown with mean curve in red. Measures of dyssyn-chrony were subsequently related to the variation in responseamong the individual subjects.


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Discussion

This is the first multicenter prospective study to assessthe relationship between acute changes in echocardio-graphic/TDI measures of mechanical dyssynchrony andclinical and remodeling responses to CRT. We did notfind significant associations between acute changes or base-line values of measures of mechanical dyssynchrony andclinical responses to CRT as measured by the 6MWT orthe MLHFQ. The acute improvement in radial dyssyn-chrony measured by STE explained a large portion (73%)of the individual variance in reverse remodeling response

Table 5. Variables Significantly Related

Variable n Regression Coefficient*

Mechanical dyssynchronyAcute change (1 week)IVCT (ms) 60 0.18 (0.02 to 0.36)SD Rad-6 (ms) 43 0.36 (0.22 to 0.50)BaselineIVCT (ms) 63 �0.24 (e0.40 to e0TTS-L delay (ms) 63 �0.14 (e0.24 to e0TVIS-L delay (ms) 63 �0.12 (e0.24 to e0SD Rad-6 (ms) 54 �0.20 (e0.36 to e0Clinical/echocardiogramBaselineAge (y) 64 0.92 (0.10 to 0.1.7IHD 64 17.8 (0.72 to 35.0)QRS (ms) 64 �0.32 (e0.54 to e0EF (%) 64 1.36 (0.20 to 2.5)

IHD, ischemic heart disease; AVC, aortic valve closure; EF, ejection fraction; Lplitude; TDI, tissue Doppler Imaging; TT, tissue tracking; TVI, tissue velocity imawith Heart Failure Questionnaire; 6MWT, 6-minute walk test.

*Estimated milliliter change in LVESV over 6 months for 1 unit change in ex

to CRT as measured by changes in LVESV over 6 months.Four measures of baseline mechanical dyssynchrony (SDRad-6, TTS-L delay, TVIS-L delay, and IVCT) were also as-sociated with increased reverse remodeling responses toCRT.

Baseline Dyssynchrony and Response to CRT

All patients enrolled in this study met standard indica-tions for CRT based on the large randomized clinical trialsof this therapy. The average clinical and echocardiographicresponses to CRT were consistent with that reported in pre-vious studies. We observed significant reductions in the ad-verse effect of heart failure on patients’ lives as measuredby the MLHFQ, improvements in physical function as mea-sured by the 6MWT, improvements in symptoms as mea-sured by the NYHA Class, and improvements in LVvolumes, EF, and mitral regurgitation. However, as is typi-cal, there was substantial individual variation about themean responses. We did not find any baseline or acutechanges in echocardiographic variables that were signifi-cantly associated with the clinical responses to CRT. Thiscould be a result of an insufficient number of subjects stud-ied given the noise in measurements, an inadequate dura-tion of follow-up or from placebo effects that can occurduring unblinded treatment with invasive devices. Interest-ingly, clinical response, unlike remodeling response, hasnot been shown to predict long-term survival after CRT.15

Four baseline measures of cardiac mechanical dyssyn-chrony were associated with the individual LVESV re-sponses to CRT. TTS-L delay explained nearly 30% ofindividual variation in LVESV response. TVIS-L delay ex-plained much less of the variation. In addition, the SDTVI-12, one of the measures most commonly used in retro-spective studies of CRT, was not associated with reverse re-modeling and did not improve significantly at any of the 3time points measured after CRT. Our findings related to us-ing the timing of peak systolic velocity curves as measures

to Estimated Change in LVESV

(95% CIs) Variance Explained P Value

12.9% .0572.8% !.001

.06) 20.0% .01

.06) 29.7% !.001

.01) 11.6% .04

.04) 21.8% .01

2) 14.4% .0316.4% .04

.08) 18.1% !.0112.6% .02

VESV, left ventricular end-systolic volume; SCA, systolic contraction am-ging; STE, speckle-tracking echocardiography; MLHFQ, Minnesota Living

planatory variable.

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1-Week Change in Radial Dyssynchrony

Est

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th C

hang

e in

LV

ESV

Fig. 3. Changes in radial dyssynchrony at 1 week after cardiac re-synchronization therapy vs. estimated 6-month change in left ven-tricular end-systolic volume.


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of dyssynchrony are consistent with those found in thePROSPECT study10 and are not surprising given the highintraobserver and interobserver (and interlaboratory) vari-ability found in the PROSPECT study and also in our study.The results of this study are also consistent with a recentstudy that showed a high prevalence of dyssynchrony innormal subjects using SD TVI-12.16

The baseline SD Rad-6 explained 21% of the individualvariation in LVESV response. In addition, a baseline SDRad-6 value of O55 ms was predictive of a O15 mLchange in LVESV with 75% accuracy (positive predictivevalue). This is the first prospective multicenter study tomeasure radial dyssynchrony with STE. Measures of radialstrain dyssynchrony have been studied in a retrospectivesingle-center study of 64 heart failure patients receivingCRT.9 Using time difference in peak septal-to-posteriorwall strain, the investigators showed that baseline radialdyssynchrony was associated with immediate improvementin stroke volume and long-term improvement in LVEF. Ra-dial dyssynchrony as measured by STE strain was associ-ated with reverse remodeling response to CRT in another

50 100 150 200 250

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Baseline Radial Dyssynchrony

Est

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hang

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ESV

Fig. 4. Baseline radial dyssynchrony vs. estimated 6-monthchange in left ventricular end-systolic volume.

study as well, and was more strongly correlated to this re-sponse than strain measured in the longitudinal or circum-ferential planes.8 Our laboratory has observed ina retrospective study of 70 consecutive CRT patients thatmeasurement of dyssynchrony using STE radial strainwas associated with LVESV response to CRT with a corre-lation coefficient of e0.51 between baseline dyssynchronyand change in LVESV.14 Assessment of radial strain bySTE may offer several advantages as a measure of mechan-ical dyssynchrony in patients with heart failure as comparedwith longitudinal TDI variables. The ability to discriminatenormal subjects from patients with heart failure with re-spect to mechanical dyssynchrony is greater using STEanalysis of radial dyssynchrony than using longitudinalTDI variables in our laboratory. This may be because cir-cumferential or short-axis myocardial mechanics becomeabnormal sooner, or to a greater extent, than longitudinalmechanics during the development of heart failure.17 TheSTE technique appears to have less intraobserver and inter-observer variability too. Among all the dyssynchrony vari-ables measured in our laboratory, SD Rad-6 had the highestintraclass correlation coefficient. The STE strain analysishas the additional advantages of not being dependent onDoppler angle and of assessing myocardial thickeningwith less chance of being influenced by either translationalmotion or tethering.

Acute Change Dyssynchrony and Remodeling

Several studies12,18,19 have described acute improve-ments in LV mechanical dyssynchrony with CRT. The larg-est of these12 analyzed 100 consecutive patients meetingstandard criteria for CRT at a single center with mechanicaldyssynchrony, defined as a $65 ms time delay among peaksystolic velocities of 4 basal LV walls in the longitudinalplane. The immediate reduction in LV longitudinal dyssyn-chrony was 65%, with a 69% reduction by 6 months. Wedid not show significant acute improvements in mechanicaldyssynchrony in the longitudinal plane. Our study differedfrom this retrospective study, in that we did not require lon-gitudinal mechanical dyssynchrony as an entrance criterion.However, patients in our study had significant baseline lon-gitudinal mechanical dyssynchrony. We demonstrateda 32% decrease in radial dyssynchrony by 1 week anda 38% decrease by 6 months after CRT. This improvementin radial mechanical dyssynchrony is likely a very impor-tant contributor to LV remodeling as it was associatedwith change in LVESV at 6 months and explained a highpercentage (73%) of the individual variation in LVESVresponse to CRT.

Clinical Applicability of Findings

The only other published prospective multicenter studyof mechanical dyssynchrony variables as predictors ofCRT response is the PROSPECT study.11 In this study, mul-tiple echocardiographic and TDI mechanical dyssynchronymeasures were analyzed. Some baseline measures


ARTICLE IN PRESS

demonstrated modest sensitivity and specificity for predict-ing clinical or remodeling response to CRT, but there washigh intraobserver, interobserver, and interlaboratory vari-ability in these measures. In clear contrast to a number ofsingle-center retrospective studies, no single measure ofmechanical dyssynchrony stood out as robust enough tobe recommended for clinical use in selecting patients forCRT. Our study design was similar to PROSPECT with re-spect to the entrance criteria, time course of follow-up, anduse of multiple dyssynchrony measures (many, but not all,the same as those in PROSPECT). As with the PROSPECTstudy, we also found significant variability in TVI and TTmeasures of longitudinal dyssynchrony. However, our studydiffered from PROSPECT in a number of important re-spects. PROMISE-CRT was a smaller study of 71 patientsperformed at 9 centers within a 250-mile radius, as com-pared with PROSPECT, which enrolled 498 patients across3 continents. We had a single core echocardiographic labo-ratory and used only 1 manufacturer as compared withPROSPECT, which used 3 core laboratories and a numberof different manufacturers of echocardiographic equipment.These differences likely accounted for the much higher per-centage of patients with analyzable echocardiographic lon-gitudinal dyssynchrony and LVESV data in our study (64/64, 100% vs. 286/498, 57%).

Our study was primarily designed as an association studylooking at acute changes in mechanical dyssynchronyvariables whereas PROSPECT only assessed baselinemechanical dyssynchrony measures. However, baselinemeasurements, not acute changes, are needed to help clini-cians select patients most likely to respond to CRT. Ourstudy, unlike PROSPECT, measured STE radial strain andfound both baseline and acute change measurements to beassociated with the individual extent of reverse remodelingas measured by LVESV. Clearly, there is a need to furtherrefine and define echocardiographic and TDI measures toreduce variability and improve the ability to apply this tech-nology for patient selection across a broad clinical spec-trum. At this time, the clinical decision to place a CRTdevice in a given patient may not be best based on a singlevariable, but rather on a number of clinical and laboratoryvariables (including measures of mechanical dyssynchrony)that each provide information regarding the likelihood ofsuccess. Because our data set was modest in size, we didnot attempt to develop or validate a prediction model to inte-grate the variables that were associated with response to CRT.

LV lead placement is thought to be an important factoraffecting response to CRT. We attempted to place the LVlead in a lateral or posterior position in all patients andwere successful in 60 of the 64 patients. We performed a de-tailed radiographic assessment of lead position in 2 planes.There was no specific lead location that was significantlybetter than any other location (approximately 50% remod-eling response rate) except that none of the 3 patientswith a posterior lead location had a O15 mL decrease inLVESV. It is hard to come to conclusions from these databecause of the modest sample size. In addition, we did

not attempt to determine the presence or location of scar tis-sue in this study. Scar tissue has been shown to influencethe CRT response20 and scar location may impact CRTresponse with respect to LV lead location.

Limitations

The mechanical dyssynchrony measures as well as theLVESV response measure are prone to measurement errorwith significant intraobserver and interobserver measure-ment noise. To try and minimize the variability in the me-chanical dyssynchrony measurements, we not only useda single echocardiographic machine, but we also providedextensive education and training to the technicians acquir-ing the echocardiographic data. The noise inherent in themeasurement of both the potential explanatory variable(mechanical dyssynchrony) and response variable (LVESV)can greatly attenuate observed associations based on a sin-gle follow-up assessment, and can mislead practitionersabout a patient’s true response to CRT. To address this is-sue, we prospectively designed a statistical approach thatwas different than the typical approach used previously.We estimated individual response to CRT not as a dichoto-mous variable with a single threshold value (eg, decrease inLVESV of O 15%), but rather as a slope, estimated fromdata collected at 4 time points (preimplant, 1 week, 3month, 6 month). By taking this statistical approach, andby acquiring data at several time points post-CRT, wewere able to average out noise in LVESV measurementsto test for associations between remodeling response andmechanical dyssynchrony.

Although this study was prospective and multicenter, itwas a relatively small study, with 64 patients completingthe study and included in the final analyses. Good qualityradial strain curves at both baseline and 1 week for assess-ment of mechanical dyssynchrony were obtained in only 43of 64 patients (67%). Although this was a limitation of thisstudy, STE is a relatively new methodology. More carefulattention to the acquisition of high quality 2-dimensionalshort axis images in our laboratory since this study wascompleted has resulted in acquisition of radial strain datasuitable for analysis in a significantly higher percentageof patients.

All patients in this study received CRT and there was norandomization to medical therapy or ability to blind the pa-tients or physicians with respect to treatment. Therefore,placebo effects or potential assessment biases cannot be ex-cluded. However, the major findings of this study related toechocardiographic measures of mechanical dyssynchrony,and all echocardiographic measurements were analyzed ina blinded fashion.

Conclusions

This multicenter, prospective study found a number of base-line clinical, standard echocardiographic, and mechanicaldyssynchrony variables that were associated with reverse


ARTICLE IN PRESS

remodeling, but not clinical response to CRT. The acute im-provement in STE-measured radial dyssynchrony explained73% of the individual variation in LVESV response. In addition,4 baseline measures of mechanical dyssynchrony explained12% to 30% of the individual remodeling response. Base lineradial dyssynchrony (SD Rad-6 O55ms) had a positive predic-tive value of 75 % for a significant reduction in LVESV. Thesedata support the hypothesis that improvement in mechanicaldyssynchrony is an important mechanism contributing to thebeneficial effects of CRT on LV reverse remodeling. Furtherprospective multicenter studies are needed to evaluate the useof radial dyssynchrony, and perhaps other measures of mechan-ical dyssynchrony, in identifying patients who have a high likeli-hood of responding to CRT.

Acknowledgments

The authors wish to acknowledge multiple Guidant (BostonScientific) research scientists for their assistance and supportduring this study.

Appendix

The following persons participated in the PROMISE-CRTStudy: Minnesota Heart Failure Consortium: S. Goldsmith, S.Mackedanz; Coordinating Site (St. Paul Heart Clinic, St. Paul,MN): J. Gilliam, J. Lundberg, A. Metzig, L. Nelson, A. Snyder;Investigators/Coordinators (St. Paul Heart Clinic, St. Paul,MN): S. Adler, A. Bank, D. Dunbar, G. Granrud, T. Schenk,L. Tindell, D. Underwood, P. Vatterott; (Minneapolis Heart In-stitute, Minneapolis, MN): A. Almquist, R. Burns, P. Demmer,C. Gornick, B. Katsiyiannis, C. Lawler, D. Melby, M. Olivari,C.Tang; (University of Wisconsin, Madison, WI): D. Kopp,P. Rahko, M. Washburn; (Regions Hospital, St. Paul, MN):B. Foster, J. Tunio, D. Zhu; (St. Mary’s Medical Center,Duluth, MN): P. Lipinski, N. Saleh; (Minnesota Heart Clinic,Edina, MN): J. Nemec, S. Sturm; (VA Medical Center, Minne-apolis, MN): I. Anand, K. Doerfler, S. Lectner; (Metro Cardiol-ogy, Coon Rapids, MN): S. Halvorsen, S. Hustead, M. Kramer;(Hennepin County Medical Center, Minneapolis, MN):M. Guerrero; ECHO Core Laboratory (St. Paul Heart Clinic,St. Paul, MN): K. Burns, C. Kaufman, A. Kelly; Statistician:T. Rector.

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Documents

Results of the PROspective MInnesota Study of ECHO/TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) Study