TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) Study

Journal of Cardiac Failure Vol. 15 No. 5 2009

Clinical Investigations

Results of the PROspective MInnesota Study of ECHO/TDI in Cardiac 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 STUART W. 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

ABSTRACT Background: Retrospective single-center studies have shown that measures of mechanical dyssynchrony before cardiac resynchronization therapy (CRT), or acute changes after CRT, predict response better than QRS duration. The Prospective Minnesota Study of Echocardiographic/TDI in Cardiac Resynchronization Therapy (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 with standard indications for CRT. Left ventricular (LV) size, function, and mechanical dyssynchrony (echocardiography [ECHO], tissue Doppler imaging [TDI], speckle-tracking echocardiography [STE]) as well as 6-minute walk distance and Minnesota Living with Heart Failure Questionnaire scores were measured at baseline and 3 and 6 months after CRT. Acute change in mechanical dyssynchrony was not associated with clinical response to CRT. Acute change in STE radial dyssynchrony explained 73% of the individual variation in reverse remodeling. Baseline measures of mechanical dyssynchrony were associated with reverse remodeling (but not clinical) response, with 4 measures each explaining 12% to 30% of individual variation. Conclusions: Acute changes in radial mechanical dyssynchrony, as measured by STE, and other baseline mechanical dyssynchrony measures were associated with CRT reverse remodeling. These data support the hypothesis that acute improvement in LV mechanical dyssynchrony is an important mechanism contributing to LV reverse remodeling with CRT. (J Cardiac Fail 2009;15:401e409) Key Words: Heart failure, pacemakers, echocardiography, reverse remodeling.

heart failure.1e4 However, approximately 25% to 30% of patients who meet standard criteria for CRT fail to derive substantial benefit. One potential explanation is that electrical dyssynchrony, as measured by QRS duration, rather than mechanical dyssynchrony, has been used as a major criterion for receiving a CRT device. Several retrospective studies have shown that, as compared with QRS duration, preimplant tissue Doppler imaging (TDI)5e7 or speckle tracking echocardiography (STE)8e10 indices of mechanical dyssynchrony have superior sensitivity and specificity for identifying patients who benefit. The only prospective multicenter trial examining preimplant echocardiographic/ TDI measures of mechanical dyssynchrony failed to show clinically significant sensitivity and specificity for predicting response to CRT.11 Previous retrospective analyses have shown that acute resynchronization of LV mechanical dyssynchrony is

Cardiac resynchronization therapy (CRT) improves symptoms, functional status, ventricular size and function, hospitalization rate, and mortality in patients with advanced From the 1Minnesota Heart Failure Consortium, Minneapolis, Minnesota; 2The St. Paul Heart Clinic, St. Paul, Minnesota; 3Minneapolis VA Medical Center and 4University of Minnesota, Minneapolis, Minnesota. Manuscript received November 24, 2008; revised manuscript received December 12, 2008; revised manuscript accepted December 17, 2008. Correspondence to: Alan J. Bank, MD, St. Paul Heart Clinic, 225 N. Smith Avenue, #400, St. Paul, MN 55102. Phone: 651-726-6767; Fax: 651-233-5080. E-mail: [email protected] Supported by a grant from Guidant Corporation (now Boston Scientific). Drs Bank, Kaufman, Kelly, and Adler receive honoraria and/or research grant support from Medtronic and Boston Scientific. Linda Nelson is currently an employee at Medtronic, Inc. All other authors report no conflict of interest. 1071-9164/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2008.12.009

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402 Journal of Cardiac Failure Vol. 15 No. 5 June 2009 associated with LV reverse remodeling12 and long-term clinical response.13 However, no prospective studies have examined the relationship between acute resynchronization and response to CRT. Therefore, the purpose of the Prospective Minnesota Study of Echocardiographic/TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) study was to assess the relationship between acute changes in mechanical dyssynchrony, as measured by STE and TDI, and response to CRT in patients with heart failure who met standard criteria for this therapy. Methods Study Design The PROMISE-CRT study was a multicenter observational cohort study designed to test the primary hypothesis that acute changes in echocardiographic/TDI measures of left ventricular (LV) mechanical dyssynchrony would correlate with clinical response as measured by the 6-minute walk test (6MWT) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) after 3 months of CRT. The secondary hypothesis was that acute changes in echocardiographic/TDI measures of LV mechanical dyssynchrony would correlate with reverse remodeling responses as measured by change in LV end-systolic volume (LVESV) after 6 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 duration $120 ms). Patients were required to be stable on optimal medical therapy and in sinus rhythm with a heart rate $50 beats per minute. Exclusion criteria included advanced renal disease (Cr O 3.5), recent (within 30 days) myocardial infarction, unstable angina, or coronary revascularization procedure, previous pacemaker or CRT, primary valvular heart disease, dyspnea from lung disease, inability to perform a 6MWT, or a life expectancy 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 settings were based on the implanting physician’s preference and available coronary veins. The LV lead was placed in a lateral or posterolateral position whenever possible. The implanters did not have any knowledge of mechanical dyssynchrony to influence lead placement. The AV delay was programmed using the formula described and used in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (ie, COMPANION) study.4 AV and/or VV optimization was not performed because of the difficulty of performing this consistently at all sites and the lack of general 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 assessments were made before CRT and at 3- and 6-month follow-up visits by the same individual at each site. These individuals were blinded to the echocardiographic data.

Echocardiography and Measurement of Mechanical Dyssynchrony Echocardiographic information was collected using the same commercially available equipment (Vivid 7, GE Vingmed Ultrasound, Milwaukee, WI) for all patients. Images were obtained in end-expiratory apnea using a 3.5-MHz transducer at depths of 12 to 20 cm. Mitral regurgitation (MR) was assessed using a semiquantitative visual ranking system (0 5 none through 6 5 severe MR). For TDI, ultrasound settings were optimized to provide maximum frame rates (80 to 135 frames/second, velocity range of 616 cm/second). Digital routine gray-scale 2-dimensional and TDI cine loops from 3 consecutive beats were obtained from apical 4-chamber, 2-chamber, long-axis, and mid-LV short-axis views. Pulsed Doppler echocardiography of transmitral and transaortic blood flow was recorded for a minimum of 5 beats for determining timing of valve opening and closure. All echocardiographic analysis was performed at a single core laboratory (St Paul Heart Clinic Echo Core Laboratory). One individual (K.V.B.) performed the 2-dimensional and TDI analyses and a second individual (C.L.K.) performed the STE analysis. Images were analyzed offline with commercially available software (Echopac 6.3.6, GE Vingmed Ultrasound). LVEF was calculated using the biplane Simpson’s method. Sphericity index was calculated as the ratio of LV length to width at end-diastole. TDI was used 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 placed along the LV endocardial border and the LV was divided into 6 standard segments (anteroseptum, anterior, lateral, posterior, inferior, and septum). An algorithm within the software tracks speckles created by the ultrasonic interference pattern of the myocardium. The software provides a yes/no indication of adequate myocardial segment tracking. Only patients with adequate tracking for all segments were included in the analysis. Of the 64 patients included in the final analysis, 43 patients (67%) had adequate analyzable images for STE analysis of both the preimplant and 1-week echocardiograms. The 43 patients with adequate images were no different with respect to age, LVEF, LVESV, or longitudinal dyssynchrony than the 21 patients without adequate images for STE. To characterize LV longitudinal myocardial function, systolic displacement at aortic valve closure and peak systolic velocity (PSV; peak velocity during systole) were identified for 6 basal and 6 mid-LV segments. Segmental values were averaged to derive 2 separate longitudinal function scores. Global systolic contraction amplitude was calculated as the average longitudinal displacement of 12 segments.5 Mean PSV (PSVmean) was calculated as the average velocity of 12 segments.7 Radial LV systolic function was calculated as the average strain of 6 segments. Examples of the curves generated for the three main TDI/STE modalities are shown in Fig. 1. LV mechanical dyssynchrony was evaluated using multiple previously published, and a few novel, measures (Table 1). Mitral valve closure was used as the zero reference point for all timing events because it marks the end of mechanical diastole and is independent of QRS morphology or ECG lead placement. Reproducibility indices from 15 randomly selected heart failure patients for the major TDI and STE measurements are summarized in Table 2.

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degrees), lateral (45 to 135 degrees), or posterior (135 to 180 degrees) and as basal, mid, or apical. Data Analysis Patient characteristics and responses to CRT are described as means and standard deviations or percentages. Repeated measurements during follow-up were compared by analysis of variance and post hoc paired t-tests using the Bonferroni correction for 2 comparisons to baseline values. Friedman’s rank-based analysis of variance and the Wilcoxon signed-ranks tests were used for ordinal variables. The primary study objective was to test for associations between changes in measures of mechanical dyssynchrony and responses to CRT. Changes in 6MWT distance, and the MLHFQ scores at 3 months and changes in LVESV at 6 months were the primary and secondary endpoints. These longitudinal measures were analyzed using growth curve models with random coefficients representing individual variation in baseline values and responses to CRT using xtmixed in Stata software, version 9.0. The LVESV data were fit to a linear growth model where the estimated slope (change in ESV per 6 months) represents the response to CRT. The MLHFQ scores and 6MWT data were fit using a growth model with dummy variables representing the changes from baseline to 3 months and from 3 months to 6 months. Variation in the estimated individual responses was hierarchically modeled as the mean value plus a random parameter for individual variation about the mean. Measures of cardiac dyssynchrony were then entered into the second level models of individual variation in intercepts and slopes and tested for significance using Wald tests. Estimated P values are cited without adjustment for multiple comparisons. Relationships between individual responses to CRT and echocardiographic variables are summarized as regression coefficients with 95% confidence intervals that indicate the estimated difference in response per 1-unit increase in an explanatory variable. Whenever a difference of 1 unit was implausibly large or small the regression coefficients were rescaled to provide more meaningful values. The percent reduction in the variance of the estimated random individual effects was calculated as an indicator of how much of the individual variation in responses was related to an explanatory variable. The covariance (correlation) between individual random intercept and response effects was included in the model and provides an assessment of how individual responses were related to initial values. The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.

Results Fig. 1. Tissue tracking, tissue velocity, and speckle tracking measures of mechanical dyssynchrony. Tissue Doppler Imaging (TDI) curves in the longitudinal plane as either displacement (A) or velocity (B). (C) Speckle-tracking echocardiography (STE) radial strain curves. All 3 modalities indicate a delayed lateral or posterior wall.

Determination of Lead Position Biplane radiographs were reviewed by a single physician. Right ventricular lead location was described as either high, mid, or apical septum. LV lead location was categorized as anterior (0 to 45

Patient Characteristics

There were 71 patients enrolled in the study. Two patients were withdrawn because of pocket infection and 2 from lead dislodgement. One implant was unsuccessful, 1 patient voluntarily withdrew, and 1 patient died during the 6-month follow-up period. Therefore, 64 patients completed the study and were included in the final analyses. Preimplant patient characteristics are summarized in Table 3. On average, the subjects exhibited substantial electrical dyssynchrony as measured by the QRS duration. More than 90% of patients were receiving b-blocker

404 Journal of Cardiac Failure Vol. 15 No. 5 June 2009 Table 1. Measures of Mechanical Dyssynchrony Variable

Definition

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

Standard echocardiography IVCT AV-PV delay

Tissue tracking TTS-L delay No. walls with DLC Total time DLC

No. walls with DOA SD TT-12 Tissue velocity imaging TVIS-L delay

SD TVI-12

Speckle tracking SD Rad-6

Time between mitral valve closure and aortic valve opening Time delay between aortic valve opening and pulmonic valve opening (ie, interventricular dyssynchrony measure) Time delay between peak displacement of septal and lateral wall Number of segments (out of 12) with peak longitudinal displacement occurring after aortic valve closure Time (ms) from aortic valve closure to peak longitudinal displacement summed for each of 12 possible segments Number of segments displaying an initial negative displacement $0.5 mm Standard deviation of time to peak displacement of 6 basal and 6 midLV segments Time delay between peak systolic (between aortic valve opening and closure) velocity of septal and lateral wall Standard deviation of time to peak systolic velocity of 6 basal and 6 mid-LV segments (ie, Yu index or Ts-SD) Standard deviation of time to peak radial strain of 6 mid-LV short-axis segments

therapy and either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Clinical Response

On average, the MLHFQ score improved significantly from 46 6 20 to 29 6 17 over the first 3 months (P ! .01), then remained stable (31 6 21) at 6 months. The 6MWT averaged 349 6 99 meters at baseline and increased significantly to 381 6 94 meters at 3 months (P ! .01) and was maintained at 382 6 107 meters after 6 months. All but 1 patient (NYHA Class IV) was classified as NYHA Class III at baseline. The NYHA classification improved significantly (P ! .05) after 3 months (47% Class II, 7% Class I) and 6 months (32% Class II, 14% Class I). No subject deteriorated to NYHA Class IV. Echocardiographic Response

Table 4 summarizes echocardiographic variables at baseline and during follow-up. At baseline, LVEF was 28 6 7%. Measures of LV systolic function and mechanical dyssynchrony in the longitudinal and radial planes were abnormal, consistent with moderate-to-severe heart failure. Overall, as compared with baseline, LVEF and LV volumes improved significantly at 3 and 6 months. Figure 2

Intraobserver variability IVCT (ms) AV-PV delay (ms) TTS-L delay (ms) TT: no. walls with DLC TT: no. walls with DOA SD TT-12 (ms) TVIS-L delay (ms) SD TVI-12 (ms) SD Rad-6 Interobserver variability IVCT (ms) AV-PV delay (ms) TTS-L delay (ms) TT: no. walls with DLC TT: no. walls with DOA SD TT-12 (ms) TVIS-L delay (ms) SD TVI-12 (ms) SD Rad-6

Mean 6 SD Correlation

Intraclass

2 6 30 165 5 6 21 0.3 6 2.3

0.56 0.97 0.92 0.89

0.3 6 1.0

0.40

3 6 22 7 6 34 0.7 6 14 0.4 6 7.4

0.88 0.68 0.77 0.97

16 6 34 0.8 6 8 4 6 32 0.3 6 2.2

0.36 0.95 0.86 0.85

0.3 6 1.0

0.82

7 6 18 11 6 35 6 6 14 0.7 6 9.7

0.90 0.53 0.74 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 are same as Table 1.

shows the overall mean and individual estimated changes in the ESV end point over the 6-month follow-up period. Mitral regurgitation was significantly reduced at 1 week and remained reduced at 3 and 6 months. The TDI-based indices of longitudinal mechanical dyssynchrony were not significantly better at any time over the 6-month followup period. However, radial dyssynchrony as determined by STE, tended to be reduced after 1 week with continued improvement resulting in a significant (P ! .05) reduction at 6 months as compared with baseline. Isovolumic contraction time and interventricular dyssynchrony were significantly improved within 1 week and remained so throughout follow-up. Responses in Relation to Mechanical Dyssynchrony

Neither the baseline nor 1-week changes in mechanical dyssynchrony were related to the individual variation in the clinical response variables (6MWT or MLHFQ). Table 5 shows the univariate 1-week changes in variables and baseline variables that were significantly related to the individual variation in LVESV response to CRT. The change in radial dyssynchrony (SD Rad-6) at 1 week explained 73% of the individual variation in LVESV response to CRT. The estimated SD Rad-6 regression coefficient of 0.36 mL/6 months indicates that a patient with a 20-ms decrease in SD RAD-6 at 1 week (approximately the average change observed in this study) would be expected to have a 7.2 mL greater decrease in ESV over 6 months. Figure 3

PROMISE-CRT Study Results Table 3. Preimplant Clinical Characteristics of Study Cohort Variable Male/female (n) Age (y) HF ischemic etiology (n, %) HF duration (y) QRS duration (ms) Diuretic therapy (n, %) ACE/ARB therapy (n, %) b-Blocker therapy (n, %) 6-minute walk distance (m) MLHFQ score

49/15 67 6 10 40 (63%) 5.6 6 4.8 155 6 25 55 (86%) 59 (92%) 59 (92%) 349 6 99 45 6 20

HF, heart failure; ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MLHFQ, Minnesota Living with Heart Failure Questionnaire. Data are mean 6 standard deviation.

depicts a scatter plot of the changes in radial dyssynchrony after 1 week and the estimated change in ESV at 6 months. Of the 27 patients who had an improvement in radial dyssynchrony 1 week post-CRT, 18 (67%) had an estimated decrease in LVESV of O15 mL (positive predictive value) and only 1 (3.7%) had an increase in LVESV. Of the 16 patients who had a worsening of radial dyssynchrony 1 week after CRT, 11 (69%) had an estimated decrease in LVESV of !15 mL (negative predictive value). Decreases in time between mitral valve closure and aortic valve opening (IVCT) after 1 week were also significantly related to the individual variation in LVESV response, explaining 13% of the individual variation. Increases in the sphericity index (an increase indicates a less spherical LV) were also associated with decreases in LVESV. Four baseline measures of mechanical dyssynchrony were also associated with LVESV response to CRT: SD Rad-6, TTS-L delay, TVIS-L delay, and IVCT. These variables each explained 12% to 30% of the individual variation in LVESV changes to CRT. The estimated regression coefficient for TTS-L delay was e0.14, indicating a patient



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with a 50 ms greater baseline TTS-L delay had a 7 mL greater decrease in ESV over 6 months. Figure 4 shows baseline radial dyssynchrony measurements (n 5 51) versus estimated change in LVESV over 6 months. We divided patients into responders and nonresponders using a cutoff value of 15 mL change in LVESV. We chose a cutoff value for SD Rad-6 of 55 ms based on a previous retrospective study performed in our laboratory.14 Of the 24 patients with SD Rad-6 O 55 ms, 18 (75%) had a decrease in LVESV O15 mL (positive predictive value). Of the 27 patients with SD Rad-6 ! 55 ms, 16 (59%) had a decrease in LVESV !15 mL (negative predictive value). Other baseline variables that were associated with improvements in LVESV included younger age, the absence of ischemic heart disease, lower EF, a wider QRS, and lower sphericity index (more spherical LV). Baseline QRS duration did not significantly correlate with any of the 4 baseline measures of mechanical dyssynchrony that were significant predictors of LVESV response. The baseline 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 LV lead location, 34 a mid-LV lead location, and 12 an apical LV lead location. Four patients had an anterior and 3 had a posterior lead position. Approximately 50% of patients with LV leads in each of the lateral positions or in the anterior positions had a decrease in LVESV O15 mL. None of the 3 patients with a posterior lead location had an LVESV response of this magnitude. Discussion This is the first multicenter prospective study to assess the relationship between acute changes in echocardiographic/TDI measures of mechanical dyssynchrony and

Table 4. Echocardiographic Measurements Variable EF (%) LVEDV (mL) LVESV (mL) Moderate or worse MR (%) GSCS (mm) PSVmean (cm/s) Radial strain (%) IVCT (ms) AV-PV (ms) TTS-L Delay (ms) SD TT-12 (ms) TVIS-L Delay (ms) SD TVI-12 (ms) SD Rad-6 (ms)

Pre-CRT

1 Week

3 Month

6 Month

28 6 7 170 6 69 125 6 60 30% 4.7 6 9.1 2.8 6 0.9 15.7 6 11.0 96 6 46 29 6 39 33 6 91 78 6 33 34 6 75 49 6 20 65 6 56

30 6 9 169 6 68 121 6 63 14%* 4.5 6 2.2 2.9 6 1.2 17.6 6 10.6 73 6 29* 15 6 24* 48 6 89 78 6 31 21 6 63 52 6 36 44 6 38

33 6 8* 159 6 64* 110 6 58* 11%* 4.8 6 2.2 3.2 6 1.9 21.1 6 14.6 73 6 29* 15 6 24* 38 6 77 73 6 29 26 6 66 47 6 18 52 6 45

34 6 8* 154 6 62* 105 6 57* 16%* 4.8 6 2.1 3.1 6 1.4 22.2 6 14.3* 71 6 29* 14 6 25* 48 6 83 74 6 25 37 6 69 48 6 19 40 6 40*

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 comparisons.

406 Journal of Cardiac Failure Vol. 15 No. 5 June 2009 Baseline Dyssynchrony and Response to CRT

All patients enrolled in this study met standard indications for CRT based on the large randomized clinical trials of this therapy. The average clinical and echocardiographic responses to CRT were consistent with that reported in previous studies. We observed significant reductions in the adverse effect of heart failure on patients’ lives as measured by the MLHFQ, improvements in physical function as measured by the 6MWT, improvements in symptoms as measured by the NYHA Class, and improvements in LV volumes, EF, and mitral regurgitation. However, as is typical, there was substantial individual variation about the mean responses. We did not find any baseline or acute changes in echocardiographic variables that were significantly associated with the clinical responses to CRT. This could be a result of an insufficient number of subjects studied given the noise in measurements, an inadequate duration of follow-up or from placebo effects that can occur during unblinded treatment with invasive devices. Interestingly, clinical response, unlike remodeling response, has not been shown to predict long-term survival after CRT.15 Four baseline measures of cardiac mechanical dyssynchrony were associated with the individual LVESV responses to CRT. TTS-L delay explained nearly 30% of individual variation in LVESV response. TVIS-L delay explained much less of the variation. In addition, the SD TVI-12, one of the measures most commonly used in retrospective studies of CRT, was not associated with reverse remodeling and did not improve significantly at any of the 3 time points measured after CRT. Our findings related to using the timing of peak systolic velocity curves as measures of dyssynchrony are consistent with those found in the PROSPECT study10 and are not surprising given the high intraobserver and interobserver (and interlaboratory) variability found in the PROSPECT study and also in our study. The results of this study are also consistent with a recent

Fig. 2. Estimated mean and individual change in left ventricular end-systolic volume (ESV) over 6 months. Individual estimated ESV lines are shown with mean curve in red. Measures of dyssynchrony were subsequently related to the variation in response among the individual subjects.

clinical and remodeling responses to CRT. We did not find significant associations between acute changes or baseline values of measures of mechanical dyssynchrony and clinical responses to CRT as measured by the 6MWT or the MLHFQ. The acute improvement in radial dyssynchrony measured by STE explained a large portion (73%) of the individual variance in reverse remodeling response to CRT as measured by changes in LVESV over 6 months. Four measures of baseline mechanical dyssynchrony (SD Rad-6, TTS-L delay, TVIS-L delay, and IVCT) were also associated with increased reverse remodeling responses to CRT.

Table 5. Variables Significantly Related to Estimated Change in LVESV Variable Mechanical dyssynchrony Acute change (1 week) IVCT (ms) SD Rad-6 (ms) Baseline IVCT (ms) TTS-L delay (ms) TVIS-L delay (ms) SD Rad-6 (ms) Clinical/echocardiogram Baseline Age (y) IHD QRS (ms) EF (%)

n

Regression Coefficient* (95% CIs)

Variance Explained

P Value

60 43

0.18 (0.02 to 0.36) 0.36 (0.22 to 0.50)

12.9% 72.8%

.05 !.001

63 63 63 54

0.24 0.14 0.12 0.20

(e0.40 (e0.24 (e0.24 (e0.36

e0.06) e0.06) e0.01) e0.04)

20.0% 29.7% 11.6% 21.8%

.01 !.001 .04 .01

64 64 64 64

0.92 17.8 0.32 1.36

(0.10 to 0.1.72) (0.72 to 35.0) (e0.54 to e0.08) (0.20 to 2.5)

14.4% 16.4% 18.1% 12.6%

.03 .04 !.01 .02

to to to to

IHD, ischemic heart disease; AVC, aortic valve closure; EF, ejection fraction; LVESV, left ventricular end-systolic volume; SCA, systolic contraction amplitude; TDI, tissue Doppler Imaging; TT, tissue tracking; TVI, tissue velocity imaging; STE, speckle-tracking echocardiography; MLHFQ, Minnesota Living with Heart Failure Questionnaire; 6MWT, 6-minute walk test. *Estimated milliliter change in LVESV over 6 months for 1 unit change in explanatory variable.

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Estimated 6-Month Change in LVESV

30 20 10

-200

-100

100

-10 -20 -30 -40 -50 -60 -70

1-Week Change in Radial Dyssynchrony

Fig. 3. Changes in radial dyssynchrony at 1 week after cardiac resynchronization therapy vs. estimated 6-month change in left ventricular end-systolic volume.

Estimated 6-Month Change in LVESV

study that showed a high prevalence of dyssynchrony in normal subjects using SD TVI-12.16 The baseline SD Rad-6 explained 21% of the individual variation in LVESV response. In addition, a baseline SD Rad-6 value of O55 ms was predictive of a O15 mL change in LVESV with 75% accuracy (positive predictive value). This is the first prospective multicenter study to measure radial dyssynchrony with STE. Measures of radial strain dyssynchrony have been studied in a retrospective single-center study of 64 heart failure patients receiving CRT.9 Using time difference in peak septal-to-posterior wall strain, the investigators showed that baseline radial dyssynchrony was associated with immediate improvement in stroke volume and long-term improvement in LVEF. Radial dyssynchrony as measured by STE strain was associated with reverse remodeling response to CRT in another study as well, and was more strongly correlated to this response than strain measured in the longitudinal or circumferential planes.8 Our laboratory has observed in a retrospective study of 70 consecutive CRT patients that measurement of dyssynchrony using STE radial strain

30 20 10 0 -10

50

100

150

200

250

-20 -30 -40 -50 -60 -70

Baseline Radial Dyssynchrony

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



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was associated with LVESV response to CRT with a correlation coefficient of e0.51 between baseline dyssynchrony and change in LVESV.14 Assessment of radial strain by STE may offer several advantages as a measure of mechanical dyssynchrony in patients with heart failure as compared with longitudinal TDI variables. The ability to discriminate normal subjects from patients with heart failure with respect to mechanical dyssynchrony is greater using STE analysis of radial dyssynchrony than using longitudinal TDI variables in our laboratory. This may be because circumferential or short-axis myocardial mechanics become abnormal sooner, or to a greater extent, than longitudinal mechanics during the development of heart failure.17 The STE technique appears to have less intraobserver and interobserver variability too. Among all the dyssynchrony variables measured in our laboratory, SD Rad-6 had the highest intraclass correlation coefficient. The STE strain analysis has the additional advantages of not being dependent on Doppler angle and of assessing myocardial thickening with less chance of being influenced by either translational motion or tethering. Acute Change Dyssynchrony and Remodeling

Several studies12,18,19 have described acute improvements in LV mechanical dyssynchrony with CRT. The largest of these12 analyzed 100 consecutive patients meeting standard criteria for CRT at a single center with mechanical dyssynchrony, defined as a $65 ms time delay among peak systolic velocities of 4 basal LV walls in the longitudinal plane. The immediate reduction in LV longitudinal dyssynchrony was 65%, with a 69% reduction by 6 months. We did not show significant acute improvements in mechanical dyssynchrony in the longitudinal plane. Our study differed from this retrospective study, in that we did not require longitudinal mechanical dyssynchrony as an entrance criterion. However, patients in our study had significant baseline longitudinal mechanical dyssynchrony. We demonstrated a 32% decrease in radial dyssynchrony by 1 week and a 38% decrease by 6 months after CRT. This improvement in radial mechanical dyssynchrony is likely a very important contributor to LV remodeling as it was associated with change in LVESV at 6 months and explained a high percentage (73%) of the individual variation in LVESV response to CRT. Clinical Applicability of Findings

The only other published prospective multicenter study of mechanical dyssynchrony variables as predictors of CRT response is the PROSPECT study.11 In this study, multiple echocardiographic and TDI mechanical dyssynchrony measures were analyzed. Some baseline measures demonstrated modest sensitivity and specificity for predicting clinical or remodeling response to CRT, but there was high intraobserver, interobserver, and interlaboratory variability in these measures. In clear contrast to a number of singlecenter retrospective studies, no single measure of

408 Journal of Cardiac Failure Vol. 15 No. 5 June 2009 mechanical dyssynchrony stood out as robust enough to be recommended for clinical use in selecting patients for CRT. Our study design was similar to PROSPECT with respect to the entrance criteria, time course of follow-up, and use of multiple dyssynchrony measures (many, but not all, the same as those in PROSPECT). As with the PROSPECT study, we also found significant variability in TVI and TT measures of longitudinal dyssynchrony. However, our study differed from PROSPECT in a number of important respects. PROMISE-CRT was a smaller study of 71 patients performed at 9 centers within a 250-mile radius, as compared with PROSPECT, which enrolled 498 patients across 3 continents. We had a single core echocardiographic laboratory and used only 1 manufacturer as compared with PROSPECT, which used 3 core laboratories and a number of different manufacturers of echocardiographic equipment. These differences likely accounted for the much higher percentage of patients with analyzable echocardiographic longitudinal dyssynchrony and LVESV data in our study (64/ 64, 100% vs. 286/498, 57%). Our study was primarily designed as an association study looking at acute changes in mechanical dyssynchrony variables whereas PROSPECT only assessed baseline mechanical dyssynchrony measures. However, baseline measurements, not acute changes, are needed to help clinicians select patients most likely to respond to CRT. Our study, unlike PROSPECT, measured STE radial strain and found both baseline and acute change measurements to be associated with the individual extent of reverse remodeling as measured by LVESV. Clearly, there is a need to further refine and define echocardiographic and TDI measures to reduce variability and improve the ability to apply this technology for patient selection across a broad clinical spectrum. At this time, the clinical decision to place a CRT device in a given patient may not be best based on a single variable, but rather on a number of clinical and laboratory variables (including measures of mechanical dyssynchrony) that each provide information regarding the likelihood of success. Because our data set was modest in size, we did not attempt to develop or validate a prediction model to integrate the variables that were associated with response to CRT. LV lead placement is thought to be an important factor affecting response to CRT. We attempted to place the LV lead in a lateral or posterior position in all patients and were successful in 60 of the 64 patients. We performed a detailed radiographic assessment of lead position in 2 planes. There was no specific lead location that was significantly better than any other location (approximately 50% remodeling response rate) except that none of the 3 patients with a posterior lead location had a O15 mL decrease in LVESV. It is hard to come to conclusions from these data because of the modest sample size. In addition, we did not attempt to determine the presence or location of scar tissue in this study. Scar tissue has been shown to influence the CRT response20 and scar location may impact CRT response with respect to LV lead location.

Limitations

The mechanical dyssynchrony measures as well as the LVESV response measure are prone to measurement error with significant intraobserver and interobserver measurement noise. To try and minimize the variability in the mechanical dyssynchrony measurements, we not only used a single echocardiographic machine, but we also provided extensive education and training to the technicians acquiring the echocardiographic data. The noise inherent in the measurement of both the potential explanatory variable (mechanical dyssynchrony) and response variable (LVESV) can greatly attenuate observed associations based on a single follow-up assessment, and can mislead practitioners about a patient’s true response to CRT. To address this issue, we prospectively designed a statistical approach that was different than the typical approach used previously. We estimated individual response to CRT not as a dichotomous variable with a single threshold value (eg, decrease in LVESV of O 15%), but rather as a slope, estimated from data collected at 4 time points (preimplant, 1 week, 3 month, 6 month). By taking this statistical approach, and by acquiring data at several time points post-CRT, we were able to average out noise in LVESV measurements to test for associations between remodeling response and mechanical dyssynchrony. Although this study was prospective and multicenter, it was a relatively small study, with 64 patients completing the study and included in the final analyses. Good quality radial strain curves at both baseline and 1 week for assessment of mechanical dyssynchrony were obtained in only 43 of 64 patients (67%). Although this was a limitation of this study, STE is a relatively new methodology. More careful attention to the acquisition of high quality 2-dimensional short axis images in our laboratory since this study was completed has resulted in acquisition of radial strain data suitable for analysis in a significantly higher percentage of patients. All patients in this study received CRT and there was no randomization to medical therapy or ability to blind the patients or physicians with respect to treatment. Therefore, placebo effects or potential assessment biases cannot be excluded. However, the major findings of this study related to echocardiographic measures of mechanical dyssynchrony, and all echocardiographic measurements were analyzed in a blinded fashion. Conclusions This multicenter, prospective study found a number of baseline clinical, standard echocardiographic, and mechanical dyssynchrony variables that were associated with reverse remodeling, but not clinical response to CRT. The acute improvement in STE-measured radial dyssynchrony explained 73% of the individual variation in LVESV response. In addition, 4 baseline measures of mechanical dyssynchrony explained 12% to 30% of the individual remodeling response. Base line radial

PROMISE-CRT Study Results

dyssynchrony (SD Rad-6 O55ms) had a positive predictive value of 75 % for a significant reduction in LVESV. These data support the hypothesis that improvement in mechanical dyssynchrony is an important mechanism contributing to the beneficial effects of CRT on LV reverse remodeling. Further prospective multicenter studies are needed to evaluate the use of radial dyssynchrony, and perhaps other measures of mechanical dyssynchrony, in identifying patients who have a high likelihood of responding to CRT.

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Acknowledgments

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The authors wish to acknowledge multiple Guidant (Boston Scientific) research scientists for their assistance and support during this study.

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Appendix The following persons participated in the PROMISE-CRT Study: 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 Institute, 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, Minneapolis, MN): I. Anand, K. Doerfler, S. Lectner; (Metro Cardiology, 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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