Patient Population and Study Protocol

One hundred forty patients in sinus rhythm with left bundle branch block (QRS width ≥ 120 msec), NYHA functional class III or IV heart failure, and impaired LV systolic function (LV ejection fraction ≤ 35%) despite receiving maximally tolerated optimal medical treatment were assessed. The study was conducted in two consecutive groups, with hypothesis testing in the first group ( n = 65), to derive the optimal cutoff of low-amplitude radial strain that negatively predicted CRT response (derivation group) followed by validation in a second prospective cohort ( n = 75). All 140 patients underwent detailed clinical assessment including evaluation of 6-min walking distance and Minnesota Living With Heart Failure Questionnaire and baseline echocardiography to ascertain LV volumes and function before scheduled device therapy. Radial strain speckle-tracking analysis was performed on the parasternal 2D grayscale images of the 12 nonapical segments in each patient. Following CRT, baseline clinical and echocardiographic assessments were repeated at 6 months, and response was defined as a ≥15% reduction in LV end-systolic volume (LVESV) index (LVESVI). The study was approved by the local ethics committee, and the study protocol complied with the guidelines set out in the Declaration of Helsinki. All participants gave fully informed written consent.

CRT Device Implantation

An 8Fr guiding catheter was used to position the LV lead (Easytrak 2, Guidant Corporation, St Paul, MN; or Attain-SD 4189, Medtronic, Inc, Minneapolis, MN) in all patients preferentially to a lateral or posterolateral vein.

The right atrial lead was placed in the right atrial appendage, and the position of the right ventricular (RV) lead was left to the discretion of the implanting physician. The RV lead was placed in the mid septum in 46.4% of patients ( n = 65) and at the RV apex in 53.6% of patients ( n = 75). Fifty-eight patients (41.4%) received CRT defibrillators, with the remaining 82 patients (58.6%) receiving CRT pacing alone (Contak Renewal; Guidant Corporation). The AV delays were optimized according to the highest velocity-time integrals from the pulsed-wave Doppler of the transmitral inflow. At the optimized AV delay, VV delays were adjusted in 20-ms increments in all patients according to the highest velocity-time integrals from the pulsed-wave Doppler of the LV outflow tract between +60 msec (RV preactivation) and −60 msec (LV preactivation). Devices were programmed in DDD mode (lower rate limit, 40 beats/min) to achieve atrial synchronous biventricular pacing. The position of the LV lead was determined by postimplantation chest radiography and biplane fluoroscopy as either basal, mid, or apical in the anterior-posterior and right anterior oblique projections and as anterior, lateral, posterior, or inferior in the left anterior oblique views.

Conventional Echocardiography

Standard 2D imaging was performed using a commercial machine (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway) equipped with a 3.5-MHz phased-array transducer. The images were acquired in cine loop format and digitally stored for postprocessing offline (EchoPAC version 7.0; GE Vingmed Ultrasound AS). LV end-diastolic volume, LVESV, and LV ejection fraction were calculated using Simpson’s biplane method according to the guidelines of the American Society of Echocardiography. Mitral regurgitation was assessed on a three-point scale as mild (jet area/left atrial area < 20%), moderate (jet area/left atrial area, 20%–45%), or severe (jet area/left atrial area ≥ 45%).

Speckle-Tracking Echocardiography

Speckle-tracking analysis of the baseline grayscale basal and mid LV parasternal short axis was performed as previously described. All images were recorded with a frame rate of ≥40 Hz (mean, 61 ± 25 Hz; range, 40–92 Hz), and the endocardial border was traced using a point-and-click technique in end-systole, with special care taken to adjust tracking of all segments. A second larger concentric circle was then automatically generated and manually adjusted near the epicardium. Speckle-tracking software automatically analyzed the frame-by-frame movement of the stable patterns of natural acoustic markers, or speckles, to generate time-strain curves over the cardiac cycle. For each of the 12 nonapical segments the time to maximal peak radial strain from QRS onset as well as the amplitude of the peak was determined. All speckle strain measurements were performed by a single operator blinded to the clinical and 2D echocardiographic LV volume measurements and to the assessment of the LV lead position. For each patient, the paced segment was ascertained, and patients were regarded as having concordant LV lead positions if the LV leads were pacing the latest segment and discordant if not. The latest segment was defined by the time to peak of maximal strain. For the paced segment, the radial strain amplitude was also determined ( Figure 1 ). Of the 1,680 radial segments assessed, the tracking quality was adequate in a total of 1,493 (88.9%). Image quality was too poor for analysis by speckle tracking in five patients, who were not included in the study from the outset.

(Left) Lateral chest radiograph of patient showing an LV lead in the lateral position. (Right) Speckle-tracking radial time strain curves of the same patient showing latest site of contraction in the lateral segment ( green ; denoted by white arrow ) consistent with a concordant LV lead position. Significant LV dyssynchrony is also shown with an anteroseptal (yellow) to posterior (purple) wall (AS-P) delay of ≥130 msec. The paced area, however, is an LAS with peak radial strain amplitude of only 7%, suggesting attenuated myocardial contraction, which has the potential to effect CRT response.

Dyssynchrony Assessment

VV dyssynchrony was determined as the difference in time from QRS onset of the pulmonary and aortic continuous Doppler measurements in the pulmonary and aortic outflow tracts respectively. Intraventricular dyssynchrony was defined by 2D radial strain speckle analysis as the time delay between the maximal peak strain of the anteroseptal and posterior segments, and as previously reported, a cutoff value of ≥130 msec was considered significant.

Follow-Up and Study End Point

All patients were reassessed 6 months after device implantation. The primary determinant of CRT response was defined by echocardiography as a reduction of LVESV ≥15%. Clinical response was defined as an improvement of at least one class in NYHA functional status. All patients who died from cardiac causes during the follow-up period were classified as nonresponders.

Statistical Analysis

Statistical analysis was performed using commercially available software (GraphPad Prism 5 for Windows, GraphPad Software, San Diego, CA; and SPSS version 14.0, SPSS, Inc, Chicago, IL). Continuous variables are expressed as mean ± SD. Categorical variables are presented as frequencies and percentages. Differences in continuous variables were assessed using paired and unpaired Student’s t tests or χ ² tests for noncontinuous variables when appropriate. A P value < .05 was considered statistically significant. Receiver operating characteristic curves were determined to evaluate the effect of the radial strain amplitude of the paced segment on CRT response, and optimal cutoff values were chosen. Correlation analysis was used to compare LVESVI reduction and radial strain amplitude of the pacing segment. Reproducibility was assessed in 10 randomly selected patients. Interobserver and intraobserver variability were expressed as the SD of the difference between two paired measurements and as a percentage of variability (SD was divided by the average value of the variable). Univariate and multivariate logistic regression analyses were used to assess the relationship of LVESVI change at follow up to the presence or absence of either LV dyssynchrony, LV lead concordance to the most delayed segment, or low-amplitude segments (LAS) at the LV pacing site in addition to age, sex, and etiology.

Baseline Characteristics and Response to CRT

At baseline, among the entire study population, the mean age was 71 ± 10 years, with a mean LV ejection fraction of 23 ± 7% and a mean QRS duration of 157 ± 22 msec. Baseline characteristics of all patients and a breakdown of patients in the validation and derivation groups are provided in Table 1 .

In the entire study population after 6 months of CRT, NYHA class improved in 95 patients (67.9%), was unchanged in 35 patients, and worsened in eight patients. At follow-up, two patients died of progressive heart failure and were classified as nonresponders. LVESVI reduced by ≥15% in 78 patients (55.7%) and by 0% to 15% in 47 patients and was increased in 15 patients. The changes in functional and echocardiographic variables before and after treatment for both the derivation and validation groups are reported in Table 2 . Responders by volume reduction, compared with nonresponders, showed better functional improvements with lower NYHA classes, longer 6-min walking distances, and improved quality-of-life scores. There were, however, discrepancies between clinical and volume responders: seven of the 78 volume responders showed no clinical response, and 24 of the 62 volume nonresponders had at least a one-class improvement in NYHA functional status.

Derivation Group

Validation Group

LAS and CRT Response

Of the 75 patients in the validation group, the LV leads were placed over segments with radial strain amplitudes of <10% (LAS) in 16 patients. The baseline characteristics of patients according to the presence of LAS at the LV pacing site are shown in Table 3 . In patients in whom the LV leads were overlying LAS, the mean peak amplitude was 5.13 ± 1.6%, compared with the remaining 59 patients, in whom the peak amplitude at the LV pacing site was significantly higher (19.8 ± 19.4%) ( P < .001). The LV pacing thresholds were similar in patients with and without LAS at the pacing site (LAS vs no LAS, 1.8 ± 1.4 vs 1.7 ± 1.4 V; P = .74) The mean reduction of LVESVI at follow-up was significantly lower in the LAS group compared with patients in whom there were no LAS at the LV pacing site (12.5 ± 8.7% vs 24.3 ± 15.2%, P = .01). CRT response as a proportion of patients with ≥15% reductions in LVESVI was also significantly lower in the LAS group than in the group without LAS (25.0% vs 62.7%, P < .05).

Table 3

Baseline characteristics and response to CRT in patients according to the presence or absence of LAS at LV pacing site, LV dyssynchrony, and LV lead concordance

	LAS			Dyssynchrony			Concordance
Characteristic	Present ( n = 16)	Absent ( n = 59)	P	Present ( n = 45)	Absent ( n = 30)	P	Present ( n = 33)	Absent ( n = 42)	P
NYHA class
Baseline	3.2 ± 0.4	3.2 ± 0.4	.80	3.1 ± 0.3	3.1 ± 0.3	.81	3.1 ± 0.3	3.1 ± 0.3	.87
Follow-up	2.5 ± 0.9	2.0 ± 0.8	.03	2.3 ± 0.8	2.2 ± 1.0	.19	2.1 ± 0.8	2.2 ± 1.0	.15
6-min walking distance (m)
Baseline	203 ± 95	228 ± 116	.44	231 ± 114	210 ± 111	.46	224 ± 110	220 ± 106	.37
Follow-up	234 ± 126	273 ± 117	.33	291 ± 113	272 ± 120	.81	269 ± 114	260 ± 84	.81
% change	+15	+47	.12	+43	+26	.22	+48	+30	.22
MLHFQ score
Baseline	54 ± 21	56 ± 21	.33	51 ± 20	50 ± 21	.11	53 ± 20	55 ± 21	.11
Follow-up	40 ± 17	35 ± 22	.52	37 ± 20	39 ± 23	.57	32 ± 19	41 ± 19	.74
% change	−26	−38	.04	−27	−22	.63	−40	−25	.13
LVEDVI (mL/m 2 )
Baseline	101 ± 37	102 ± 37	.66	100 ± 35	98 ± 34	.23	99 ± 39	101 ± 40	.23
Follow-up	93 ± 23	83 ± 28	.06	86 ± 41	90 ± 33	.21	82 ± 48	88 ± 54	.21
% change	−8	−19	.003	−14	−10	.10	−17	−13	.10
LVESVI (mL/m 2 )
Baseline	80 ± 47	77 ± 28	.66	78 ± 43	76 ± 30	.43	79 ± 29	77 ± 30	.43
Follow-up	70 ± 35	58 ± 30	.04	61 ± 35	65 ± 31	.71	59 ± 30	68 ± 35	.05
% change	−12	−24	.01	−22	−14	.15	−25	−13	.02
LVEF (%)
Baseline	22 ± 6	24 ± 7	.35	24 ± 7	24 ± 6	.76	23 ± 7	24 ± 6	.76
Follow-up	25 ± 7	31 ± 9	.23	30 ± 9	29 ± 9	.98	31 ± 9	28 ± 9	.23
% change	+13	+29	.04	+25	+21	.16	+35	+17	.05

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