Study Population

All ambulatory patients with stable heart failure caused by LV systolic dysfunction (LV ejection fraction < 35%), wide QRS intervals (>120 msec) related to LBBB configuration on electrocardiography, and New York Heart Association (NYHA) class II to IV heart failure referred to our tertiary center for CRT device implantation were prospectively enrolled in this single-center study. LBBB was defined as (1) a broad, notched R wave in the lateral precordial leads (V ₅ and V ₆ ) and usually leads I and aVL; (2) smaller or absent initial r waves in the right precordial leads (V ₁ and V ₂ ) followed by deep S waves; and (3) absent q waves in the left-sided leads.

Exclusion criteria were (1) myocardial infarction, acute coronary syndrome, or coronary revascularization during the previous 3 months; (2) primary mitral or aortic valvular disease; (3) uncontrolled rapid atrial fibrillation; (4) right bundle branch block and intraventricular conduction delay; and (5) patient unwillingness to provide informed consent according to our institutional review board. This resulted in a final study population of 101 patients.

Clinical data (age, gender, body mass index, NYHA functional class) and medical history (hypertension, hypercholesterolemia, diabetes mellitus, chronic obstructive pulmonary disease, and coronary artery disease [CAD]) were prospectively assessed. Documented CAD was defined as a history of previous myocardial infarction or the presence of significant CAD on angiography (>50% stenosis of an epicardial vessel). Patients received maximum tolerated doses of β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and spironolactone, as recommended by current guidelines. Blood was sampled in the supine position for serum creatinine and B-type natriuretic peptide levels (Triage assay; Beckman, Villepinte, France) on the day before CRT device implantation. Glomerular filtration rate was estimated using the four-component Modification of Diet in Renal Disease equation incorporating age, race, sex, and serum creatinine level: estimated glomerular filtration rate = 186 × [serum creatinine level (mg/dL) ^−1.154 × [age (years)] ^−0.203 . For women, the product of this equation was multiplied by a correction factor of 0.742.

Echocardiography

Echocardiography was performed by experienced echocardiographers using a Vivid E9 commercial ultrasound scanner (release BT11; GE Vingmed Ultrasound AS, Horten, Norway) with a phased-array transducer (M5S-D) on the day before CRT device implantation and at 9-month follow-up.

Speckle-Tracking Echocardiography and Dyssynchrony Measurements

Apical chamber views recorded at frame rates of 55 to 90 frames/sec (mean, 65 ± 10 frames/sec) were used for strain analysis. Longitudinal two-dimensional speckle-tracking strain curves were analyzed offline using a dedicated workstation (EchoPAC PC release BT11; GE Vingmed Ultrasound AS). Longitudinal strain and strain rate values were computed after determining aortic valve opening and closure onset using Doppler recordings. Automatic tracking of the endocardial contour on an end-systolic frame was carefully verified and the region of interest was manually corrected to ensure optimal tracking and to cover the entire thickness of the LV myocardium.

Speckle-tracking software was used to derive septal deformation from the single-wall recordings. The region of interest was set along the endocardial border from base to apex, excluding the apical cap and adapted to match wall thickness. The speckle-tracking performed by the software was visually checked and adjusted as necessary. Global wall deformation (i.e., calculated over the entire length of the wall) was used for the analysis. Septal deformation patterns were classified on the basis of the septal shortening and stretching sequence. Three patterns were characterized ( Figure 1 ): double-peaked systolic shortening (pattern 1); early pre-ejection shortening peak followed by prominent systolic stretch (pattern 2); and pseudonormal shortening with a late systolic shortening peak, no or minimal pre-ejection septal lengthening, and less pronounced end-systolic stretch (pattern 3). If the first peak was less but within 150% of the second peak, pattern 1 was adjudicated. Septal strain tracing and pattern recognition were performed offline on 20 randomly selected echocardiograms by two investigators (S.M., A.L.C.) blinded to patients’ clinical and follow-up data to assess the reproducibility of this approach. All acquired apical four-chamber views were available for septal strain tracing. The quality of the echocardiograms was graded semiquantitatively into four grades (1: excellent; 2: good; 3: average; and 4: poor).

Septal patterns obtained from speckle-tracking longitudinal strain: double-peaked systolic shortening ( A, pattern 1), early pre-ejection shortening peak followed by prominent systolic stretch ( B, pattern 2), and pseudonormal shortening with a late-systolic shortening peak and less pronounced end-systolic stretch ( C, pattern 3).

Global longitudinal strain (GLS) was the average of segmental peak systolic longitudinal strain values occurring before aortic valve closure from the three apical views. The three apical views were used to calculate the difference between time to peak systolic strain of the basal-septal (BS) and basal-lateral (BL) LV segment (BS-BL delay) and the standard deviation of time to peak systolic strain for the 12 basal and medial segments (SDt _12S ). Given the complex multipeak pattern of septal strain, the maximal negative value of strain before aortic valve closure was used.

Color-coded Doppler tissue imaging (DTI) was also performed to assess LV dyssynchrony. For DTI data acquisition, color Doppler frame rates were minimally set at 150 frames/sec; the pulse repetition frequency was 1 KHz, resulting in aliasing velocities of 16 cm/sec. DTI parameters were measured offline from color-coded images on three consecutive heartbeats. The sample volume (6 × 12 mm) was placed in the LV basal segments of the septal and lateral walls (four-chamber apical view). LV dyssynchrony was defined as the maximum delay between peak systolic velocities of the septal and lateral walls (Ts lateral-septal). A cutoff of ≥65 msec was used on the basis of previously published reports. The analysis of peak systolic velocities was limited to the LV ejection period, and pre-ejection and postejection peaks were not included.

CRT Device Implantation

Boston Scientific (Natick, MA), Medtronic (Minneapolis, MN), St Jude (St Paul, MN), Sorin (Milan, Italy), and Biotronik (Berlin, Germany) CRT devices were implanted by electrophysiologists targeting a lateral or posterior coronary sinus vein for LV lead positioning. To promote biventricular pacing, CRT devices were commonly programmed with short atrioventricular (AV) delays. Interventricular timing was set to zero. Other parameters were set to nominal values or at the clinician’s discretion. Using pulsed Doppler mitral inflow, the AV delay was selected before hospital discharge to allow adequate E-wave and A-wave separation and termination of the A wave before mitral valve closure.

Outcomes

During follow-up, patients were monitored by their personal physicians. Events (cardiac death and hospitalization for heart failure) were ascertained by clinical interviews and/or by phone calls to physicians, patients, and (if necessary) next of kin. Follow-up was complete in 100% of cases.

End Points

Changes in LV end-diastolic volume, end-systolic volume, LV ejection fraction, and GLS were analyzed. The primary end point was the response to CRT, defined by a relative reduction in LV end-systolic volume of ≥15% from baseline to 9-month follow-up. Super-response to CRT was defined as an absolute LV ejection fraction of ≥50% associated with a relative reduction in LV end-systolic volume of ≥15% and an improvement in NYHA functional class at follow-up. The secondary end point was death from cardiac causes and hospitalizations for heart failure after CRT.

Statistical Analysis

Continuous variables are expressed as mean ± SD or median (interquartile range) in case of skew. Categorical variables are expressed as absolute numbers and percentages. Continuous variables for the three groups of septal deformation patterns were compared using one-way analysis of variance. The Shapiro-Wilk test was used to verify if residuals obtained on analysis of variance did approximate a normal distribution. If the test failed, nonparametric analysis of variance (Kruskal-Wallis test) was used. Post hoc comparisons were performed using either Scheffé’s comparison or Mann-Whitney U tests with Bonferroni’s correction for multiple comparisons as appropriate. Categorical variables were compared using χ ² or Fisher’s exact tests, as appropriate. Paired continuous variables were compared using paired Student’s t tests or Wilcoxon’s rank-sum tests. Survival curves were plotted using the Kaplan-Meier method and compared using a log-rank test. The mean duration of follow-up was computed using the reverse Kaplan-Meier method. Agreement between readers for the septal deformation pattern (1, 2, or 3) was assessed using the κ statistic. A two-tailed type 1 error < .05 indicated statistical significance. Statistical analyses and figures were obtained using PASW version 18.0 (IBM, Bois-Colombes, France), GraphPad Prism (GraphPad Software, La Jolla, CA), and MedCalc for Windows version 12.5.0 (MedCalc Software, Mariakerke, Belgium).

Clinical Characteristics

The study involved 101 patients (mean age, 69 ± 12 years) with heart failure due to LV systolic dysfunction (mean LV ejection fraction, 26 ± 4%; mean GLS, −8.1 ± 2.6%) undergoing CRT with either pacemakers ( n = 14 [14%]) or pacemaker-defibrillator ( n = 87 [86%]). Baseline characteristics of the study population are detailed in Table 1 . Fifty-five patients (55%) were in NYHA functional class III or IV. QRS width was ≥150 msec in 72 patients (71%).

Correlates of Septal Deformation Patterns

A total of 1,748 segments (96%) were adequately tracked by speckle-tracking software. The mean echocardiographic quality score was 1.7 ± 0.8. It is noteworthy that septal strain was feasible with adequate tracking in all patients, even in patients with poor echocardiographic windows. Clinical and laboratory variables according to the three septal deformation patterns are depicted in Table 1 . Plasma B-type natriuretic peptide levels were higher in patients with pattern 3 compared with those with pattern 1 ( P = .005). Female sex was less frequent in patients with pattern 3 compared with those with pattern 1 ( P = .005) or 2 ( P < .0001). CAD was more frequent in patients with pattern 3 compared with those with a pattern 2 ( P = .009).

Echocardiographic variables according to these patterns are presented in Table 2 . LV ejection fraction was significantly higher in patients with pattern 1 compared with those with pattern 2. LV diameters and volumes were higher in patients with pattern 2 compared with those with pattern 1. Patients with pattern 1 had higher GLS values than those with pattern 2 or 3. Ts lateral-septal by DTI was similar among the three groups of patients. The proportion of patients with Ts lateral-septal by DTI ≥ 65 msec was not different among the three groups of patients.

Septal Deformation Patterns and LV Remodeling after CRT

LV remodeling was studied in 96 patients, as five patients died before 9-month follow-up echocardiography. As shown in Table 3 , both relative and absolute changes in LV end-systolic volume expressed as continuous variables were significantly different according to the three patterns of septal deformation. Relative ( Figure 2 ) and absolute ( Figure 3 A) changes in LV end-systolic volumes were significantly lower in patients with pattern 3 compared with those with pattern 1 or 2 ( Table 3 ). Similar results were observed for absolute changes in LV end-diastolic volume, with lower changes in patients with pattern 3 compared with those with pattern 1 or 2 ( Table 3 , Figure 3 B). Changes in LV ejection fraction also differed among the three groups ( Table 3 , Figure 3 C). Changes in LV ejection fraction were higher in patients with pattern 1 or 2 compared with those with pattern 3 ( Table 3 ). Changes in GLS varied according to septal deformation pattern, with no significant changes in patients with pattern 3 compared with significant changes in patients with pattern 1 or 2 ( Table 3 , Figure 3 D). As shown in Table 4 , SDt _12S and BS-BL delay decreased significantly in patients with pattern 1 or 2 but remained unchanged in patients with pattern 3. In addition, changes in SDt _12S and BS-BL delay were higher in patients with pattern 1 or 2 compared with those with pattern 3, indicating better success of resynchronization in patients with pattern 1 or 2 compared with patients with pattern 3 ( Table 3 ).

Table 3

Relationship between septal deformation patterns and changes in echocardiographic and clinical data after CRT

Variable	All (n = 96)	Pattern 1 (n = 42)	Pattern 2 (n = 20)	Pattern 3 (n = 34)	Patterns 1 and 2 (n = 62)	P	P value, pattern 1 vs pattern 2	P value, pattern 1 vs pattern 3	P value, pattern 2 vs pattern 3	P value, patterns 1 and 2 vs pattern 3
Responders ∗	77 (80%)	40 (95%)	17 (85%)	20 (59%)	57 (92%)	<.0001	.317	<.0001	.045	<.0001
Super-responders †	22 (23%)	15 (36%)	3 (15%)	4 (12%)	18 (29%)	.037	.093	.017	1.0	.054
LVESV absolute change (mL)	62 ± 45	73 ± 36	85 ± 48	36 ± 39	77 ± 40	<.0001	.568	.001	<.0001	<.0001
LVESV relative change (%)	36 ± 24	45 ± 18	42 ± 21	22 ± 25	44 ± 19	<.0001	.847	<.0001	.007	<.0001
LVEDV absolute change (mL)	54 ± 53	66 ± 48	74 ± 62	30 ± 44	69 ± 52	.002	.858	.009	.010	<.0001
LVEF absolute change (%)	−14 ± 11	−18 ± 8	−17 ± 12	−8 ± 11	−17 ± 10	<.0001	.969	<.001	.010	<.0001
GLS change (%)	1.8 ± 3.2	2.9 ± 3.1	2.4 ± 3.6	0.2 ± 2.4	2.7 ± 3.2	.001	.859	.001	.040	<.0001
SDt 12S changes (msec)	14 (−20 to 67)	50 (−4 to 86)	28 (−1 to 78)	−19 (−32 to 17)	42 (−3 to 85)	<.0001	.649	<.0001	.002	<.0001
BS-BL delay change (msec)	49 (25 to 103)	62 (6 to 92)	89 (−72 to 230)	11 (−91 to 61)	65 (1 to 175)	.019	.590	.008	.051	.005

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