Abstract
Objectives.
Using ECG-gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), we sought to develop and validate a new method to recommend left ventricular (LV) lead positions in order to improve volumetric response and long-term prognosis after cardiac resynchronization therapy (CRT).
Methods.
Seventy-nine patients received gated SPECT MPI at baseline, and echocardiography at baseline and follow-up. The volumetric response referred to a reduction of ≥ 15% in LV end-systolic volume 6 months after CRT. After excluding apical, septal, and scarred segments, there were three levels of recommended segments: (1) the optimal recommendation: the latest contracting viable segment; (2) the 2nd recommendation: the late contracting viable segments whose contraction delays were within 10 of the optimal recommendation; and (3) the 3rd recommendation: the viable segments adjacent to the optimal recommendation when there was no late contracting viable segment.
Results.
After excluding 11 patients whose LV lead was placed in apical or scarred segments, 75.6% of the patients concordant to recommended LV segments (n = 41) responded to CRT while 51.9% of those with non-recommended LV lead locations (n = 27) were responders (P = .043). Response rates were 76.9%, 76.9%, and 73.3% (P = .967), respectively, when LV lead was implanted in the optimal recommendation (n = 13), the 2nd recommendation (n = 13), and the 3rd recommendation (n = 15). LV leads placed at recommended segments reduced composite events of all-cause mortality or heart failure (HF) rehospitalization compared with pacing at non-recommended segments (log-rank χ2 = 5.623, P = .018).
Conclusions.
Pacing in the recommended LV lead segments identified on gated SPECT MPI was associated with improved volumetric response to CRT and long-term prognosis.
Keywords: Cardiac resynchronization therapy, heart failure, left ventricular lead position, SPECT, myocardial perfusion imaging
INTRODUCTION
Cardiac resynchronization therapy (CRT) is a standard treatment for patients with chronic heart failure. However, 30% to 40% of CRT recipients do not respond to this costly treatment.1 Non-response to CRT may be related to myocardial viability and mechanical dyssynchrony of left ventricular (LV) pacing sites.2,3
The LV lead is usually deployed in the lateral or posterolateral myocardium.4 However, pacing at the scarred site may be associated with poor response to CRT.2,5 Studies using late gadolinium enhancement(LGE) cardiovascular magnetic resonance (CMR) and speckle-tracking echocardiography have shown that LV lead in the viable segments with the latest activation results in favorable acute haemodynamic response and reverse remodeling at follow-up.6,7 Due to its low cost, high reproducibility, and non-invasiveness, gated SPECT MPI has been investigated to recommend the optimal LV lead site in a number of studies.8,9 Nevertheless, the optimal LV lead position is unique and cannot always be reachable on account of variable coronary sinus (CS) anatomy.
Our recent research proposed a new automatic approach using gated SPECT MPI to recommend the late contracting viable segments for LV lead placement,10 which may increase the chance of placing LV lead in the recommended LV sites and thus improve CRT response. This study presents our latest investigation, and the major aim is to develop and validate a new multi-recommendation method to recommend LV lead positions from gated SPECT MPI to improve volumetric response and long-term prognosis after CRT.
METHODS
A total of 79 CRT patients were enrolled in nine Chinese centers from March 2012 to May 2014. All the patients had an LV ejection fraction (LVEF) ≤ 35%, QRS duration > 120 ms, New York Heart Association (NYHA) functional class II to IV symptoms, and optimal medical therapy at least 3 months before CRT.
All the patients underwent resting gated SPECT MPI, echocardiography, and NYHA function classification at baseline and 6 months after CRT (4 patients did not receive post-CRT SPECT MPI). The actual LV lead position was identified by post-CRT CT venography. Through telephone follow-ups, we collected outcome data on any-cause mortality and heart failure (HF) rehospitalization till July 2017. The study complied with the Declaration of Helsinki and was approved by local ethics committees. All patients gave written informed consent.
Evaluation of LV Function by Echocardiography
Echocardiographic data of all patients were assessed by one experienced ultrasound expert blinded to any other clinical data before and 6 months after CRT, including the actual LV lead position, NYHA class, ECG, SPECT MPI, and medication. LV volumes and LV ejection fractions (LVEF) were measured by using the 2-dimensional modified biplane Simpson method.
The present study adopted a reduction of ≥ 15% in LV end-systolic volume (LVESV) to define volumetric response to CRT, which has been widely accepted as the boundary between responders and non-responders.7,11,12 In CRT-related studies and heart failure drug trials, the change of LVESV has been frequently used to assess the efficacy and prognosis.13,14 LVESV has been an effective indicator of LV reverse remodeling and a better survival predictor compared with LVEF, LV end-diastolic volume (LVEDV), or clinical parameters.15,16
Evaluation of LV Myocardial Scar and Mechanical Dyssynchrony from SPECT MPI
Resting ECG-gated SPECT MPI images were acquired using technetium-99 m methoxyisobutylisonitrile (99mTc-MIBI). The gated SPECT scan was performed 60–90 minutes after injection with 25–30 mCi of 99mTc-MIBI at rest. Image acquisition was performed based on a one-day resting gated SPECT MPI protocol with a dual-head or triple-head camera system, equipped with a low-energy, general-purpose collimator. The pixel size was a 64 × 64 matrix at least, and the zoom factor was set to 1.0. Gated images were acquired with a photopeak window of the 99mTc set as a 20% energy window centered over 140 keV. The division of the electrocardiographic R-R interval was 8 frames per cardiac cycle, using a 50% beat acceptance window. A total of 60 or 64 planar projections of more than 20 seconds/projection were acquired for the 180° acquisition from right anterior oblique 45° to left posterior oblique 45°. Emory Reconstruction Toolbox (ERToolbox; Atlanta, GA) was uniformly applied to SPECT image reconstruction and reorientation.
The ungated short-axis images were input into an automatic sampling algorithm by searching in 3D for the maximal count circumferential profiles to represent the regional perfusion level.17,18 The percentage of tracer uptake was displayed on the polar map using a 13-segment model (one apical segment, 6 mid-segments, and 6 basal segments). The apical segment encompasses all 5 apical segments in the standard 17-segment model (apical anterior, apical septal, apical inferior, apical lateral, and apex segments).10 LV sample with less than 50% of maximum uptake was defined as myocardial scar and regions with > 50% scar were identified as scarred segments. The phase analysis technique based on 1-harmonic Fourier function was applied to approximate the regional uptake count changes over the cardiac cycle and to calculate the regional onset of mechanical contraction represented as a phase angle.8,9,19 A phase distribution polar map was accordingly generated to visualize LV mechanical dyssynchrony. Two parameters, phase standard deviation (PSD, unit:degree) and 95% bandwidth of phase histogram(PHB, unit:degree), were measured from the phase histogram to characterize the global LV mechanical dyssynchrony.
Recommendation of LV Lead Positions
Excluding LV apex, septal segments, and segments with more than 50% scar, the remaining segments were ranked for lead position recommendation based on their contraction delays from gated SPECT MPI for each patient. The recommendation rank was increasing with the degree of contraction delay. Three levels of recommended segments were applied as follows:
the optimal recommendation(the optimal segment): the latest contracting viable segment;
the 2nd recommendation(late contracting viable segments): excluding the optimal segment, the viable segments whose contraction delays were within 10° of the largest phase angle.
the 3rd recommendation(adjacent segments): the viable segments which were adjacent to the optimal segment.
The 3rd recommendation was applied only when there was no late contracting viable segment. If there were more than one segment in the 2nd and 3rd recommendations, they were ranked based on the phase angles (Figure 1).
Figure 1.
Examples illustrating how the left ventricular lead positions were recommended. (A) A patient example with late contracting viable segments. Following the second recommendation level, 4 viable segments whose phase angles were within 10° of the largest phase angle were recommended for LV lead placement, ranked by the phase angles. (B) A patient example without late contracting viable segments. Following the third recommendation level, 3 adjacent viable segments were recommended for LV lead placement, ranked by the phase angles. Numbers in the regional contraction polar maps are the mean phase angle in each segment; numbers in the regional scar polar maps are the scar percentage in each segment. The recommended LV lead positions marked with numbers in the guidance maps were ranked based on the phase angles. The septal and apical segments (whiteout regions) were first ruled out.
In the “recommended” and “non-recommended” groups, the LV lead position was concordant to the recommended or non-recommended position according to CT venography. Patients with LV lead in the apex or scarred segment were classified into the “apex or scar” group. The first three late contracting viable segments which satisfied the recommended conditions were referred to as “the first 3 recommended segments.” Accordingly, “the last 5 non-recommended segments” were the last five relatively early contracting viable segments which were not recommended.
Implantation of Cardiac Resynchronization Therapy
All patients underwent implantation of a biventricular pacemaker. The LV lead was transvenously inserted into the CS system and steadily implanted in an anterolateral, lateral, or posterolateral coronary vein by experienced electrophysiologists following the standard-of-care implantation guideline. During operation, the pacing thresholds, sensing and impedance of the LV pacing site were measured without phrenic nerve stimulation. The right ventricular septal lead was systematically placed in the RV apex following standard protocols. For each patient, V-V intervals were set to 0 ms with A-V intervals programmed to 120/100 ms. No adjustments were made to these parameters during the first 6 months of device implantation.
Identification of LV Lead Position Using CT Venography
A standard protocol of CT venography was implemented in all 79 patients within 7 days after implantation of CRT. Except for apex, LV surface was classified as basal or mid-segments in anteroseptal, anterior, anterolateral, posterolateral, posterior, and posteroseptal wall. CT venography was performed to establish a retrospective correlation between the LV lead position and the recommended segment by SPECT MPI.
Statistical Analysis
One-way ANOVA was used to compare between groups for continuous data expressed as mean ± standard deviation. χ2 test or Fisher’s exact test was used for categorical variables expressed as counts or percentages. Death from any cause and cardiac death or HF rehospitalization were assessed using Kaplan-Meier analysis and differences in event free were compared by a Log-rank test. Univariate and multivariate binary logistic regression analysis was performed to identify independent predictors of volumetric response to CRT. The multivariate analysis only adopted factors with P value < .10 determined by univariate analysis. Two-sidedP value < .05 was considered to be statistically significant. Statistical analyses were performed with IBM SPSS Statistics (IBM, Chicago, IL, USA) version 24.0.
RESULTS
Study Population
Baseline characteristics are summarized in Table 1 for the 79 patients included in this study (25 female, age 60.8 ± 12.8 years). The entire cohort had wide QRS, depressed LVEF and severe LV mechanical dyssynchrony indicated by PSD and PHB. After 6 months, CRT improved LV function: LVEF increased from 27.4 ± 5.4% to 37.4 ± 11.8% (P < .001), LVEDV reduced from 253.0 ± 102.0 ml to 210.3 ± 118.8 ml (P = .017), and LVESV decreased from 186.2 ± 82.5 ml to 139.5 ± 94.4 ml (P = .001). In addition, LV systolic synchrony seemed to improve with a reduction in PSD (49.4° ± 19.5° to 37.2° ± 21.6°, P < .001) and PHB (168.8° ± 77.4° to 122.7° ± 78.9°, P < .001) (Table 2).
Table 1.
Baseline characteristics of patients in groups of recommended, non-recommended, and apex or scar
| All patients (n = 79) | Recommended (n = 41) | Non-recommended (n = 27) | Apex or scar (n = 11) | P value* | P value† | P value‡ | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| Age (years) | 60.8 ± 12.8 | 59.1 ± 11.7 | 65.5 ± 10.4 | 54.0 ± 17.9 | .112 | .682 | .032 |
| NYHA class, II/III/IV, n(%) | 23(29.1)/47(59.5)/9(11.4) | 15(36.6)/23(56.l)/3(7.3) | 6(22.2)/16(59.3)/5(18.5) | 2(18.2)/8(72.7)/1(9.1) | .240 | 1.000 | 1.000 |
| Female sex, n(%) | 25(31.6) | 12(29.3) | 11(40.7) | 2(18.2) | .328 | .705 | .268 |
| BMI (kg/m2) | 23.7 ± 3.4 | 23.8 ± 2.9 | 23.4 ± 3.4 | 23.9 ± 5.0 | 1.000 | 1.000 | 1.000 |
| LBBB, n(%) | 68(86.1) | 37(90.2) | 22(81.5) | 9(81.8) | .466 | .595 | 1.000 |
| QRS duration, ms | 165.6 ± 24.1 | 168.7 ± 23.2 | 160.7 ± 21.5 | 166.2 ± 32.7 | .560 | 1.000 | 1.000 |
| QRS duration <150 ms, n(%) | 22 (27.8) | 9 (22.0) | 9 (33.3) | 4 (36.4) | .298 | .435 | 1.000 |
| Ischemic etiology, n (%) | 14 (17.7) | 5 (12.2) | 7 (25.9) | 2 (18.2) | .197 | .630 | 1.000 |
| Moderate/severe MR, n(%) | 36 (45.6) | 19 (46.3) | 13 (48.1) | 4 (36.4) | .884 | .735 | .721 |
| LV scar burden, % | 30.1 ± 13.2 | 27.7 ± 11.0 | 30.3 ±16.1 | 38.2 ± 10.5 | 1.000 | .059 | .281 |
| PSD, degree | 49.4 ±19.5 | 45.6 ± 18.0 | 51.1 ± 19.0 | 59.7 ± 23.8 | .756 | .100 | .639 |
| PHB, degree | 168.8 ± 77.4 | 156.0 ± 74.2 | 174.0 ± 76.6 | 204.0 ± 85.5 | 1.000 | .206 | .831 |
| LVEDD, mm | 72.5 ± 10.5 | 71.2 ± 8.9 | 71.2 ± 8.7 | 81.0 ± 15.7 | 1.000 | .016 | .021 |
| LVEDD < 80 mm, n(%) | 62 (78.5) | 33 (80.5) | 23 (85.2) | 6 (54.5) | .751 | .116 | .088 |
| LVEDV, ml | 253.0 ± 102.0 | 237.2 ± 86.5 | 242.8 ± 88.2 | 337.0 ± 148.1 | 1.000 | .010 | .025 |
| LVESV, ml | 186.2 ± 82.5 | 172.9 ± 69.3 | 177.8 ± 71.3 | 256.3 ± 119.6 | 1.000 | .007 | .020 |
| LVEF, % | 27.4 ± 5.4 | 28.0 ± 5.2 | 27.2 ± 5.5 | 25.4 ± 5.8 | 1.000 | .467 | 1.000 |
| Beta blocker, n(%) | 56 (70.9) | 29 (70.7) | 21 (77.8) | 6 (54.5) | .519 | .470 | .238 |
| ACEi or ARB, n(%) | 64 (81.0) | 34 (82.9) | 22 (81.5) | 8 (72.7) | 1.000 | .424 | .667 |
| Diuretic agent, n(%) | 73 (92.4) | 38 (92.7) | 26 (96.3) | 9 (81.8) | 1.000 | .283 | .196 |
| Digoxin, n(%) | 41 (51.9) | 20 (48.8) | 14 (51.9) | 7 (63.6) | .804 | .381 | .721 |
NYHA, New York Heart Association; BMI, Body Mass Index; LBBB, left bundle branch block; MR, mitral regurgitation; LV, left ventricular; PSD, phase standard deviation; PHB, phase histogram bandwidth; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker
Recommended vs. non-recommended
Recommended vs. apex or scar
non-recommended vs. apex or scar
Table 2.
NYHA class, echocardiography, and SPECT MPI at follow-up according to LV lead position
| All patients (n = 79) | Recommended (n = 41) | Non-recommended (n = 27) | Apex or scar (n = 11) | P value* | P value† | P value‡ | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| NYHA class, n(%) | |||||||
| 6 months, I/II/III | 21 (26.6)/48(60.8)/10(12.7) | 11 (26.8)/23(56.1)/7(17.1) | 9(33.3)/17(63.0)/1(3.7) | 1(9.1)/8(72.7)/2(18.2) | .242 | 1.000 | .238 |
| Improvement by ≥ 1 class | 58(73.4) | 28(68.3) | 22(81.5) | 8(72.7) | .228 | 1.000 | .298 |
| LVEDV, ml | |||||||
| 6 months | 210.3 ± 118.8 | 183.0 ± 82.3 | 204.3 ± 98.1 | 327.2 ± 199.5 | 1.000 | .001 | .008 |
| Δ | −42.7 ± 82.5 | −54.2 ± 56.3 | −38.6 ± 63.7 | −9.8 ± 167.4 | 1.000 | .347 | .993 |
| LVESV, ml | |||||||
| 6 months | 139.5 ± 94.4 | 118.6 ± 72.0 | 136.8 ± 85.2 | 224.3 ± 142.2 | 1.000 | .002 | 0.022 |
| Δ | −46.6 ± 64.7 | −54.3 ± 47.3 | −41.0 ± 53.6 | −32.0 ± 125.3 | 1.000 | .948 | 1.000 |
| Relative change, % | −26.4 ± 30.7 | −33.5 ± 23.7 | −23.5 ± 33.2 | −7.2 ± 40.5 | .542 | .033 | 0.387 |
| LVEF, % | |||||||
| 6 months | 37.4 ± 11.8 | 39.1 ± 11.8 | 36.7 ± 12.8 | 32.9 ± 8.7 | 1.000 | .373 | 1.000 |
| Δ | 10.1 ± 10.4 | 11.1 ± 10.0 | 9.5 ±11.8 | 7.6 ± 8.5 | 1.000 | .948 | 1.000 |
| PSD, degree | |||||||
| 6 months | 37.2 ± 21.6 | 28.1 ± 15.2 | 42.9 ± 22.2 | 57.9 ± 23.4 | .010 | < .001 | .099 |
| Δ | −13.1 ± 22.1 | −17.8 ± 20.0 | −10.4 ± 19.7 | −1.8 ± 30.3 | .561 | .099 | .841 |
| PHB, degree | |||||||
| 6 months | 122.7 ± 78.9 | 88.2 ±51.3 | 140.4 ± 75.9 | 209.6 ± 93.5 | .011 | < .001 | .018 |
| Δ | −49.5 ± 86.1 | −69.1 ± 78.5 | −42.3 ± 75.6 | 5.6 ± 112.5 | .648 | .031 | .355 |
NYHA, New York Heart Association; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; PSD, phase standard deviation; PHB, phase histogram bandwidth
Recommended vs. non-recommended
Recommended vs. apex or scar
non-recommended vs. apex or scar
Baseline and 6-Month Follow-Up After CRT
41 patients (51.9%) had a recommended LV lead position, whereas 27 patients (34.2%) had an LV lead position located in the non-recommended segment and 11 patients (13.9%) had LV lead pacing in the apex or scarred region. The comparison of baseline and 6-month characteristics among these 3 groups is shown in Table 1. No significant differences were found in any baseline characteristic between the recommended and non-recommended groups. Both PSD (28.1° ± 15.2° vs. 42.9° ± 22.2°, P = .010) and PHB (88.2° ± 51.3° vs. 140.4° ± 75.9°, P = .011) became statistically lower in the recommended group than in the non-recommended group at 6 months after CRT (Table 2). The LVESV and LVEDV of patients in the apex or scar group were the largest at baseline (Table 1). At 6-month follow-up, only the recommended group showed a significant percent reduction of LVESV compared with the apex or scar group (− 33.5 ± 23.7% vs. − 7.2 ± 40.5%, P = .033) but not the non-recommended group (−23.5 ± 33.2% vs. − 7.2 ± 40.5%, P = .387). Importantly, patients with LV lead located at the apex or scarred segment showed the most unfavorable changes on echocardiography and mechanical dyssynchrony (Table 2).
Volumetric Response
The volumetric response rates were 66.2% (45 of 68) in the patients whose LV lead was in the non-apical or scarred segments, and 27.3% (3 of 11) in the patients with LV lead positioning in the apex or scarred segments (P = .014) (Figure 2). Except for 11 patients whose LV lead was placed in the apex or scarred regions, 75.6% (31 of 41) of the patients whose LV leads were placed in the recommended segments responded to CRT compared with 51.9% (14 of 27) of the patients whose LV leads were placed in non-recommended segments (P = .043) (Figure 3). When the LV lead position was in the first three late contracting viable segments (defined as the first 3 segments), the response rate was 69.4% (25 of 36); by contrast, it was 62.5% (20 of 32) when the LV lead position was in the last five relatively early contracting viable segments (defined as the last 5 segments) (P = .546) (Figure 4A). Furthermore, when the LV lead position was in the first 3 and recommended segments (meeting the recommended conditions), the response rate was 76.7%, but it dropped to 57.1% when the LV lead position was in the last 5 and non-recommended segments (neither the 2nd nor the 3rd recommendations) (P = .139) (Figure 4B). Among 41 patients with recommended LV lead positions, the CRT response rates were 76.9% when LV lead placed in the optimal recommendation (n = 13), 76.9% when in the 2nd recommendation (n = 13), and 73.3% when in the 3rd recommendation (n = 15) (P = .967) (Figure 5).
Figure 2.
Response rates from the non-apex or scar group and the apex or scar group. Volumetric response rates after CRT in patients whose LV leads were in the non-apex and viable segments (n = 68) and patients whose LV leads were in apex or scarred segments (n = 11) (66.2% vs. 27.3%, P = .014).
Figure 3.
Response rates from recommended and non-recommended segments. Volumetric response rates in patients with recommended LV lead positions (n = 41) and patients with non-recommended LV lead positions (n = 27) (75.6% vs. 51.9%, P = .043).
Figure 4.
Response rates when left ventricular lead was at the site with different contraction delays. Volumetric response rates after CRT in (A) patients whose LV lead positions were in the first three late contracting segments (n = 36) and patients whose LV leads were in the last five relatively early contracting segments (n = 32) (69.4% vs. 62.5%, P = .546); (B) patients whose LV lead positions were in the first three late contracting and recommended segments (n = 30) and patients whole LV leads were in the last five relatively early contracting but non-recommended segments (n = 21) (76.7% vs. 57.1%, P = .139).
Figure 5.
Response rates from three levels of recommendation. Volumetric response rates after CRT in patients concordant with the optimal recommendation (n = 13), patients concordant with the 2nd recommendation (n = 13), and patients concordant with the 3rd recommendation (n = 15) (76.9%, 76.9%, and 73.3%, P = .967).
In the univariate logistic regression analysis (Table 3), there was a significant association between volumetric response to CRT and QRS duration ≥ 150 ms, LVEDD < 80 mm, and recommended LV lead position. In the multivariable logistic regression analyses, LV lead placed in the recommended segments was still independently associated with volumetric response compared to in the non-recommended positions (odds ratio [OR] 3.397; 95% confidence interval [CI] 1.041–11.086) or in the apex or scarred region (OR 6.076; 95% CI 1.169–31.594).
Table 3.
Logistic regression analyses to identify binary variables associated with volumetric response to CRT
| Univariate | Multivariate | |||
|---|---|---|---|---|
|
|
|
|||
| OR (95% CI) | P value | OR (95% CI) | P value | |
|
| ||||
| Female | 2.057 (0.738–5.733) | .168 | ||
| Ischemic etiology | 1.200 (0.361–3.986) | .766 | ||
| QRS duration < 150 ms | 0.243 (0.086–0.685) | .008 | 0.227 (0.070–0.728) | .013 |
| LBBB | 2.064 (0.571–7.462) | .269 | ||
| ACEi/ARB | 0.731 (0.224–2.387) | .604 | ||
| PSD ≥ 43° | 1.263 (0.494–3.232) | .626 | ||
| PHB ≥ 140° | 0.884 (0.351–2.225) | .794 | ||
| LVEDD < 80 mm | 5.432 (1.678–17.583) | .006 | 6.404 (1.650–24.847) | .007 |
| LV lead segment | ||||
| Recommended vs. non-recommended | 2.879 (1.109–8.130) | .046 | 3.397 (1.041–11.086) | .043 |
| Recommended vs. apex or scar | 8.267 (1.833–37.280) | .006 | 6.076 (1.169–31.594) | .032 |
| Non-recommended vs. apex or scar | 2.872 (0.624–13.218) | .176 | ||
LBBB, left bundle branch block; ACEi, angiotensin-converting enzyme Inhibitors; ARB, angiotensin receptor blockers; PSD, phase standard deviation; PHB, phase histogram bandwidth; LVEDD, left ventricular end-diastolic diameter
Long-Term Prognosis
Over a median follow-up of 49 months (IQR 40–57 months), 16 (20.3%) of the 79 patients died, including 4 (9.8%) in the recommended group, 7 (25.9%) in the non-recommended group, and 5 (45.5%) in the apex or scar group. The analytical focus for these mortalities was not on any specific cause of death. There were 9 (22.0%) composite events (all-cause mortality or HF rehospitalization) in the recommended group, 14 (51.9%) in the non-recommended group, and 7 (63.6%) in the apex or scar group. The recommended group had lower all-cause mortality and fewer composite events compared with the apex or scar group (log-rank χ2 = 7.478, P = .006; log-rank χ2 = 8.007, P = .005, respectively). Meanwhile, no significant differences in Kaplan-Meier survival analyses were found for all-cause mortality (log-rank χ2 = 1.429, P = .232) and composite events (log-rank χ2 = 1.118, P = .290) between the non-recommended group and the apex or scar group. In terms of all-cause mortality or HF rehospitalization, the recommended group showed better long-term prognosis than the non-recommended group (log-rank χ2 = 5.623, P = .018) (Figure 6).
Figure 6.
Kaplan-Meier curves comparing three groups. Survival and cardiovascular death or HF rehospitalization after CRT. Kaplan-Meier survival curves for (A) all-cause mortality and (B) the composite events of all-cause mortality or HF rehospitalization among three groups: recommended, non-recommended, and apex or scar.
DISCUSSION
The significant findings of this retrospective analysis study were as follows: (1) CRT patients with the recommended LV lead site from SPECT MPI had a significantly higher volumetric response and better long-term prognosis. (2) When the LV leads were placed in the three recommended levels (the optimal, 2nd, and 3rd), there was a similar and favorable effect on CRT volumetric response. (3) The apex or scarred LV segment was associated with lower CRT response and poorer long-term prognosis.
The Significance of Mechanical Dyssynchrony and LV Lead Position to CRT
The purpose of CRT is to recover atrioventricular, interventricular, and left intraventricular mechanical synchronization. LV systolic function similarly improves when either biventricular or LV pacing resynchronizing intraventricular contractions, which suggests that LV mechanical dyssynchrony may be the most important to therapeutic effect.14 LV electrical dyssynchrony manifesting as prolonged QRS duration generates both early and late contracting regions. However, QRS morphology and duration only represent global ventricular depolarization and cannot convey the extent of delayed conduction in the single ventricular segment. Electromechanical dissociation was observed in various studies so the QRS duration failed to correlate positively with LV mechanical dyssynchrony.20 A number of studies showed that the baseline QRS duration was unable to predict response to CRT,20 whereas the presence of LV mechanical dyssynchrony improved response rate and predicted long-term benefit from CRT.11,21,22 Among patients with coronary heart disease, left ventricular mechanical dyssynchrony measured by gated SPECT MPI has a stronger relationship with adverse outcomes.23,24 In the present study, PSD and PHB at baseline (49.0° ± 16.7° vs. 50.0° ± 23.6°, P = .854; 164.4° ± 68.7° vs. 175.7° ± 90.0°, P = .553) did not show any difference between responders and non-responders but became statistically lower at 6-month follow-up in responders compared with non-responders (29.0° ± 16.9° vs. 49.5° ± 22.4°, P < .001; 93.0° ± 62.7° vs. 167.2° ± 80.7°, P < .001) . We hypothesized that patients who showed a volumetric response to CRT were accompanied by the reestablishment of left ventricular systolic synchrony. Mechanical resynchronization makes the left ventricle work more efficiently which has a beneficial effect on LV reverse remodeling.
As mechanical rather than electrical dyssynchrony is important for CRT, pacing at the latest contracting LV site should be the guiding recommendation to generate mechanical coordination. Recently, myocardial imaging techniques, including echocardiography, CMR and gated SPECT MPI have been used to recommend LV lead positions for CRT. Several clinical studies, such as the TARGET,7 the STARTER,25 the CMR-CRT,26 and the Imaging CRT,27 have claimed that pacing at the latest contracting LV site improves the CRT response. Dekker et al28 showed that a small displacement of LV lead was related to a great variation of LV stroke volume and dP/dtmax, indicating that the distribution of LV mechanical dyssynchrony was heterogeneous. The standard strategy for CRT device implantation is to target LV lead to the non-apex and lateral or posterolateral wall.4 However, the gated SPECT MPI in our study showed that the optimal LV leads position should be segments of the anterior wall in 30 patients (38.0%), of the anterolateral wall in 17 patients (21.5%), of the posterolateral wall in 27 patients (34.2%), and of the posterior wall in 5 patients (6.3%). A considerable proportion of optimal LV lead positions were in the region of the anterior wall. Therefore, a patient-specific recommendation of LV lead positions may improve the CRT response.
Multiple Recommendations for LV Lead Segments and CRT Efficacy
This study tested a novel method of recommendation that the late contracting viable segments can be candidate sites for the LV lead placement. However, the number of LV segments whose contraction delays were within 10° of the largest phase angle might be very limited if LV synchronization was poor. Our previous study showed that it is uncommon to recommend multiple late contracting segments (52.8% for only one segment and 11.1% for four alternative segments, respectively).10 In the present study, 44.3% of the patients (35 of 79) did not have any late contracting viable segment; furthermore, in the other patients (55.7%, 44 of 79) with the presence of late contracting viable segments, there were two candidate segments for 17 patients (38.6%), three segments for 17 patients (38.6%), and four segments at maximum for 10 patients (22.7%). Based on these findings, we would recommend the segments adjacent to the optimal site for implantation of LV lead if the late contracting viable segment did not exist.
In the TARGET study,7 70% of patients in the target group showed volumetric response after 6 months of CRT compared with 55% in the control group. The overall volumetric response rate in our study was 60.8%, and the recommended group had an improved rate of 75.6%. Stimulating the recommended segments was also independently associated with volumetric response to CRT in the multivariable logistic regression analysis. Our results indicated that pacing at any of the three recommendations brings a similar CRT response rate. In terms of the long-term prognosis, the benefit from the recommended LV lead position was statistically superior to the non-recommended group for the composite events of all-cause mortality or HF rehospitalization.
The Clinical Significance of Multiple Recommendations for the LV Lead Position
The MADIT-CRT study demonstrated an unfavorable clinical prognosis when LV leads were implanted in the apex site.29 In the present study, we also found that patients pacing at the LV apex site had a low volumetric response to CRT (25%, 1 of 4) and poor long-term prognosis. Adelstein et al30 and White et al31 reported that a high scar burden in CRT patients was associated with reduced clinical outcomes and lack of LV systolic improvement, while our results showed that baseline LV scar burden was higher in non-responders than responders (34.9 ± 13.8% vs. 27.0 ± 12.0%, P = .009), which together indicated the possible inadequacy of CRT for patients with severe LV scar burden. Furthermore, several studies have shown that pacing at the LV sites of scarred myocardium relates to inferior efficacy.2,7 Even though LV lead was routinely implanted in the posterolateral wall, transmural scar at LV pacing site was associated with non-response to CRT.32 Electrical stimulation in scarred segments could not transform into valid mechanical activation due to the delayed conduction and poor kinematic performance of those nonviable sites.14 Our results showed that implanting LV lead in the scarred region brought negative influence on LV reverse remodeling and increased clinical events.
The latest contracting viable segment from myocardial imaging, recommended as the optimal LV pacing site, is usually unique and may not match with any available venous branch due to the variability of CS anatomy or lead stability.33 Our results demonstrate that multiple recommendations by gated SPECT MPI can improve the possibility of pacing at recommended LV segments and increase volumetric response rate after CRT. In our study, the volumetric response rates were 76.9%, 76.9%, and 73.3%, respectively, when pacing in the optimal recommendation, the 2nd recommendation, and the 3rd recommendation. Possible reasons to explain why the response rate from the optimal recommendation was not higher are summarized as follows: (1) As QRS duration ≥ 130 ms at least has been recognized as a powerful predictor of CRT response,34 1 of the 3 non-responders had a relatively narrow intrinsic QRS duration of 128 ms; (2) The pre-CRT LVEDDs of 2 non-responders were both 87 mm indicating that the LV size was too large. Rickard et al35 have reported that the larger baseline LVEDD was merely associated with mild improvement of LV function.
More importantly, it is worth noticing that several kinds of LV segments should be avoided from lead placement. Firstly, we found that pacing at the LV apex or scarred region resulted in a low response rate and poor long-term prognosis. Secondly, the segments with relatively early contraction may reduce the response rate, so they should be avoided. In the patients (n = 9) whose LV lead positions were at the last 3 segments (early contracting), but not adjacent to the optimal segment, the volumetric response rate was as low as 44.4%. We also classified patients into two groups, the first 3 segments and the last 5 segments. However, the response rates did not exhibit any statistical difference. Based on SPECT MPI, patients whose LV lead position was in the first 3 segments meeting the recommendation conditions had an increased response rate while the response rate of patients whose LV lead position was in the last 5 non-recommended segments decreased.
After recommending LV lead segments, it is important to place the LV lead in the target segments with the guidance of our 3D fusion tool.33 A large prospective clinical trial will be scheduled to validate our approach for CRT, which not only recommends the LV lead positions but also guides the real-time procedure by 3D fusion. Accordingly, the present results are essential to guide future trials.
STUDY LIMITATIONS
This is a retrospective and observational study with a small number of patients. Large randomized prospective trials are needed to validate the clinical values of gated SPECT MPI for guiding the placement of CRT LV lead.
The echocardiographic volumetric response was used to measure the main outcome, but other indices such as LVEF and NYHA class did not show significant change. Moreover, important clinical parameters, such as quality of life or 6-minute walking test were not assessed. The follow-up period covered by this study was relatively short. The gated SPECT MPI has a relatively low spatial and temporal resolution, which may influence the recommendation of CRT LV pacing sites.
CONCLUSIONS
Pacing in the recommended LV segments identified on gated SPECT MPI was associated with improved CRT volumetric response and long-term prognosis. The findings in the present study merit larger and prospective studies in the future.
Supplementary Material
Acknowledgments
We appreciate Daniel McGonigle, a master student of Computer Science at USM and Zhuo He, a PhD student of Computer Science at USM for proofreading the manuscript.
This research was supported by grants from the Science and Technology Department of Jiangsu Province (Social Development-Clinical Frontier Technology Foundation) (Project Number: BE2016764, PI: Jiangang Zou) and the American Heart Association (Project Number: 17AIREA33700016, PI: Weihua Zhou).
Abbreviations
- CRT
Cardiac resynchronization therapy
- CS
Coronary sinus
- LV
Left ventricle/ventricular
- MPI
Myocardial perfusion imaging
- SPECT
Single-photon emission computed tomography
Footnotes
Disclosure
Ernest V. Garcia receives royalties from the sales of Emory Cardiac Toolbox. The terms of this arrangement have been reviewed and approved by Emory University in accordance with it is conflict-of-interest practice. Xinwei Zhang, Zhiyong Qian, Haipeng Tang, Wei Hua, Yangang Su, Geng Xu, Xingbin Liu, Xiaolin Xue, Jie Fan, Lin Cai, Li Zhu, Yao Wang, Xiaofeng Hou, Weihua Zhou and Jiangang Zou do not have anything to declare.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12350-019-01735-7) contains supplementary material, which is available to authorized users.
The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarises the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.com.
References
- 1.Birnie DH, Tang AS. The problem of non-response to cardiac resynchronization therapy. Curr Opin Cardiol 2006;21:20–6. [DOI] [PubMed] [Google Scholar]
- 2.Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, de Roos A, van der Wall EE, Schalij MJ, Bax JJ. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 2006;113(7):969–76. [DOI] [PubMed] [Google Scholar]
- 3.Marsan NA, Westenberg JJ, Ypenburg C, van Bommel RJ, Roes S,Delgado V, Tops LF, van der Geest RJ, Boersma E, de Roos A, Schalij MJ, Bax JJ. Magnetic resonance imaging and response to cardiac resynchronization therapy: Relative merits of left ventricular dyssynchrony and scar tissue. Eur Heart J 2009;30:2360–7. [DOI] [PubMed] [Google Scholar]
- 4.Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2013;34:2281–329. [DOI] [PubMed] [Google Scholar]
- 5.Wong JA, Yee R, Stirrat J, Scholl D, Krahn AD, Gula LJ, Skanes AC, Leong-Sit P, Klein GJ, McCarty D, Fine N, Goela A, Islam A, Thompson T, Drangova M, White JA. Influence of pacing site characteristics on response to cardiac resynchronization therapy. Circ Cardiovasc Imaging 2013;6:542–50. [DOI] [PubMed] [Google Scholar]
- 6.Shetty AK, Duckett SG, Ginks MR, Ma Y, Sohal M, Bostock J, Kapetanakis S, Singh JP, Rhode K, Wright M, O’Neill MD, Gill JS, Carr-White G, Razavi R, Rinaldi CA. Cardiac magnetic resonance-derived anatomy, scar, and dyssynchrony fused with fluoroscopy to guide LV lead placement in cardiac resynchronization therapy: A comparison with acute haemodynamic measures and echocardiographic reverse remodelling. Eur Heart J Cardiovasc Imaging 2013;14:692–9. [DOI] [PubMed] [Google Scholar]
- 7.Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O’Halloran D, Elsik M, Read PA, Begley D, Fynn SP, Dutka DP. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET Study: A randomized, controlled trial. J Am Coll Cardiol 2012;59:1509–18. [DOI] [PubMed] [Google Scholar]
- 8.Friehling M, Chen J, Saba S, Bazaz R, Schwartzman D, Adelstein EC, Garcia E, Follansbee W, Soman P. A prospective pilot study to evaluate the relationship between acute change in left ventricular synchrony after cardiac resynchronization therapy and patient outcome using a single-injection gated SPECT protocol. Circ Cardiovasc Imaging 2011;4:532–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Boogers MJ, Chen J, van Bommel RJ, Borleffs CJ, Dibbets-Schneider P, van der Hiel B, Al Younis I, Schalij MJ, van der Wall EE, Garcia EV, Bax JJ. Optimal left ventricular lead position assessed with phase analysis on gated myocardial perfusion SPECT. Eur J Nucl Med Mol Imaging 2011;38:230–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zhou W, Tao N, Hou X, Wang Y, Folks RD, Cooke DC, Moncayo VM, Garcia EV, Zou J. Development and validation of an automatic method to detect the latest contracting viable left ventricular segments to assist guide CRT therapy from gated SPECT myocardial perfusion imaging. J Nucl Cardiol 2018;25(6):1948–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Beela AS, Ünlü S, Duchenne J, Ciarka A, Daraban AM, Kotrc M, Aarones M, Szulik M, Winter S, Penicka M, Neskovic AN, Kukulski T, Aakhus S, Willems R, Fehske W, Faber L, Stankovic I, Voigt JU. Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy. Eur Heart J Cardiovasc Imaging 2018;0:1–9. [DOI] [PubMed] [Google Scholar]
- 12.Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J 3rd, St John Sutton M, De Sutter J, Murillo J. Results of the predictors of response to CRT (PROSPECT) trial. Circulation 2008;117:2608–16. [DOI] [PubMed] [Google Scholar]
- 13.St John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, Moyé LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation 1994;89:68–75. [DOI] [PubMed] [Google Scholar]
- 14.Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–94. [DOI] [PubMed] [Google Scholar]
- 15.White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1986;1:44–51. [DOI] [PubMed] [Google Scholar]
- 16.Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, Chan YS, Kong SL, Bax JJ. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580–6. [DOI] [PubMed] [Google Scholar]
- 17.Garcia EV, Cooke CD, Van Train KF, Folks R, Peifer J, DePuey EG, Maddahi J, Alazraki N, Galt J, Ezquerra N. Technical aspects of myocardial SPECT imaging with technetium-99 m sestamibi. Am J Cardiol 1990;66:23E–31E. [DOI] [PubMed] [Google Scholar]
- 18.Zhou W, Garcia EV. Nuclear image-guided approaches for CRT. Curr Cardiol Rep 2016;18:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Chen J, Garcia EV, Folks RD, Cooke CD, Faber TL, Tauxe EL, Iskandrian AE. Onset of left ventricular mechanical contraction as determined by phase analysis of ECG-gated myocardial perfusion SPECT imaging: Development of a diagnostic tool for assessment of cardiac mechanical dyssynchrony. J Nucl Cardiol 2005;12:687–95. [DOI] [PubMed] [Google Scholar]
- 20.Khan FZ, Virdee MS, Fynn SP, Dutka DP. Left ventricular lead placement in cardiac resynchronization therapy: Where and how? Europace 2009;11:554–61. [DOI] [PubMed] [Google Scholar]
- 21.Tayal B, Gorcsan J, Bax JJ, Risum N, Olsen NT, Singh JP, Abraham WT, Borer JS, Dickstein K, Gras D, Krum H, Brugada J, Robertson M, Ford I, Holzmeister J, Ruschitzka F, Sogaard P. Cardiac resynchronization therapy in patients with heart failure and narrow QRS complexes. J Am Coll Cardiol 2018;71:1325–33. [DOI] [PubMed] [Google Scholar]
- 22.Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Doppler Myocardial imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing. J Am Coll Cardiol 2002;39:489–99. [DOI] [PubMed] [Google Scholar]
- 23.Hess PL, Shaw LK, Fudim M, Iskandrian AE, Borges-Neto S. The prognostic value of mechanical left ventricular dyssynchrony defined by phase analysis from gated single-photon emission computed tomography myocardial perfusion imaging among patients with coronary heart disease. J Nucl Cardiol 2017;24:482–90. [DOI] [PubMed] [Google Scholar]
- 24.Fudim M, Fathallah M, Shaw LK, Liu PR, James O, Samad Z, Piccini JP, Hess PL, Borges-Neto S. The prognostic value of diastolic and systolic mechanical left ventricular dyssynchrony among patients with coronary heart disease. JACC Cardiovasc Imaging 2018;18:1876–7591. [DOI] [PubMed] [Google Scholar]
- 25.Saba S, Marek J, Schwartzman D, Jain S, Adelstein E, White P, Oyenuga OA, Onishi T, Soman P, Gorcsan J 3rd. Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: Results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial. Circ Heart Fail 2013;6:427–34. [DOI] [PubMed] [Google Scholar]
- 26.Kočková R, Sedláček K, Wichterle D, Šikula V, Tintěra J, Jansová H, Pravečková A, Langová R, Krýže L, El-Husseini W, Segetová M, Kautzner J. Cardiac resynchronization therapy guided by cardiac magnetic resonance imaging: A prospective, single-centre randomized study (CMR-CRT). Int J Cardiol 2018;270:325–30. [DOI] [PubMed] [Google Scholar]
- 27.Sommer A, Kronborg MB, Nørgaard BL, Poulsen SH, Bouche-louche K, Böttcher M, Jensen HK, Jensen JM, Kristensen J, Gerdes C, Mortensen PT, Nielsen JC. Multimodality imaging-guided left ventricular lead placement in cardiac resynchronization therapy: a randomized controlled trial. Eur J Heart Fail 2016;18:1365–74. [DOI] [PubMed] [Google Scholar]
- 28.Dekker AL, Phelps B, Dijkman B, van der Nagel T, van der Veen FH, Geskes GG, Maessen JG. Epicardial left ventricular lead placement for cardiac resynchronization therapy: optimal pace site selection with pressure-volume loops. J Thorac Cardiovasc Surg 2004;127:1641–7. [DOI] [PubMed] [Google Scholar]
- 29.Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, Cannom D, Goldenberg I, McNitt S, Daubert JP, Zareba W, Moss AJ. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011;123:1159–66. [DOI] [PubMed] [Google Scholar]
- 30.Adelstein EC, Tanaka H, Soman P, Miske G, Haberman SC, Saba SF, Gorcsan J 3rd. Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy. Eur Heart J 2011;32:93–103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.White JA, Yee R, Yuan X, Krahn A, Skanes A, Parker M, Klein G, Drangova M. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol 2006;48:1953–60. [DOI] [PubMed] [Google Scholar]
- 32.Delgado V, van Bommel RJ, Bertini M, Borleffs CJ, Marsan NA, Arnold CT, Nucifora G, van de Veire NR, Ypenburg C, Boersma E, Holman ER, Schalij MJ, Bax JJ. Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy. Circulation 2011;123:70–8. [DOI] [PubMed] [Google Scholar]
- 33.Zhou W, Hou X, Piccinelli M, Tang X, Tang L, Cao K, Garcia E, Zou J, Chen J. 3D fusion of LV venous anatomy on fluoroscopy venograms with epicardial surface on SPECT myocardial perfusion images for guiding CRT LV lead placement. JACC 2014;7:1239–48. [DOI] [PubMed] [Google Scholar]
- 34.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–200.27206819 [Google Scholar]
- 35.Rickard J, Brennan DM, Martin DO, Hsich E, Tang WH, Lindsay BD, Starling RC, Wilkoff BL, Grimm RA. The impact of left ventricular size on response to cardiac resynchronization therapy. Am Heart J 2011;162:646–53. [DOI] [PubMed] [Google Scholar]
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