Biventricular paced QRS predictors of left ventricular lead locations in relation to mortality in cardiac resynchronization therapy

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ScienceDirect Journal of Electrocardiology 48 (2015) 226 – 235 www.jecgonline.com

Biventricular paced QRS predictors of left ventricular lead locations in relation to mortality in cardiac resynchronization therapy John M. Fontaine, MD, MBA,⁎ Ashwani Gupta, MD, Sona M. Franklin, MD, Christina U. Kang, DO, Latrisha A. Whigham, MS Division of Cardiology, Electrophysiology Section, Drexel University College of Medicine, Philadelphia, PA, USA

Abstract

Background: Left ventricular (LV) lead location during cardiac resynchronization therapy (CRT) has influenced mortality and heart failure events; however the biventricular paced QRS morphology has not been established as a predictor of LV lead location or mortality. Methods: We evaluated the biventricular paced QRS morphology in 306 patients undergoing CRT in relation to specific anatomic locations. A logistic regression model and Kaplan–Meier survival estimates were used to determine predictors of LV lead location and survival. Results: The mean age was 68 ± 13 years. Predictors of LV lead location from anterior, lateral, and posterior segments were: absence of R in V1, QS in aVL; and R in aVL, respectively. Absence of an R in II, III, or aVF predicted an inferior site. A QS in V4–V6 differentiated apical from basal sites (p = 0.01). LV pacing from sites along the middle cardiac vein revealed a higher mortality (34%), than lateral sites (20%, p = 0.02). Conclusions: Biventricular paced QRS criteria were predictive of LV lead locations. The proposed algorithm enhanced the predictive accuracy of these criteria. LV pacing sites along the middle cardiac vein were associated with increased mortality. © 2015 Elsevier Inc. All rights reserved.

Keywords:

Biventricular pacing; Cardiac resynchronization therapy; Congestive heart failure; Electrocardiogram; Implantable defibrillator

Introduction Cardiac resynchronization therapy (CRT) is an effective treatment modality in the management of patients with congestive heart failure, reduced left ventricular ejection fraction (LVEF), prolonged QRS duration; and has resulted in improvement in functional capacity, reduced mortality and hospitalization for worsening heart failure [1–5]. Nonresponders comprise approximately 30% of patients undergoing such therapy [1,4]. Previous studies revealed that pacing the left ventricle (LV) from the lateral or posterolateral wall is preferred for effective CRT [1,6–8]. The ability to pace from optimal LV sites is limited by local myocardial fibrosis, lack of suitable coronary veins, lead stability, phrenic nerve stimulation, and high pacing threshold. Biventricular pacing from anterior, apical and posterior vein sites has been associated with increased mortality or adverse outcomes indicating that the response to CRT is in-part related to LV lead location [9–12]. ⁎ Corresponding author at: Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA 19102-1192, USA. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2014.12.011 0022-0736/© 2015 Elsevier Inc. All rights reserved.

A recent meta-analysis concluded that the baseline QRS duration (N 140 ms) is a powerful predictor of responders to CRT [13]. However, the biventricular paced QRS duration has not been viewed similarly nor has its morphology been evaluated in relation to LV pacing sites. Despite fair characterization of the biventricular paced QRS morphology from a previous investigation and that of others, specific criteria predictive of optimal or suboptimal LV lead locations or outcomes are lacking [14,15]. The objectives of this study were to determine the electrocardiographic manifestation of the QRS complex during biventricular pacing from LV sites identified radiographically, assess its relation to LV lead location, and determine QRS criteria that predict optimal and suboptimal LV pacing sites. Additionally, we provided corroboration of optimal and suboptimal sites via an assessment of survival outcome associated with pacing from those sites. Methods The biventricular paced QRS morphology from the 12-lead electrocardiogram (ECG) was evaluated in 306 patients with an

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LVEF ≤ 35%, baseline QRS duration ≥ 120 ms, and New York Heart Association (NYHA) functional class II–IV heart failure who underwent initial device implantation for CRT or generator change at our institution. To confirm the relationship between LV lead location and adverse outcome, we evaluated death from all-causes in relation to biventricular pacing. Employing radiographic assessment of the cardiac silhouette in the short and long-axis, as done in previous studies, we identified anterior, lateral, inferior and posterior segments, as well as apical, mid and basal LV segments for analysis (Fig. 1) [9–12]. Radiographic segments were determined by dividing the short and long-axis views into equidistant regions. The borders of the long axis (posterior-anterior view) were drawn between the apex and the coronary sinus os which identified the left AV groove or base of the heart; whereas the short axis borders (lateral view) were defined by the anterior and posterior margins of the cardiac silhouette. A total of 175 permutations of QRS morphologies during biventricular pacing were studied. We evaluated the presence of a dominant R wave in lead V1 (R/S ratio N 1), simulating a right bundle branch block (RBBB), a QS or qR in lead I and aVL, a left bundle branch block (LBBB) pattern in V1, and presence or absence of R waves in leads II, III or aVF independently and collectively. The sensitivity, specificity, predictive value, receiver operating characteristics, and area under the curve (AUC) of these dichotomous variables for LV lead location were calculated. QRS morphologies that differentiated LV

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pacing sites within the short and long-axis were determined. Since beneficial responses to CRT have been documented from lateral and posterolateral pacing sites, we combined all lateral sites, considered them an optimal site, and determined survival outcome from that site compared with anterior, mid-posterior, posterobasal, inferior and apical sites. Since the apical site is generally accessed via the middle cardiac vein (MCV), we combined these sites (posterobasal-septal, inferior-posterior and apical sites), which are located along the course of this vessel, and compared survival outcome from the MCV site with lateral and other sites. A QRS morphology algorithm was developed to identify pacing from precise LV lead locations. Biventricular pacing was performed with the right ventricular lead positioned at the apex. LV to right ventricular activation time was simultaneous, or the LV was paced first by varying time values of pre-activation. None of the patients had right ventricular pre-activation programmed. Interpretation of LV lead location and ECG analysis were performed by an investigator (JMF) in a blinded fashion. Patients with evidence of LV lead dislodgement or malfunction of any lead were excluded. Patient profile included age, gender, race, type of heart disease, laboratory data and medication use. Only patients with complete datasets who underwent device implantation at our institution were included. Data were collected prospectively and subsequently analyzed with appropriate blinding of study variables relative to LV lead location. The study protocol was approved by the university's institutional review board.

Fig. 1. Chest X-rays in the posterior-anterior and left lateral views depicting anatomic segments and LV lead locations. The left lateral view (panels B and D) includes anterior, lateral, inferior and posterior segments; and posterior-anterior view (panels A and C) includes apical, mid and basal segments. Panels A and B illustrate an LV lead positioned in a basal lateral site (arrowhead); whereas panels C and D show an LV lead placed within the middle cardiac vein that courses through the posterobasal-septal, and inferior LV regions with its final position in the apex (arrowhead).

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Statistics Continuous variables are reported as mean ± SD. Categorical data are expressed as percentages or numeric values. Continuous variables were compared using the Student's t-test, and the Kruskal–Wallis rank test for nonparametric data. Multiple comparisons of continuous data were analyzed using analysis of variance. Pearson's chi-square and Fisher's exact tests were used to analyze categorical data. Calculation of sensitivity, specificity and predictive value of the biventricular paced QRS was performed to determine which criteria predicted LV lead location from radiographic segments in the short and long-axis. Multiple logistic regression analysis was used to determine independent predictors of anterior, lateral, posterior and inferior LV lead locations, and for the presence of interaction among covariates. A binary logistic regression model was also applied to assess predictors of lead location from all LV pacing sites. Death from all-causes was the only outcome variable studied. Survival was calculated from the time of initial device implantation. Kaplan–Meier survival estimates were calculated in relation to LV lead locations and several clinical predictor variables. Pairwise comparisons of survival in patients with lateral LV leads with other lead locations were undertaken. A Cox proportional regression model was used to determine hazard rates. Log-rank and Wilcoxon tests were used to compare survival estimates. Survival data were derived from follow-up data and the Social Security Death Index. A P value of b 0.05 was considered statistically significant. Statistical analysis was performed using the IBM SPSS Inc. Statistics software package version 20 (Chicago, IL, USA).

Results There were 306 patients with a mean age of 68 ± 13 years, followed for 4.3 ± 2.7 years (range 1–12). Baseline clinical characteristics of study patients are shown in Table 1. A threedimensional representation of the 10 LV pacing sites and frequency distribution are shown in Fig. 2. The mean QRS duration was 148 ± 20 ms; however in 41 patients, analysis of the baseline intrinsic QRS duration was not feasible due to a paced QRS secondary to complete heart block. Biventricular paced QRS morphology criteria ascribed to specific LV lead locations, sensitivity, specificity and predictive values are shown in Table 2. Illustrated are univariate criteria used to differentiate LV pacing sites in the short and long-axis. Based on the AUC, criteria that best predicted LV lead location in anterior, lateral, posterior, and inferior segments were: absence of dominant R in lead V1 (an LBBB pattern), a QS in aVL, R or r in aVL, and absence of an R in leads II, III, or aVF, respectively. Those criteria that best predicted LV pacing from basal, mid and apical segments were: R in leads II, III, or aVF, R in lead III, respectively; a QS pattern in leads V4–V6 differentiated the apical from the posterobasal site (p = 0.01). The criterion that predicted LV pacing from the posterobasal septum was an LBBB pattern in V1. Multiple logistic regression analysis revealed the independent predictors of anterior, lateral, posterior and inferior LV lead locations were: an LBBB pattern in V1 (OR 3.63, 95% CI 1.53–8.64,

Table 1 Baseline clinical characteristics of study patients. Variable Gender (%) Male Female Caucasian (%) African-Americans (%) Other (%) LVEF (%) Conduction abnormality (%) LBBB Other QRS duration (ms) Cardiomyopathy (%) Ischemic Non-ischemic NYHA functional class (%) II III IV Device (%) CRT-D CRT-P LV assist device (%) CKD (%) GFR (ml/min/1.73 m2) Diabetes (%) Atrial fibrillation (%) CABG (%) Beta-blockers (%) ACE-I (%) ARB (%) Aldosterone antagonist (%) Diuretics (%)

(N = 306) 67 33 53 43 4 23 ± 9.4 54 46 148 ± 20 57 43 5 90 5 92 8 3 52 60 ± 24 37 37 29 89 54 20 21 74

ACE-I = angiotensin converting enzyme-inhibitor; ARB = angiotensin receptor blocker; CABG = coronary artery bypass graft; CKD = chronic kidney disease; CRT = cardiac resynchronization therapy (D = defibrillator, P = pacemaker); GFR = glomerular filtration rate; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; MCV = middle cardiac vein; NYHA = New York Heart Association.

p = 0.004), QS in aVL (2.79, 95% CI 1.38–5.63, p =0.004), R or r in aVL (2.56, 95% CI 1.36–4.82, p = 0.004), and absence of an R in II, III or aVF (3.17, 95% CI 1.27–7.88, p = 0.01), respectively (Table 3). Representative paced QRS morphologies in select study patients are shown in Fig. 3. Survival outcome based on LV lead location Baseline characteristics relative to LV pacing site are shown in Table 4. Patients with LV leads in lateral sites were compared with those from MCV, mid-posterior and anterior sites. No significant difference in baseline characteristics was noted except for a greater proportion of African-Americans in the MCV and mid-posterior pacing sites which remained unexplained. Kaplan–Meier 6-year survival estimates and pairwise comparisons between lateral LV pacing sites with other sites are shown in Fig. 4. There were 81 deaths representing a six-year mortality of 26%. With respect to LV pacing sites, the mortality was 11, 20, 25, 28, and 34% for anterior, lateral, apical, mid-posterior and MCV sites, respectively. Kaplan–Meier survival estimates comparing all LV pacing sites revealed no significant differences among

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Fig. 2. A three-dimensional representation of cardiac segments in a polar view illustrates LV lead locations and frequency distribution in study patients.

groups (log-rank, p = 0.06). Pairwise comparisons of survival estimates between lateral sites, and sites along the MCV (posterobasal, inferior-posterior and apical sites) revealed a significantly higher mortality in MCV sites (34%) when compared with lateral sites (20%), (HR 1.97; 95% CI 1.08–3.58; p = 0.02). Cox proportional regression analysis showed a significantly higher risk of death in the posterobasal (septal) site (41%, HR 2.33; 95% CI 1.13–4.78; p = 0.02) and inferior-posterior site (31%, HR 1.82; 95% CI 0.90–3.70; p = 0.04); whereas no significant difference was noted in the apical subgroup (25%, HR 1.55; 95% CI 0.52– 4.76; p = 0.43). There was no significant difference in mortality relative to all covariates (Table 4). A QRS morphology algorithm was proposed to simplify analysis of the ECG and enhance the prediction of LV lead location (Fig. 5). Characteristically, a QS complex in lead I suggests biventricular pacing with capture at an LV site; whereas a Qr or qR complex is consistent with LV pacing from a location intermediate between the septum and lateral

wall. Absence of a QS or either Qr or qR in lead I suggests loss of LV capture, fusion with an intrinsic QRS complex, a short programmed AV delay precluding recognition of a small Q wave, right ventricular pre-activation, or right ventricular anodal stimulation. A dominant R in V1 was consistent with LV pacing from the posterior or posterolateral LV; whereas its absence signified pacing from an anterior or anterolateral site. Pacing from an anterior site may produce an Rs complex in V1. Absence of an R in V1 may be associated with LV pacing from a septal or posterobasal septal site. A posterobasal-septal lead positioned in the proximal MCV is postulated to activate the posterior septum and results in absence of an R in V1 despite the lead's posterior location [16]. Biventricular pacing from the lateral LV almost always produced a QS complex in aVL; whereas the presence of a Qr or qR in aVL suggests pacing from a septal or intermediate location between the septum and lateral LV. Pacing from basal sites yielded an R in leads II, III, or aVF either independently or more often collectively;

Table 2 Univariate paced QRS predictors of LV lead location. Cardiac segment

QRS criteria

Sensitivity

Specificity

PPV

NPV

AUC

p value

Anterior

Presence of LBBB in V1 Negative concordance R in II, III or aVF QS or qR in lead I QS in aVL R in II, III or aVF Dominant R in V1 R or r in aVL QS or qR in lead I Absence of R in II, III or aVF Absence of R in II, III and aVF Absence of R in II, III or aVF R in V1 QS in V4-V6 Presence of LBBB in V1 Negative concordance R in aVR R in III R in II, III and aVF R in II, III or aVF R in aVR Absence of RBBB in V1

61% 23% 69% 93% 52% 56% 74% 78% 80% 62% 97% 81% 81% 75% 19% 0% 98% 49% 26% 58% 72% 40%

74% 94% 57% 18% 74% 58% 39% 48% 5% 60% 26% 50% 31% 62% 71% 97% 9% 64% 83% 59% 8% 74%

19% 28% 15% 23% 36% 26% 74% 78% 67% 79% 22% 26% 18% 48% 3% 0% 60% 65% 68% 23% 15% 26%

95% 93% 95% 91% 84% 83% 39% 48% 11% 40% 97% 93% 90% 84% 94% 95% 74% 47% 45% 86% 59% 85%

0.68 0.59 0.64 0.56 0.64 0.58 0.57 0.63 0.57 0.61 0.61 0.65 0.56 0.62 0.45 0.50 0.54 0.57 0.55 0.59 0.41 0.43

b0.001 0.001 0.008 0.028 b0.001 0.035 0.026 b0.001 0.003 b0.001 b0.001 b0.001 0.086 0.01 0.488 0.473 0.011 0.019 0.05 0.02 b0.001 0.033

Lateral

Posterior

Inferior

Apical

Mid

Basal

AUC = area under the curve, NPV = negative predictive value, PPV = positive predictive value, RBBB = right bundle branch block (other abbreviations see Table 1).

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Table 3 Multiple logistic regression analysis of two-dimensional paced QRS criteria. Cardiac segment

QRS criteria

Odds ratio

95% confidence interval

Anterior

Presence of LBBB in V1 R in II, III or aVF QS or qr in lead I QS in aVL R in II, III or aVF Dominant R in V1a R or r in aVL QS or qR in lead I Absence of R in II, III or aVF Absence of R in II, III or aVF Absence of R in II, III and aVF Absence of R in V1 Presence of LBBB in V1 Absence of Dominant R in V1 R in III R in II, III and aVF R in aVR R in II, III or aVF Absence of RBBB in V1 R in aVR

3.63 2.29 1.57 2.79 1.36 0.60 2.56 0.44 1.22 3.17 2.86 1.37 1.19 2.20 1.47 1.73 1.14 1.58 1.32 0.54

1.53–8.64 0.93–3.66 0.56–4.25 1.38–5.63 0.68–2.73 0.34–1.05 1.36–4.82 0.18–1.08 0.66–2.26 1.27–7.88 0.56–14.89 0.61–3.06 0.27–52.6 0.50–96.99 0.82–2.63 0.76–3.91 0.42–3.13 0.83–3.00 0.65–2.68 0.19–1.53

0.004 0.07 0.40 0.004 0.38 0.07 0.004 0.07 0.52 0.01 0.21 0.45 0.93 0.69 0.20 0.19 0.80 0.17 0.45 0.25

3.42 4.01 .349 2.62 .203

1.15–10.1 2.02–7.97 0.14–0.85 1.47–4.65 0.09–0.45

0.02 b 0.0001 0.02 0.001 b 0.0001

Lateral

Posterior

Inferior

Apical Mid

Basal

p value

Comment No interaction No interaction No interaction No interaction No interaction No interaction Interaction No interaction No interaction No interaction No interaction No interaction Interaction Interaction Interaction Interaction Interaction Interaction Interaction Interaction

Multiple logistic regression analysis of 3-dimensional criteria Basal lateral Mid-lateral Mid-posterolateral Mid-posterior Inferior-posterior a

QS in aVL QS in aVL R in aVLa R in aVL R in II, III, or aVFa

-

Denotes an odds ratio b1 was less predictive of an LV pacing site (other abbreviations see Tables 1 and 2).

whereas pacing from an inferior LV segment was associated with absence of an R in these inferior leads. Biventricular pacing from the mid-posterior LV site may result in one or more R waves in the inferior leads generally of low amplitude. A large R in the inferior leads favors a basal pacing site; whereas any r in these leads can be seen in either location. Pacing from the apical LV segment was associated with absence of a dominant R in V1, and a QS in V4–V6; whereas a posterior apical site was observed to produce an R in V1. An apical LV lead location can be differentiated from a basal location as the former is associated with a QS in leads V4–V6; whereas a basal LV lead produces an R or r in leads II, III or aVF. The efficacy of this algorithm is shown in Table 5.

Discussion We propose biventricular paced QRS morphology criteria that correlate with LV lead location and an algorithm that enhances the predictive accuracy of these criteria. The criteria for optimal and suboptimal lead locations were validated by mortality data. The mean baseline QRS duration for study patients exceeded 140 ms, indicating that these patients were appropriately selected as potential responders to CRT. Absence of significant differences among clinical covariates suggests that LV lead location impacted mortality more than any other variable. Multiple logistic regression analysis revealed the best independent predictors of LV lead locations. Disparate results have been reported relative to the impact of LV lead location on outcomes [6,8–12]. For example, Rossillo

et al. reported that lateral and posterolateral pacing sites were associated with significant improvement in functional capacity and LV function, but had no adverse influence on mortality when compared with the anterior lead location; however the relationship between the biventricular paced QRS complex and LV lead locations was not evaluated [6]. Wilton et al. found the anterior LV lead location to be associated with a two to three-fold higher risk of nonresponse to CRT, cardiovascular death and all-cause mortality, but did not evaluate the biventricular paced QRS to identify predictors of the anterior LV lead location [11]. We did not find an increase in mortality associated with the anterior location. In MADIT-CRT, one of the largest studies that evaluated the impact of LV lead position on clinical outcome, the apical LV pacing site was associated with increased risk of death (hazard ratio 2.91, 95% confidence interval 1.42–5.97, p = 0.004) and the authors recommended that this site should be avoided [10]. Unfortunately, aside from the baseline pre-procedure QRS duration, the 12-lead ECG during biventricular pacing was not evaluated or available for analysis; therefore biventricular paced QRS morphology predictors of an apical lead location were not proposed. Merchant et al. also reported that the apical site was associated with worse outcomes when compared with nonapical sites and suggested a preferential lead position to a more basal location [9]. Our results revealed an increase in mortality associated with the apical lead location but only in combination with sites along the MCV. In the REVERSE study, Thébault et al. observed a more favorable outcome of CRT relative to reverse remodeling, and a composite endpoint of time to death or first hospitalization, when the LV lead tip was positioned in the lateral wall,

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Fig. 3. Representative ECGs illustrating typical QRS morphology criteria during biventricular pacing. Posterobasal septal location shows characteristic large R waves in II, III, aVF with absence of an R in V1 despite a posterior location. Basal lateral site pacing shows typical QS pattern in leads I and aVL with an R in V1. Anterior basal site shows R waves in II, III, and aVF, and an LBBB pattern in V1. Mid-posterior site reveals an R in V1, QS in lead I and qR in aVL consistent with pacing from a location intermediate between the septum and lateral wall. Mid posterolateral site shows an R in V1, QS in leads I and aVL. Mid lateral site shows a QS in I and aVL with R waves in II, III and aVF, with an unusual lack of an R in V1. Mid Anterolateral site shows a QS in I, Qr in aVL with absence of an R in V1. Mid anterior site shows a QS in I, Qr in aVL, small r in III, aVF and absence of R in V1. Apical site shows a QR in I, aVL, absence of an R in V1 and QS in V4–6. Inferior site reveals a tiny q in I, and aVL with absence of R waves inferiorly.

away from the apex [8]. However, the proportion of worsened heart failure clinical composite did not correlate with the LV lead position. In that study the biventricular paced QRS duration was evaluated once at 12 months, and its morphological characteristics were not evaluated [8]. Recent studies evaluated the baseline QRS duration parameters as predictors of a response to CRT but did not provide any information on morphology descriptors [17,18]. To affirm our results it was paramount to validate optimal and suboptimal lead locations by mortality data, a hard endpoint. We also utilized the proposed algorithm to enhance the predictive accuracy of the biventricular paced QRS criteria.

We observed an interaction among a few biventricular paced QRS morphology predictors and attributed it to the three-dimensional LV lead orientation, thus considered clinically insignificant (Table 3). We did not address the impact of LV to right ventricular intervals as it was shown to minimally influence the paced QRS morphology over a wide range of values [19]. A major finding noted was that LV pacing sites along the MCV were associated with worse survival when compared with lateral, mid-posterior or anterior sites. Since the MCV courses along the inferior-posterior septum it is not expected to be a late activated LV site. To support this

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Table 4 Baseline characteristics stratified by LV lead location. Variable

Age Gender (%) Male Female Caucasian (%) African-American (%) Other (%) LVEF (%) Conduction abnormality (%) LBBB Other QRS duration (ms) Cardiomyopathy (%) Ischemic Non-ischemic NYHA functional class (%) II III IV Device (%) CRT-D CRT-P LV assist device (%) CKD (%) GFR (ml/min/1.73 m2) Diabetes (%) Atrial fibrillation (%) CABG (%) Beta-blockers (%) ACE-I (%) ARB (%) Aldosterone antagonist (%) Diuretics (%)

LV lead location Lateral (N = 81)

MCV (N = 98)

Mid-posterior (N = 108)

Anterior (N = 19)

p value

67 ± 14

68 ± 14

68 ± 12

72 ± 11

0.587 0.349

68 32 64 32 4 25 ± 10

61 39 44 52 4 22 ± 10

70 30 50 46 4 23 ± 9

79 21 74 21 5 23 ± 8

54 46 148

65 35 150

47 53 145

58 42 154

54 46

56 44

58 42

68 32

5 93 2

4 90 6

6 88 6

5 90 5

86 14 4 51 62 ± 25 46 33 32 90 62 14 22 83

93 7 1 46 61 ± 21 31 35 24 90 53 22 17 68

96 4 4 56 58 ± 25 38 41 30 88 54 20 21 74

95 5 0 63 56 ± 22 26 37 32 89 49 19 25 74

0.008

0.318 0.075

0.278 0.71

-

0.08

0.393 0.575 0.150 0.532 0.699 0.964 0.384 0.251 0.536 0.162

(Abbreviations see Table 1.)

finding we referred to a recent study by Khan et al. in which candidates for CRT underwent speckle-tracking echocardiography to target late activated LV sites. They reported lower rates of death and heart failure hospitalization in the targeted group when compared with the control group [20]. Inferior basal and inferoseptal sites were rarely late activated (b 1%), and correspond with sites along the MCV. Pacing sites along the MCV are adjacent to the posterior interventricular septum, and uncommonly encompass late activated myocardium. Echocardiographic assessment was not feasible in 11% of their patients, and is a limitation of this methodology. Radiographically, LV lead placement that maximizes the interlead distance between the RV apex and lateral wall produced beneficial hemodynamics thus providing further evidence against the use of sites along the MCV [21]. Currently, a useful independent predictor of reverse remodeling is a surface Q wave to LV duration of ≥ 95 ms measured at the targeted LV lead site. Although this approach is useful, it requires intrinsic AV conduction and cannot be applied to patients with complete heart block [22]. Clinical implications Our results suggest that clinicians may identify target vessels during implantation while avoiding suboptimal sites

along the MCV. However, given the variability in venous anatomy it is feasible to reach a targeted or late activated site via a tributary of the MCV. During implantation pacing from a posterobasal site that demonstrates absence of an R in V1 (which may be recorded in the procedure suite), or an LBBB pattern, is indicative of posteroseptal activation and can be excluded as an appropriate target for LV lead placement. During follow-up evaluation of CRT patients, the biventricular paced QRS criteria may be used to determine optimal or suboptimal lead location and a course of action in nonresponders. Confirmation of persistent dyssynchrony in a nonresponder may lead to epicardial lead placement or other intervention [23]. The proposed algorithm was useful in differentiating LV pacing sites (Table 5), and regions along the MCV that adversely impacted survival. Limitations This was a single-center study with retrospective analysis of data collected prospectively; therefore our results may not be applicable to other centers. The study was nonrandomized, hence may include inherent bias; however the lack of significant differences in covariates among patients within each subgroup stratified by LV lead location suggests that minimal bias existed. Randomization

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Fig. 4. Kaplan–Meier survival estimates and pairwise comparisons for patients classified in anterior, lateral, mid-posterior, and MCV sites.Kaplan–Meier survival estimates and pairwise comparisons are shown. Panel A shows survival curves for patients classified in anterior, lateral, mid-posterior, and MCV sites. Panels B, C, and D depict pairwise comparisons of lateral LV pacing sites with MCV, posterobasal, and inferior-posterior sites.

to LV sites associated with adverse outcomes may not be justifiable since targeted sites are preferred. Moreover, the limitations of lead placement may confound randomization. All-cause mortality was the only outcome evaluated;

hence a suboptimal site was not broadly defined. Although other clinical variables may have influenced mortality, the focus of this study was to determine biventricular paced QRS parameters that can be used to identify optimal and

Fig. 5. Algorithm for predicting LV lead locations. Sites in red denote areas along the MCV (see Results section under Survival outcome based on LV lead location for details).

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Table 5 Efficacy of algorithm in predicting left ventricular lead locations. Cardiac segment (N)

Paced QRS criteria (N)

Lateral (81) Mid-lateral (40)

QS in aVL (23)/QS or qr in lead I (15) Basal lateral (14) QS in aVL (8)/QS or qr in lead I (5) Mid antero-lateral (6) LBBB in V1 (4)/QS in aVL (1) Mid-posterolateral (21) R in V1 (17)/QS in aVL (3) Anterior (19) LBBB (11)/RS in V1 (3) Apical (16) R in V1 (13)/QS in V4–V6 (3) Inferior-posterior (48) QS or qr in lead I (35)/absence of R in leads II, III and aVF (12) Mid-posterior (108) R in V1 (81)/QS or qr in lead I (19) Posterobasal (34) QS or qr in lead I (29)/R in leads II, III and aVF (1)

Predicted (%) 95 93 83 95 74 100 98

93 88

(Abbreviations see Table 1.)

suboptimal sites with validation of these sites as suboptimal via mortality data. Unrecognized cardiac rotation and conduction block distal to LV pacing sites may have influenced our results.

Conclusions The biventricular paced QRS morphology may be used to identify LV pacing from optimal and suboptimal sites. LV pacing from anterior, lateral, apical, mid-posterior and MCV sites was associated with a mortality of 11, 20, 25, 28, and 34%, respectively. Independent predictors of LV pacing from anterior, lateral, posterior and inferior LV lead locations during CRT were: an LBBB pattern in V1, QS in aVL, R or r in aVL, and absence of an R in II, III or aVF, respectively. A QS pattern in leads V4–V6 only differentiated the apical from the posterobasal site. The proposed algorithm was associated with high predictive accuracy for detecting LV lead location, and could be clinically useful during device implantation and follow-up. Suboptimal LV pacing sites were associated with increased mortality.

Author contributions Dr. Fontaine participated in all aspects of the study including study design, data analysis and manuscript preparation. Drs. Gupta, Franklin and Kang were involved in data collection and analysis, as well as manuscript preparation. Ms. Whigham performed data collection and statistical analysis. All authors approved the manuscript under submission.

Conflict of interest None.

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