The anatomic and electrical location of the left ventricular lead predicts ventricular arrhythmia in cardiac resynchronization therapy

The anatomic and electrical location of the left ventricular lead predicts ventricular arrhythmia in cardiac resynchronization therapy Daniel J. Friedman, MD, Gaurav A. Upadhyay, MD, Robert K. Altman, MD, Mary Orencole, ANP-BC, Conor D. Barrett, MB, BCh, Theofanie Mela, MD, FHRS, E. Kevin Heist, MD, PhD, FHRS, Jagmeet P. Singh, MD, DPhil, FHRS From the Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. BACKGROUND Both anatomic and electrical locations of the left ventricular (LV) lead have been identified as important predictors of clinical outcomes in cardiac resynchronization therapy (CRT). The impact of LV lead location on incident device-treated ventricular arrhythmia (VA), however, is not well understood. OBJECTIVE To assess the relationship between electrical and anatomic LV lead location and device treated VAs in CRT. METHODS Sixty-nine patients undergoing CRT implantation for standard indications were evaluated. Anatomic LV lead location was assessed by means of coronary venography and chest radiography and categorized as apical or nonapical. Electrical LV lead location was assessed by LV electrical delay (LVLED) and was calculated as the time between the onset of the native QRS on the surface electrocardiogram and sensed signal on the LV lead during implantation and corrected for native QRS. Incident appropriate device-treated VA was assessed via device interrogation. RESULTS Apical lead placement was an independent predictor of VAs (hazard ratio 5.29; 95% confidence interval 1.69–16.5; P ¼ .004). Among patients with a nonapical lead, LVLED o50% native QRS was an independent predictor of VAs (hazard ratio 6.90; 95% confidence interval 1.53–31.1; P ¼ .012). Those with a nonapical

Introduction Cardiac resynchronization therapy (CRT) is a wellestablished therapeutic modality for patients with congestive

Dr Heist has received honoraria from Biotronik, Boston Scientific, Sorin, and St Jude Medical; research grants from Biotronik, Sorin, and St Jude Medical; and consulting fees from Boston Scientific, Sorin, and St Jude Medical. Dr Mela has received honoraria from Boston Scientific, Medtronic, and St Jude Medical and consulting fees from St Jude Medical. Ms Orencole has received honoraria from Boston Scientific. Dr Singh has received research grants from St Jude Medical, Medtronic, Boston Scientific, and Biotronik; consulting fees from Boston Scientific, Biotronik, St Jude Medical, Medtronic, CardioInsight, Thoratec, and Biosense Webster; and honoraria from Medtronic, Biotronik, Guidant, St Jude Medical, and Sorin. Address reprint requests and correspondence: Dr Jagmeet P. Singh, Cardiac Arrhythmia Service, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail address: [email protected].

1547-5271/$-see front matter B 2013 Heart Rhythm Society. All rights reserved.

lead and LVLED Z50% native QRS were at substantially lower risk for first incident and recurrent VAs when compared to all other patients. CONCLUSIONS The apical lead position is associated with an increased risk of VAs in CRT patients. Among patients with a nonapical lead position, an LVLED of o50% of the native QRS is associated with an increased risk of VAs. KEYWORDS Congestive heart failure; Heart failure; Cardiac resynchronization therapy; Lead; Ventricular tachycardia; Ventricular fibrillation ABBREVIATIONS ATP ¼ antitachycardia pacing; CI ¼ confidence interval; CRT ¼ cardiac resynchronization therapy; CRT-D ¼ cardiac resynchronization therapy-defibrillator; HR ¼ hazard ratio; LBBB ¼ left bundle branch block; LV ¼ left ventricular; LVEDD ¼ left ventricular end diastolic diameter; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end systolic diameter; LVLED ¼ left ventricular lead electrical delay; VA ¼ ventricular arrhythmia; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia (Heart Rhythm 2013;10:668–675) I 2013 Heart Rhythm Society. All rights reserved.

heart failure and a prolonged QRS interval on the surface electrocardiogram.1–5 CRT has also been associated with improved electrical stability, as evidenced by a decreased risk of both atrial and ventricular arrhythmias (VAs).6–10 Although CRT represents an important advance in the care of patients with heart failure, a substantial proportion of patients do not derive benefit from this therapy.11 Consequently, improvements in patient selection12 and device implantation12,13 have become important topics of investigation. Left ventricular (LV) lead position has emerged as an important determinant of outcomes.12,13 Current implantation strategies typically involve anatomic targeting of the posterior or lateral wall along the short axis.13 Additional studies have suggested that nonapical leads14,15 and those with maximal electrical separation16,17 may be associated with improved clinical outcomes.

http://dx.doi.org/10.1016/j.hrthm.2012.12.025

Friedman et al

LV Lead Position and Ventricular Arrhythmias in CRT

Although the relationship between optimal lead position and mortality and hospitalization has become increasingly clear, there is a paucity of data on the impact of LV lead location on incident ventricular tachycardia (VT) and ventricular fibrillation (VF) in this high-risk population. Therefore, in this study, we aimed to assess the relationship between anatomic and electrical lead location on the incidence of sustained VT and VF in patients with heart failure after CRT implantation.

Methods Subjects All patients implanted with cardiac resynchronization therapy-defibrillator (CRT-D) at our institution between December 2004 and September 2009 with intraprocedural left ventricular lead electrical delay (LVLED) measurements were enrolled. Patients underwent CRT-D implantation for approved indications during the enrollment period (New York Heart Association class III/IV symptoms, left ventricular ejection fraction [LVEF] o35%, and QRS duration 4120 ms) and were followed at our multidisciplinary CRT clinic. Patients with primary and secondary prevention ICD indications were included in the analyses.

Baseline characteristics and echocardiography Standard echocardiographic, clinical, and demographic data were obtained for all patients. Transthoracic echocardiograms were obtained before CRT device implantation and 6 months after. LV end diastolic and end systolic dimensions (left ventricular end diastolic diameter [LVEDD] and left ventricular end systolic diameter [LVESD], respectively) were measured from the parasternal long-axis view. LV ejection fraction was calculated by using the biplane method of discs from the apical 4- and 2-chamber views.

LV lead location Anatomic lead position was assessed via intraprocedural coronary venography and examination of posteroanterior and lateral chest x-rays obtained at the time of implantation. Lead position was classified within the long and short axes of the left ventricle. The long axis was divided into the apical, basal, and mid-ventricular segments, and the short axis was divided into the anterior, anterolateral, lateral, posterolateral, and posterior segments. For the analyses, anatomic lead location was dichotomized along the long axis into apical vs nonapical on the basis of previous work.14,15,18 Electrical lead position was measured intraprocedurally at the time of device implantation, as described previously.17 Briefly, the electrical delay was calculated as the time between the onset of the QRS on the surface electrocardiogram and the sensed signal on the LV lead. This delay was indexed by the intraprocedurally measured QRS and expressed as a percentage of the baseline QRS duration. For analyses, LVLED was dichotomized by using a 50% partition on the basis of previous work.17

669

Device implantation, programming, and follow-up CRT-D implantation, programming, and device selection was at the discretion of the treating electrophysiologist. Devices were usually programmed to initially treat VT with antitachycardia pacing (ATP), followed by high-voltage shocks if ATP was unsuccessful. VF was treated with high-voltage shocks. Detection and therapy zones were not standardized and were determined on an individual basis, although generally therapy zones began at 160–190 beats/ min. Recurrent episodes of symptomatic slow VT prompted lowering of therapy zones in certain instances. All patients were followed at our institution and underwent routine device interrogations at 3–6-month intervals.

End points The primary end point of this study was the first incident sustained VA receiving appropriate device therapy after the implantation of CRT-D. Arrhythmias were classified as VT, VF, electric storm (appropriate therapy for 3 VAs within o24 hours), or pair of arrhythmias (appropriate therapy for 2 VAs within o24 hours). All events were verified by the electrophysiologist review of device electrograms. A single episode of VA requiring multiple therapies (ie, multiple rounds of ATP, multiple rounds of shock, or ATP followed by shock(s)) for termination was classified as a single event. This end point excluded nonsustained VT and inappropriate therapies and does not imply that first therapy attempt was successful.

Statistical analysis All analyses were performed by using SPSS software, version 20.0 (SPSS Inc, Chicago, IL). Values are presented as mean ⫾ SD for continuous variables and as proportions for categorical variables. Differences were assessed by using Fisher exact test, Student t tests, or Wilcoxon rank-sum test, where appropriate. Kaplan-Meier curves were constructed to compare event rates in different subgroups and formally assessed by using log-rank testing. Univariate and multivariate analyses were performed by using Cox proportional hazards models; forward stepwise selection was used for multivariate analyses. Multivariate models adjusted for all variables in which there was a difference (P o .10) among the subgroups in Table 2, as well as history of VT/VF, age, LVEF o20%, and sex; covariates included apical vs nonapical lead position, LVLED, age, sex, LVEDD, LVESD, hypertension (HTN), LVEF o20%, and chronic atrial fibrillation. For all tests, a P value of o.05 was required for statistical significance.

Results Baseline characteristics and incident devicetreated arrhythmia Sixty-nine patients (mean age 67.8 ⫾ 12.5 years; 28% women; 52% ischemic; 9% New York Heart Association class IV symptoms; 20% with prior sustained VA) were followed for 853 ⫾ 510 days after CRT-D implantation.

670 Table 1

Heart Rhythm, Vol 10, No 5, May 2013 Baseline characteristics of the entire population

Characteristic

Frequency or mean

Age (y) Sex: Female (%) NYHA IV (%) Baseline QRS (ms) QRS 4150 ms (%) Transvenous LV lead (%) Upgrade (%) Apical lead (%) LVLED o50% of baseline QRS LBBB Medical comorbidities CABG (%) CAD (%) Chronic atrial fibrillation (%) Cr Diabetes (%) Hypertension (%) Ischemic CM (%) Paroxysmal atrial fibrillation (%) PCI (%) Previous VT/VF (%) Valve surgery (%) Echocardiographic characteristics MR grade Left atrial size (mm) LVEDD (mm) LVEF,% LVESD (mm) Medications ACE/ARB (%) Aldosterone antagonist (%) Beta-blockers (%) Digoxin (%) Diuretics (%) Amiodarone (%) Mexiletine (%) Sotalol (%)

67.8 (12.5) 27.5 8.8 158.4 (27.0) 62.3 98.5 31.9 20.3 21.7 60.6 33.3 56.5 29.0 1.39 (0.6) 39.1 71.0 52.2 17.4 23.2 20.3 18.8 2.34 (0.91) 43.7 (6.7) 63.85 (9.2) 24.1 (6.9) 55.77 (9.6) 88.4 42.0 87.0 27.5 73.9 15.9 4.3 4.3

ACE/ARB ¼ angiotensin-converting enzyme or angiotensin receptor blocker; CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; CM ¼ cardiomyopathy; Cr ¼ creatinine; LBBB ¼ left bundle branch block; LV ¼ left ventricle; LVEDD ¼ left ventricular end diastolic diameter; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end systolic diameter; LVLED ¼ left ventricular lead electrical delay; MR ¼ mitral regurgitation; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

Lead distribution along the long axis was as follows: apical 20% (n ¼ 14), mid-ventricular 68% (n ¼ 47), and basal 12% (n ¼ 8). Lead distribution along the short axis was as follows: anterolateral 4% (n ¼ 3), lateral 43% (n ¼ 30), and posterolateral 52% (n ¼ 36); no patients had an LV lead in the anterior or posterior position. Twenty-two percent of patients had an LVLED of less than 50% of the baseline QRS (LVLED o50% QRS). Baseline characteristics of the entire population are further detailed in Table 1. There were no significant differences between patients with apical vs nonapical leads (Table 2). Those with LVLED o50% QRS were more likely to have a greater LVEDD (66.3 ⫾ 8.5 mm vs 59.3 ⫾ 9.8 mm; P ¼ .039) but were otherwise similar (Table 2).

During follow-up, 23% (n ¼ 16) patients had an appropriate therapy for VA. Of first events, 13 were VT, 1 was VF, and 2 were electrical storms. The mean rate was 197 ⫾ 29 beats/min and the range was 151–260 beats/min; 7 episodes were o188 beats/min, 7 were between 188 and 250 beats/ min, and 1 was 4250 beats/min; heart rate data were unavailable for 1 episode of VT that was successfully treated with ATP. Estimated 1-, 2-, and 3-year incidences of appropriate therapy were 21%, 25%, and 28%, respectively, in the overall cohort. Six patients experienced Z1 VA.

LV lead position and VA In univariate analyses, the apical lead position was associated with a nearly 3-fold increase in the risk of VA (hazard ratio [HR] 2.99; 95% confidence interval [CI] 1.11–8.02; P ¼ .030) compared to a basal or mid-ventricular position. LVLED o50% QRS was also associated with a nearly 3fold increase in the risk of incident VA (HR 2.77; 95% CI 1.05–7.31; P ¼ .039). The apical lead position was associated with an increased 3-year incidence of VA (51% vs 18%; overall P ¼ .023) as was LVLED o50% QRS (49% vs 21%; overall P ¼ .031; Figure 1). A longer LVESD (assessed as a continuous variable and with an upper quartile cutoff) was not associated with an increased risk of VA. In a multivariate analysis, the apical lead position (but not short electrical delay) was associated with an increased risk of VAs (HR 5.29; 95% CI 1.69–6.5; P ¼ .004). Among patients with a nonapical lead (n ¼ 54), LVLED o50% QRS was associated with an increase in the risk of VAs in Kaplan-Meier analysis (P ¼ .012; Figure 2) and a nearly 7-fold increase in the risk of VA (HR 6.90; 95% CI 1.53– 31.1; P ¼ .012) after multivariate adjustment. Additional analysis demonstrated a significant interaction between the apical lead position and LVLED o50% QRS in the prediction of VAs (P ¼ .038). Given that both anatomic and electrical lead locations provide complementary information regarding risk of sustained VAs, we performed further analyses to assess the impact of combining these 2 metrics. For these analyses, we defined optimal lead placement as one placed in the basal or mid-ventricle with an electrical delay of Z50% of the native QRS and all other lead locations as suboptimal. Using this classification, 63% (n ¼ 43) of the patients had an optimal lead placement and 37% (n ¼ 25) had a suboptimal lead placement. (Since anatomic lead position data were missing for 1 individual, the patient had to be excluded from this analysis.) Of those with suboptimal lead placement, 5 (20%) had an apical lead with short electrical delay, 10 (40%) had a nonapical lead with short electrical delay, and 10 (40%) had an apical lead with long electrical delay. Suboptimal lead position was associated with a significantly increased 4-year risk of VA compared to a suboptimal lead location in Kaplan-Meier analysis (49% vs 14%; P ¼ .001; Figure 3) and multivariate analysis (HR 6.43; 95% CI 1.79–23.1; P ¼ .004). Thus, the incorporation of both electrical and anatomic lead location metrics allows for improved risk stratification.

Friedman et al Table 2

LV Lead Position and Ventricular Arrhythmias in CRT

671

Baseline characteristics of the entire population when divided by lead placement or LVLED Anatomic location

Characteristic

Apical lead (n ¼ 14)

Nonapical lead (n¼54)*

Age (y) 69.5 (12.1) 67.7 (12.5) Sex: Female (%) 14.3 31.5 NYHA IV (%) 0.0 11.3 Baseline QRS (ms) 163.4 (36.9) 158.0 (23.1) QRS 4150 ms (%) 73.3 58.8 Transvenous LV lead (%) 93.3 100.0 Upgrade (%) 33.3 31.4 Apical lead (%) --LVLED o50% of baseline QRS 64.3 83.3 LBBB (%) 66.7 58.8 Medical comorbidities CABG (%) 42.9 29.6 CAD (%) 71.4 51.9 Chronic atrial fibrillation (%) 50.0 24.1 Cr 1.4 (0.5) 1.4 (0.7) Diabetes (%) 35.7 38.9 Hypertension (%) 78.6 68.5 Ischemic CM (%) 71.4 46.3 Paroxysmal atrial fibrillation 7.1 20.4 (%) PCI (%) 35.7 18.5 Previous VT/VF (%) 28.6 16.7 Valve surgery (%) 14.3 20.4 Echocardiographic characteristics MR grade 2.29 (1.1) 2.35 (0.9) Left atrial size (mm) 43.2 (6.8) 43.8 (6.7) LVEDD (mm) 63.7 (9.8) 60.1 (9.9) LVEF (%) 25.7 (6.7) 23.6 (7.0) LVESD (mm) 52.6 (11.9) 52.5 (9.9) Medications ACE/ARB (%) 92.9 87.0 Aldosterone antagonist (%) 28.6 46.3 Beta-blockers (%) 92.9 85.2 35.7 25.9 Digoxin (%) Diuretics (%) 71.4 74.1 Amiodarone (%) 14.3 16.7 Mexiletine (%) 0.0 5.6 Sotalol (%) 7.1 3.7

Electrical location LVLED o50% QRS (n¼15)

P

LVLED Z50% QRS (n¼54)

P .948 1.000 1.000 167.3 (26.3) .218 1.000 .520 .144 -1.000

.626 .319 .330 .500 .376 .227 1.000 -.144 .765

68.0 (12.4) 26.7 26.7 167.3 (26.3) 78.6 100.0 21.4 35.7 -64.3

67.7 (12.7) 27.8 27.8 155.82 (23.5) 57.7 100.0 34.6 16.7 -59.6

.356 .189 .097 .939 .828 .532 .094 .435

46.7 73.3 20.0 1.27 (0.4) 46.7 93.3 73.3 13.3

29.6 51.9 31.5 1.42 (0.70) 37.0 64.8 46.3 18.5

.216 .138 .526 .467 .499 .051 .064 1.000

20.0 23.1 6.7

24.1 18.5 22.2

1.000 1.000 .270

2.31 (0.9) 43.9 (7.0) 59.3 (9.8) 27.8 51.0 (10.1)

.678 .678 .039 1.000 .069

88.9 40.7 83.3 29.6 72.2 13.0 5.61 3.7

1.000 .681 .189 .534 .743 .237 1.000 .527

.275 .445 1.000

.808 2.43 (1.0) .772 43 (5.6) .287 66.3 (8.5) .319 26.7 .970 57.5 (9.8) 1.000 .232 .673 .512 1.000 1.000 1.000 .505

86.7 46.7 100.0 20.0 80.0 26.7 0.0 6.7

ACE/ARB ¼ angiotensin-converting enzyme or angiotensin receptor blocker; CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; CM ¼ cardiomyopathy; Cr ¼ creatinine; LBBB ¼ left bundle branch block; LV ¼ left ventricle; LVEDD ¼ left ventricular end diastolic diameter; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end systolic diameter; LVLED ¼ left ventricular lead electrical delay; MR ¼ mitral regurgitation; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia. * Anatomic lead position data were missing for 1 patient.

Optimal vs suboptimal lead placement and recurrent arrhythmias We further explored the relationship between lead position and VA by assessing the burden of recurrent arrhythmias among patients who met the primary end point when stratified on the basis of lead placement (Table 3). Compared to those with optimal lead placement, those with suboptimal lead position had increased rates of arrhythmic events (VT, VF, or electrical storms; 5.83 ⫾ 7 vs 1.48 ⫾ 3 per 1000 days; P ¼ .045), total therapies (ATP plus shocks; 6.22 ⫾ 19 vs 1.48 ⫾ 3 per 1000 days; P ¼ .011), and shocks (0.92 ⫾ 3 vs 0.00 ⫾ 0 per 1000

days; P ¼ .039). No patients in the optimal lead position group required shock therapy during follow-up. We subsequently assessed the relative risk of VA among the 4 potential lead locations when assessed by both anatomic and electric means. Figure 4 represents an analysis of the entire population divided based on electric and anatomic location assessing the relative incidence of VAs. Although the overall plot is highly significant (P ¼ .005), a repeat analysis excluding the patients with optimal lead position (nonapical and long LVLED) is no longer significant (P ¼ .726), indicating that any difference in VA risk

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Heart Rhythm, Vol 10, No 5, May 2013

Figure 1 Incidence of VT/VF among the entire study population when stratified on the basis of (A) apical vs nonapical lead placement and (B) a partition of LVLED o50% native QRS. LVLED ¼ left ventricular lead electrical delay; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

among those with the various suboptimal lead positions is unable to be detected in this small study.

analysis, the HR for treated VAs remained essentially unchanged (HR 6.10; 95% CI 1.68–22.2; P ¼ .006), suggesting that the relationship between lead position and VA may be at least partially independent of reverse remodeling.

Reverse remodeling, lead position, and VAs We assessed whether the reduction in arrhythmia burden associated with optimal lead placement was related to the degree of reverse remodeling among the patients with baseline and 6-month echocardiograms. When comparing those with optimal vs suboptimal lead position, there was a trend toward greater LVEF improvement among those with optimal lead position (8.1% ⫾ 6.8% vs 3.4% ⫾ 7.3%; P ¼ .051) but no significant change in either LVESD (3.7 ⫾ 7.2 vs 2.0 ⫾ 9.4; P ¼ .505) or LVEDD (4.1 ⫾ 6.4 vs 2.1 ⫾ 7.2; P ¼ .327). When optimal vs suboptimal lead position is adjusted for change in LVEF in a multivariate

Figure 2 Incidence of VT/VF among the study population of patients with nonapical lead placement when stratified on the basis of a partition of LVLED o50% native QRS. LVLED ¼ left ventricular lead electrical delay; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

Discussion Our study demonstrates that among patients with CRT, LV lead location, as assessed by both anatomic and electrical means, is significantly associated with a risk of VAs. LV leads in the apical position and those associated with short electrical delays (as measured by LVLED) were associated with a substantially increased risk of incident VAs. Furthermore, an integrated approach combining both metrics to assess optimal vs suboptimal LV lead location was superior to either method alone in the prediction of first incident arrhythmias as well as risk of recurrent arrhythmias. This study represents the first published report demonstrating a

Figure 3 Incidence of VT/VF among those with optimal and suboptimal lead positions. VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

Friedman et al Table 3

LV Lead Position and Ventricular Arrhythmias in CRT

673

Differences in arrhythmic events and device therapies among subjects with incident arrhythmias divided by lead position

Events/1000 d Shocks/1000 d ATP/1000 d Therapies/1000 d

Optimal lead placement

Suboptimal lead placement

Median

Interquartile Range

Median

Interquartile Range

P*

1.48 0.00 1.48 1.48

3 0 3 3

5.83 0.92 6.67 6.22

7 3 23 19

.045 .039 .205 .011

ATP ¼ antitachycardia pacing. * Wilcoxon rank-sum test.

relationship between anatomic lead location and VA, electrical lead location and VA, as well as the first to use a multimodal approach for lead localization in the risk stratification of VA.

Relationship between lead position and outcomes in CRT Optimal resynchronization of the left ventricle requires pacing at the site of most delayed activation. Electroanatomic mapping has demonstrated that the site of most delayed activation in left bundle branch block is typically along the posterolateral wall,19–21 though some amount of variability has been noted.20,21 Prior work22,23 and a recent analysis of the REVERSE cohort18 have generally been consistent with electroanatomic mapping, though notably an analysis of the MADIT-CRT cohort did not identify any pacing site along the short axis to be associated with adverse or improved outcomes.15 As such, optimal lead location along the short axis remains somewhat controversial. Our findings are consistent with a number of previous studies that have demonstrated that a basal or mid-ventricular location along the long axis is preferable to an apical location.14,15,18 Although anatomic targeting is a valuable tool for improving outcomes in CRT, it may be limited in its ability to fully optimize results.12,13 This limitation is due to the

reality that the site of most delayed activation of the LV myocardium may be influenced by a number of factors,18,19 including scar, ischemia, wall thickness, non-left bundle branch block conduction delays, level of conduction block within the arborization of the conduction system, line of functional block,19 and chamber size and geometry. Nonetheless, anatomic targeting has become an important component of contemporary LV lead implantation in CRT. Electrical lead position, as measured by LVLED, helps define the LV lead location in relation to the native electrical conduction and provides additive information over conventional anatomic localization.17 LVLED measures the LV lead location relative to the region of most delayed electrical activation during AV conduction by measuring the delay between the onset of the native QRS on the surface electrocardiogram and the detection of the intrinsic electrical activity at the LV lead, which is corrected for the native QRS duration.17 Notably, previous work has demonstrated that LVLED 450% QRS is associated with acute hemodynamic response and long-term outcomes, and as such this may be a reasonable target threshold when intraprocedural mapping for the region of maximal electrical delay is used.17 A recent analysis of the SMART-AV study has provided further evidence that electrical lead location has important predictive value in CRT.16 This study demonstrated that longer electrical delay as measured by using the QLV, a similar measure of electrical delay except that it is not indexed for baseline QRS, was associated with increased reverse remodeling and improved quality of life. We suggest that electrical delay may best be assessed when indexed for baseline QRS, as it allows the electrical location to be assessed in the context of an individual’s electrical activation sequence, thus potentially affording a more personalized approach to LV lead implantation.

CRT and arrhythmogenesis

Figure 4 Incidence of VT/VF among all patients when divided by LVLED (long vs short) and anatomic (apical vs nonapical) lead location criteria. LVLED ¼ left ventricular lead electrical delay; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

Initial reports suggested that CRT might be associated with an increase in VAs.24,25 A number of potential mechanisms have been proposed, including epicardial pacing leading to a reversal of the transmural gradient with an increased heterogeneity of repolarization, functional reentry, and torsades de pointes24; and biventricular pacing causing a collision of multiple wave fronts in proximity to a susceptible anatomic substrate may in turn be proarrhythmic. Although these mechanisms may lead to arrhythmias in certain patients with

674 biventricular pacing, a number of antiarrhythmic mechanisms likely predominate and typically outweigh such deleterious effects. These antiarrhythmic mechanisms likely include decreased neurohormonal activation (ie, norepinephrine),26 wall tension,27 and LV size,28,29 LV mass,9,29 and oxygen consumption,30 which are hypothesized to be important for arrhythmogenesis.31 In addition, biventricular pacing decreases pauses and conduction delays, which are important mechanisms for pause-dependent and macroreentrant arrhythmias, respectively.32

Relationship between lead position and VAs Early studies demonstrated that CRT was associated with a decreased risk of VAs.7,32 Subsequent analyses have demonstrated that reverse remodeling was associated with this decreased risk of arrhythmias,6,9,27 and as such, improvements in LV size and function have been thought to represent fundamental mechanisms underlying the improvements in electrical stability observed in CRT. Our analysis is consistent with these findings, as the patients with optimal lead position demonstrated both arrhythmia reduction and a greater extent of ejection fraction improvement compared with those with suboptimal lead placement. However, after adjustment for ejection fraction improvement, suboptimal lead location remained a robust predictor of arrhythmias, suggesting that the relationship between lead placement and arrhythmias may not be entirely mediated by reverse remodeling. It could be speculated that this may be a direct effect of pacing from an optimal lead location on favorable systemic neurohormonal activation,26 optimal interactions between the colliding wave fronts, or a local impact on wall tension27 and dyssynchrony.33,34 It should be noted that Kleemann et al35 were unable to find a relationship between LV lead position and VA in a study of 187 patients with CRT. However, the determination of lead position along the short axis was dichotomized into anterior vs nonanterior using nonstandard anatomic definitions and lead position along the long axis was not determined. This is in contrast to the accepted and validated norm of subsegmenting the heart into 15 distinct anatomic segments.14,15

Clinical implications This study demonstrates that multimodal assessment of lead location by both electrical and anatomic means provides superior prognostic information regarding risk of VAs. Precise lead location data may prove beneficial when assessing nonresponders and considering patients for therapy with antiarrhythmic drugs or catheter ablation for VAs. Furthermore, these studies suggest that an integrated approach to coronary sinus branch selection via anatomic and electrical localization may result in improved outcomes. This multimodal approach may be of particular benefit in assessing lead position in an anatomically favorable (eg, nonapical) segment. This hypothesis, however, warrants further study in a prospective manner.

Heart Rhythm, Vol 10, No 5, May 2013

Study limitations This study was a retrospective analysis of a small prospectively acquired cohort and thus was subject to all these inherent limitations. This was a single center study including patients followed at a multidisciplinary CRT clinic at a tertiary care academic medical center, and thus the results may not be immediately applicable to all patients with CRT. Device programming, including therapy zones, was not uniform and was left to the discretion of the treating electrophysiologist. This study was underpowered to detect a difference in VAs among the patients with suboptimal lead positions when classified based on electric and anatomic lead positions. Our study did not have patients with anterior lead locations to address whether anatomic lead placement along the short axis was associated with an increased risk of VA. Finally, since we do not have prospective information regarding why certain patients received apical leads (although most often determined by venous anatomy constraints and phrenic nerve pacing), we cannot exclude the possibility that the relationship between apical lead location and arrhythmias may be mediated by a confounder, for example, dense scar in the nonapical position that would preclude adequate lead capture. As such, a prospective study is needed to validate these findings prior to universally recommending the inclusion of intraprocedural LVLED for routine LV lead implantation.

Conclusions The apical lead position is associated with an increased risk of VAs in patients undergoing CRT. Among patients with a nonapical lead position, LVLED o50% QRS is associated with an increased risk of VAs. Combining these 2 metrics improves risk stratification for first incident and recurrent VAs.

References 1. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–2150. 2. Cleland JG, Daubert JC, Erdmann E, et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase]. Eur Heart J 2006;27:1928–1932. 3. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834–1843. 4. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329–1338. 5. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. 6. Barsheshet A, Wang PJ, Moss AJ, et al. Reverse remodeling and the risk of ventricular tachyarrhythmias in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). J Am Coll Cardiol 2011;57:2416–2423. 7. Ermis C, Seutter R, Zhu AX, et al. Impact of upgrade to cardiac resynchronization therapy on ventricular arrhythmia frequency in patients with implantable cardioverter-defibrillators. J Am Coll Cardiol 2005;46:2258–2263. 8. Gold MR, Linde C, Abraham WT, Gardiwal A, Daubert JC. The impact of cardiac resynchronization therapy on the incidence of ventricular arrhythmias in mild heart failure. Heart Rhythm 2011;8:679–684.

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LV Lead Position and Ventricular Arrhythmias in CRT

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