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Archives of cardiovascular diseases
Volume 110, n° 11
pages 590-598 (novembre 2017)
Doi : 10.1016/j.acvd.2017.03.005
Received : 16 November 2016 ;  accepted : 23 Mars 2017
Three-dimensional interlead distance predicts response and outcomes after cardiac resynchronization therapy
La distance tridimensionnelle entre les deux sondes ventriculaires prédit la réponse des patients après resynchronisation cardiaque et leur pronostic
 

Nicolas Clementy , Guillaume Laborie, Bertrand Pierre, Nazih Benhenda, Dominique Babuty, Laurent Fauchier
 Cardiology Department, François Rabelais University, Tours, France 

Corresponding author. Service de cardiologie B, hôpital Trousseau, 37044, Tours, France.
Summary
Background

Approximately one-third of patients do not respond favourably to cardiac resynchronization therapy (CRT). A longer distance between ventricular leads may improve response.

Aim

To study the impact of the true three-dimensional interlead distance (ILD) on outcomes.

Methods

Consecutive patients undergoing CRT device implantation were included prospectively. Interlead separation was measured from postprocedural anterior-posterior and lateral chest X-rays. The three-dimensional ILD was calculated using the Pythagorean theorem. Response to CRT was defined using a composite clinical score at 6 months.

Results

Forty-two patients were included (mean age 70±9 years; QRS duration 154±31ms; left ventricular ejection fraction 26±7%; 50% ischaemic). At 6 months, 71% of patients were considered to be responders. Responders had a significantly longer ILD (108±17 vs. 87±21mm; P =0.002). When the ILD was corrected for cardiac size, the optimal cut-off value was ≥ 0.53 for predicting response (sensitivity 83%, specificity 75%, area under the curve 0.84; P =0.0002). Similar results were obtained in a historical retrospective cohort. The use of proximal electrodes on the left ventricular lead was associated with a longer ILD in 95% of patients, compared with more distal pacing configurations. In the total cohort of 74 patients (median follow-up, 420 days), those with an indexed ILD ≥ 0.53 had a 70% reduction in risk of hospitalization for heart failure (P =0.004).

Conclusion

Longer three-dimensional ILD corrected for cardiac size measured on chest radiographs can accurately predict response to CRT and outcomes. This simple variable may be used to identify optimal lead placement and pacing configuration during CRT implantation.

The full text of this article is available in PDF format.
Résumé
Contexte

Environ un tiers des patients ne sont pas répondeurs à une thérapie de resynchronisation biventriculaire. Une distance plus longue entre les deux sondes ventriculaires pourrait être associée à une meilleure réponse.

Objectif

Nous avons étudié le rôle de la vraie distance tridimensionnelle inter-sondes sur le pronostic des patients après implantation d’un système de resynchonisation biventriculaire.

Méthodes

Les patients consécutifs bénéficiant de l’implantation d’un système de resynchronisation ont été inclus de manière prospective. La distance inter-sondes était calculée en 3 dimensions à l’aide du théorème de Pythagore sur les radiographies post-opératoires (incidences orthogonales latérale et antéro-postérieure). La réponse à la resynchronisation était définie à 6 mois à l’aide d’un critère clinique composite.

Résultats

Quarante-deux patients ont été inclus (âge 70±9 ans, QRS 154±31ms, fraction d’éjection ventriculaire gauche 26±7%, 50% de patients avec cardiopathie ischémique). À 6 mois, 71% des patients étaient répondeurs. Les répondeurs avaient une distance inter-sondes plus grande (108±17 contre 87±21mm; p =0,002). Lorsque la distance inter-sondes était indexée à la largeur de la silhouette cardiaque, une valeur ≥0,53 prédisait la réponse à la resynchronisation avec une sensibilité de 83%, une spécificité de 75%, et une aire sous la courbe ROC de 0,84 (p =0,0002). Des résultats similaires étaient obtenus avec une cohorte contrôle indépendante. L’utilisation des électrodes proximales sur la sonde ventriculaire gauche était associée à une plus grande distance inter-sondes chez 95% des patients. Dans une cohorte totale de 74 patients (suivi médian, 420jours), une distance inter-sondes indexée ≥0,53 était associée à une réduction de 70% du risque d’hospitalisation pour insuffisance cardiaque (p =0,004).

Conclusions

Une distance tridimensionnelle plus longue entre les 2 sondes ventriculaires indexée sur la largeur de la silhouette cardiaque mesurée sur les radiographies du thorax est associée à une meilleure réponse à la resynchronisation biventriculaire et un meilleur pronostic. Ce paramètre simple pourrait permettre d’identifier le meilleur site et la meilleure configuration de stimulation lors de l’implantation d’un dispositif de resynchronisation.

The full text of this article is available in PDF format.

Keywords : Cardiac resynchronization therapy, Interlead distance, Outcome, Left ventricular lead, Quadripolar lead

Mots clés : Resynchronisation cardiaque, Distance inter-sondes, Pronostic, Sonde ventriculaire gauche, Sonde quadripolaire

Abbreviations : AUC, C, CI, CRT, D, D0, H, ILD, LAO, LV, LVEF, NYHA, RAO, ROC, RV, V


Background

Cardiac resynchronization therapy (CRT) has been proven to improve outcomes in patients with heart failure, left ventricular (LV) dysfunction and prolonged QRS complexes. However, about one-third of patients–so-called “non-responders” – do not derive any benefit from this therapy.

Non-response may be related, in part, to an inadequate LV lead position, as LV pacing ought to be performed at the latest electromechanical activation site [1, 2]. It has already been suggested that a maximized interlead distance (ILD), between the right and left ventricular leads, might be associated with a better outcome [2, 3, 4].

We sought to evaluate the effect of the real three-dimensional ILD, measured on simple chest X-rays, on response to CRT and, thus, on long-term outcomes.

Methods
Initial cohort

This was a non-interventional, prospective and retrospective observational study. Consecutive patients who successfully underwent CRT device implantation in our centre between September 2013 and April 2014 were included prospectively after the procedure. Inclusion criteria were age ≥18 years, New York Heart Association (NYHA) class II or III under optimized medical therapy, left ventricular ejection fraction (LVEF) ≤ 35% and QRS complexes ≥ 120ms in width. Exclusion criteria were valvular cardiomyopathy, NYHA class IV and failure of endovascular LV lead implantation.

The protocol of this study was approved by our local ethics committee, the “Comité de Protection des Personnes en Recherche Biomédicale de Tours–Région Centre (Ouest-1)”. Written informed consent was obtained from all included patients.

Control cohort

All patients included in the international MORE-CARE study in our centre were included retrospectively as controls [5]. The MORE-CARE study inclusion criteria were sinus rhythm, LVEF ≤35%, NYHA class III or IV despite optimized medical treatment, and QRS complexes ≥120ms in width.

Initial evaluation

An extensive clinical examination was performed, including NYHA classification, evaluation of quality of life with the “Minnesota Living with Heart Failure Questionnaire”, and a 6-minute hall-walk test. QRS complex width was measured automatically on a 12-lead electrocardiogram at a sweep speed of 50mm/s. Laboratory work-up included B-type natriuretic peptide and glomerular filtration rate estimated with the Modification of Diet in Renal Disease (MDRD) study formula.

Echocardiography was also performed systematically in patients with stable haemodynamics (Vivid 9; GE Healthcare, Milwaukee, WI, USA). Evaluation comprised acquisition of two-dimensional loops (duration ≥ 3 cardiac cycles; rate ≥ 70 frames/s), and measurement of LV diameters, volumes and LVEF using Simpson's method was performed a posteriori by a single experienced operator (EchoPac; GE Healthcare, Milwaukee, WI, USA).

CRT implantation

A defibrillator was implanted in patients with an estimated life expectancy ≥ 1 year and good functional status. The right atrial lead, when required, was implanted at the appendage. The right ventricular (RV) lead was implanted systematically at the apex. The LV lead was implanted through the coronary sinus, at the implanter's discretion, and depending on anatomical and electrical possibilities, preferentially in a lateral basal position.

Postoperative management

All devices were programmed with a fixed detected and paced atrioventricular delay of 120ms, both at rest and exercise, and no interventricular delay [6]. The chosen LV lead pacing configuration (best pacing threshold without phrenic nerve stimulation) was noted. Biventricular pacing QRS width was also measured at a sweep speed of 50mm/s. Interlead electrical delay (average of RV>LV and LV>RV delays, from spike to alternate ventricular chamber electrocardiogram onset) was measured on the electrogram device printout using RV (RV>LV delay) and LV (LV>RV delay) monoventricular pacing.

Chest X-rays were performed systematically, with the patient in a standing position, on the day after CRT implantation, with anterior-posterior, lateral, left anterior oblique (LAO) (–45o) and right anterior oblique (RAO) (+45o) projections. The position of the LV pacing cathode was noted on both LAO (anterior-lateral, lateral or inferior-lateral) and RAO (basal, median or apical) projections [7]. Direct (D), horizontal (H) and vertical (V) ILDs were measured on both anterior-posterior (D1, H1 and V1) and lateral (D2, H2, and V2) projections between the RV lead tip and the LV lead cathode of the final pacing configuration (Figure 1). The cardiac silhouette maximum width was measured on anterior-posterior (C) and lateral (C’) X-rays. The thorax maximum width was also measured. Finally, the direct three-dimensional ILD (D0) was calculated using the Pythagorean theorem (Figure 1). All measurements were performed blinded by two experienced electrophysiologists for interobserver variability assessment, and twice randomly by a single electrophysiologist for intraobserver variability.



Figure 1


Figure 1. 

Method for calculation of direct three-dimensional interlead distance (D0), using the Pythagorean theorem, on two chest radiographs with orthogonal projections. AP: anterior-posterior; D: direct interlead distance (ILD); H: horizontal ILD; L: lateral; V: verticaI ILD.

Zoom

Follow-up

Clinical examination (NYHA, quality of life) and echocardiography were performed 6 months after CRT implantation, as at baseline. Adverse events (hospitalizations for heart failure, all-cause deaths) were collected prospectively using medical records and a questionnaire.

Response was defined using a composite criterion at 6 months, as follows: no death, no hospitalization for heart failure, and either a clinical response (improvement in NYHA class of at least one or in Minnesota score of ≥5) or a volumetric response (decrease in LV end-systolic volume ≥15%).

Statistical analyses

Analyses were performed using JMP 9.0 software (SAS Institute Inc., Cary, NC, USA). Numeric variables are expressed as mean±standard deviation (95% confidence interval [CI]). Comparisons between groups were performed using non-parametric tests. The predictive value of response for different baseline variables was assessed using receiver operating characteristic (ROC) curve analyses. ROC curve comparisons were performed using the χ2 test. Survival curves were obtained using the Kaplan-Meier method, and the log-rank test was used for comparisons between groups. Intraobserver and interobserver variabilities were assessed using the intraclass correlation (ICC) coefficient (95% CI), with a two-way mixed model and absolute agreement on single measurements. A variable with an ICC coefficient value ≥0.80 was considered to be highly reliable. A P value ≤0.05 was considered to be statistically significant.

Results
Population

Forty-two patients were included prospectively. The mean age was 70±9 years, 86% were men and the mean LVEF was 26±7% (50% ischaemic). Characteristics are summarized in Table 1.

LV lead

The final achieved position of the LV lead was basal in 57% of patients and lateral in 55% of patients. Twenty-five patients (60%) were implanted with a bipolar LV lead (distal electrode as cathode in 20 patients), one (2%) with a unipolar LV lead and 16 (38%) with a quadripolar LV lead (a more proximal “4” electrode as cathode in two patients, a mid “2” or “3” electrode as cathode in four patients and a distal “1” electrode as cathode in the remaining 10 patients).

Response to CRT

At 6 months, five patients had been hospitalized for decompensated heart failure, and three patients had died. A total of 30 patients (71%) were considered to be responders (clinical responders, 76%; volumetric responders, 69%). Responders were younger, had a larger LV end-systolic volume and were more likely to be implanted with a defibrillator (Table 1).

Predictive values for response (composite criterion) for different clinical, echocardiographic, radiographic and electrical variables are displayed in Table 2.

Interlead distance

The vertical ILD measurements V1 and V2 were similar (r =0.87; P <0.0001), as were D0 measurements using D1/H2 or D2/H1 (r =0.97; P <0.0001). All radiographic measurements had excellent intraobserver and interobserver agreements (Table 3).

D0 was significantly longer in responders than in non-responders (108±17 vs. 87±21mm; P =0.002). Using ROC curve analyses, a ratio D0/C ≥ 0.53 had the best predictive value for response at 6 months (Table 2), with an area under the curve (AUC) of 0.84 (95% CI 0.71–0.97) versus 0.65 (95% CI 0.44–0.87) for interlead electrical delay (χ2 P =0.02). After multivariable analysis, D0/C independently predicted response at 6 months (odds ratio 1.16, 95% CI 1.05–1.34 per 0.01 unit increase; P =0.001).

D0 was longer when calculated with the more proximal LV lead electrode in 95% of patients. There was a non-significant trend towards a longer D0 using the quadripolar lead (n =16, 38%) versus the bipolar lead when measuring with the more proximal electrode (120±20 vs. 110±21mm; P =0.11) (Figure 2).



Figure 2


Figure 2. 

Direct three-dimensional interlead distance (D0) according to the type of lead (bipolar or quadripolar) and the different left ventricular lead electrodes, in the initial cohort (n =42).

Zoom

A basal LV lead position (RAO projection) was associated with a longer D0 (111±3 vs. 91±5mm; P =0.001). Conversely, an inferior-lateral position (LAO projection) was associated with a shorter D0 (86±5 vs 107±3mm; P =0.005) (Figure 3).



Figure 3


Figure 3. 

Direct three-dimensional interlead distance (D0) according to the final position of the left ventricular lead in the left anterior oblique and right anterior oblique projections, in the initial cohort (n =42). A: apical; AL: anterior-lateral; B: basal; IL: inferior-lateral; L: lateral; M: median.

Zoom

ILD correlated moderately with interlead electrical delay (R2=0.12; P =0.03), but not with QRS duration variation after CRT (ΔQRS) (R2=0.02; P =0.42).

Validation on the control cohort

Data from 32 patients from the MORE-CARE trial were analysed retrospectively for validation of the D0/C ratio. Using the same criterion for response at 6 months, 27 patients were responders (84%). ROC curve analyses found the identical cut-off of ≥0.53 for predicting response at 6 months (same composite criterion), with a sensitivity of 89% and a specificity of 80% (AUC 0.78, P =0.01).

When merging prospective and control cohorts (n =74), 92% of patients with a D0/C ratio ≥ 0.53 (n =52) were responders at 6 months (sensitivity 84%, specificity 76%, AUC 0.82; P <0.0001).

Outcomes

When analysing merged prospective and control cohorts (n =74), after a mean follow-up of 607±528 days (median 420 days, range 60–1987 days), 20 patients (27%) were hospitalized for heart failure. Patients with a D0/C ratio ≥0.53 (n =52, 70%) had a 70% reduction in the risk of hospitalization for heart failure (hazard ratio 0.30, 95% CI 0.12–0.73; P =0.004) (Figure 4).



Figure 4


Figure 4. 

Comparison of long-term survival (median follow-up, 420 days) from heart failure hospitalization using Kaplan-Meier analyses, in the merged cohort (n =74), between patients with a direct three-dimensional interlead distance/cardiac silhouette maximum width measured on anterior-posterior X-ray (D0/C) ratio ≥ 0.53 (n =52, 70%) and<0.53 (non-adjusted hazard ratio [HR]).

Zoom

Discussion

This study shows that direct three-dimensional ILD calculation indexed on cardiac silhouette width on chest X-rays is the best independent predictor of response to CRT at 6 months, and can predict outcomes; second, interlead separation is a simple and highly reliable variable; and third, interlead separation can be increased with an anterior-lateral-basal or lateral-basal LV lead position, a more proximal LV lead pacing configuration and by using quadripolar LV leads.

In our study, direct three-dimensional ILD emerged as a better independent predictor of response to CRT than QRS width shortening [8] or even interlead electrical delay [9, 10, 11, 12]. Heist et al. had shown that a longer direct ILD measured on a lateral radiograph, rather than anterior-posterior, was associated with an acute improvement in haemodynamics in patients undergoing CRT [13]. Buck et al. confirmed these results in terms of volumetric response at 6 months [14].

Before our study, only Ariga et al. had studied the impact of real three-dimensional ILD, easily measurable on two orthogonal radiographic projections [3]. They showed that ILD corrected for cardiac size was 27% longer in responders (0.62±0.13 vs. 0.49±0.16; P =0.001). However, in that retrospective study, CRT response was clinical, defined as a reduction in NYHA class by at least one, which has a limited impact on long-term outcomes [15]. In our study, response was defined with a composite score that included harder endpoints, such as hospitalization for heart failure or all-cause mortality. Moreover, a cut-off was calculated for this radiographic variable, and then validated in a second cohort of patients. Finally, our analyses of intraobserver and interobserver agreements showed that this variable was highly reliable.

These results suggest that a maximum ILD should be obtained during CRT implantation. Specifically, with an RV lead at the apex, lateral-basal or anterior-lateral-basal positions should be targeted. These results confirm those of Shimano et al. [16]. Because the RV lead position is traditionally apical, the shorter ILD with an apical LV lead position may reflect the poorer response associated with this position [17]. This is supported by the relatively good accuracy of the variable H2 alone, which roughly represents the basal-to-apical ILD. With an apical RV lead position, the implanter should then favour an LV position as basal as possible. A longer ILD might result in better electromechanical resynchronization and a shorter total ventricular activation time, in the absence of a significant scar-related line of block [18]. Thus, in patients where D0/C ≥ 0.53 cannot be achieved during the standard procedure [19], a different LV lead implantation technique (surgical or endocardial) might be preferred.

Optimization of LV lead configuration may also be helpful. We have shown that the use of a more proximal cathode for the LV lead improved ILD in 98% of patients, which may further improve haemodynamics. Finally, although not statistically significant, a trend towards a longer ILD in patients with a quadripolar lead may add value to this new type of lead [20].

Study limitations

The main limitations of this study were the relatively small sample size and the systematic apical position for the RV lead. The impact of ILD on outcomes in patients with a RV septal position remains unclear.

Conclusions

A longer three-dimensional ILD, indexed on cardiac width, calculated simply on two orthogonal chest radiographs, independently predicts response to CRT at 6 months and long-term hospitalization for heart failure. Optimization of interlead separation during implantation and programming may improve outcomes in this population.

Disclosure of interest

The authors declare that they have no competing interest.

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