Abstract
Introduction
Left bundle branch area pacing (LBBAP) seems to be an alternative to coronary sinus pacing in patients with non-ischaemic dilated cardiomyopathy (NI-DCM) with left bundle branch block (LBBB) and in pacing-induced cardiomyopathy (PICM). The aim of the study was to compare the response of LBBAP in severe forms of both entities.
Material and methods
Prospective study of patients with severe forms of PICM and NI-DCM in NYHA II-IV who underwent LBBAP. Clinical, electrocardiographic, echocardiographic and electrical parameters were analysed and the medium-term prognostic impact was assessed.
Results
Eighty patients were included, 25 with PICM and 55 with NI-DCM. PICM patients were older (PICM 75 [IQR 71-83.5] y.o vs NI-DCM 72 [IQR 60-78.5] y.o;p=0.01) and with longer baseline QRS duration (PICM 180 [IQR 167-194] ms vs NI-DCM 168 [IQR 153-178] ms;p<0.01), with no differences in left ventricular ejection fraction (LVEF) or medical treatment. QRS reduction occurred in both groups, being greater in PICM (PICM CI 95% 54±20 ms, p<0.01; NI-DCM CI 95% 40±15 ms;p<0.01). A NT-ProBNP levels reduction and LVEF improvement were observed without differences between groups. At follow-up, there were no differences in admissions for HF (PICM 4.2% vs NI-DCM 11%;p=0.413), cardiac mortality (PICM 14.9% vs NI-DCM 2.9%;p=0.13) and all-cause mortality (PICM 21.7% vs NI-DCM 10.9%;p=0.08).
Conclusion
LBBAP is an effective technique with a NT-ProBNP levels reduction and LVEF improvement in both groups without differences. At follow-up, both groups had a low rate of HF readmissions and there was a non-significant trend toward higher total mortality in PICM.
Graphical Abstract
We included 25 patients in the severe-PICM group and 55 patients with NI-DCM and left bundle branch block, all of them with LVEF <40% and in NYHA II-IV despite optimal medical treatment. During follow-up, we observed a significant improvement in LVEF in both groups with a trend towards to a greater increase in the NI-DCM group, a reduction in NT-PRoBNP levels and an improvement in NYHA functional class. With a median follow-up of 18.5 months, both groups had a low incidence of admissions for heart failure and cardiac mortality with no differences between them. LVEF: Left ventricular ejection fraction; NI-DCM: Non ischemic dilated cardiomyopathy; PICM: Pacing induced cardiomyopathy.
Introduction
Right ventricular pacing (RVP) induces abnormal ventricular activation as seen in patients with left bundle branch block (LBBB). Thus, inter and intraventricular asynchrony is observed with an initial contraction of the interventricular septum (IVS) and later activation of the inferolateral aspect of the left ventricle (LV). This depolarization pattern in patients with RVP can lead to degenerative cellular changes and perfusion alterations in patients without prior heart disease, resulting the development of pacing-induced cardiomyopathy (PICM), characterized by a decrease in left ventricular ejection fraction (LVEF), left ventricular dilation and functional mitral regurgitation (MR) occurrence.
The criteria for defining PICM are heterogeneous. The incidence varies between 5.9% and 12.3% if we define PICM as the presence of a LVEF ≤ 40% at follow-up when baseline LVEF was ≥ 50%, or an absolute drop in LVEF of ≥ 10% when baseline LVEF was ≤ 50%. In contrast, if the criterion for the diagnosis of PICM is an absolute reduction in LVEF ≥ 10% regardless of the final LVEF the incidence rises to 39%. Although PICM can be observed at any time after device implantation, its incidence increases with longer follow-up and its occurrence is associated with increased mortality and admissions for heart failure. , Among the factors associated with the development of PICM those consistently observed in different studies are baseline LVEF, , higher percentage of RVP (> 20% or > 40% ) and longer duration of paced QRS (QRSp). ,
Currently, clinical practice guidelines recommend resynchronisation therapy with coronary sinus pacing (CRT-CS) in symptomatic patients with LVEF ≤35% despite optimal medical treatment (OMT), in both NI-DCM patients with LBBB and PICM, with good results after up-grade to CRT-CS in PICM.
In this group of patients, His bundle pacing (HBP) or left bundle branch area pacing (LBBAP) can be an alternative to CRT-CS. HBP has good results in patients with PICM, but with suboptimal electrical parameters at follow-up. In contrast, since LBBAP has proven useful in patients with dilated cardiomyopathy (DCM) and has more efficient electrical parameters at follow-up compared to HBP, it may be an alternative in patients with PICM. In this context, LBBAP has previously been evaluated with good results in PICM, but the patients included in the previously published series had non-severe forms with mean LVEF >35%, furthermore, the response after LBBAP has not been compared between patients with PICM and NI-DCM.
The aim of our study was to assess clinical, analytical and echocardiographic response differences between NI-DCM and severe-PICM after LBBAP.
Methods
Design and study population
Observational, prospective, longitudinal, analytical and single-centre study conducted at the Reina Sofia Hospital (Cordoba, Spain) between August 2020 and March 2023. Two groups of patients were consecutively included in whom LBBAP were performed: Group 1) I) LVEF ≤ 40 %; II) previous right ventricular (RV) pacemaker implantation with at least 20 % of RVP; III) LVEF > 50 % before to pacemaker implantation; IV) NYHA II-IV; V) OMT during at least 3 months. Patients with fulfilled Group 1 criteria were defined as Severe-PICM.
Group 2 I) NI-DCM; II) LVEF ≤40%; III) LBBB; IV) QRS >130 ms; V) New York Heart Association (NYHA) II-IV; VI) OMT during at least 3 months.
Exclusion criteria for both groups were: I) <18 years old; II) pregnant; III) severe primary heart valve disease; IV) previous myocardial infarction; V) atrial fibrillation (AF) with uncontrolled rate response (mean heart rate >110 bpm in 24-hours Holter); VI) frequent premature ventricular complex (PVC) (>10,000/24 hours) before LBBAP.
End points and follow up
The main aim of our study was to compare changes in follow-up in LVEF after LBBAP between Group 1 and Group 2. As secondary endpoints we evaluated and compared in follow-up: A) Clinical outcomes: (I) NYHA(I-IV), (II) heart failure (HF) admissions, (III) cardiac mortality (including heart failure mortality and sudden death), (IV) all-cause mortality, (V) HF treatment; B) Echocardiographic parameters: (I) Left Ventricular End-Diastolic Volume (LVEDV) (mL/m 2 ), (II) Left Ventricular End-Systolic Volume (LVESV) (mL/m 2 ), (III) mitral regurgitation (MR) severity (I-IV), (IV) tricuspid regurgitation (TR) severity (I-IV); C) Electrical parameters: (I) basal and paced QRS duration (ms), (II) threshold (V/0,4ms), (III) R wave detection (mV), (IV) lead impedance (Ohm); D) Blood test results (I) NT-proBNP (pg/mL) (II) Creatinine level (mg/dL) and Glomerular filtration rate (GFR) (mL/min/1.73m 2 ).
The minimum follow-up in all patients was 6 months and, after this assessment, follow-up was continued yearly until February 2024.
Left bundle branch implantation procedure
All patients signed informed consent prior to the procedure. Antibiotic prophylaxis and vascular access were carried out according to current recommendations. Before puncture, venography was performed to assess the permeability of the vascular access and to plan the need for recanalization of the previous venous access in patients with PICM. Typically, in cases of PICM, if the previous RV lead was implanted <1-2 years an attempt to extraction with simple traction was made and, in case of longer time since implantation, abandonment was chosen. LBBAP was used as the first option in all patients with no previous attempt of HBP or coronary sinus pacing. The technique used is as previously described but with a simplified approach, implantation was performed with the C315 double-loop sheath (Medtronic, Inc, Minneapolis, MN) and Select-SecureTM lead (model 3830, 69 cm; Medtronic, Inc, Minneapolis, MN). In cases where the implant was initially unsuccessful, the SL10 sheath (Medtronic, Inc, Minneapolis, MN) was used. To monitor the implant and for interval measurement the LabSystem Pro™ recording system was used (Boston Scientific, Charlestown, MA, USA; bipolar filter 30-250 Hz, unipolar Filter: 1-250 Hz, electrocardiogram [ECG] filter 1-100 Hz; sweep speed: 100 mm/s). Based on the paced QRS morphology and the electrical parameters analysed we divided patients into 3 groups according to current criteria:
- 1.
Left bundle branch pacing (LBBP). The QRSp in unipolar configuration has right bundle branch block (RBBB) morphology along with any of the following parameters:
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Interval between the pacing stimulus and the peak of the R wave in V6 (V6-RWPT) < 100 ms.
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Interval between peak R wave in V6 and peak R wave in V1 > 33 ms (V6-V1 interpeak interval).
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Transition from non-selective RI capture (NS-LBBP) to selective capture (S-LBBP) with constant V6-RWPT, or transition from NS-LBBP to left ventricular septal pacing with V6-RWPT prolongation ≥ 15 ms.
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- 2.
Left ventricular septal pacing (LVSP). The QRSp in unipolar configuration has RBBB morphology but not meet any of the criteria for LBBP.
- 3.
Deep septal pacing (DSP). The QRSp has no RBBB morphology showing a “W” or “QS” pattern in lead V1.
We considered the procedure successful if LBBP or LVSP was obtained, including both locations within LBBAP term. DSP was considered procedural failure. The concomitant implantation of an implantable cardioverter defibrillator (ICD) during the procedure was at the discretion of the operator based on age, diagnosis of genetic cardiomyopathy with high arrhythmic risk, presence of fibrosis on cardiac magnetic resonance imaging (MRI) in Group 2 and patient comorbidities.
Pre-procedural clinical, analytical and echocardiographic analysis
Baseline demographics, analytical parameters, comorbidities and time between initial pacemaker implantation and development of PICM were collected. Symptoms of heart failure (HF) were established according to NYHA functional class and we assessed admissions with a diagnosis of worsening heart failure (WHF) in the 12 months prior to the procedure.
The diagnosis of severe-PICM was established on the date of the baseline echocardiogram. The following echocardiographic variables were collected and analysed: LVEDV, LVESV, LVEF determined by the Simpson method, MR severity, RV function assessed by tricuspid annulus plane systolic excursion (TAPSE) and TR severity according to current recommendations. In addition, the degree of MR and TR was classified as non-significant (absent or mild) and significant (moderate or severe).
Analysis of procedure parameters
The following procedure-related data were recorded: LBBAP capture threshold (V/0,4 ms), detection (mV), impedance (ohm), acute complications, device type, procedural success, need for venous recanalization in Group 1, abandonment or removal the previous RV lead in Group 1 and changes in QRS duration after LBBAP. QRS duration was measured at a sweep speed of 100 mm/s from the first to the last deflection by analysing all electrocardiogram leads.
Clinical, analytical, echocardiographic and electrical parameter analysis at follow-up
In each follow-up visit NYHA functional class, device electrical parameters, analytical values, echocardiogram data and device-related complications were assessed.
In the follow-up echocardiogram patients were classified as responders if we observed an absolute increase in LVEF ≥ 5%, as hyper-responders if LVEF ≥ 50% at the end of follow up or as non-responders if we observed a worsening of LVEF or an improvement of LVEF < 5%. In addition, the concept of LVEF improvement was included according to the criteria established in the Universal Definition of HF in 2021.
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HF with improved LVEF (HFimpEF). Patients with an initial LVEF ≤40% with an increase of ≥ 10 points from baseline and a second determination of LVEF >40%.
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HF with persistently reduced LVEF . Patients who do not meet the criteria of the previous group.
Statistical analysis
All quantitative data are presented as mean and standard deviation (or, if the distribution of values does not conform to normality, median and interquartile range) for continuous variables. Qualitative variables are expressed as absolute values and percentages.
The normality of all variables was studied using the Shapiro-Wilk test. In the comparison of categorical qualitative variables, the Chi-square statistic or Fisher’s exact test was used when necessary. In case of paired data, McNemar’s test was used. In the comparison of quantitative variables, the Student’s t-test for independent data or the Mann-Whitney U-test was used, as appropriate. In the comparison between intra-group data for paired data (before-after), Student’s t-test for paired data was used as a parametric test or Wilcoxon as a non-parametric test.
Event-free survival (HF readmissions, cardiovascular mortality and all-cause mortality) in both groups was studied by the Kaplan-Meier method and differences between the survival curves of the two groups were analysed by the Log-Rank test.
In all statistical tests a value of p<0.05 (95% confidence interval) was considered statistically significant. All statistical analyses were performed with IBM-SPSS software (version 25.0 for Macintosh, SPSS Corp., New York, Armonk).
Ethical considerations
The study was approved by the local ethics committee (committee reference 5748). The study was subject to the standards of good clinical practice and always complied with the ethical precepts contained in the Declaration of Helsinki and its latest updates, including the Oviedo agreement. The confidentiality of the data was always respected through data anonymity in accordance with Regulation (EU) 2016/679 of the European Parliament and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and guarantee of digital rights.
Results
Baseline characteristics
Eighty patients who met the inclusion criteria and underwent LBBAP were included, 25 patients in Group 1 (severe-PICM) and 55 patients in Group 2 (NI-DCM with LBBB). One patient died of a non-cardiovascular cause before the first follow-up in Group 1, while all patients in Group 2 completed at least 6 months of follow-up.
Group 1 patients were older ( Group 1 75 y.o. [IQR 71-83] vs Group 2 72 y.o. [IQR 60-78]; p=0.01) and had a higher proportion of AF ( Group 1 60% vs Group 1 27.3%; p<0.01), but no significant differences in cardiovascular risk factors prevalence, baseline NT-proBNP levels and baseline LVEF were observed compared to the Group 2. However, patients in NYHA functional class III-IV were more frequent in Group 1 ( Group 1 60% vs Group 2 31.9%; p=0.01) ( Table 1 ). The number of HF admissions in the 12 months prior to the procedure was similar between groups (Table S1).
