Dataset Information

HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates.

ABSTRACT: This study sought to test the hypothesis that hyperpolarization-activated cyclic nucleotide-gated (HCN)-based biological pacing might be improved significantly by hyperpolarizing the action potential (AP) threshold via coexpression of the skeletal muscle sodium channel 1 (SkM1).Gene-based biological pacemakers display effective in vivo pacemaker function. However, approaches used to date have failed to manifest optimal pacemaker properties, defined as basal beating rates of 60 to 90 beats/min, a brisk autonomic response achieving maximal rates of 130 to 160 beats/min, and low to absent electronic backup pacing.We implanted adenoviral SkM1, HCN2, or HCN2/SkM1 constructs into left bundle branches (LBB) or left ventricular (LV) epicardium of atrioventricular-blocked dogs.During stable peak gene expression on days 5 to 7, HCN2/SkM1 LBB-injected dogs showed highly stable in vivo pacemaker activity superior to SkM1 or HCN2 alone and superior to LV-implanted dogs with regard to beating rates (resting approximately 80 beats/min; maximum approximately 130 beats/min), no dependence on electronic backup pacing, and enhanced modulation of pacemaker function during circadian rhythm or epinephrine infusion. In vitro isolated LV of dogs overexpressing SkM1 manifested a significantly more negative AP threshold.LBB-injected HCN2/SkM1 potentially provides a more clinically suitable biological pacemaker strategy than other reported constructs. This superiority is attributable to the more negative AP threshold and injection into the LBB.

SUBMITTER: Boink GJ

PROVIDER: S-EPMC5490253 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates.

Boink Gerard J J GJ Duan Lian L Nearing Bruce D BD Shlapakova Iryna N IN Sosunov Eugene A EA Anyukhovsky Evgeny P EP Bobkov Eugene E Kryukova Yelena Y Ozgen Nazira N Danilo Peter P Cohen Ira S IS Verrier Richard L RL Robinson Richard B RB Rosen Michael R MR

Journal of the American College of Cardiology 20130206 11

<h4>Objectives</h4>This study sought to test the hypothesis that hyperpolarization-activated cyclic nucleotide-gated (HCN)-based biological pacing might be improved significantly by hyperpolarizing the action potential (AP) threshold via coexpression of the skeletal muscle sodium channel 1 (SkM1).<h4>Background</h4>Gene-based biological pacemakers display effective in vivo pacemaker function. However, approaches used to date have failed to manifest optimal pacemaker properties, defined as basal ...[more]

PMID: 23395072

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Project description:BackgroundAlthough right ventricular pacing (RVP) is recommended by most of the guidelines for atrioventricular block, it can cause electrical and mechanical desynchrony, impair left ventricular function, and increase the risk of atrial fibrillation. Recently, the His-Purkinje system pacing, including His bundle pacing (HBP) and left bundle branch pacing (LBBP), has emerged as a physiological pacing modality. However, few studies have compared their efficacy and safety in atrioventricular block (AVB).Methods and resultsThe PubMed, Web of Science, Cochrane Library, and ScienceDirect databases were searched for observational studies and randomized trials of patients with atrioventricular block requiring permanent pacing, from database inception until 10 January 2022. The primary outcomes were complications and heart failure hospitalization. The secondary outcomes included changes in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD), pacing parameters, procedure duration, and success rate. After extracting the data at baseline and the longest follow-up duration available, a pairwise meta-analysis and a Bayesian random-effects network meta-analysis were performed. Odds ratios (ORs) with 95% confidence intervals (CIs) or 95% credible intervals (CrIs) were calculated for dichotomous outcomes, whereas mean differences (MDs) with 95% CIs or 95% CrIs were calculated for continuous outcomes. Seven studies and 1,069 patients were included. Overall, 43.4% underwent LBBP, 33.5% HBP, and 23.1% RVP. Compared with RVP, LBBP and HBP were associated with a shorter paced QRS duration and a more preserved LVEF. HBP significantly increased the pacing threshold and reduced the R-wave amplitude. There was no difference in the risk of complications or the implant success rate. The pacing threshold remained stable during follow-up for the three pacing modalities. The pacing impedance was significantly reduced in HBP, while a numerical but non-significant pacing impedance decrease was observed in both LBBP and RVP. LBBP was associated with an increased R-wave amplitude during follow-up.ConclusionIn this systematic review and network meta-analysis, HBP and LBBP were superior to RVP in paced QRS duration and preservation of LVEF for patients with atrioventricular block. LBBP was associated with a lower pacing threshold and a greater R-wave amplitude than HBP. However, the stability of the pacing output of LBBP may be a concern. Further investigation of the long-term efficacy in left ventricular function and the risk of heart failure hospitalization is needed.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=315046], identifier [CRD42022315046].

Project description:BackgroundQRS transition criteria during dynamic manoeuvers are the gold-standard for non-invasive confirmation of left bundle branch (LBB) capture, but they are seen in <50% of LBB area pacing (LBBAP) procedures.ObjectiveWe hypothesized that transition from left ventricular septal pacing (LVSP) to LBB pacing (LBBP), when observed during lead penetration into the deep interventricular septum (IVS) with interrupted pacemapping, can suggest LBB capture.MethodsQRS transition during lead screwing-in was defined as shortening of paced V6-R wave peak time (RWPT) by ≥10 ms from LVSP to non-selective LBBP (ns-LBBP) obtained during mid to deep septal lead progression at the same target area, between two consecutive pacing manoeuvres. ECG-based criteria were used to compared LVSP and ns-LBBP morphologies obtained by interrupted pacemapping.ResultsSixty patients with demonstrated transition from LVSP to ns-LBBP during dynamic manoeuvers were compared to 44 patients with the same transition during lead screwing-in. Average shortening in paced V6-RWPT was similar among study groups (17.3 ± 6.8 ms vs. 18.8 ± 4.9 ms for transition during dynamic manoeuvres and lead screwing-in, respectively; p = 0.719). Paced V6-RWPT and aVL-RWPT, V6-V1 interpeak interval and the recently described LBBP score, were also similar for ns-LBBP morphologies in both groups. LVSP morphologies showed longer V6-RWPT and aVL-RWPT, shorter V6-V1 interpeak interval and lower LBBP score punctuation, without differences among the two QRS transition groups. V6-RWPT < 75 ms or V6-V1 interpeak interval > 44 ms criterion was more frequently achieved in ns-LBBP morphologies obtained during lead screwing-in compared to those obtained during dynamic manoeuvres (70.5% vs. 50%, respectively p = 0.036).ConclusionsDuring LBBAP procedure, QRS transition from LVSP to ns-LBBP can be observed as the lead penetrates deep into the IVS with interrupted pacemapping. Shortening of at least 10 ms in paced V6-RWPT may serve as marker of LBB capture.

Project description:AimsStable coronary artery disease (CAD) is a prevalent comorbidity among patients requiring pacemaker implantation. This comorbidity may have an impact on the safety and prognosis of traditional right ventricular pacing (RVP). Left bundle branch area pacing (LBBaP) is a new physiological pacing modality. Our aim was to investigate the feasibility and safety of LBBaP in patients with the stable CAD.MethodsThis study included 309 patients with symptomatic bradycardia who underwent LBBaP from September 2017 to October 2021. We included 104 patients with stable CAD (CAD group) and 205 patients without CAD (non-CAD group). Additionally, 153 stable CAD patients underwent RVP, and 64 stable CAD patients underwent His-bundle pacing (HBP) were also enrolled in this study. The safety and prognosis of LBBaP was assessed by comparing pacing parameters, procedure-related complications, and clinical events.ResultsDuring a follow-up period of 17.4 ± 5.3 months, the safety assessment revealed that the overall rates of procedure-related complications were similar between the stable CAD group and the non-CAD group (7.7% vs. 3.9%). Likewise, similar rates of heart failure hospitalization (HFH) (4.8% vs. 3.4%, stable CAD vs. non-CAD) and the primary composite outcome including death due to cardiovascular disease, HFH, or the necessity for upgrading to biventricular pacing (6.7% vs. 3.9%, stable CAD vs. non-CAD), were observed. In stable CAD patients, LBBaP demonstrated lower pacing thresholds and higher R wave amplitudes when compared to HBP. Additionally, LBBaP also had significantly lower occurrences of the primary composite outcome (6.7% vs. 19.6%, P = 0.003) and HFH (4.8% vs. 13.1%, P = 0.031) than RVP in stable CAD patients, particularly among patients with the higher ventricular pacing (VP) burden (>20% and >40%).ConclusionCompared with non-CAD patients, LBBaP was found to be attainable in stable CAD patients and exhibited comparable mid-term safety and prognosis. Furthermore, in the stable CAD population, LBBaP has demonstrated more stable pacing parameters than HBP, and better prognostic outcomes compared to RVP.

Project description:Biventricular endocardial (BIV-endo) pacing and left bundle pacing (LBP) are novel delivery methods for cardiac resynchronization therapy (CRT). Both pacing methods can be delivered through leadless pacing, to avoid risks associated with endocardial or transvenous leads. We used computational modelling to quantify synchrony induced by BIV-endo pacing and LBP through a leadless pacing system, and to investigate how the right-left ventricle (RV-LV) delay, RV lead location and type of left bundle capture affect response. We simulated ventricular activation on twenty-four four-chamber heart meshes inclusive of His-Purkinje networks with left bundle branch block (LBBB). Leadless biventricular (BIV) pacing was simulated by adding an RV apical stimulus and an LV lateral wall stimulus (BIV-endo lateral) or targeting the left bundle (BIV-LBP), with an RV-LV delay set to 5 ms. To test effect of prolonged RV-LV delays and RV pacing location, the RV-LV delay was increased to 35 ms and/or the RV stimulus was moved to the RV septum. BIV-endo lateral pacing was less sensitive to increased RV-LV delays, while RV septal pacing worsened response compared to RV apical pacing, especially for long RV-LV delays. To investigate how left bundle capture affects response, we computed 90% BIV activation times (BIVAT-90) during BIV-LBP with selective and non-selective capture, and left bundle branch area pacing (LBBAP), simulated by pacing 1 cm below the left bundle. Non-selective LBP was comparable to selective LBP. LBBAP was worse than selective LBP (BIVAT-90: 54.2 ± 5.7 ms vs. 62.7 ± 6.5, p < 0.01), but it still significantly reduced activation times from baseline. Finally, we compared leadless LBP with RV pacing against optimal LBP delivery through a standard lead system by simulating BIV-LBP and selective LBP alone with and without optimized atrioventricular delay (AVD). Although LBP alone with optimized AVD was better than BIV-LBP, when AVD optimization was not possible BIV-LBP outperformed LBP alone, because the RV pacing stimulus shortened RV activation (BIVAT-90: 54.2 ± 5.7 ms vs. 66.9 ± 5.1 ms, p < 0.01). BIV-endo lateral pacing or LBP delivered through a leadless system could potentially become an alternative to standard CRT. RV-LV delay, RV lead location and type of left bundle capture affect leadless pacing efficacy and should be considered in future trial designs.

Dataset Information

HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates.

Publications

HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates.

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