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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].

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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