Dataset Information

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.

ABSTRACT:

Background

Slowed Na⁺ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na⁺ channel gating in CRT remains unexplored.

Methods and results

Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). INa and INa-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of INa availability by -3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF-induced slowed recovery. DHF markedly increased INa-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca²⁺/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na⁺ channels. In a canine AP model, alterations of INa-L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes.

Conclusions

CRT improves DHF-induced alterations of Na⁺ channel function, especially suppression of INa-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca²⁺/Calmodulin protein kinase II suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart.

SUBMITTER: Aiba T

PROVIDER: S-EPMC4114055 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Publications

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.

Aiba Takeshi T Barth Andreas S AS Hesketh Geoffrey G GG Hashambhoy Yasmin L YL Chakir Khalid K Tunin Richard S RS Greenstein Joseph L JL Winslow Raimond L RL Kass David A DA Tomaselli Gordon F GF

Circulation. Arrhythmia and electrophysiology 20130506 3

<h4>Background</h4>Slowed Na⁺ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na⁺ channel gating in CRT remains unexplored.<h4>Methods and results</h4>Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followe ...[more]

PMID: 23650309

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Project description:BackgroundCardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored.Methods and resultsAdult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K(+) current (I(K1)), delayed rectifier K(+) current (I(K)), and transient outward K(+) current (I(to)) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I(K1) and I(K) but not I(to), consistent with trends in the changes in steady state K(+) channel mRNA and protein levels. DHF reduced the peak inward Ca(2+) current (I(Ca)) density and slowed I(Ca) decay in lateral compared with anterior cells, whereas CRT restored peak I(Ca) amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca(V)1.2 (alpha1C) mRNA or protein expression, but reduced Ca(V)beta2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca(2+) ATPase and increased Na(+)-Ca(2+) exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca(2+) ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT.ConclusionsCRT partially restores DHF-induced ion channel remodeling and abnormal Ca(2+) homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

Project description:Approximately 40% of patients with heart failure (HF) who are eligible for cardiac resynchronization therapy (CRT) either fail to respond or are untreatable due to anatomical constraints. To assess the safety and efficacy of a novel, leadless, left ventricular (LV) endocardial pacing system for patients at high risk for a CRT upgrade or whose coronary sinus (CS) lead placement/pacing with a conventional CRT system failed. The SOLVE-CRT study was a prospective multicenter trial, enrolling January 2018 through September 2022, with follow-up in March 2023. Data were analyzed from DATE MONTH, YEAR, through DATE MONTH, YEAR. The trial combined data from an initial randomized, double-blind study (n = 108) and a subsequent single-arm part (n = 75). It took place at 36 centers across Australia, Europe, and the US. Participants were nonresponders, previously untreatable (PU), or high-risk upgrades (HRU). All participants contributed to the safety analysis. The primary efficacy analysis (n = 100) included 75 PU-HRU patients from the single-arm part and 25 PU-HRU patients from the randomized treatment arm. Patients were implanted with the WiSE CRT System (EBR Systems) consisting of a leadless LV endocardial pacing electrode stimulated with ultrasound energy delivered by a subcutaneously implanted transmitter and battery. The primary safety end point was freedom from type I complications. The primary efficacy end point was a reduction in mean LV end systolic volume (LVESV). The study included 183 participants; mean age was 68.1 (SD, 10.3) years and 141 were male (77%). The trial was terminated at an interim analysis for meeting prespecified stopping criteria. In the safety population, patients were either New York Heart Association Class II (34.6%) or III (65.4%). The primary efficacy end point was met with a 16.4% (95% CI, -21.0% to -11.7%) reduction in mean LVESV (P = .003). The primary safety end point was met with an 80.9% rate of freedom from type I complications (P < .001), which included 12 study device system events (6.6%), 5 vascular events (2.7%), 3 strokes (1.6%), and 7 cardiac perforations which mostly occurred early in the study (3.8%). The SOLVE-CRT study has demonstrated that leadless LV endocardial pacing with the WiSE CRT system is associated with a reduction in LVESV in patients with HF. This novel system may represent an alternative to conventional CRT implants in some HF patient populations. ClinicalTrials.gov Identifier: NCT0292203.

Dataset Information

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.

Background

Methods and results

Conclusions

Publications

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.

Similar Datasets

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