Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study

Trappe, Kerstin; Thomas, Dierk; Bikou, Olympia; Kelemen, Kamilla; Lugenbiel, Patrick; Voss, Frederik; Becker, Rüdiger; Katus, Hugo A.; Bauer, Alexander

doi:10.1093/eurheartj/ehr269

Cited by 87 publications

(82 citation statements)

References 40 publications

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“…Ventricular cell loss has been confirmed in AF patients with tachycardia-induced cardiomyopathy (15,16). However, in the present study, myocardial injury was confirmed in the CHF-AF patients, irrespective of whether the heart rate was strictly controlled.…”

Section: Mechanisms Of Myocardial Damage In Af Patientscontrasting

confidence: 57%

Prognostic Value of Myocardial Damage Markers in Patients with Chronic Heart Failure with Atrial Fibrillation

et al. 2014

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Objective The aim of the present study was to examine the relationship between myocardial damage caused by atrial fibrillation (AF) and subsequent cardiovascular events in AF patients with chronic heart failure (CHF). Methods and ResultsWe measured the serum levels of heart-type fatty acid binding protein (H-FABP) and high-sensitivity troponin T in 402 consecutive CHF patients with chronic AF (CHF-AF, n=201) or sinus rhythm (CHF-SR, n=201). The patients with CHF-AF had higher H-FABP and troponin T levels than those with CHF-SR. In order to examine the prognostic value of myocardial damage markers in CHF-AF and CHF-SR patients, we followed the above patients and analyzed their clinical outcomes. A multivariate Cox proportional hazard analysis revealed that both the serum H-FABP and troponin T levels independently predicted subsequent cardiovascular events. A Kaplan-Meier analysis demonstrated that the rate of cardiovascular events was higher in the patients with elevated H-FABP and troponin T levels. The optimal cut-off values for the myocardial damage markers of cardiovascular events were higher in the CHF-AF patients than in the CHF-SR patients (H-FABP, 5.4 vs. 4.6 ng/mL and troponin T, 0.030 vs. 0.013 ng/mL). Conclusion Myocardial damage advances in association with the presence of AF and is associated with subsequent cardiovascular events in both CHF-AF and CHF-SR patients. In this study, the cut-off values for the myocardial damage markers were higher in the CHF-AF patients than in the CHF-SR patients.

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Section: Mechanisms Of Myocardial Damage In Af Patientscontrasting

confidence: 57%

Prognostic Value of Myocardial Damage Markers in Patients with Chronic Heart Failure with Atrial Fibrillation

et al. 2014

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“…Cells were cultured in supplemented Claycomb medium (JRH Biosciences, Lenexa, KS, USA) as previously described [36,37].…”

Section: Hl-1 Cell Culturementioning

confidence: 99%

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Lugenbiel

Govorov

Rahm

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K⁺ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD₉₀ in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K⁺ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K⁺ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

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“…Cells were cultured and maintained in Claycomb medium, supplemented with 10% FBS, 1% norepinephrine (Sigma-Aldrich, Steinheim, Germany), 2 mM L-glutamine, 100 U mL -1 penicillin G sodium and 100 mg mL -1 streptomycin sulphate (G418; Gibco BRL) as described (Claycomb et al, 1998;Lugenbiel et al, 2012;Trappe et al, 2012). Drug treatment was performed when cells were 80% confluent.…”

Section: Cell Culturementioning

confidence: 99%

Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K⁺ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

Jehle

Ficker

Wan

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEZolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K + channels. EXPERIMENTAL APPROACHTwo-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. KEY RESULTSZolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 mM) and in HEK 293 cells (IC50 = 65.5 mM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage-and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I-V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. CONCLUSIONS AND IMPLICATIONSZolpidem inhibits cardiac hERG K + channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose.

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Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study

Cited by 87 publications

References 40 publications

Prognostic Value of Myocardial Damage Markers in Patients with Chronic Heart Failure with Atrial Fibrillation

Prognostic Value of Myocardial Damage Markers in Patients with Chronic Heart Failure with Atrial Fibrillation

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K⁺ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

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Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study

Cited by 87 publications

References 40 publications

Prognostic Value of Myocardial Damage Markers in Patients with Chronic Heart Failure with Atrial Fibrillation

Prognostic Value of Myocardial Damage Markers in Patients with Chronic Heart Failure with Atrial Fibrillation

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

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Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K⁺ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells