Dysfunctional Hyper Polarization Activated Cyclic Nucleotide-Gated Ion Channels in Cardiac Diseases

Zhao, Xiaobo; Gu, Tingting

doi:10.5935/1678-9741.20160030

Cited by 3 publications

(5 citation statements)

References 46 publications

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“…With a smart clinical study design leading to novel findings, Mert et al [2] indicate today an anti-arrhythmic effect of "ventricular" If blockade with ivabradine leading to reduction in ventricular arrhythmias in the presence of background adrenergic stimulation in human HF. This work [2] opens a new clinical research avenue and it should encourage further studies of the relevance of "ventricular" If blockade in the field of research that remains continuously active [9,22,23,[28][29][30][31] due to the fundamental clinical implications for HF patients.…”

Section: Discussionmentioning

confidence: 93%

“…The popular assumption that the action of If inhibitors is limited to the sinoatrial node [1] is true for the healthy heart [5,22] because in the healthy heart f-channels are functionally expressed only in sinoatrial node cells. In myocardial disease, and in HF in particular, the f-channels undergo a pathologic, functional expression in the ventricular myocardium [6,7,12,23]. By favouring spontaneous diastolic depolarisation in ventricular myocytes, the If current in human failing cardiomyocytes may contribute to the increased risk of malignant ventricular arrhythmias and death in patients with HF [6][7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…Ventricular If contribution to the increased risk of malignant ventricular arrhythmias and sudden death through favouring spontaneous diastolic depolarisation in ventricular myocytes [22,23], has been recently studied in a model of forced expression of f-channels in normal myocardium using somatic gene transfer [8]. These studies demonstrated that f-channels overexpression in undiseased ventricular myocytes, mimicking their spontaneous pathologic expression in HF, indeed leads to abnormal ventricular automaticity via If-dependent spontaneous depolarisations in the ventricular myocardium [8].…”

Section: If-dependent Ventricular Arrhythmogenecity: Mechanismsmentioning

confidence: 99%

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Drug action(s), drug marketing, and clinical medicine. Suppression of ventricular arrhythmogenicity with If blockade in human heart failure: emerging clinical evidence for ivabradine treatment benefit beyond heart rate control

Musiałek

2017

Kardiol Pol

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: If-dependent Ventricular Arrhythmogenecity: Mechanismsmentioning

confidence: 99%

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Drug action(s), drug marketing, and clinical medicine. Suppression of ventricular arrhythmogenicity with If blockade in human heart failure: emerging clinical evidence for ivabradine treatment benefit beyond heart rate control

Musiałek

2017

Kardiol Pol

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“…Notably, downstream targets of the transcription factor Tbx5, a key regulator of cardiac rhythm, 22 were affected. Specifically, genes that have been previously linked to the development of atrial arrhythmias 52,53 Hcn1 and Ryr2 (Ryanodine Receptor 2), the major Ca 2+ channel protein in cardiomyocytes, showed 2-and 4-fold higher expression in Playrr Ex1sj mutant atria, respectively (Fig. 6C-D).…”

Section: Chromatin Run-on and Sequencing Maps Demonstrate Changes In ...mentioning

confidence: 88%

The Long Noncoding RNA Playrr Regulates Pitx2 Dosage and Protects Against Cardiac Arrhythmias

Chen

Oxford

Chou

et al. 2022

Preprint

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Rationale: The most significantly associated atrial fibrillation (AF) risk loci in humans map to a noncoding gene desert upstream of the evolutionarily conserved left-right (LR) transcription factor Pitx2, a master regulator of LR asymmetric organ development. Pitx2 dosage is fundamentally linked to the development of sinus node dysfunction (SND) and AF, the most common cardiac arrhythmia affecting adults, but the mechanistic basis for this remains obscure. We identified a conserved long noncoding RNA (lncRNA), Playrr, which is exclusively transcribed on the right side of the embryo, opposite to Pitx2 on the left, that participates in mutually antagonistic transcriptional regulation with Pitx2. Objective: The objective of this study was to investigate a role of Playrr in regulating Pitx2 transcription and protecting against the development of cardiac rhythm disturbances. Methods and Results: Playrr expression in the developing heart was analyzed with RNA in situ hybridization. Playrr was expressed asymmetrically (on the right) to Pitx2 (on the left) in developing mouse embryos, including in mouse embryonic sinoatrial node cells. We utilized CRISPR/Cas9 genome editing in mice to target Playrr, generating mice lacking Playrr RNA transcript (PlayrrEx1sj allele). Using qRT-PCR we detected upregulation of the cardiac isoform, Pitx2c, during visceral organ morphogenesis in PlayrrEx1sj mutant embryos. Surface ECG (AliveCor) and 24-hour telemetry ECG detected bradycardia and irregular interbeat (R-R) intervals suggestive of SND in PlayrrEx1sj mutant adults. Programmed stimulation of PlayrrEx1sj mutant adults resulted in pacing-induced AF. Within the right atrium of PlayrrEx1sj mutant hearts, Masson trichrome stain revealed increased collagen deposition indicative of fibrosis, and immunofluorescence demonstrated mis-localization of Connexin 43 in atrial cardiomyocytes. These findings suggested an altered atrial substrate in PlayrrEx1sj adult mice. Finally, transcriptomic analysis by chromatin run-on and sequencing (ChRO-seq) in atria of PlayrrEx1sj mutant mice compared to wild type controls revealed differential expression of genes involved in cell-cell adhesion and motility, fibrosis, and dysregulation of the key cardiac genes Tbx5 and Hcn1. Conclusions: Adult mice lacking functional Playrr lncRNA transcript have baseline bradyarrhythmia and increased susceptibility to AF. These cardiac phenotypes are similar to those observed in Pitx2 heterozygous mice. Interactions between Pitx2 and Playrr may provide a genetic mechanism for modulating Pitx2 dosage and susceptibility to SND and AF.

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“…Thus, targeting the I f in such pathological conditions has proven to be therapeutically advantageous. 64 …”

Section: Introductionmentioning

confidence: 99%

Cardiac Potassium Channels: Physiological Insights for Targeted Therapy

Jeevaratnam

Chadda

Huang

et al. 2017

J Cardiovasc Pharmacol Ther

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The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K+ channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K+ channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them.

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Dysfunctional Hyper Polarization Activated Cyclic Nucleotide-Gated Ion Channels in Cardiac Diseases

Cited by 3 publications

References 46 publications

Drug action(s), drug marketing, and clinical medicine. Suppression of ventricular arrhythmogenicity with If blockade in human heart failure: emerging clinical evidence for ivabradine treatment benefit beyond heart rate control

Drug action(s), drug marketing, and clinical medicine. Suppression of ventricular arrhythmogenicity with If blockade in human heart failure: emerging clinical evidence for ivabradine treatment benefit beyond heart rate control

The Long Noncoding RNA Playrr Regulates Pitx2 Dosage and Protects Against Cardiac Arrhythmias

Cardiac Potassium Channels: Physiological Insights for Targeted Therapy

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