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Human cardiomyocyte progenitor cells expressing HCN4-GFP functionally couple to neonatal rat ventricular myocytes and induce physiologically controlled pacemaker activity and may therefore provide an attractive delivery platform for sustained pacemaker function.
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The authors report here the first evidence for a heterozygous gain-of-function mutation in the pacemaker HCN4 channel associated with symptoms of familial Inappropriate Sinus Tachycardia.
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Three HCN4 mutations identified in sick sinus syndrome patients caused loss of function in vitro. Loss of function may have resulted from significantly reduced functional HCN4 channel availability and cell surface expression due to defective trafficking.
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These findings indicate that HCN4(G811E) may not be a monogenic factor to cause the cardiac disorders.
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We here report on multiple families harboring HCN4 mutations, who show significant dilation of the aorta ascendens
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A novel splice site HCN4 gene mutation was identified in a large family with familial bradycardia.
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Sick sinus syndrome (SSS) with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with atrial fibrillation and left ventricular noncompaction.
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This study has identified 4 synonymous variants in the HCN4 gene and 3 SNPs in the CYP3A4 gene. None of the variants appear to have a major effect on the reduction of HR produced by ivabradine.
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HCN4 channel remodeling following exercise and subsequent sinus bradycardia in athletes is controlled by miR-423-5p.
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Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.
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Identified in Brugada syndrome patient HCN4 mutation results in reduced channel function in HEK293 cells.
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S672R mutation results in a constitutive shift of the dynamic auto-inhibitory equilibrium toward inactive states of HCN4 and broadens the free-energy well of the apo-form, enhancing the millisecond to microsecond dynamics of the holo-form at sites critical for gating cAMP binding.
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Our results confirm the genetic evidence for the involvement of the HCN4 mutations in the combined bradycardia-non compaction cardiomyopathy phenotype and illustrates that.
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Aged patients with sinus rhythm exhibited significantly higher expression levels of HCN2 and HCN4 channel mRNA and protein (P<0.05), but significantly lower expression levels of miR1 and 133, compared with those of adult patients with sinus rhythm.
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study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels
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The study analyzed HCN4 intracellular region dynamics in the four states of the thermodynamic cycle arising from the coupling between cAMP binding and tetramerization equilibria.
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study identified a novel trafficking-defective mutation in the amino-terminus of HCN4 channel in individuals with early-onset atrial fibrillation (AF); findings support that novel loss-of-function mutations in the HCN4 channel may increase susceptibility and have a role in AF pathogenesis
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used NMR to probe the changes caused by the binding of cAMP and of cCMP, a partial agonist, to the apo-cAMP-binding domain of HCN4
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Here, we review the changes in expression and kinetics of HCN4 mutant channels and provide an overview of their effects on If during the time course of a human SAN action potential, both under resting conditions and upon adrenergic stimulation. [review]
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The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.
