Role of HCN4 channel in preventing ventricular arrhythmia

Ueda, Kazuo; Hirano, Yuji; Higashiuesato, Yasushi; Aizawa, Yoshifusa; Hayashi, Takeharu; Inagaki, Natsuko; Tana, Takeshi; Ohya, Yusuke; Takishita, Shuichi; Muratani, Hiromi; Hiraoka, Masayasu; Kimura, Akinori

doi:10.1038/jhg.2008.16

Cited by 83 publications

(50 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has been recognized that bradycardia can cause tachycardia, a phenomenon called bradycardia-tachycardia syndrome (1,38). In patients with deep bradycardia caused by dysfunctional HCN4 pacemaker channel, prolonged QT interval and polymorphic ventricular tachycardia have also been observed (31,32).…”

Section: Discussionmentioning

confidence: 99%

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor

Lin

Huang

Hileman

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Leptin has been proposed to modulate cardiac electrical properties via ␤-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1-30 g/kg) decreased resting heart rate; at high doses (150 -300 g/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03-0.3 g/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of ␤-adrenergic receptor stimulation. During inhibition of ␤-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias.leptin; leptin receptor; resting heart rate; QT interval NEW & NOTEWORTHYLeptin is believed to increase heart rate via adrenergic receptor stimulation. We found evidence that leptin can exert local direct inhibition of heart rate and prolongation of QTc interval via its receptor. The findings offer better understanding of higher incidence of prolonged QT and sudden cardiac death in obesity.LEPTIN IS A 16-KDA ADIPOKINE released from adipocytes acting via its receptor. Detection of adipocytes in obese human heart (21, 30) and leptin receptors in human cardiac ventricles (19) has suggested that leptin can have autocrine and paracrine effects on cardiac functions.Leptin has been demonstrated to play an important role in cardiac contractility (19, 37), development of hypertrophy (12,19,37,39), and apoptosis (20). However, studies of leptin on cardiac electrical properties are rare and limited to indirect effects via adrenergic receptor stimulation. It has been widely accepted that leptin increases the heart rate through increasing sympathetic activity (5, 9, 10). Leptin-mediated increase in sympathetic activity can explain obese subjects with higher heart rate to meet the increased metabolic demands (25), but it cannot explain why many of them exhibit unchanged or decreased resting heart rate (2, 7).In heart failure patients, fatty infiltration of cardiomyocytes has been demonstrated. The percentage of fat in myocardium is positively correlat...

show abstract

Section: Discussionmentioning

confidence: 99%

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor

Lin

Huang

Hileman

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…HCN4 is found in the sinus node and cells of the cardiac conduction system, and loss-of-function pathogenic variants in the gene are associated with sinus nodal dysfunction. 67 Several BrS-associated genes have been shown to regulate calcium channels. Pathogenic variations in calcium channel, voltage-dependent, L-type, α-1C subunit (CACNA1C) and calcium channel, voltage-dependent, L-type, β-2B subunit (CACNB2B) cause a loss of calcium channel function.…”

Section: Genetic Basismentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

128

View full text Add to dashboard Cite

Review ARticleMore than 20 years ago, eight individuals were resuscitated from sudden cardiac death (SCD) caused by documented ventricular fibrillation (VF); all showed a characteristic ST segment elevation in the right precordial leads and a structurally normal heart. 1 In 1996, the term "Brugada syndrome" (BrS) was used to describe what was previously known as "right bundle branch block, persistent ST segment elevation, and sudden death syndrome. " 2 A year later, BrS was reported to be the same disease as sudden unexplained nocturnal death syndrome (SUNDS). In other countries, BrS has different names: Lai Tai (Thailand), Pokkuri (Japan), and Bangungut (Philippines). Currently, the prevalence of BrS is estimated at ~3-5 in 10,000 people, and it is higher in young men of Southeast Asian origin. It is the main cause of death among young healthy men in Southeast Asia. 3 Recent reports suggest that BrS could be responsible for 4% of all SCD and up to 12% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, at a mean age of 41 years, and it is 8-to 10-times more frequent in males. Frequently, sudden death can be the first manifestation of the disease. 4 In 1998, the genetic basis of BrS was established when the sodium channel protein type V subunit α gene (SCN5A), which encodes the α-subunit of the voltage-gated Na v 1.5 cardiac sodium channel responsible for regulating rapid sodium current (I Na ), was associated with the disease. 5 Currently, BrS is recognized as a rare, inherited cardiac channelopathy caused by an alteration of ionic currents that leads to ventricular arrhythmias and SCD. It is clinically characterized by ST segment elevation in leads V1-V3 of the electrocardiogram, but incomplete penetrance and variable expressivity confound the diagnosis. 6 Despite the identification of 18 associated genes, 65-70% of clinically diagnosed cases remain without an identifiable genetic cause. 4 CLINICAL DIAGNOSIS Diagnostic criteriaThe clinical diagnosis of BrS requires the identification of the ST segment elevation in the right precordial leads at baseline or after the use of sodium blockers. Three different electrocardiographic (ECG) patterns can be often observed in families with BrS: type I, which consists of a coved-type ST segment elevation greater than 2 mm followed by a descending negative T wave in at least two right precordial leads (V1 to V3); type II ST elevation, saddleback-shaped patterns with a high initial increase followed by an ST elevation greater than 2 mm; and saddleback-shaped patterns with a high initial increase followed by an ST elevation less than 2 mm (Figure 1). The second Brugada Consensus Report proposed that only type I is diagnostic for BrS 7 and, in 2013, it was proposed that a definitive diagnosis of BrS considers both spontaneous type I pattern and a provoked type I pattern (with a baseline type II or III pattern) in at least one right precordial lead (V1 or V2). 8 The diagnosis of BrS is currently accepted in those patients ...

show abstract

“…However, later ablation of Hcn4 utilizing an Hcn4-inducible Cre does not affect viability but results in sinus pauses and increased heart-rate variability (19). Mutations in the human Hcn4 gene also lead to sinus bradycardia and have been associated with inherited sick sinus syndrome (12)(13)(14)(15)(16)(17).…”

Section: Isl1 Is Upstream Of Ion Channels and Transcription Factors Rmentioning

confidence: 99%

“…During development, HCN4 expression is initiated in the cardiac crescent and is progressively confined to and later maintained in the SAN during later development and in the adult (9)(10)(11). Mutations in the human HCN4 gene lead to sinus bradycardia and have been associated with inherited sick sinus syndrome, long QT syndrome with bradycardia, and ventricular tachycardia (12)(13)(14)(15)(16)(17). Mouse embryos that are null for Hcn4 exhibit long pauses in heartbeat and die around E10.5, demonstrating a critical requirement for Hcn4 in early pacemaker function of the heart (11).…”

Section: Introductionmentioning

confidence: 99%

Transcription factor ISL1 is essential for pacemaker development and function

Liang¹,

Zhang²,

Cattaneo³

et al. 2015

J. Clin. Invest.

102

125

View full text Add to dashboard Cite

(X. Liang).Statistics. Data are presented as mean ± SEM, and a 2-tailed t test was used for 2-group comparisons. Differences were considered statistically significant at a value of P < 0.05.Study approval. All the experiments involving mice were carried out in accordance with protocols approved by the Institutional Animal Care and Use Committee of USCD (A3033-01) and by the Animal Committee of Tongji University School of Medicine (TJmed-010-10).

show abstract

Role of HCN4 channel in preventing ventricular arrhythmia

Cited by 83 publications

References 32 publications

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor

Brugada syndrome: clinical and genetic findings

Transcription factor ISL1 is essential for pacemaker development and function

Contact Info

Product

Resources

About