• Arrhythmias
• Base editor
• HCN4
• Mutation
• Sinoatrial node

• Atrial fibrillation
• Bioinformatics
• Drug development
• GWAS
• Systematic review

• Atrial Fibrillation/genetics
• Atrial Fibrillation/drug therapy
• Humans
• Drug Development
• Computational Biology/methods
• Genetic Association Studies/methods
• Genetic Predisposition to Disease
• Drug Repositioning/methods
• Drug Discovery
• Anti-Arrhythmia Agents/therapeutic use
• Anti-Arrhythmia Agents/pharmacology

• PG/18/50/33837 British Heart Foundation
• PG/22/10989 British Heart Foundation

• Humans
• Atrial Fibrillation/genetics
• Atrial Fibrillation/diagnosis
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism
• Male
• Female
• Middle Aged
• Pedigree
• Adult
• GATA5 Transcription Factor/genetics
• Aged
• Spain/epidemiology
• Potassium Channels/genetics
• Exome Sequencing/methods
• Animals
• Genetic Predisposition to Disease
• Electrocardiography, Ambulatory/methods
• Genetic Variation
• Muscle Proteins

• action potentials
• autonomic nervous system
• heart rate
• myocytes, cardiac
• sinoatrial node

• Humans
• Animals
• Heart Rate
• Sinoatrial Node/metabolism
• Sinoatrial Node/physiopathology
• Sinoatrial Node/physiology
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism
• Biological Clocks

• Anticancer drugs
• Atrial fibrillation
• Drug-induced atrial fibrillation
• Treatment

• Humans
• Aged
• Atrial Fibrillation/chemically induced
• Atrial Fibrillation/drug therapy
• Atrial Fibrillation/epidemiology
• Anti-Arrhythmia Agents/adverse effects
• Risk Factors
• Drug-Related Side Effects and Adverse Reactions/drug therapy
• Incidence

• Apoptosis
• Atrial fibrillation
• Carvedilol
• Ivabradine
• Mitral regurgitation

• Humans
• Rats
• Animals
• Carvedilol/therapeutic use
• Ivabradine/therapeutic use
• Ivabradine/pharmacology
• Mitral Valve Insufficiency/complications
• Mitral Valve Insufficiency/drug therapy
• Rats, Sprague-Dawley
• Adrenergic beta-Antagonists/therapeutic use
• Adrenergic beta-Antagonists/pharmacology
• Heart Failure/drug therapy
• Heart Failure/etiology
• Atrial Fibrillation/complications
• Atrial Fibrillation/drug therapy
• Fibrosis

• NSTC 109-2326-B-384 -001 -MY3 National Science and Technology Council
• Chi-Mei Medical Center
• NHRI-EX111-11138SI National Health Research Institutes
• National Science and Technology Council
• Chi‐Mei Medical Center
• National Health Research Institutes

• atrial fibrillation
• cardiac arrhythmias
• cardiovascular risk
• intracellular pathways
• ion channels

• Humans
• Middle Aged
• Atrial Fibrillation/etiology
• Atrial Fibrillation/therapy
• Anti-Arrhythmia Agents/therapeutic use
• Heart Atria
• Alcoholism
• Autoantibodies
• Lewis Blood Group Antigens

• atrial fibrillation
• genetic polymorphism
• hypertrophic cardiomyopathy
• next generation sequencing
• variant

• Humans
• Atrial Fibrillation/complications
• Atrial Fibrillation/genetics
• Atrial Remodeling/genetics
• Cardiomyopathy, Hypertrophic/complications
• Cardiomyopathy, Hypertrophic/genetics
• Cohort Studies
• Heart Atria
• Romania
• Voltage-Gated Sodium Channel beta-1 Subunit/genetics
• European People/genetics

• HCN domain
• HCN4
• inappropriate sinus tachycardia
• mutation
• single channel

• Adult
• Humans
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics
• Tachycardia, Sinus
• Potassium Channels/genetics
• Ivabradine/pharmacology
• Cyclic Nucleotide-Gated Cation Channels/genetics
• Cyclic Nucleotide-Gated Cation Channels/metabolism
• Gain of Function Mutation
• Muscle Proteins/genetics
• Muscle Proteins/metabolism
• Sinoatrial Node
• Cardiomyopathies/genetics

• PID2020-118694RB-I00 Ministerio de Ciencia e Innovación (MCIN)
• P2022/BMD-7229 Comunidad de Madrid (Community of Madrid)

• atrial fibrillation
• cardiomyopathies
• genotype
• heart atria
• ventricular dysfunction

• Humans
• Cardiomyopathies/diagnosis
• Cardiomyopathies/genetics
• Cardiomyopathies/complications
• Atrial Fibrillation/diagnosis
• Atrial Fibrillation/genetics
• Heart Atria
• Genotype
• Ventricular Dysfunction

• Atrial fibrillation
• HCN channel
• Membrane clock
• Reactive oxygen species
• Sinoatrial node
• p21-activated kinase 1

• Male
• Female
• Mice
• Animals
• p21-Activated Kinases/metabolism
• Sinoatrial Node/metabolism
• Atrial Fibrillation/metabolism
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism
• Reactive Oxygen Species/metabolism
• Sick Sinus Syndrome/metabolism
• Heart Rate

• R01 HL128330 NHLBI NIH HHS
• R01 HL155762 NHLBI NIH HHS
• R25 HL145817 NHLBI NIH HHS
• R01 HL164453 NHLBI NIH HHS
• T32 HL007444 NHLBI NIH HHS

Mutations in the hyperpolarization-activated nucleotide-gated channel 4 (HCN4) are known to be associated with arrhythmias in which QT prolongation (delayed ventricular repolarization) is rare. Here, we identified a HCN4 mutation, HCN4-R666Q, in two sporadic arrhythmia patients with sinus bradycardia, QT prolongation, and short bursts of ventricular tachycardia. To determine the functional effect of the mutation, we conducted clinical, genetic, and functional analyses using whole-cell voltage-clamp, qPCR, Western blot, confocal microscopy, and co-immunoprecipitation. The mean current density of HEK293T cells transfected with HCN4-R666Q was lower in 24 to 36 h after transfection and was much lower in 36 to 48 h after transfection relative to cells transfected with wildtype HCN4. Additionally, we determined that the HCN4-R666Q mutant was more susceptible to ubiquitin-proteasome system–mediated protein degradation than wildtype HCN4. This decreased current density for HCN4-R666Q could be partly rescued by treatment with a proteasome inhibitor. Therefore, we conclude that HCN4-R666Q had an effect on HCN4 function in two aspects, including decreasing the current density of the channel as a biophysical effect and weakening its protein stability. Our findings provide new insights into the pathogenesis of the HCN4-R666Q mutation.

• Atrial fibrillation
• COVID-19
• Environment
• Genetics
• Preventative care

• Atrial Fibrillation/epidemiology
• Atrial Fibrillation/genetics
• COVID-19
• Humans
• Incidence
• Risk Factors
• SARS-CoV-2
• United States

• R00 HL146969 NHLBI NIH HHS
• R01 HL139348 NHLBI NIH HHS
• K99 HL146969 NHLBI NIH HHS
• R01 HL134824 NHLBI NIH HHS
• R35 HL135754 NHLBI NIH HHS
• R01 AG057046 NIA NIH HHS

• Atrial Fibrillation/diagnosis
• Atrial Fibrillation/epidemiology
• Atrial Fibrillation/etiology
• Humans

• R01 AA024769 NIAAA NIH HHS
• R01 HL146744 NHLBI NIH HHS

• HCN channels
• atrial fibrillation
• automaticity
• hyperpolarization-activated current
• ivabradine
• sinus node dysfunction

• Arrhythmias, Cardiac
• Cyclic Nucleotide-Gated Cation Channels/pharmacology
• Cyclic Nucleotide-Gated Cation Channels/physiology
• Heart Rate/physiology
• Humans
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• Ivabradine/pharmacology
• Ivabradine/therapeutic use
• Myocytes, Cardiac/physiology

• G0E7120N, GOC2319N, GOA4919N, 12W7822N F.W.O. Vlaanderen
• PDM/19/164 KU Leuven

• Ageing
• Athletic training
• Cardiac arrhythmias
• Cardiac conduction system
• Circadian rhythm
• Heart failure

• Action potential clamp
• Heart rate
• Human
• Hyperpolarization-activated current
• Sinoatrial node
• β-adrenergic stimulation

Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects. Importantly, these phenotypes were rescued upon loss of CUGexp RNA expression. Transcriptome analysis revealed gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from mice expressing CUGexp RNA. These results identify potential tissue-specific mechanisms contributing to cardiac pathogenesis in DM1 and demonstrate the utility of reversible phenotypes in our model to facilitate development of targeted therapeutic approaches.

• Arrhythmias
• Cardiology
• Cell Biology
• RNA processing

Background: Previous studies have proved that low-level vagus nerve stimulation (LLVS) could suppress acute obstructive sleep apnea (OSA), which is associated with atrial fibrillation (AF).

Objective: This study investigates the underlying electrophysiological, neural, and cardiomyocyte injury mechanisms on acute OSA-induced AF, examining whether LLVS can attenuate or reverse this remodeling.

Methods and Results: Eighteen mongrel dogs received endotracheal intubation under general anesthesia and were randomly divided into three groups: the OSA group (simulated OSA with clamping of the trachea cannula at the end of expiration for 2min followed ventilation 8min, lasting 6h, n=6), the OSA+LLVS group (simulated OSA plus LLVS, n=6), and a control group (sham clamping the trachea cannula without stimulation, n=6). In the OSA+LLVS group, the atrial effective refractory period was significantly lengthened while the sinus node recovery time and AF duration decreased after the 4th hour, and the expression level of Cx40 and Cx43 was significantly increased compared to the OSA group. Norepinephrine, TH, and ChAT were significantly decreased in the OSA+LLVS group compared with the OSA group. Mitochondrial swelling, cardiomyocyte apoptosis, and glycogen deposition, along with a higher concentration of TNF-α, IL-6 were observed in the OSA group, and the LLVS inhibited the structural remodeling and expression of inflammatory cytokines.

Conclusion: LLVS decreased the inducibility of AF partly by ameliorating sympathetic hyperactivity and atrial myocyte injury after acute OSA-induced AF.

• atrial fibrillation
• atrial myocyte injury
• low-level vagus nerve stimulation
• obstructive sleep apnea
• sympathetic hyperactivity

• Atrial fibrillation
• Epidemiology
• Genetics
• Risk factors

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca²⁺-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks

• atrial fibrillation
• epigenetics
• gene regulation

• STARR-seq
• atrial fibrillation
• chromatin
• gene expression
• genetics
• genome-wide association study
• regulation
• variants

Atrial fibrillation (AF) is the most common clinical tachyarrhythmia. In Europe, AF is expected to reach a prevalence of 18 million by 2060. This estimate will increase hospitalization for AF to 4 million and 120 million outpatient visits. Besides being an independent risk factor for mortality, AF is also associated with an increased risk of morbidities. Although there are many well-defined risk factors for developing AF, no identifiable risk factors or cardiac pathology is seen in up to 30% of the cases. The heritability of AF has been investigated in depth since the first report of familial atrial fibrillation (FAF) in 1936. Despite the limited value of animal models, the advances in molecular genetics enabled identification of many common and rare variants related to FAF. The importance of AF heritability originates from the high prevalence of lone AF and the lack of clear understanding of the underlying pathophysiology. A better understanding of FAF will facilitate early identification of people at high risk of developing FAF and subsequent development of more effective management options. In this review, we reviewed FAF epidemiological studies, identified common and rare variants, and discussed their clinical implications and contributions to developing new personalized therapeutic strategies.

• arrhythmia
• electrophysiology
• familial atrial fibrillation
• genetics
• personalized medicine

Atrial fibrillation (AF) is a common arrhythmia seen in clinical practice. Occasionally, no common risk factors are present in patients with this arrhythmia. This suggests the potential underlying role of genetic factors associated with predisposition to developing AF.

We conducted a comprehensive review of the literature through large online libraries, including PubMed. Many different potassium and sodium channel mutations have been discussed in their relation to AF. There have also been non–ion channel mutations that have been linked to AF. Genome‐wide association studies have helped in identifying potential links between single‐nucleotide polymorphisms and AF. Ancestry studies have also highlighted a role of genetics in AF. Blacks with a higher percentage of European ancestry are at higher risk of developing AF. The emerging field of ablatogenomics involves the use of genetic profiles in their relation to recurrence of AF after catheter ablation.

The evidence for the underlying role of genetics in AF continues to expand. Ultimately, the role of genetics in risk stratification of AF and its recurrence is of significant interest. No established risk scores that are useful in clinical practice are present to date.

• ablatogenomics
• ancestry studies
• atrial fibrillation
• genetics
• genome‐wide association studies

• anxiety disorders
• cardiomyopathies
• sick sinus syndrome
• sinoatrial node
• ventricular fibrillation

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate rhythmic electrical activity of cardiac pacemaker cells, and in neurons play important roles in setting resting membrane potentials, dendritic integration, neuronal pacemaking, and establishing action potential threshold. Block of HCN channels slows the heart rate and is currently used to treat angina. However, HCN block also provides a promising approach to the treatment of neuronal disorders including epilepsy and neuropathic pain. While several molecules that block HCN channels have been identified, including clonidine and its derivative alinidine, lidocaine, mepivacaine, bupivacaine, ZD7288, ivabradine, zatebradine, and cilobradine, their low affinity and lack of specificity prevents wide-spread use. Different studies suggest that the binding sites of these inhibitors are located in the inner vestibule of HCN channels, but the molecular details of their binding remain unknown. We used computational docking experiments to assess the binding sites and mode of binding of these inhibitors against the recently solved atomic structure of human HCN1 channels, and a homology model of the open pore derived from a closely related CNG channel. We identify a possible hydrophobic groove in the pore cavity that plays an important role in conformationally restricting the location and orientation of drugs bound to the inner vestibule. Our results also help explain the molecular basis of the low-affinity binding of these inhibitors, paving the way for the development of higher affinity molecules.

• Atrial fibrillation
• PITX2
• SNPs
• hypertension
• hyperthyroidism
• non-coding RNAs.

• Animals
• Atrial Fibrillation/genetics
• Gene Expression Regulation
• Gene Regulatory Networks
• Homeodomain Proteins/genetics
• Humans
• Polymorphism, Single Nucleotide
• Transcription Factors/genetics
• Homeobox Protein PITX2

• HCN4 gene
• autopsy
• common variant
• forensic pathology
• forensic science
• single nucleotide polymorphisms
• sudden infant death syndrome
• sudden unexplained nocturnal death syndrome

Caveolinopathies are a family of genetic disorders arising from alterations of the caveolin-3 (cav-3) gene. The T78M cav-3 variant has been associated with both skeletal and cardiac muscle pathologies but its functional contribution, especially to cardiac diseases, is still controversial. Here, we evaluated the effect of the T78M cav-3 variant on cardiac ion channel function and membrane excitability.

We transfected either the wild type (WT) or T78M cav-3 in caveolin-1 knock-out mouse embryonic fibroblasts and found by immunofluorescence and electron microscopy that both are expressed at the plasma membrane and form caveolae. Two ion channels known to interact and co-immunoprecipitate with the cav-3, hKv1.5 and hHCN4, interact also with T78M cav-3 and reside in lipid rafts. Electrophysiological analysis showed that the T78M cav-3 causes hKv1.5 channels to activate and inactivate at more hyperpolarized potentials and the hHCN4 channels to activate at more depolarized potentials, in a dominant way. In spontaneously beating neonatal cardiomyocytes, the expression of the T78M cav-3 significantly increased action potential peak-to-peak variability without altering neither the mean rate nor the maximum diastolic potential. We also found that in a small cohort of patients with supraventricular arrhythmias, the T78M cav-3 variant is more frequent than in the general population. Finally, in silico analysis of both sinoatrial and atrial cell models confirmed that the T78M-dependent changes are compatible with a pro-arrhythmic effect.

This study demonstrates that the T78M cav-3 induces complex modifications in ion channel function that ultimately alter membrane excitability. The presence of the T78M cav-3 can thus generate a susceptible substrate that, in concert with other structural alterations and/or genetic mutations, may become arrhythmogenic.

• Arrhythmia
• Caveolin
• Electrophysiology
• Genetic diseases
• Ion channels

Clinical trials and studies with ivabradine implicate cardiac pacemaker channels (HCN4) in the pathogenesis of atrial arrhythmias. Because acute changes in cardiac autonomic tone predispose to atrial arrhythmias, we studied humans in whom profound cardiac sympathetic activation was rapidly relieved to test influences of HCN4 inhibition with ivabradine on atrial arrhythmias. We tested 19 healthy participants with ivabradine, metoprolol, or placebo in a double blind, randomized, cross-over fashion on top of selective norepinephrine reuptake inhibition with reboxetine. Subjects underwent combined head up tilt plus lower body negative pressure testing followed by rapid return to the supine position. In the current secondary analysis with predefined endpoints before data unblinding, continuous finger blood pressure and ECG recordings were analyzed by two experienced cardiac electrophysiologists and a physician, blinded for treatment assignment. The total atrial premature activity (referred to as atrial events) at baseline did not differ between treatments. After backwards tilting, atrial events were significantly higher with ivabradine compared with metoprolol or with placebo. Unlike beta-adrenoreceptor blockade, HCN4 inhibition while lowering heart rate does not protect from atrial arrhythmias under conditions of experimental cardiac sympathetic activation. The model in addition to providing insight in the role of HCN4 in human atrial arrhythmogenesis may have utility in gauging potential atrial pro-arrhythmic drug properties.

• Atrial fibrillation
• Molecular genetics
• Reporter gene assay
• SHOX2
• Transcription factor

• Atrial Fibrillation
• Genomics
• Hypertension
• Stroke