Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels mediate pacemaker currents in the atrium. The microRNA (miR) families miR-1 and miR-133 regulate the expression of multiple genes involved in myocardial function, including HCN channels. It was hypothesized that age­dependent changes in HCN2, HCN4, miR­1 and miR­133 expression may contribute to age­associated atrial fibrillation, and therefore the correlation between expression levels, among adult (≤65 years) and aged patients (≥65 years), and sinus rhythm was determined. Right atrial appendage samples were collected from 60 patients undergoing coronary artery bypass grafting. Reverse transcription-quantitative polymerase chain reaction (PCR) and western blot analyses were performed in order to determine target RNA and protein expression levels. Compared with aged patients with sinus rhythm, aged patients with atrial fibrillation exhibited significantly higher HCN2 and HCN4 channel mRNA and protein expression levels (P<0.05), but significantly lower expression levels of miR­1 and miR­133 (P<0.05). In addition, 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 (P<0.05), compared with those of adult patients with sinus rhythm. Expression levels of HCN2 and HCN4 increased with age, and a greater increase was identified in patients with age­associated atrial fibrillation compared with that in those with aged sinus rhythm. These electrophysiological changes may contribute to the induction of ectopic premature beats that trigger atrial fibrillation.

Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation.

BACKGROUND: Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent. MATERIAL/METHODS: Twelve aging dogs (8-10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated. RESULTS: As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased. CONCLUSIONS: Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.

Association between reversal in the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and age-related atrial fibrillation.

BACKGROUND: We compared cardiac electrophysiological indicators and regional expression levels of cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) channels between adult and aged dogs to identify possible mechanisms of age-related atrial fibrillation. MATERIAL/METHODS: Corrected sinus node recovery time (SNRTc) and effective refractory period (ERP) of the atrium and pulmonary veins were measured in 10 adult (3-6 years old) and 10 aged dogs (>9 years old). Expression levels of HCN2 and HCN4 channel mRNAs and proteins were measured in the sinoatrial node, atrium, and pulmonary veins by real-time PCR and Western blotting. RESULTS: Aged dogs exhibited a higher induction rate of atrial fibrillation (AF) in response to electrical stimulation, longer AF duration after induction, longer SNRTc, longer right atrial effective refractory period (AERP), shorter left AERP, and increased AERP dispersion compared to adults. Expression levels of HCN2 and HCN4 channel mRNAs and proteins were lower in the sinoatrial node but higher in the atrium and pulmonary veins of aged dogs. CONCLUSIONS: Changes in atrial electrophysiological indicators in aged dogs revealed sinoatrial node dysfunction. There was a reversal in the local tissue distribution of HCN2 and HCN4 channel mRNA and protein, a decrease in sinoatrial node expression, and increase in atrial and pulmonary vein expression with age. Changes in atrial electrophysiological characteristics and regional HCN channel expression patterns were associated with the onset and maintenance of age-related atrial fibrillation.