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(Targu Mures) Hyperpolarization-activated inward current (If) blockade – a new approach to lone atrial fibrillation therapy
Romania (FASMR) - University of Medicine and Pharmacy Targu-Mures, Targu-Mures
Department of Physiology
Prof. Dan DOBREANU, MD, PhD
Prof. Alina ȘERBAN, MD, PhD; Lecturer Marcel PERIAN, MD, PhD
Type of Research Project
- Basic science
What is the background of the project?
Atrial fibrillation is the most common form of cardiac arrhythmia found in clinical practice. Commonly used antiarrhythmic drugs are often inefficient and can sometimes induce proarrhythmic effects themselves. Up to 30% of patients with atrial fibrillation develop the arrhythmia in the absence of any predisposing factor (lone atrial fibrillation). Although recent studies have demonstrated the role of the hyperpolarization-activated inward current (If) hyperactivity in the occurrence of lone atrial fibrillation, as well as the ability of Ivabradine (an If current blocker) to modulate this current, the antiarrhythmic effect of this drug has never been evaluated in vivo.
What is the aim of the project?
The present project aims to develop an experimental model of atrial stimulation- induced lone atrial fibrillation in rats and to assess the role of If hyperactivity and expression changes in several genes encoding for the If current in the genesis of arrhythmias in this model and to assess, for the first time in vivo, the antiarrhythmic effect of Ivabradine in the aforementioned experimental model by quantifying the spontaneous arrhythmic burden using continuous radiotelemetry ECG monitoring and to elucidate the mechanisms underlying this antiarrhythmic effect.
What techniques and methods are used?
This experimental study relies on continuous radiotelemetry ECG monitoring in conscious rats, If current activity evaluation by patch-clamp technique, transcriptomic analysis of the genes encoding for the If current. The study is conducted in accordance with International Council for Laboratory Animal Science guidelines, Directive 2010/63/EU, with the approval of the Ethics Committee of the University. The study is performed on male Wistar rats randomized into three groups: control group (in which a stimulation electrode is placed, but no stimulation is applied); atrial fibrillation group (rats with atrial stimulation-induced atrial fibrillation); atrial fibrillation group treated with Ivabradine (rats with atrial stimulation-induced atrial fibrillation treated with Ivabradine). Animals are implanted (in series of four) with radiotelemetry ECG transmitters and undergo an initial 24-h ECG recording before the onset of the stimulation protocol. With the exception of control rats, in which a transesophageal stimulation electrode is placed, but no stimulation is applied, all other animals are subjected to programmed atrial stimulation. Stimulation protocols are performed daily, 5 days/week, for two weeks. Thereafter, all animals undergo three weeks of continuous ECG monitoring. For four weeks prior to the stimulation protocol, as well as throughout the three weeks of monitoring, the animals in the atrial fibrillation group treated with Ivabradine receive 10 mg/kg of body weight/day of Ivabradine in the drinking water, while the animals in the other two groups receive standard tap water. At the end of the monitoring period, all animals are euthanized; left atrial tissue is sampled and used for electrophysiological and transcriptomic studies; right atrial tissue is sampled and used for histological analysis; left ventricular tissue is sampled and used for electrophysiological, histological, and transcriptomic studies.
What is the role of the student?
What are the tasks expected to be accomplished by the student?
All activities will be performed under the supervision of the lab tutors. The students are not allowed to perform activities without supervision. The students will be allowed to assist the team during device implantation, stimulation protocols, ECG and animal monitoring, device explantation, tissue sampling, electrophysiological studies. The students will be involved in interpreting ECG data recorded during stimulation, as well as during continuous ECG monitoring.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report - The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Knowledge of cardiovascular physiology. Knowledge of general safety rules and ethical issues applicable in animal experimentation. Subject passed: Cardiovascular physiology
Are there any legal limitations in the student’s involvement
The students do not have the authority to discuss the experimental protocols, the results, or the conclusions of the project with people outside the research team. The students do not have the right to use the results obtained within the project without the specific, written approval of the team leader (Prof. Alina ȘERBAN).
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system
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- Burashnikov A; et al. Late-phase 3 EAD: A unique mechanism contributing to initiation of atrial fibrillation. Pacing Clin Electrophysiol 2006;29:290-5.
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