Arrhythmia is a condition where the heart beats with an irregular rhythm, due to a change in the electrical impulses to the heart. These changes affect the heart’s ability to pump blood effectively, leading to other organs (i.e. lungs) becoming damaged.
In safety pharmacology studies, assessing the potential of pharmaceuticals to cause arrhythmic events, such as atrial fibrillation, bradycardia, tachycardia or ventricular fibrillation, is a major concern.
Understanding cardiac arrhythmia with cardiac conductivity studies
Some arrhythmias arise from conduction disorders.
The study of cardiac conduction is the investigation of the movement of electrical impulses through the conduction pathways of the heart. These are conserved across most mammals, and therefore animal models including mice, dogs and pigs provide a useful tool for furthering our understanding of the cardiac conduction system.
Standard studies are performed by applying pacing and recording protocols from inside the heart or through the esophagus to determine electrical properties of the atrium and the ventricle. Programmed electrical stimulation is also applied through the catheter for induction of abnormal heartbeats.
Studying ventricular repolarization with action potentials duration measurement
When ventricular repolarization is delayed, there is an increased risk of ventricular arrhythmia.
Ventricular repolarization is determined by the duration of the cardiac action potential. At the cellular lever, the action potential is the electrical signal that initiates the contraction of heart muscle. Thus, it can be measured in vitro, during electrophysiology studies.
A cardiac action potential preparation typically consists of a muscle fibre taken from the ventricle (VAP) or from the Purkinje tissue. The fibre is laid down horizontally in a bath which is perfused with buffer solution (or Krebs solution) and oxygenated. In VAP preparations, it is also very common to simultaneously measure the whole muscle contraction, using a papillary muscle preparation.
If the muscle fibre does not have spontaneous pacemaker activity, an external trigger is required. Typically, this is achieved with a voltage square pulse using a contact electrode gently touching the tissue.
Action potentials and other changes in membrane potentials are detected at a single cell level by means of a microelectrode whose tip lies inside the cell and can be measured by IOX2 software.
Extending your studies with QT interval analysis
When ventricular repolarization is delayed, the QT interval is prolonged. Therefore, the QT interval of the ECG is the most commonly used endpoint to gauge effects of a test substance on ventricular repolarization.
ICH S7B guideline proposes to complement in vitro studies (ECG measured from perfused isolated hearts), by in vivo investigations, to estimate risk for QT interval prolongation.
Conscious or anesthetized dog, monkey, swine, rabbit, ferret, and guinea pig are prescribed for the ECG parameters measurements. ECG acquisition by telemetry, implanted or non-invasive, is the gold standard system and has been reported in the literature for years.
rodentPACK, head mounted system for rat
Implants for large animals
In vivo analysis of torsadogenic potential of an antipsychotic drug paliperidone using the acute atrioventricular block rabbit as a proarrhythmia model
Mihoko Hagiwara et al, Journal of Pharmacological Sciences 132, 48-54, 2016
Inhaled ambient-level traffic-derived particulates decrease cardiac vagal influence and baroreflexes and increase arrhythmia in a rat model of metabolic syndrome
Carll et al, Particle and Fibre Toxicology, 2017
Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress, vagal dominance, arrhythmia and pulmonary inflammation in heart failure-prone rats
Carll et al, Inhalation Toxicology, 2015
An Autonomic Link Between Inhaled Diesel Exhaust and Impaired Cardiac Performance: Insight From Treadmill and Dobutamine Challenges in Heart Failure–Prone Rats
Carll et al, Toxicological sciences, 2013
Diesel Exhaust Inhalation Increases Cardiac Output, Bradyarrhythmias, and Parasympathetic Tone in Aged Heart Failure–Prone Rats
Carll et al, Toxicological sciences, 2013