Ventricular arrhythmia

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.

Description

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.