At the cellular lever, the action potential (AP) is the electrical signal that initiates the contraction of heart muscle.

APs are triggered by cells in the sinoatrial node, then travel along each myocardial cell and from cell to cell. The spread of APs throughout the heart leads to the series of contractions that we know as the heart beat.

It has been demonstrated that there is a direct link between ECG and the AP. Specifically, that QT prolongation is determined by the duration of the AP (as measured by APD₉₀, action potential duration to 90% repolarization).

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. Of course, it is imperative to maintain the fibre at a constant temperature of ~37°C. 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.

In AP studies, the different phases of the AP are of particular interest. The figure below illustrates the five phases of a cardiac AP (specifically VAP):

Each phase is associated with the opening and closing of specific ion channels:

phase 0: rapid depolarization.

phase 1: inactivation of fast Na+ channels.

phase 2 or "plateau" phase: Membrane potential is sustained by a balance between inward movement of Ca2+ (I_Ca) through L-type calcium channels and outward movement of K+ through the slow delayed rectifier potassium channels, I_Ks.

phase 3: The L-type Ca2+ channels close, while the slow delayed rectifier (I_Ks) K⁺ channels are still open.

phase 4: resting membrane potential.

phase 3 has been the subject of intense research, because of the human Ether-a-go-go Related Gene or hERG, which encodes the Kv11.1 potassium ion channel responsible for the repolarizing (I_Kr) current in the cardiac AP.

According to recent research, this potassium ion channel is very sensitive to drug binding, as well as decreased extracellular potassium levels; both of which can result in decreased channel function, and give rise to the so-called "acquired long QT syndrome".

Thus, if a drug binds with the potassium ion channel, repolarization will be impaired, leading to alteration of phase 3 (and higher APD₉₀). In turn, this leads to a longer QT and therefore an increased risk of fatal cardiac arrhythmia (i.e. Torsades de Pointe).

This is why the hERG-encoded potassium channel is first studied using patch-clamp techniques,  then confirmed by AP studies. The next stage in preclinical development, if the drug gets this far, is to perform QT measurements in a Langendorff heart preparation, and finally, whole-animal safety studies with emkaPACK non-invasive telemetry and implantable telemetry. Toxicological studies look for potential arrhythmic effects with the emkaPACK and ecg amplifier. 

emka TECHNOLOGIES provides a complete line-up of products and services, from AP to QT, for preclinical drug development.