by Dr Jay Lu
In this post, we’d like to discuss the effective refractory period (ERP), which is one of the most important indices in cardiac electrophysiology. ERP simply means during cardiac action potential phase 0, 1, 2, and part of phase 3, the cells is refractory to the initiation of new action potential. In other words, during ERP, depolarization on adjacent cardiac muscles does not generate a new depolarization in the current cell.
But why is the ERP important in Cardiology?
The heart needs to beat rhythmically to circulate blood to the body. Imagine if there are multiple & compounded action potentials firing in the heart, the heart would fail to adequately pump and fill with blood. Therefore, ERP acts as a protective mechanism in the heart, keeping the heart rate in order and prevents arrhythmias by stopping action potentials from firing prematurely in the refractory phases. The length of the refractory period limits the frequency of action potentials (and hence contractions) that can be initiated by the heart.
The ERP analysis is particularly useful when it comes to arrhythmia research, especially atrial fibrillation (AF) studies as AF has been shown to shorten the atrial ERP and make the atrium more vulnerable to AF. Anti-arrhythmic agents used for arrhythmias usually prolong the ERP. For example, potassium channel blocker (eg, amiodarone) and some sodium channel blockers (eg, Class IA) increase action potential duration and therefore increase the ERP. Drugs that increase the ERP can be fairly effective in abolishing reentry currents that lead to tachyarrhythmias.
Here are some examples of papers for ERP analysis
https://pubmed.ncbi.nlm.nih.gov/35344886/
https://pubmed.ncbi.nlm.nih.gov/35965820/
https://pubmed.ncbi.nlm.nih.gov/35935820/
How can we measure ERP in preclinical studies?
Experimentally, ERP is measured by performing an S1-S2 pacing protocol with a laboratory-grade stimulator, while the heart’s ECG or field potential is closely monitored. It is determined as the first S1-S2 coupling interval that failed to produce a ventricular response.
Briefly, the pacing protocol consists of repeats of stimulus trains. Each pacing train contains several stimuli with a basic cycle length (known as S1 stimuli), followed by a single stimulus applied after a reduced coupling interval (known as an S2 stimulus) (1). The pacing train is repeated, with the S1 stimuli retaining their basic cycle length and a sequentially decreasing coupling interval between the last S1 stimulus and the S2 stimulus (Figure 1). We identify the ERP as soon as the heart does not depolarize at a certain S2 coupling interval, where the heart initiates its protective mechanism and enters its refractory period.
It is equally important to identify the threshold current (the amount of current needed to cause depolarization) in the first place, as we need to make sure the amount of current used can stably provoke depolarization of the heart without causing atrial or ventricular fibrillation.
Fig 1. An example setup image of S1S2 pacing protocol (VCS-3001 stimulator) for the rat model.
Reference
- Narayan, Sanjiv M et al. “Repolarization and activation restitution near human pulmonary veins and atrial fibrillation initiation: a mechanism for the initiation of atrial fibrillation by premature beats.” Journal of the American College of Cardiology vol. 52,15 (2008): 1222-30.
