The human heart beats over a billion times during a human lifespan, rarely skipping more than a beat. This fascinating organ can readily adapt its rhythm and contractility to physiological changes, e.g. a fight-or-flight reaction. Most of the changes in contractility and frequency are mediated by effectors such as epinephrine or acetylcholine. The rhythm of the human heart is usually dictated by the primary pacemaker, which consists of a group of cells termed the “pacemaker” cells, located in the in the Sinoatrial Node. The reason the primary pacemaker dictates the rhythm is mainly because it has the fastest frequency, while the backup/alternative systems such as the atrioventricular node and the Purkinje fibers operate at a slower rhythm.

Biology

Several pacemaker cells can be found throughout the body. The most well-known pacemaker cells reside in the heart, located in the sinoatrial node, the atrioventricular node and in Purkinje fibers. Other oscillating cells can be found throughout the central nervous system, where the frequency of de- and repolarization is often higher.

Our team was intrigued by the way that such a tiny group of cells could have such a rapid and profound impact on the frequency of the heart. These properties inspired us to recreate a system based on the remarkable pacemaker cells.

The sinoatrial cell

The origin of stable oscillations in sinoatrial cells is a topic that is widely debated. One hypothesis states that the internal calcium cycling is the most important factor contributing to the stable rhythm, while others suggest that the oscillating membrane potential has the biggest influence on the pacing. Experimental data as well as computational simulations support both hypotheses, depending on the experimental setup. Current understanding suggests that both systems are simultaneously responsible for maintaining a stable rhythm.

The slow upstroke is mediated by both HCN and calcium channels, while the fast upstroke is mediated mostly by calcium channels. On the other hand, the repolarization is mainly mediated by potassium outflux.

Purkinje fiber:

The main function of Purkinje fibers is to rapidly propagate a depolarization across the ventricles, namely, to achieve a uniform contraction across the heart. However, the Purkinje fibers also serve as a last-resort pacemaker system. It is characterized by a slow rate that ranges between 15-40 beats per minute. The most important current for the pacemaker activity is the HCN current, or the so-called funny current (If). The rapid upstroke is mediated by a voltage-sensitive sodium and calcium channel. The depolarization is followed by a plateau phase, mediated by a balance between calcium influx and potassium outflux. The repolarization occurs due to an increase in potassium outflux compared to the calcium influx, which lowers the membrane potential until the cycle repeats itself.

Neuronal pacemaker cells:

Neuronal pacemaker cells often have a faster rhythm, due to the properties of the expressed HCN channels. These cells express HCN1 and HCN2, as opposed to HCN2 and HCN4, present in the human heart. HCN1 has a quicker activation rate than HCN4, which partially explains the difference in rhythm present in both cells. The duration of the depolarization is also shorter, due to the difference in ion channels responsible for the action potential. Oscillating neurons use a fast voltage-sensitive sodium channel for depolarization and a fast voltage-sensitive potassium channel for repolarization.

To write:

About what we aim to measure and how we can work towards it. Different ways on how we could measure in our project.