ACADEMIA Letters

The long-lasting cardiac action potentials are related to

pressure generation in the heart
José Guilherme Chaui-Berlinck, Universidade de São Paulo
Vitor Rodrigues da Silva, Universidade de São Paulo

Introduction
Both the cardiac and the skeletal muscles belong to the striated group of muscular cells. De-
spite of this, the activating action potential (AP) is rather different between them. While
skeletal myocytes present a brief spiking-like AP of a few milliseconds, the cardiomyocytes
have an AP that lasts for some tens of a second, usually in the order of 200 ms in human
beings (Fig.1). This contrasting divergence between the action potentials of these cells is due
to the long phase-2 in the cardiac cells, i.e., these cells stay in a positive membrane potential,
a depolarization plateau, for a much longer time than the skeletal ones.

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
1
Figure 1. Comparison between the action potential duration of skeletal (blue) and cardiac
(red) muscle cells. The phases of the AP are indicated. Notice the long-lasting phase-2 in the
cardiac AP.

Such a notorious difference did not pass unnoticed and two lines of non-excluding finalist
explanations came out during the 20th century: (a) the phase-2 plateau would be a safe-guard
against a tetanic contraction of the heart (e.g., [1,2]); and (b) the phase-2 plateau would be a
safe-guard against AP reentry (e.g., [3]).
The problem with these explanations is that both rely on cardiac frequency. The higher the
frequency in relation to the AP duration, the higher the probability of a tetanic contraction of
a muscle; and, in the heart, the higher the probability of a reentry [3]. Therefore, contrary to
what a long phase-2 could represent, a safe-guard mechanism would rely on a short phase-2.
From now on, we shall refer the phase-2 time as T2.
The QT interval of the electrocardiogram is a proxy of the time T2. By this proxy, one
can see that what is empirically observed is in line with the short T2 prediction made above,
not only on an individual basis [3] but also along the phylogeny of mammals [4]. That is, the
increase in heartrate is accompanied by a decrease in T2. These observations leave us with
the dilemma of the relevance in the T2 duration.
Force in skeletal muscles depends on two types of summations: spatial and temporal.
Both of these processes are related to the activation of motor units. The cardiac muscle does
not possess any of these mechanisms and pressure, to be effective, must rely on a degree of

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
2
superposition in contracting cells along the organ. In other words, if the first cells to be acti-
vated are relaxing when the last ones are beginning their contraction, pressure will decrease
and do not effectively eject blood to the arteries.
Therefore, it seems that the most probable explanation for the long-lasting T2 is neither as
a safe-guard of tetanic contraction nor of AP reentry. Instead, the adequate generation of pres-
sure in the ventricular cavity seems a much more plausible hypothesis from an evolutionary
standpoint.
The aim of this study is to develop a simple cellular automata model to test the hypothesis
that the primary function of a long T2 in the cardiac AP is to act as temporal and spatial
summations simultaneously.

Model
The model comprises three distinct types of cells: (1) pacemaker - defined to send out an
electric signal at a predefined rate; (2) electrical conducting system - cells which do not gen-
erate force and have high transmission velocity; and (3) cardiac muscle. The latter have three
electrical states that simulate the AP, as well as six contracting states related to the electrical
phases as shown in Fig.2.

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
3
Figure 2. The electrical (in red) and mechanical (in black) states of a force-generating cell
in the model. Form the resting potential represented by the E0-state, once its neighborhood
attains the threshold value, the cell goes to the E2-state, that lasts for ฀2 time units. During
the electrical state-2 phase, the cell transits from the zero-force mechanical condition of the
M0-state to progressively greater forces, represented by states M1, M2, etc. (see panel A).
If ฀2 lasts enough, the maximal force of the M5-state is attained (panel B). Once repolariza-
tion begins, the cell shifts to the E1-state, which represents a hyperpolarized condition of the
membrane and, therefore, during this state, a much stronger stimulus would be necessary to
trigger a depolarization. The mechanical decrease in force occurs in another progressive way,
but in a faster pace than the increase counterpart. This is due to the dynamics of calcium
upraise/clearance from the cytosol and cross-bridge attachment/detachment dynamics.

The rules for electrical state transitions for muscle cells are as follows (illustrated in Fig.3):
• Depolarization. A cell in the resting state-0, is stimulated to state-2 if four or more of
its neighbors are depolarized, or if in direct contact with a depolarized conducting cell.

• Repolarization. A depolarized state-2 cell goes to a hyperpolarized state-1 if time in

state-2 is greater than T2

• The resting state. A hyperpolarized state-1 cell will return to the resting state-0 after a
determined amount of time, if most of its neighbors are not in state-2.
Repolarization time is also dependent on the electrotonic propagation of electrical poten-
tial, i.e., a repolarizing cell creates a repolarizing wave [5–7]. This electrotonic propagation
was simulated through a probabilistic transition from state-2 to state-1 depending on the recent
repolarizations in the vicinity of a cell.
An algorithm to record the macroscopic flow of the electric signal was implemented, sim-
ulating an electrocardiogram (ECG). This information is obtained by computing the change of

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
4
electrical state of the muscle cells depending on the directionality of the depolarization wave.
This serves to legitimize the results and to compare them to experimental data.
The internal pressure of the chamber was considered as the sum of the forces produced by
the individual cells at any given time of the simulation normalized to the maximum sum of
all cells. The normalization was done because the actual value of the force does not represent
any real measurement.

Figure 3. Left panel: initial grid with conducting cells (white), muscle cells (grey) and the
ventricular chamber (red). Notice the three branches of the conducting system that travel
through the chamber emulating the 3D structure of this system. Middle and right panels:
snapshots during a depolarization wave (white). Model built in Python, simulations ran in
google cloud machines.

Results
Fig.4 shows the result of increasing T2 from 80 ms to 240 ms. It can be seen that while the
QT time is related to T2, the QRS amplitude is quite the same irrespective to this time, as
expected from real data. Therefore, the model seems to reproduce essential features of the
cardiac electrical signal. As it is clear, the increase in T2 leads to an increase in ventricular
pressure due to the increase in the concomitant force exerted by the distant parts of the grid.

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
5
Figure 4. Left-hand panels show the fraction of ventricular cells in a given mechanical state
(M0 = red, M1 = black, M2 to M5 in progressively light shades of grey) as a function of sim-
ulation time. Notice the increase in the fraction of cells simultaneously in the maximal force
state M5 as ฀2 increases. Right-hand panels show the ECG (red) and total pressure (black)
obtained for the respective left-hand panel. Notice the increase in QT time as ฀2 increases
(as expected from real ECG data) and the increase in the total pressure from 40% to 100%
(right-hand y-axis). Panels: upper ฀2 = 80 ms; middle ฀2 = 160 ms, lower ฀2 = 240 ms.

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
6
 Fig.5 shows a partial tetanic state of the ventricle obtained by increasing pacemaker fre-
quency. Fig.6 shows the comparison between real data of force generated by isolated ventric-
ular cells as the action potential total time is experimentally elongated and the results for the
whole organ simulated in the present report.

Figure 5. Partial tetanic contraction of the ventricular wall in simulations with high cardiac
frequency and ฀2 close to the heart cycle period. Notice the irregular force peak and the
absence of a completely relaxed state between systolic events.

Figure 6. (A) Relationship of pressure developed by the ventricular wall as a function of ฀2.
(B) Empirical data showing amplitude of contraction as a function of duration of the AP for
single ventricular cells [8].

Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
7
Discussion
In the present study, an automata cellular model was designed to test the hypothesis that the
long-lasting phase-2 of the cardiac action potential is related to pressure development by the
heart. This contrasts to the suggestion that this extended phase would be related to prevent
cardiac tetanus and/or electrical reentry.
The electrocardiogram generated by the model is in agreement with real data, what in-
dicates the adequacy of the model. Also, the time relationship between the ECG and the
mechanical phenomenon in the model is well within the observed real ones.
A most striking feature of the model was to reproduce, at the whole-organ level, the force
pattern observed for isolated ventricular cells / stripes [8,9] as function of the phase-2 dura-
tion (Fig.6). The results of the model show a S-shaped curve that implies the dependence of
pressure on the duration of the action potential and indicates saturation for very long T2. The
model also shows that, at least partially, tetanic contractions are not prevented by the long
phase-2 of the cardiac action potential, as empirical studies demonstrate as well [10–12].
In conclusion, the model corroborates our hypothesis that natural selection probably acts
on the phase-2 duration of the cardiac action potential in order to give the ventricular mus-
cle the temporal and spatial summations necessary to generate the pressure requirements to
circulate blood.

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Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
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Academia Letters, September 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0

Corresponding Author: José Guilherme Chaui-Berlinck, jgcb@usp.br

Citation: Chaui-Berlinck, J.G., Rodrigues da Silva, V. (2021). The long-lasting cardiac action potentials are
related to pressure generation in the heart. Academia Letters, Article 3598.
https://doi.org/10.20935/AL3598.
9